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Surgery_Schwartz. mixture on human collagen deposition. Ann Surg. 2002;236(3):369-374. 84. Levenson SM, Seifter E, VanWinkle W. Nutrition. In: Hunt TK, Dunphy JE, eds. Fundamentals of Wound Management in Surgery. New York: Appleton-Century-Crofts; 1979:286. 85. Jeejeebhoy KN, Cheong WK. Essential trace metals: defi-ciencies and requirements. In: Fischer JE, ed. Nutrition and Metabolism in the Surgical Patient. Boston: Little, Brown and Company; 1996:295. 86. Wilkinson EAJ, Hawke CI. Oral zinc for arterial and venous ulcers (Cochrane Review), in The Cochrane Library, 1:2002. Oxford: Update Software. 87. Robson MC. Wound infection: a failure of wound healing caused by an imbalance of bacteria. Surg Clin North Am. 1997;77(3):637-650. 88. Birkmeyer NJO, Birkmeyer JD. Strategies for improving surgical quality—should payers reward excellence or effort? N Engl J Med. 2006;354(8):864-870. 89. Classen DC, Evans RS, Pestotnik SL, Horn SD, Menlove RL, Burke JP. The timing of prophylactic administration of


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Surgery_Schwartz. payers reward excellence or effort? N Engl J Med. 2006;354(8):864-870. 89. Classen DC, Evans RS, Pestotnik SL, Horn SD, Menlove RL, Burke JP. The timing of prophylactic administration of antibi-otics and the risk of surgical-wound infection. N Engl J Med. 1992;326(5):281-286. 90. Anonymous. Antimicrobial prophylaxis for surgery. Med Letter. 2012;10(122):73-78. 91. Gupta N, Kaul-Gupta R, Carstens MM, et al. Analyzing pro-phylactic antibiotic administration in procedures lasting more than four hours: are published guidelines being followed? Am Surg. 2003;69(8):669-673. 92. Arnold MA, Barbul A. Surgical site infections. In: Cameron JL, ed. Current Surgical Therapy. 9th ed. St. Louis: Mosby-Elsevier; 2008:1152-1160. 93. Liese JG, Jendrossek V, Jannson A, et al. Chronic granuloma-tous disease in adults. Lancet. 1996;347(8996):220-223. 94. Ramos M, Khalpey Z, Lipsitz S, et al. Relationship of peri-operative hyperglycemia and postoperative infections in patients who undergo general and


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Surgery_Schwartz. in adults. Lancet. 1996;347(8996):220-223. 94. Ramos M, Khalpey Z, Lipsitz S, et al. Relationship of peri-operative hyperglycemia and postoperative infections in patients who undergo general and vascular surgery. Ann Surg. 2008;248:585-591. 95. Van den Berghe G, Wouters P, Weekers P, et al. Inten-sive insulin therapy in critically ill patients. N Engl J Med. 2001;345:1359-1367. 96. Lazar HL, Chipkin SR, Fitzgerald CA, et al. Tight glyce-mic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent isch-emic events. Circulation. 2004;109:1497-1502. 97. Gandhi GY, Nuttall GA, Abel MD, et al. Intensive intraop-erative insulin therapy versus conventional glucose manage-ment during cardiac surgery: a randomized trial. Ann Int Med. 2007;146:233-243. 98. Lazar HL, McDonnell MM, Chipkin S, et al. Effects of aggressive versus moderate glycemic control on clinical out-comes in diabetic coronary artery bypass patients. Ann Surg.


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Surgery_Schwartz. 2007;146:233-243. 98. Lazar HL, McDonnell MM, Chipkin S, et al. Effects of aggressive versus moderate glycemic control on clinical out-comes in diabetic coronary artery bypass patients. Ann Surg. 2011;254:458-463. 99. Gottrup F, Firmin R, Rabkin J, et al. Directly measured tissue oxygen tension and arterial oxygen tension assess tissue perfu-sion. Crit Care Med. 1987;15:1030-1036. 100. Sheffield CW, Sessler DI, Hopf HW, et al. Centrally and locally mediated thermoregulatory responses alter subcutane-ous oxygen tension. Wound Repair Regen. 1996;4:339-345. 101. Maragakis LL, Cosgrove SE, Martinez EA, et al. Intraopera-tive fraction of inspired oxygen is a modifiable risk factor for surgical site infection after spinal surgery. Anesthesiology. 2009;110:556-562. 102. Meyhoff C, Weyyerslev J, Jorgensen LN, et al. Effect of high perioperative oxygen fraction on surgical site infection and pulmonary complications after abdominal surgery: the PROXI Randomized Clinical Trial. JAMA.


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Surgery_Schwartz. J, Jorgensen LN, et al. Effect of high perioperative oxygen fraction on surgical site infection and pulmonary complications after abdominal surgery: the PROXI Randomized Clinical Trial. JAMA. 2009;302:1543-1550. 103. Falanga V, Eaglstein WH. The “trap” hypothesis of venous ulceration. Lancet. 1993;341(8851):1006-1008. 104. Lobmann R, Ambrosch A, Schultz G, Waldmann K, Schiweck S, Lehnert H. Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia. 2002;45(7):1011-1116. 105. Stanley A, Osler T. Senescence and the healing rates of venous ulcers. J Vasc Surg. 2001;33(6):1206-1211. 106. Kim BC, Kim HT, Park SH, et al. Fibroblasts from chronic wounds show altered TGF-β-signaling and decreased TGF-β type II receptor expression. J Cell Physiol. 2003;195(3):331-336. 107. Hopf HW, Ueno C, Aslam R, et al. Guidelines for the treat-ment of arterial insufficiency ulcers. Wound Repair Regen. 2006;14(6):693-710. 108. Hopf HW, Ueno


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Surgery_Schwartz. J Cell Physiol. 2003;195(3):331-336. 107. Hopf HW, Ueno C, Aslam R, et al. Guidelines for the treat-ment of arterial insufficiency ulcers. Wound Repair Regen. 2006;14(6):693-710. 108. Hopf HW, Ueno C, Aslam R, et al. Guidelines for the pre-vention of lower extremity arterial ulcers. Wound Repair Regen. 2008;16(2):175-188. 109. Robson MC, Cooper DM, Aslam R, et al. Guidelines for the treatment of venous ulcers. Wound Repair Regen. 2006;14(6):649-662. 110. Kirsner RS, Marston WA, Snyder RJ, et al. Sprayed-applied cell therapy with human allogeneic fibroblasts and keratino-cytes for treatment of chronic venous leg ulcers: a phase 2, multicenter, double-blind, randomized, place-controlled trial. Lancet. 2012;380:977-985. 111. Robson MC, Cooper DM, Aslam R, et al. Guidelines for the prevention of venous ulcers. Wound Repair Regen. 2008;16(2):147-150. 112. Steed DL, Attinger C, Colaizzi T, et al. Guidelines for treatment of diabetic ulcers. Wound Repair Regen.


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Surgery_Schwartz. Guidelines for the prevention of venous ulcers. Wound Repair Regen. 2008;16(2):147-150. 112. Steed DL, Attinger C, Colaizzi T, et al. Guidelines for treatment of diabetic ulcers. Wound Repair Regen. 2006;14(6):680-692. 113. Jeffcoate WJ, Harding KG. Diabetic foot ulcers. Lancet. 2003;361(9368):1545-1551.Brunicardi_Ch09_p0271-p0304.indd 30201/03/19 4:50 PM 303WOUND HEALINGCHAPTER 9 114. Steed DL, Attinger C, Brem H, et al. Guidelines for the prevention of diabetic ulcers. Wound Repair Regen. 2008;16(2):169-174. 115. Whitney J, Phillips L, Aslam R, et al. Guidelines for the treatment of pressure ulcers. Wound Repair Regen. 2006;14(6):663-679. 116. Stechmiller JK, Cowan L, Whitney J, et al. Guidelines for the prevention of pressure ulcers. Wound Repair Regen. 2008;16(2):151-168. 117. Niessen FB, Spauwen PH, Schalkwijk J, et al. On the nature of hypertrophic scars and keloids: a review. Plast Reconstr Surg. 1999;104(5):1435-1458. 118. Marneros AG, Norris JE, Olsen BR, Reichenberger E.


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Surgery_Schwartz. FB, Spauwen PH, Schalkwijk J, et al. On the nature of hypertrophic scars and keloids: a review. Plast Reconstr Surg. 1999;104(5):1435-1458. 118. Marneros AG, Norris JE, Olsen BR, Reichenberger E. Clinical genetics of familial keloids. Arch Dermatol. 2001; 137(11):1429-1434. 119. Gauglitz GG, Korting HC, Pavicic T, et al. Hypertrophic scar-ring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med. 2011;17:113-125. 120. Butler PD, Longaker MT, Yang GP. Current progress in keloid research and treatment. J Am Coll Surg. 2008;206(4):731-741. 121. Mustoe TA. Evolution of silicone therapy and mecha-nism of action in scar management. Aesthetic Plast Surg. 2008;32(1):82-92. 122. Dijkstra FR, Nieuwenhuijzen M, Reijnen MM, van Goor H. Recent clinical developments in pathophysiology, epidemiol-ogy, diagnosis and treatment of intra-abdominal adhesions. Scand J Gastroenterol Suppl. 2000;232:52-59. 123. Cheong YC, Laird SM, Shellton JB, Ledger WL, Li TC, Cooke ID. The


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Surgery_Schwartz. epidemiol-ogy, diagnosis and treatment of intra-abdominal adhesions. Scand J Gastroenterol Suppl. 2000;232:52-59. 123. Cheong YC, Laird SM, Shellton JB, Ledger WL, Li TC, Cooke ID. The correlation of adhesions and peritoneal fluid cytokine concentrations: a pilot study. Hum Reprod. 2002;17:1039-1045. 124. Zeng Q, Yu Z, You J, Zhang Q. Efficacy and safety of Seprafilm for preventing postoperative abdominal adhe-sion: systematic review and meta-analysis. World J Surg. 2007;31(11):2125-2131. 125. Armstrong DG, Lavery L; Diabetic Foot Study Consortium. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial. Lancet. 2005;366:1704-1710. 126. Kim PJ, Heilala M, Stenverg JS, Weinraub GM. Bioen-gineered alternative tissues and hyperbaric oxygen in lower extremity wound healing. Clin Podiatr Med Surg. 2007;24(3):529-546. 127. Veves A, Falanga V, Armostrong DG, Sabolinski ML; Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin


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Surgery_Schwartz. oxygen in lower extremity wound healing. Clin Podiatr Med Surg. 2007;24(3):529-546. 127. Veves A, Falanga V, Armostrong DG, Sabolinski ML; Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic dia-betic foot ulcers: a prospective randomized multicenter clini-cal trial. Diabetes Care. 2001;24(2):290-295. 128. Kim PJ, Attinger CE, Steinberg JS, Evans KK. Integra bilayer wound matrix application for complex lower extremity soft tissue reconstruction. Surg Technol Inter. 2014;24:65-73. 129. Felder JM, Goyal SS, Attinger CE. A systematic review of skin substitutes for foot ulcers. Plast Recontr Surg. 2012;130(1):145-164. 130. Gu C, Huang S, Gao D, et al. Angiogenic effect of mesenchy-mal stem cells as a therapeutic target for enhancing diabetic wound healing. Int J Low Extrem Wounds. 2014;13(2):88-93. 131. Zelen CM, Snyder RJ, Serena TE, Li WW. The use of human amnion/chroion membrane in the clinical setting for


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Surgery_Schwartz. for enhancing diabetic wound healing. Int J Low Extrem Wounds. 2014;13(2):88-93. 131. Zelen CM, Snyder RJ, Serena TE, Li WW. The use of human amnion/chroion membrane in the clinical setting for lower extremity repair: a review. Clin Podiatr Med Surg. 2015;32:135-146. 132. Martinez-Zapata MJ, Marti-Carvajal AJ, Sola I, et al. Autol-ogous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst Rev. 2012;10:CD006899. 133. Rodriguez PG, Felix FN, Woodley DT, Shim EK. The role of oxygen in wound healing: a review of the literature. Dermatol Surg. 2008:34:1159-1169. 134. De Smet GH, Kroese LF, Menon AG, et al. Oxygen thera-pies and their effects on wound healing. Wound Rep Reg. 2017;25(4):591-608. 135. Weaver LK, ed. The Undersea and Hyperbaric Medical Soci-ety Manual on Hyperbaric Oxygen Therapy Indications. 13th ed. North Palm Beach, FL: Best Publishing Company; 2014, ix-xi. 136. Wang C, Schwaitzberg S, Berliner E, Zarin DA, Lau J. Hyper-baric oxygen for treating wounds:


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Surgery_Schwartz. Oxygen Therapy Indications. 13th ed. North Palm Beach, FL: Best Publishing Company; 2014, ix-xi. 136. Wang C, Schwaitzberg S, Berliner E, Zarin DA, Lau J. Hyper-baric oxygen for treating wounds: a systemic review of the literature. Arch Surg. 2003;138:272-280. 137. Londahl M, Katzman P, Nilson A, Hammarlund C. Hyperbaric oxygen therapy facilitates healing of chronic wound ulcers in patients with diabetes. Diabetes Care. 2010;33(5):998-1003. 138. Ma L, Li P, Shi Z, Hou T, Chen X, Du J. A prospective, random-ized, controlled study of hyperbaric oxygen therapy: effects on healing and oxidative stress of ulcer tissue in patients with diabetic foot ulcers. Ostomy Wound Manag. 2103;59(3):18-24. 139. Duzgun AP, Satir HZ, Ozozan O, Saylam B, Kulah B, Coskun F. Effect of hyperbaric oxygen therapy on diabetic foot ulcers. J Foot Ankle Surg. 2008;47(6):515-519. 140. Kaur S, Pawar M, Banerjee N, Garg R. Evaluation of the efficacy of hyperbaric oxygen therapy in the management of chronic


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Surgery_Schwartz. therapy on diabetic foot ulcers. J Foot Ankle Surg. 2008;47(6):515-519. 140. Kaur S, Pawar M, Banerjee N, Garg R. Evaluation of the efficacy of hyperbaric oxygen therapy in the management of chronic nonhealing ulcer and role of periwound transcu-taneous oximetry as predictor of wound healing response: a randomized prospective controlled trial. J Anaesthesiol Clin Pharmacol. 2012:28(1):70-75. 141. Bjarnsholt T, Cooper R, Fletcher J, et al. Management of biofilm. WoundsInternational.com. Available at: http://www .woundsinternational.com/wuwhs/view/position-document-management-of-biofilm. Accessed June 26, 2018. 142. Wolcott R, Rhoads D, Dowd S. Biofilms and chronic wound inflammation. J Wound Care. 2008;17(8):333-341. 143. Scali C, Kunimoto B. An update on chronic wounds and the role of biofilms. J Cutan Med Surg. 2013;17(6):371-376. 144. Philips PL, Wolcott RD, Fletcher J, Schultz GS. Biofilms made easy. WoundsInternational.com. Available at: http://www


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Surgery_Schwartz. wounds and the role of biofilms. J Cutan Med Surg. 2013;17(6):371-376. 144. Philips PL, Wolcott RD, Fletcher J, Schultz GS. Biofilms made easy. WoundsInternational.com. Available at: http://www .woundsinternational.com/made-easys/view/biofilms-made-easy. Accessed June 26, 2018. 145. Thomson CH. Biofilms: do they affect wound healing? Int Wound J. 2011;8(1):63-67. 146. Bjarnshot T, Bjarnsholt T, Kirketerp-Moller K, Jensen P, et al. Why chronic wounds won’t heal: a novel hypothesis. Wound Repair Regen. 2008;16(1):2-10. 147. Leid J, Wilson C, Shirtliff M, Hassett DJ, Parsek MR, Jeffers AK. The exopolysaccharide alginate protects Pseudomonas aeruginosa biofilm bacteria from INF-gamma-mediated mac-rophage killing. J Immunol. 2005;175(1):7512-7518. 148. Hall-Stoodley L, Stoodley P. Evolving concepts in biofilm infections. Cell Microbiol. 2009;11(7):1034-1043. 149. Lawrence JR, Swerhone GD, Kuhlicke U, Neu TR. In situ evidence of microdomains in the polymer matrix of bacterial microcolonies.


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Surgery_Schwartz. in biofilm infections. Cell Microbiol. 2009;11(7):1034-1043. 149. Lawrence JR, Swerhone GD, Kuhlicke U, Neu TR. In situ evidence of microdomains in the polymer matrix of bacterial microcolonies. Can J Microbiol. 2007;53(3):450-458.Brunicardi_Ch09_p0271-p0304.indd 30301/03/19 4:50 PM


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Surgery_Schwartz. ONCOLOGY AND SURGICAL PRACTICEAs the population ages, oncology is becoming a larger portion of surgical practice. The surgeon often is responsible for the initial diagnosis and management of solid tumors. Knowledge of cancer epidemiology, etiology, staging, and natural history is required for initial patient assessment, as well as to determina-tion of the optimal surgical therapy.Modern cancer therapy is multidisciplinary, involving the coordinated care of patients by surgeons, medical oncologists, radiation oncologists, reconstructive surgeons, pathologists, radi-ologists, and primary care physicians. Primary (or defini-tive) surgical therapy refers to en bloc resection of tumor with adequate margins of normal tissues and regional lymph nodes as necessary. Adjuvant therapy refers to radiation therapy and systemic therapies, including chemotherapy, immunotherapy, hormonal therapy, and, increasingly, biologic therapy. The pri-mary goal of surgical and radiation therapy is local and


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Surgery_Schwartz. therapy and systemic therapies, including chemotherapy, immunotherapy, hormonal therapy, and, increasingly, biologic therapy. The pri-mary goal of surgical and radiation therapy is local and regional control. On the other hand, the primary goal of adjuvant therapy is systemic control by treatment of distant foci of subclinical dis-ease to prevent distant recurrence. Surgeons must be familiar with adjuvant therapies to coordinate multidisciplinary care and to determine the best sequence of therapy. They must also be aware of the potential for patients to receive effective systemic therapies prior to surgery as a means of reducing tumor volume.Recent advances in molecular biology are revolutionizing medicine. New information is being translated rapidly into clinical use, with the development of new prognostic and predictive markers and new biologic therapies. Increasingly cancer therapy is becoming personalized, incorporating information about each patient’s tumor characteristics,


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Surgery_Schwartz. of new prognostic and predictive markers and new biologic therapies. Increasingly cancer therapy is becoming personalized, incorporating information about each patient’s tumor characteristics, patient’s own genome, as well as host immune responses and tumor microenvironment, into clinical decisionmaking. It is therefore essential that surgeons understand the prin-ciples of molecular oncology to appropriately interpret these new contributions and incorporate them into practice.12OncologyWilliam E. Carson III, Funda Meric-Bernstam, and Raphael E. Pollock 10chapterOncology and Surgical Practice 305Epidemiology 306Basic Principles of Cancer Epidemiology / 306Cancer Incidence and Mortality in the United States / 306Global Statistics on Cancer Incidence and Mortality / 307Cancer Biology 310Hallmarks of Cancer / 310Cell Proliferation and Transformation / 310Cancer Initiation / 310Cell-Cycle Dysregulation in Cancer / 311Oncogenes / 313Alterations in Apoptosis in Cancer Cells / 314Autophagy


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Surgery_Schwartz. of Cancer / 310Cell Proliferation and Transformation / 310Cancer Initiation / 310Cell-Cycle Dysregulation in Cancer / 311Oncogenes / 313Alterations in Apoptosis in Cancer Cells / 314Autophagy in Cancer Cells / 315Cancer Invasion / 315Angiogenesis / 316Metastasis / 316Epithelial-Mesenchymal Transition / 317Cancer Stem Cells / 318Cancer Etiology 318Cancer Genomics / 318Tumor Heterogeneity and Molecular Evolution / 319Genes Associated With Hereditary Cancer Risk / 320APC Gene and Familial Adenomatous Polyposis / 324PTEN and Cowden Disease / 325RET Proto-Oncogene and Multiple Endocrine Neoplasia Type 2 / 325Chemical Carcinogens / 326Physical Carcinogens / 326Viral Carcinogens / 326Cancer Risk Assessment 328Cancer Screening 330Cancer Diagnosis 332Cancer Staging 333Tumor Markers 334Prognostic and Predictive Tissue Markers / 334Serum Markers / 335Circulating Tumor Cells / 336Bone Marrow Micrometastases / 337Surgical Approaches to Cancer Therapy 337Multidisciplinary Approach to Cancer /


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Surgery_Schwartz. and Predictive Tissue Markers / 334Serum Markers / 335Circulating Tumor Cells / 336Bone Marrow Micrometastases / 337Surgical Approaches to Cancer Therapy 337Multidisciplinary Approach to Cancer / 337Surgical Management of Primary Tumors / 337Surgical Management of the Regional Lymph Node Basin / 338Surgical Management of Distant Metastases / 339Chemotherapy 340Clinical Use of Chemotherapy / 340Principles of Chemotherapy / 340Anticancer Agents / 340Combination Chemotherapy / 341Drug Toxicity / 341Administration of Chemotherapy / 341Hormonal Therapy 342Targeted Therapy 342Immunotherapy 342Gene Therapy 345Mechanisms of Intrinsic and Acquired Drug Resistance 345Radiation Therapy 346Physical Basis of Radiation Therapy / 346Biologic Basis of Radiation Therapy / 346Radiation Therapy Planning / 347Side Effects / 348Cancer Prevention 348Trends in Oncology 349Cancer Screening and Diagnosis / 349Surgical Therapy / 349Systemic Therapy / 349Brunicardi_Ch10_p0305-p0354.indd 30522/02/19 2:14


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Surgery_Schwartz. / 347Side Effects / 348Cancer Prevention 348Trends in Oncology 349Cancer Screening and Diagnosis / 349Surgical Therapy / 349Systemic Therapy / 349Brunicardi_Ch10_p0305-p0354.indd 30522/02/19 2:14 PM 306Key Points1 Modern cancer therapy is multidisciplinary, involving coor-dinated care by surgeons, medical oncologists, radiation oncologists, reconstructive surgeons, pathologists, radiolo-gists, and primary care physicians.2 Understanding cancer biology is essential to successfully implement personalized cancer therapy.3 The following alterations are critical for malignant cancer growth: self-sufficiency of growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, potential for limitless replication, angiogenesis, invasion and metastasis, reprogramming of energy metabolism, and evading immune destruction.EPIDEMIOLOGYBasic Principles of Cancer EpidemiologyThe term incidence refers to the number of new cases occur-ring. Incidence is usually expressed as the


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Surgery_Schwartz. metabolism, and evading immune destruction.EPIDEMIOLOGYBasic Principles of Cancer EpidemiologyThe term incidence refers to the number of new cases occur-ring. Incidence is usually expressed as the number of new cases per 100,000 persons per year. Mortality refers to the number of deaths occurring and is expressed as the number of deaths per 100,000 persons per year. Incidence and mortality data are usually available through cancer registries. Mortality data are also available as public records in many countries where deaths are registered as vital statistics, often with the cause of death. In areas where cancer registries do not exist, mortality data are used to extrapolate incidence rates. These numbers are likely to be less accurate than registry data, as the relationship between incidence and cause-specific death is likely to vary significantly among countries owing to the variation in health care delivery.The incidence of cancer varies by geography. This is due in part to genetic


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Surgery_Schwartz. and cause-specific death is likely to vary significantly among countries owing to the variation in health care delivery.The incidence of cancer varies by geography. This is due in part to genetic differences and in part to differences in environ-mental and dietary exposures. Epidemiologic studies that moni-tor trends in cancer incidence and mortality have tremendously enhanced our understanding of the etiology of cancer. Further-more, analysis of trends in cancer incidence and mortality allows us to monitor the effects of different preventive and screening measures, as well as the evolution of therapies for specific cancers.The two types of epidemiologic studies that are conducted most often to investigate the etiology of cancer and the effect of prevention modalities are cohort studies and case-control stud-ies. Cohort studies follow a group of people who initially do not have a disease over time and measure the rate of development of a disease. In cohort studies, a group that is


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Surgery_Schwartz. and case-control stud-ies. Cohort studies follow a group of people who initially do not have a disease over time and measure the rate of development of a disease. In cohort studies, a group that is exposed to a certain environmental factor or intervention usually is compared to a group that has not been exposed (e.g., smokers vs. nonsmokers). A case-control study compares a group of patients affected with a disease to a group of individuals without the disease and looks back retrospectively to compare how frequently the exposure to a risk factor is present in each group to determine the rela-tionship between the risk factor and the disease. The results are expressed in terms of an odds ratio, or relative risk. A relative risk <1 indicates a protective effect of the exposure, whereas a relative risk >1 indicates an increased risk of developing the disease with exposure.Cancer Incidence and Mortality in the United StatesIn the year 2017, it is estimated that 1.7 million new cancer cases


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Surgery_Schwartz. risk >1 indicates an increased risk of developing the disease with exposure.Cancer Incidence and Mortality in the United StatesIn the year 2017, it is estimated that 1.7 million new cancer cases will be diagnosed in the United States, excluding carci-noma in situ of any site except bladder, and excluding basal cell and squamous cell carcinomas of the skin.1 In addition, 63,410 cases of carcinoma in situ of the breast, and 74,680 of melanoma in situ are expected.1It is estimated that in 2017 an estimated 600,920 people will die of cancer in the United States, corresponding to about 1650 deaths per day.1 The estimated new cancer cases and deaths by cancer type are shown in Table 10-1.1 The most com-mon causes of cancer death in men are cancers of the lung and bronchus, colon and rectum, and prostate; in women, the most common cancers are of the lung and bronchus, breast, and colon and rectum.1 These four cancers account for almost half of total cancer deaths among men and women.The


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Surgery_Schwartz. and prostate; in women, the most common cancers are of the lung and bronchus, breast, and colon and rectum.1 These four cancers account for almost half of total cancer deaths among men and women.The annual age-adjusted cancer incidence rates among males and females for selected cancer types are shown in Fig. 10-1.1 Incidence rates are declining for most cancer sites (Fig. 10-2).1 Incidence rates for thyroid cancer have begun to stabilize recently, possibly due to changes in clinical practice guidelines that were initiated in 2009 and included more conservative indications for biopsy. The age-adjusted incidence rate of breast cancer started to decrease from 2001 to 2004.2 This decrease in breast cancer inci-dence has at least temporally been associated with the first report of the Women’s Health Initiative, which documented an increased risk of coronary artery disease and breast cancer with the use of hormone replacement therapy; this was followed by a drop in the use of hormone


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Surgery_Schwartz. Health Initiative, which documented an increased risk of coronary artery disease and breast cancer with the use of hormone replacement therapy; this was followed by a drop in the use of hormone replacement therapy by postmenopausal women in the United States.2 Unfortunately, there was a slight increase in breast cancer incidence from 2004 to 2013. This was driven wholly by nonwhite women; rates increased by about 2% per year among women other than white or black and by 0.5% per year among black women. Thus, rates have risen slightly in women as a whole from 2013 to 2017, although rates remained stable in white women.Declines in colorectal cancer incidence have been mainly attributed to increased screening that allows for removal of pre-cancerous polyps. Prostate cancer rates rapidly increased and decreased between 1995 and 1998. These trends are thought to be attributable to increased use of prostate-specific antigen (PSA) screening.3 Due to growing concerns about overdiagno-sis and


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Surgery_Schwartz. and decreased between 1995 and 1998. These trends are thought to be attributable to increased use of prostate-specific antigen (PSA) screening.3 Due to growing concerns about overdiagno-sis and overtreatment, a U.S. Preventive Services Task Force recommended against routine use of PSA testing to screen for prostate cancer. As a result, there was more than 10% annual reduction in prostate cancer incidence from 2010 to 2013. Dif-ferences in lung cancer incidence patterns between women and men are thought to reflect historical differences in tobacco use. Differences in smoking prevalence is also thought to contribute to regional differences in lung cancer incidence. Lung cancer incidence is fourfold higher in Kentucky, which has the highest smoking prevalence, compared with Utah, which has the lowest smoking prevalence.1The 5-year survival rates for selected cancers are listed in Table 10-2. From 2010 to 2014, cancer death rates decreased by 1.8% per year in men and by 1.4% per year in


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Surgery_Schwartz. the lowest smoking prevalence.1The 5-year survival rates for selected cancers are listed in Table 10-2. From 2010 to 2014, cancer death rates decreased by 1.8% per year in men and by 1.4% per year in women.1 These declines in mortality have been consistent in the past decade and larger than what was observed in the previous decade.3 Over the Brunicardi_Ch10_p0305-p0354.indd 30622/02/19 2:14 PM 307ONCOLOGYCHAPTER 10Table 10-1Estimated new cancer cases and deaths, United States, 2017a ESTIMATED NEW CASESESTIMATED DEATHS ESTIMATED NEW CASESESTIMATED DEATHSAll cancers1,688,780600,920Genital system279,80059,100Oral cavity and pharynx49,6709700 Uterine cervix12,8204210Digestive system310,440157,700 Uterine corpus61,38010,920 Esophagus16,94015,690 Ovary22,44014,080 Stomach28,00010,960 Vulva60201150 Small intestine10,1901390 Vagina and other genital, female48101240 Colon and rectum95,520 / 39,91050,260b Prostate161,36026,730 Anus, anal canal, and anorectum82001100 Testis8850410 Liver


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Surgery_Schwartz. intestine10,1901390 Vagina and other genital, female48101240 Colon and rectum95,520 / 39,91050,260b Prostate161,36026,730 Anus, anal canal, and anorectum82001100 Testis8850410 Liver and intrahepatic bile duct40,71028,920 Penis and other genital, male2120360 Gallbladder and other biliary11,7403830Urinary system146,65032,190 Pancreas53,67043,090 Urinary bladder79,03016,870 Other digestive organs55602460 Kidney and renal pelvis63,99014,400Respiratory system243,170160,420 Ureter and other urinary organs3630920 Larynx13,3603660Eye and orbit3130330 Lung and bronchus220,500155,870Brain and other nervous system23,80016,700 Other respiratory organs7310890Endocrine system59,2503010Bones and joints32601550 Thyroid56,8702010Soft tissue (including heart)12,3904990 Other endocrine23801000Skin (excluding basal and squamous)95,36013,590Lymphoma80,50021,210 Melanoma87,1109730Multiple myeloma30,28012,590 Other nonepithelial82503860Leukemia62,13024,500Breast255,18041,070Other and unspecified primary


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Surgery_Schwartz. basal and squamous)95,36013,590Lymphoma80,50021,210 Melanoma87,1109730Multiple myeloma30,28012,590 Other nonepithelial82503860Leukemia62,13024,500Breast255,18041,070Other and unspecified primary sitesc33,77042,270aRounded to the nearest 10, cases exclude basal cell and squamous cell skin cancers and in situ carcinoma except bladder. About 63,410 cases of carcinoma in situ of the female breast and 74,680 cases of melanoma in situ were diagnosed in 2017.bDeaths for colon and rectum cancers are combined because a large number of deaths from rectal cancer are misclassified as colon.cMore deaths than cases may reflect lack of specificity in recording underlying cause of death on death certificate and/or an undercount in the case estimate.Modified with permission from Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2017, CA Cancer J Clin. 2017 Jan;67(1):7-30.past 3 decades, the 5-year relative survival rate for all cancers combined has increased by 20% among whites and 24% among blacks.


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Surgery_Schwartz. A: Cancer Statistics, 2017, CA Cancer J Clin. 2017 Jan;67(1):7-30.past 3 decades, the 5-year relative survival rate for all cancers combined has increased by 20% among whites and 24% among blacks. Improvements in survival for the most common cancers have been similar across both sexes but are more pronounced among patients age 50 to 64 years than among those older than 65 years. This difference may reflect reduced efficacy of new therapies in the elderly or perhaps lower utilization.1 Progress has been rapid for hematopoietic and lymphoid malignancies due to improved treatment protocols and the discovery of tar-geted therapies. The decrease in lung cancer death rates in men is thought to be due to a decrease in tobacco use, whereas the decreases in death rates from breast, colorectal cancer, and prostate cancer likely reflect advances in early detection and treatment. For instance, there is potential for lung cancer to be diagnosed at an earlier stage through the use of screening with


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Surgery_Schwartz. and prostate cancer likely reflect advances in early detection and treatment. For instance, there is potential for lung cancer to be diagnosed at an earlier stage through the use of screening with low-dose computed tomography.Global Statistics on Cancer Incidence and MortalityThe five most common cancers for men worldwide are lung, prostate, colorectal cancer, stomach, and liver and for women are breast, colorectal, cervix, lung, and stomach.4 Notably, for several cancer types there is wide geographical variability in cancer incidence (Fig. 10-3). The mortality rates for different cancers also vary significantly among countries. This is attribut-able not only to variations in incidence but also to variations in survival after a cancer diagnosis. The survival rates are influ-enced by treatment patterns as well as by variations in cancer screening practices, which affect the stage of cancer at diagno-sis. For example, the 5-year survival rate for stomach cancer is much higher in Japan,


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Surgery_Schwartz. patterns as well as by variations in cancer screening practices, which affect the stage of cancer at diagno-sis. For example, the 5-year survival rate for stomach cancer is much higher in Japan, where the cancer incidence is high enough to warrant mass screening, which is presumed to lead to earlier diagnosis. In the case of prostate cancer, on the other Brunicardi_Ch10_p0305-p0354.indd 30722/02/19 2:14 PM 308BASIC CONSIDERATIONSPART Ihand, the mortality rates diverge much less than the incidence rates among countries. Survival rates for prostate cancer are much higher in North America than in developing countries.5 It is possible that the extensive screening practices in the United States allow discovery of cancers at an earlier, more curable stage; however, it is also possible that this screening leads to discovery of more latent, less biologically aggressive cancers, which may not have caused death even if they had not been identified.In 2008 (the last date for which complete


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Surgery_Schwartz. this screening leads to discovery of more latent, less biologically aggressive cancers, which may not have caused death even if they had not been identified.In 2008 (the last date for which complete data are available), about 1 million new cases of stomach cancer were estimated to have occurred (988,000 cases, 7.8% of the total), making it the fourth most common malignancy in the world, behind cancers of the lung, breast, and colorectal cancer. The incidence of stomach cancer varies significantly among different regions of the world. The difference in risk by country is presumed to be primarily due to differences in dietary factors. The risk is increased by high consumption of preserved salted foods, such as meats and pick-les, and decreased by high intake of fruits and vegetables.5 There also is some international variation in the incidence of infection with Helicobacter pylori, which is known to play a major role in gastric cancer development.5 Fortunately, a steady decline is being


Surgery_Schwartz

Surgery_Schwartz. also is some international variation in the incidence of infection with Helicobacter pylori, which is known to play a major role in gastric cancer development.5 Fortunately, a steady decline is being observed in the incidence and mortality rates of gastric cancer. This may be related to improvements in preservation and storage of foods as well as due to changes in the prevalence of H pylori.5 More than 70% of cases (713,000 cases) occur in developing countries, and half the cases in the world occur in Eastern Asia (mainly in China).4 Age-standardized incidence rates are about twice as high for men as for women, ranging from 3.9 in Northern Africa to 42.4 in Eastern Asia for men, and from 2.2 in Southern Africa to 18.3 in Eastern Asia for women. Stomach cancer is the second leading cause of cancer death in both sexes worldwide.Overall, the incidence of breast cancer is rising in most countries. Incidence varies from 19.3 per 100,000 women in Eastern Africa to 89.7 per 100,000 women in


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Surgery_Schwartz. cancer death in both sexes worldwide.Overall, the incidence of breast cancer is rising in most countries. Incidence varies from 19.3 per 100,000 women in Eastern Africa to 89.7 per 100,000 women in Western Europe, and are high in developed regions of the world (except Japan) and low in most of the developing regions.4 Although breast cancer has been linked to cancer susceptibility genes, mutations in these genes account for only 5% to 10% of breast tumors, which suggests that the wide geographic variations in breast cancer incidence are not due to geographic variations in the prevalence of these genes. Most of the differences, therefore, are attributed to differences in reproductive factors, diet, alcohol, obesity, physical activity, and other environmental differences. Indeed, breast cancer risk increases significantly in females MalesFemalesBreastLung & bronchusColon & rectumUterine corpusNon-Hodgkin lymphomaThyroidMelanoma of the skinPancreasLeukemiaKidney & renal pelvisAll


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Surgery_Schwartz. cancer risk increases significantly in females MalesFemalesBreastLung & bronchusColon & rectumUterine corpusNon-Hodgkin lymphomaThyroidMelanoma of the skinPancreasLeukemiaKidney & renal pelvisAll Sites252,710105,51064,01061,38042,47034,94032,16025,84025,70023,380852,63030%12%8%7%5%4%4%3%3%3%100%MalesFemalesLung & bronchusProstateColon & rectumPancreasLiver & intrahepatic bile ductLeukemiaEsophagusUrinary bladderNon-Hodgkin lymphomaBrain & other nervous systemAll SitesLung & bronchusBreastColon & rectumPancreasOvaryLeukemiaNon-Hodgkin lymphomaUterine corpusLiver & intrahepatic bile ductBrain & other nervous systemAll Sites71,28040,61023,11020,79014,08010,92010,2009,3108,6907,080282,50025%14%8%7%5%4%4%3%3%3%100%84,59027,15026,73022,30019,61014,30012,72012,24011,4509,620318,42027%9%8%7%6%4%4%4%4%3%100%ProstateLung & bronchusColon & rectumUrinary bladderMelanoma of the skinNon-Hodgkin lymphomaKidney & renal pelvisOral cavity & pharynxLeukemiaLiver & intrahepatic bile ductAll


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Surgery_Schwartz. & bronchusColon & rectumUrinary bladderMelanoma of the skinNon-Hodgkin lymphomaKidney & renal pelvisOral cavity & pharynxLeukemiaLiver & intrahepatic bile ductAll Sites161,360116,99071,42060,49052,17040,61040,08036,29035,72029,200836,15019%14%9%7%6%5%5%4%4%3%100%Estimated new casesEstimated deathsFigure 10-1. Ten leading cancer types with the estimated new cancer cases and deaths by sex in the United States, 2013. *Excludes basal and squamous cell skin cancers and in situ carcinomas except those of the urinary bladder. Estimates are rounded to the nearest 10 (Modified with permission from Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2017, CA Cancer J Clin. 2017 Jan;67(1):7-30.)Brunicardi_Ch10_p0305-p0354.indd 30822/02/19 2:14 PM 309ONCOLOGYCHAPTER 10who have migrated from Asia to America.5 The range of breast cancer mortality rates is much less (approximately 6 to 19 per 100,000) because of the more favorable survival of breast cancer in developed regions. As a result,


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Surgery_Schwartz. to America.5 The range of breast cancer mortality rates is much less (approximately 6 to 19 per 100,000) because of the more favorable survival of breast cancer in developed regions. As a result, breast cancer ranks as the fifth cause of death from cancer overall (458,000 deaths), but it is still the most frequent cause of cancer death in women in both developing (269,000 deaths, 12.7% of total) and developed regions (estimated 189,000 deaths).4There is a 25-fold variation in colon cancer incidence world-wide.5 The incidence of colon and rectal cancer is higher in devel-oped countries than in developing countries. The incidence rates are highest in North America, Australia and New Zealand, and Western Europe, and especially in Japanese men.5 In contrast, the incidence is relatively low in North Africa, South America, and Eastern, Southeastern, and Western Asia. These geographic differences are thought to reflect environmental exposures and are presumed to be related mainly to dietary


Surgery_Schwartz

Surgery_Schwartz. North Africa, South America, and Eastern, Southeastern, and Western Asia. These geographic differences are thought to reflect environmental exposures and are presumed to be related mainly to dietary differences in con-sumption of animal fat, meat, and fiber.5Worldwide liver cancer is the fifth most common cancer in men (523,000 cases, 7.9% of the total) and the seventh in women (226,000 cases, 6.5% of the total). Almost 85% of liver cancer cases occur in developing countries, and particularly in men.4 The overall sex ratio of male to female is 2:4. The regions of high incidence are Eastern and Southeastern Asia, Middle and Western Africa, as well as Melanesia and Micronesia/Polynesia (particularly in men). Low rates are estimated in developed regions, with the exception of Southern Europe. There were an estimated 694,000 deaths from liver cancer in 2008 (477,000 in men, 217,000 in women), and because of its high fatality (overall ratio of mortality to incidence of 0.93), liver cancer


Surgery_Schwartz

Surgery_Schwartz. There were an estimated 694,000 deaths from liver cancer in 2008 (477,000 in men, 217,000 in women), and because of its high fatality (overall ratio of mortality to incidence of 0.93), liver cancer is the third most common cause of death from cancer worldwide. The geographical distribution of the mortality rates is similar to that observed for incidence. Worldwide, the major risk factors for liver cancer are infection with hepatitis B and C viruses and consumption of foods contaminated with aflatoxin. Hepatitis B immunization in children has recently been shown to reduce the incidence of liver cancer.5In summary, the incidence rates of many common cancers vary widely by geography. This is due in part to genetic dif-ferences, including racial and ethnic differences. It is due also in part to differences in environmental and dietary exposures, factors that can potentially be altered. Therefore, establishment of regional and international databases is critical to improving our


Surgery_Schwartz

Surgery_Schwartz. in part to differences in environmental and dietary exposures, factors that can potentially be altered. Therefore, establishment of regional and international databases is critical to improving our understanding of the etiology of cancer and will ultimately assist in the initiation of targeted strategies for global cancer prevention. Furthermore, the monitoring of cancer mortality rates and 5-year cancer-specific survival rates will identify regions where there are inequities of health care, so that access to health care can be facilitated and guidelines for treatment can be established.Liver*ThyroidUterine corpusMelanoma of the skinColorectumLung & bronchusBreastFemale197519801985199019952000200520102013025Year of diagnosis5075100125150175200225250025Year of diagnosisLiver*ThyroidMelanoma of the skinUrinary bladderColorectumLung & bronchusProstateMaleRate per 100,000 population5075100125150175200225250197519801985199019952000200520102013Figure 10-2. Trends in cancer incidence rates


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Surgery_Schwartz. of the skinUrinary bladderColorectumLung & bronchusProstateMaleRate per 100,000 population5075100125150175200225250197519801985199019952000200520102013Figure 10-2. Trends in cancer incidence rates for selected cancer by sex among males and females for selected cancer types, United States, 1975 to 2009. Rates are age adjusted to the 2000 U.S. standard population. +Liver includes intrahepatic bile duct. (Modified with permission from Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2017, CA Cancer J Clin. 2017 Jan;67(1):7-30.)Brunicardi_Ch10_p0305-p0354.indd 30922/02/19 2:14 PM 310BASIC CONSIDERATIONSPART ITable 10-2Five-year relative survival rates adjusted to normal life expectancy by year of diagnosis, United States, 1975–2008 RELATIVE 5-YEAR SURVIVAL RATES (%)CANCER TYPE1975–19771987–19892005-2011All cancers495669Brain222935Breast (female)758491Uterine cervix697069Colon516169Uterine corpus878383Esophagus51020Hodgkin’s


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Surgery_Schwartz. 5-YEAR SURVIVAL RATES (%)CANCER TYPE1975–19771987–19892005-2011All cancers495669Brain222935Breast (female)758491Uterine cervix697069Colon516169Uterine corpus878383Esophagus51020Hodgkin’s disease727988Kidney505774Larynx666663Leukemia344362Liver3518Lung and bronchus121318Melanoma of the skin828893Multiple myeloma252849Non-Hodgkin’s lymphoma475172Oral cavity535466Ovary363846Pancreas248Prostate688399Rectum485868Stomach152030Testis839597Thyroid929598Urinary bladder737979Data from Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2017, CA Cancer J Clin. 2017 Jan;67(1):7-30.CANCER BIOLOGYHallmarks of CancerAlthough there are >100 types of cancer, it has been proposed that there are six essential alterations in cell physiology that dic-tate malignant growth: self-sufficiency of growth signals, insen-sitivity to growth-inhibitory signals, evasion of apoptosis (programmed cell death), potential for limitless replication, angiogenesis, and invasion and metastasis.6 Recently two additional


Surgery_Schwartz

Surgery_Schwartz. insen-sitivity to growth-inhibitory signals, evasion of apoptosis (programmed cell death), potential for limitless replication, angiogenesis, and invasion and metastasis.6 Recently two additional hallmarks have emerged—reprogramming of energy metabolism and evading immune destruction.7 These hallmarks of cancer are being pursued as targets for cancer ther-apy (Fig. 10-4).Cell Proliferation and TransformationIn normal cells, cell growth and proliferation are under strict control. In cancer cells, cells become unresponsive to normal growth controls, which leads to uncontrolled cell division. Human cells require several genetic changes for neoplastic transformation. Cell type–specific differences also exist in the process by which a normal cell is transformed into a cancer-ous one. Abnormally proliferating, transformed cells outgrow normal cells in the culture dish (i.e., in vitro) and commonly display several abnormal characteristics.8 These include loss of contact inhibition (i.e.,


Surgery_Schwartz

Surgery_Schwartz. proliferating, transformed cells outgrow normal cells in the culture dish (i.e., in vitro) and commonly display several abnormal characteristics.8 These include loss of contact inhibition (i.e., cells continue to proliferate after a con-fluent monolayer is formed); an altered appearance and poor adherence to other cells or to the substratum; loss of anchorage dependence for growth; immortalization; and gain of tumorige-nicity (i.e., the ability to give rise to tumors when injected into an appropriate host).Cancer InitiationTumorigenesis is proposed to have three steps: initiation, promo-tion, and progression. Initiating events such as gain of function of genes known as oncogenes or loss of function of genes known as tumor-suppressor genes may lead a single cell to acquire a dis-tinct growth advantage. Although tumors usually arise from a sin-gle cell or clone, it is thought that sometimes not a single cell but 3Brunicardi_Ch10_p0305-p0354.indd 31022/02/19 2:14 PM


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Surgery_Schwartz. a dis-tinct growth advantage. Although tumors usually arise from a sin-gle cell or clone, it is thought that sometimes not a single cell but 3Brunicardi_Ch10_p0305-p0354.indd 31022/02/19 2:14 PM 311ONCOLOGYCHAPTER 10rather a large number of cells in a target organ may have under-gone the initiating genetic event. Thus, many normal-appearing cells may have an increased malignant potential. This is referred to as a field effect. The initiating events are usually genetic and occur as deletions of tumor-suppressor genes or amplification or mutation of oncogenes. Subsequent events can lead to accumula-tions of additional deleterious mutations in the clone.Cancer is thought to be a disease of clonal progression as tumors arise from a single cell and accumulate mutations that confer on the tumor an increasingly aggressive behavior. Most tumors go through a progression from benign lesions to in situ tumors to invasive cancers (e.g., atypical ductal hyperplasia to ductal carcinoma in situ


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Surgery_Schwartz. an increasingly aggressive behavior. Most tumors go through a progression from benign lesions to in situ tumors to invasive cancers (e.g., atypical ductal hyperplasia to ductal carcinoma in situ to invasive ductal carcinoma of the breast). Fearon and Vogelstein proposed the model for colorec-tal tumorigenesis presented in Fig. 10-5.9 Colorectal tumors arise from the mutational activation of oncogenes coupled with muta-tional inactivation of tumor-suppressor genes, the latter being the predominant change.9 Mutations in at least four or five genes are required for formation of a malignant tumor, while fewer changes suffice for a benign tumor. Although genetic mutations often occur in a preferred sequence, a tumor’s biologic properties are determined by the total accumulation of its genetic changes.Gene expression is a multistep process that starts from transcription of a gene into messenger ribonucleic acid (mRNA) and then translation of this sequence into the functional protein. There


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Surgery_Schwartz. changes.Gene expression is a multistep process that starts from transcription of a gene into messenger ribonucleic acid (mRNA) and then translation of this sequence into the functional protein. There are several controls at each level. In addition to alterations at the genome level (e.g., amplifications of a gene), alterations at the transcription level (e.g., methylation of the DNA leading to transcriptional silencing) or at the level of mRNA process-ing, mRNA stability, mRNA translation, or protein stability, all can alter the levels of critical proteins and thus contribute to tumorigenesis. Alternatively, changes in the genomic sequence can lead to a mutated product with altered function.Cell-Cycle Dysregulation in CancerThe proliferative advantage of tumor cells is a result of their ability to bypass a quiescent state. Cancer cells often show alterations in signal transduction pathways that lead to prolif-eration in response to external signals. Mutations or alterations in the


Surgery_Schwartz

Surgery_Schwartz. ability to bypass a quiescent state. Cancer cells often show alterations in signal transduction pathways that lead to prolif-eration in response to external signals. Mutations or alterations in the expression of cell-cycle proteins, growth factors, growth factor receptors, intracellular signal transduction proteins, and nuclear transcription factors all can lead to disturbance of the basic regulatory mechanisms that control the cell cycle, allow-ing unregulated cell growth and proliferation.The cell cycle is divided into four phases (Fig. 10-6).10 During the synthetic or S phase, the cell generates a single copy of its genetic material, whereas in the mitotic or M phase, the cellular components (including copies of DNA) are partitioned between two daughter cells. The G1 and G2 phases represent gap phases, during which the cells prepare themselves for All cancers< 11.2< 0.3< 0.5< 0.7< 1.0< 11.2< 0.4< 0.7< 1.0< 1.6< 4.9Liver cancerStomach cancer< 13.4< 16.6< 22.5< 31.9< 2.2< 3.1< 4.1<


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Surgery_Schwartz. gap phases, during which the cells prepare themselves for All cancers< 11.2< 0.3< 0.5< 0.7< 1.0< 11.2< 0.4< 0.7< 1.0< 1.6< 4.9Liver cancerStomach cancer< 13.4< 16.6< 22.5< 31.9< 2.2< 3.1< 4.1< 6.0< 11.4BreastFigure 10-3. Estimated cancer incidence worldwide in 2008. Age-standardized incidence rates per 100,000 for all cancers (upper left), breast cancer (upper right), liver cancer (lower left), and stomach cancer (lower right). (Modified with permission from Ferlay J, Shin HR, Bray F, et al: GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr.)Brunicardi_Ch10_p0305-p0354.indd 31122/02/19 2:14 PM 312BASIC CONSIDERATIONSPART Icompletion of the S and M phases, respectively. When cells cease proliferation, they exit the cell cycle and enter the quies-cent state referred to as G0. The two key classes of regulatory molecules that regulate


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Surgery_Schwartz. the S and M phases, respectively. When cells cease proliferation, they exit the cell cycle and enter the quies-cent state referred to as G0. The two key classes of regulatory molecules that regulate cellular progress through the cell cycle are the cyclins and the cyclin-dependent kinases (CDKs), which associate to form an activated heterodimer. CDKs are expressed constitutively and have a catalytic activity (phosphorylation of downstream proteins), whereas the cyclins serve a regula-tory function and are synthesized at specific times during the cell cycle. Two families of genes, the cip/kip (CDK interact-ing protein/Kinase inhibitory protein) family and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) family Aerobic glycolysisinhibitorsSustainingproliferativesignalingEvadinggrowthsuppressorsEnablingreplicativeimmortalityActivatinginvasion &metastasisInducingangiogenesisGenomeinstability


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Surgery_Schwartz. Frame) family Aerobic glycolysisinhibitorsSustainingproliferativesignalingEvadinggrowthsuppressorsEnablingreplicativeimmortalityActivatinginvasion &metastasisInducingangiogenesisGenomeinstability &mutationResistingcelldeathDeregulatingcellularenergeticsTumor-promotinginflammationAvoidingimmunedestructionEGFRinhibitorsCyclin-dependentkinase inhibitorsPARPinhibitorsInhibitors ofVEGF signalingInhibitors ofHGF/c-MetTelomeraseInhibitorsSelective anti-inflammatory drugsProapoptoticBH3 mimeticsImmune activatinganti-CTLA4 oranti-PD-1 mAbFigure 10-4. Hallmarks of cancer and their therapeutic implications. Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression are in clinical trials and in some cases approved for clinical use in treating forms of human cancer. The drugs listed are illustrative examples. (Reproduced with permission from Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation, CCell. 2011 Mar 4;144(5):646-674.)First Hit:


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Surgery_Schwartz. cancer. The drugs listed are illustrative examples. (Reproduced with permission from Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation, CCell. 2011 Mar 4;144(5):646-674.)First Hit: APCSomatic Mutation(Sporadic CRC)First Hit: APCGermline Mutation(FAP)K-rasGenomic InstabilitySmad 4p53OtherAlterations˜-CateninNormalEpitheliumDysplasticACFEarlyAdenomaIntermediateAdenomaLateAdenomaCarcinomaMetastasisFigure 10-5. The adenoma-carcinoma model of human colorectal carcinogenesis. The neoplastic process is initiated by mutations in the adenomatous polyposis coli (APC) or b-catenin genes. Tumor progression results from mutations in other genes (e.g., K-ras, Smad 4 and p53) and the development of genomic instability. Patients with familial adenomatous polyposis inherit mutations in the APC gene and develop multiple aberrant crypt foci. Some of these may progress to cancer as they acquire other genetic mutations. (Reproduced with permission from Li C-J, Zhang, X, Fan G-W. Updates in


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Surgery_Schwartz. APC gene and develop multiple aberrant crypt foci. Some of these may progress to cancer as they acquire other genetic mutations. (Reproduced with permission from Li C-J, Zhang, X, Fan G-W. Updates in colorectal cancer stem cell research, J Cancer Res Ther. 2014 Dec;10 Suppl:233-239.)Brunicardi_Ch10_p0305-p0354.indd 31222/02/19 2:14 PM 313ONCOLOGYCHAPTER 10prevent the progression of the cell cycle. Mutation or altered expression of these genes can lead to tumor formation.OncogenesNormal cellular genes that contribute to cancer when abnormal are called oncogenes. The normal counterpart of such a gene is referred to as a proto-oncogene. Oncogenes are usually designated by three-letter abbreviations, such as myc or ras. Oncogenes are further designated by the prefix “v-” for virus or “c-” for cell or chromosome, corresponding to the origin of the oncogene when it was first detected. Proto-oncogenes can be activated (show increased activity) or overexpressed (expressed at increased


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Surgery_Schwartz. for cell or chromosome, corresponding to the origin of the oncogene when it was first detected. Proto-oncogenes can be activated (show increased activity) or overexpressed (expressed at increased pro-tein levels) by translocation (e.g., abl), promoter insertion (e.g., c-myc), mutation (e.g., ras), or amplification (e.g., HER2/neu). More than 100 oncogenes have been identified.Oncogenes may be growth factors (e.g., platelet-derived growth factor), growth factor receptors (e.g., HER2), intracel-lular signal transduction molecules (e.g., ras), nuclear tran-scription factors (e.g., c-myc), or other molecules involved in the regulation of cell growth and proliferation. Growth factors are ubiquitous proteins that are produced and secreted by cells locally and that stimulate cell proliferation by binding specific cell-surface receptors on the same cells (autocrine stimula-tion) or on neighboring cells (paracrine stimulation). Persis-tent overexpression of growth factors can lead to


Surgery_Schwartz

Surgery_Schwartz. by binding specific cell-surface receptors on the same cells (autocrine stimula-tion) or on neighboring cells (paracrine stimulation). Persis-tent overexpression of growth factors can lead to uncontrolled autostimulation and neoplastic transformation. Alternatively, growth factor receptors can be aberrantly activated (turned on) through mutations or overexpressed (continually presenting cells with growth-stimulatory signals, even in the absence of growth factors), which leads cells to respond as if growth factor levels are altered. The growth-stimulating effect of growth fac-tors and other mitogens is mediated through postreceptor signal Cell with duplicated chromosomesChromosome separationMitosisCell divisionCell with chromosomes in the nucleusDNA synthesisChromosome duplicationMG1SG2CDKCyclinFigure 10-6. Schematic representation of the phases of the cell cycle. Mitogenic growth factors can drive a quiescent cell from G0 into the cell cycle. Once the cell cycle passes beyond the


Surgery_Schwartz

Surgery_Schwartz. 10-6. Schematic representation of the phases of the cell cycle. Mitogenic growth factors can drive a quiescent cell from G0 into the cell cycle. Once the cell cycle passes beyond the restric-tion point, mitogens are no longer required for progression into and through S phase. The DNA is replicated in S phase, and the chromo-somes are condensed and segregated in mitosis. In early G1 phase, certain signals can drive a cell to exit the cell cycle and enter a quies-cent phase. Cell-cycle checkpoints have been identified in G1, S, G2, and M phases. CDK = cyclin-dependent kinase.transduction molecules. These molecules mediate the passage of growth signals from the outside to the inside of the cell and then to the cell nucleus, initiating the cell cycle and DNA transcrip-tion. Aberrant activation or expression of cell-signaling mol-ecules, cell-cycle molecules, or transcription factors may play an important role in neoplastic transformation. Protein tyrosine kinases account for a large


Surgery_Schwartz

Surgery_Schwartz. or expression of cell-signaling mol-ecules, cell-cycle molecules, or transcription factors may play an important role in neoplastic transformation. Protein tyrosine kinases account for a large portion of known oncogenes. One of the best-studied oncogenes, HER2 is discussed as an example later.HER2, also known as neu or c-erbB-2, is a member of the epidermal growth factor receptor (EGFR) family and is one of the best-characterized tyrosine kinases. Unlike other recep-tor tyrosine kinases, HER2/neu does not have a direct soluble ligand. It plays a key role in signaling, however, because it is the preferred partner in heterodimer formation with all the other EGFR family members (EGFR/c-erbB-1, HER2/c-erbB-3, and HER3/c-erbB-4), which bind at least 30 ligands, including epidermal growth factor (EGF), transforming growth factor α (TGFα), heparin-binding EGF-like growth factor, amphiregu-lin, and heregulin.11 Heterodimerization with HER2 potenti-ates recycling of receptors rather than


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Surgery_Schwartz. factor (EGF), transforming growth factor α (TGFα), heparin-binding EGF-like growth factor, amphiregu-lin, and heregulin.11 Heterodimerization with HER2 potenti-ates recycling of receptors rather than degradation, enhances signal potency and duration, increases affinity for ligands, and increases catalytic activity.11HER2 can interact with different members of the HER fam-ily and activate mitogenic and antiapoptotic pathways (Fig. 10-7). The specificity and potency of the intracellular signals are affected by the identity of the ligand, the composition of the receptors, and the phosphotyrosine-binding proteins associated with the erbB molecules. The Rasand Shc-activated mitogen-activated protein kinase (MAPK) pathway is a target of all erbB ligands, which increase the transcriptional activity of early response genes such as c-myc, c-fos, and c-jun.12 MAPK-independent pathways such as the phosphoinositide-3 kinase (PI3K) pathway also are activated by most erbB dimers, although the


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Surgery_Schwartz. of early response genes such as c-myc, c-fos, and c-jun.12 MAPK-independent pathways such as the phosphoinositide-3 kinase (PI3K) pathway also are activated by most erbB dimers, although the potency and kinetics of activation may differ. Stimulation of the PI3K pathway through HER2 signaling also can lead to activation of survival molecule Akt, which suppresses apoptosis through mul-tiple mechanisms.The mutant rat neu gene was first recognized as an oncogene in neuroblastomas from carcinogen-treated rats.13 The HER2 gene is frequently amplified and the protein over-expressed in many cancers, including breast, ovarian, lung, gastric, and oral cancers. Overexpression of HER2 results in ligand-independent activation of HER2 kinase, which leads to mitogenic signaling. HER2 overexpression is associated with increased cell proliferation and anchorage-independent growth as well as resistance to proapoptotic stimuli. Further, overex-pression of HER2 increases cell migration and upregulates


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Surgery_Schwartz. associated with increased cell proliferation and anchorage-independent growth as well as resistance to proapoptotic stimuli. Further, overex-pression of HER2 increases cell migration and upregulates the activities of matrix metalloproteinases (MMPs) and in vitro invasiveness. In animal models, HER2 increases tumorigenic-ity, angiogenesis, and metastasis. These results all suggest that HER2 plays a key role in cancer biology. More recently, HER2 mutations have also been reported in human cancer, including 3% of patients with lung cancer.14-17 A phase 2 study of the irre-versible kinase inhibitor neratinib showed it to have efficacy in HER2-mutated breast cancer lacking HER amplification.18The critical role of HER2 in cancer biology has been lever-aged for therapeutics, leading to several HER2-targeted drugs with different mechanism of action approved by the Food and Drug Administration (FDA): monoclonal antibodies trastu-zumab and pertuzumab, small molecule inhibitor lapatinib, and


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Surgery_Schwartz. HER2-targeted drugs with different mechanism of action approved by the Food and Drug Administration (FDA): monoclonal antibodies trastu-zumab and pertuzumab, small molecule inhibitor lapatinib, and antibody-drug conjugate ado-trastuzumab emtansine. Anti-HER2 agents first showed efficacy in the metastatic setting but Brunicardi_Ch10_p0305-p0354.indd 31322/02/19 2:14 PM 314BASIC CONSIDERATIONSPART Iare now routinely used as adjuvant therapy of breast cancer and also as neoadjuvant treatments (“up-front chemotherapy”).Alterations in Apoptosis in Cancer CellsApoptosis is a genetically regulated program to dispose of cells. Cancer cells must avoid apoptosis if tumors are to arise. The growth of a tumor mass is dependent not only on an increase in proliferation of tumor cells but also on a decrease in their apoptotic rate. Apoptosis is distinguished from necrosis because it leads to several characteristic changes. Soon after undergoing apoptosis, membrane phosphatidylserine translocates


Surgery_Schwartz

Surgery_Schwartz. in their apoptotic rate. Apoptosis is distinguished from necrosis because it leads to several characteristic changes. Soon after undergoing apoptosis, membrane phosphatidylserine translocates from the inner face of the plasma membrane to the cell surface where it can be detected via the use of a fluorescent conjugate of Annexin V, a protein that exhibits a high affinity for phosphatidylserine. Late in apoptosis there are characteristic changes in nuclear morphology, such as chromatin condensation, nuclear frag-mentation, and DNA laddering, as well as membrane blebbing. Apoptotic cells are then engulfed and degraded by phagocytic cells. The effectors of apoptosis are a family of proteases called caspases (cysteine-dependent and aspartate-directed proteases). The initiator caspases (e.g., 8, 9, and 10), which are upstream, cleave the downstream executioner caspases (e.g., 3, 6, and 7) that carry out the destructive functions of apoptosis.Two principal molecular pathways signal apoptosis


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Surgery_Schwartz. 9, and 10), which are upstream, cleave the downstream executioner caspases (e.g., 3, 6, and 7) that carry out the destructive functions of apoptosis.Two principal molecular pathways signal apoptosis by cleaving the initiator caspases with the potential for crosstalk: the mitochondrial pathway and the death receptor pathway. In the mitochondrial (or intrinsic) pathway, death results from the release of cytochrome c from the mitochondria. Cytochrome c, procaspase 9, and apoptotic protease activating factor 1 (Apaf-1) form an enzyme complex, referred to as the apoptosome, that activates the effector caspases. In addition to these proteins, the mitochondria contain other proapoptotic proteins such as Smac/DIABLO (second mitochondria-derived activator of cas-pase/direct inhibitor of apoptosis-binding protein with low pI). The mitochondrial pathway can be stimulated by many factors, including DNA damage, reactive oxygen species, or the with-drawal of survival factors. The permeability of


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Surgery_Schwartz. protein with low pI). The mitochondrial pathway can be stimulated by many factors, including DNA damage, reactive oxygen species, or the with-drawal of survival factors. The permeability of the mitochon-drial membrane determines whether the apoptotic pathway will proceed. The Bcl-2 family of regulatory proteins includes both proapoptotic proteins (e.g., Bax, BAD, and Bak) and antiapop-totic proteins (e.g., Bcl-2 and Bcl-xL). The activity of the Bcl-2 proteins is centered on the mitochondria, where they regulate LigandsPI3KILKEZH2GSK3MDM2ForkheadCaspase-9CaspasesFas-LAktIKKBadI˜Bp27p214E-BP1TSC1/2sosGrb2ShcsrcMEKKMEKSEKMAPKSAPKELKMYCCREBJUNS6KS6elF4EAlterations in geneexpressionMigrationGrowthProliferationAngiogenesisSurvivalNF-˜BBcl-xLPLC-°IP31,2 diacyl-glycerolCa++mobilizationProteinkinase CRaf-1AdhesionmTORHER1/3/4HER2FAKRasFigure 10-7. The HER2 signaling pathway. HER2 can interact with different members of the HER family and activate mitogenic and antiapoptotic pathways. 4E-BP1 =


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Surgery_Schwartz. CRaf-1AdhesionmTORHER1/3/4HER2FAKRasFigure 10-7. The HER2 signaling pathway. HER2 can interact with different members of the HER family and activate mitogenic and antiapoptotic pathways. 4E-BP1 = eIF4E binding protein 1; CREB = cyclic adenosine monophosphate element binding; eIF4E = eukaryotic initiation factor 4E; EZH = enhancer of zeste homolog; FAK = focal adhesion kinase; Fas-L = Fas ligand; GSK3 = glycogen synthase kinase-3; HER = human epidermal growth receptor; IKK = IκB kinase; ILK= integrin-linked kinase; IP3 = inositol triphosphate; IκB = inhibitor of NF-κB; MAPK = mitogen-activated protein kinase; MDM2 = mouse double minute 2 homologue; MEK = mitogen-activated protein/extracel-lular signal regulated kinase kinase; MEKK = MEK kinase; mTOR = mammalian target of rapamycin; NF-κB = nuclear factor κB; PI3K = phosphoinositide-3 kinase; PLC-γ = phospholipase Cγ; SAPK = stress-activated protein kinase; SEK = SAPK/extracellular signal regulated kinase kinase; TSC = tuberous


Surgery_Schwartz

Surgery_Schwartz. NF-κB = nuclear factor κB; PI3K = phosphoinositide-3 kinase; PLC-γ = phospholipase Cγ; SAPK = stress-activated protein kinase; SEK = SAPK/extracellular signal regulated kinase kinase; TSC = tuberous sclerosis complex. (Modified with permission from Meric-Bernstam F, Hung MC. Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy, Clin Cancer Res. 2006 Nov 1;12(21):6326-6330.)Brunicardi_Ch10_p0305-p0354.indd 31422/02/19 2:14 PM 315ONCOLOGYCHAPTER 10membrane permeability. Growth factors promote survival sig-naling through the PI3K/Akt pathway, which phosphorylates and inactivates proapoptotic BAD. In contrast, growth fac-tor withdrawal may promote apoptosis through signaling by unphosphorylated BAD. The heat shock proteins, including Hsp70 and Hsp27, are also involved in inhibition of down-stream apoptotic pathways by blocking formation of the apop-tosome complex and inhibiting release of cytochrome c from the mitochondria.19The second principal


Surgery_Schwartz

Surgery_Schwartz. are also involved in inhibition of down-stream apoptotic pathways by blocking formation of the apop-tosome complex and inhibiting release of cytochrome c from the mitochondria.19The second principal apoptotic pathway is the death recep-tor pathway, sometimes referred to as the extrinsic pathway. Cell-surface death receptors include Fas/APO1/CD95, tumor necrosis factor receptor 1, and KILL-ER/DR5, which bind their ligands Fas-L, tumor necrosis factor (TNF), and TNF-related apoptosis-inducing ligand (TRAIL), respectively. When the receptors are bound by their ligands, they form a death-induc-ing signaling complex (DISC). At the DISC, procaspase 8 and procaspase 10 are cleaved, yielding active initiator caspases.20 The death receptor pathway may be regulated at the cell sur-face by the expression of “decoy” receptors for Fas (DcR3) and TRAIL (TRID and TRUNDD). The decoy receptors are closely related to the death receptors but lack a functional death domain; therefore, they bind death


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Surgery_Schwartz. of “decoy” receptors for Fas (DcR3) and TRAIL (TRID and TRUNDD). The decoy receptors are closely related to the death receptors but lack a functional death domain; therefore, they bind death ligands but do not transmit a death signal. Another regulatory group is the FADD-like interleukin-1 protease-inhibitory proteins (FLIPs). FLIPs have homology to caspase 8; they bind to the DISC and inhibit the activation of caspase 8. Finally, inhibitors of apoptosis proteins (IAPs) block caspase 3 activation and have the ability to regulate both the death receptor and the mitochondrial pathway.In human cancers, aberrations in the apoptotic program include increased expression of Fas and TRAIL decoy receptors; increased expression of antiapoptotic Bcl-2; increased expres-sion of the IAP-related protein survivin; increased expression of c-FLIP; mutations or downregulation of proapoptotic Bax, cas-pase 8, APAF1, XAF1, and death receptors CD95, TRAIL-R1, and TRAIL-R2; alterations of the p53 pathway;


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Surgery_Schwartz. survivin; increased expression of c-FLIP; mutations or downregulation of proapoptotic Bax, cas-pase 8, APAF1, XAF1, and death receptors CD95, TRAIL-R1, and TRAIL-R2; alterations of the p53 pathway; overexpression of growth factors and growth factor receptors; and activation of the PI3K/Akt survival pathway.20Autophagy in Cancer CellsAutophagy (self-eating) is a major cellular pathway for protein and organelle turnover. The autophagic pathway is a mechanism for the delivery of cellular materials to lysosomes for degra-dation. This process leads to the basal turnover of cell com-ponents and provides energy and macromolecular precursors. This process helps maintain a balance between anabolism and catabolism for normal cell growth and development. Inability to activate autophagy in response to nutrient deprivation, or consti-tutive activation of autophagy in response to stress, can lead to cell death; thus, autophagy is sometimes referred to as a second form of programmed cell death.


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Surgery_Schwartz. to nutrient deprivation, or consti-tutive activation of autophagy in response to stress, can lead to cell death; thus, autophagy is sometimes referred to as a second form of programmed cell death. Autophagy plays an essential role during starvation, cellular differentiation, cell death, and aging. Autophagy is also involved in the elimination of cancer cells by triggering a nonapoptotic cell death program, which suggests a negative role in tumor development. Mouse models that are heterozygotes for the beclin 1 gene, an important gene for autophagy, have altered autophagic response and show a high incidence of spontaneous tumors, which establishes a role for autophagy in tumor suppression.21 This also suggests that mutations in other genes operating in this pathway may con-tribute to tumor formation through deregulation of autophagy. However, autophagy also acts as a stress response mechanism to protect cancer cells from low nutrient supply or therapeu-tic insults. Thus, in cancer,


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Surgery_Schwartz. formation through deregulation of autophagy. However, autophagy also acts as a stress response mechanism to protect cancer cells from low nutrient supply or therapeu-tic insults. Thus, in cancer, autophagy can have opposing and context-dependent roles, and interventions to both stimulate and inhibit autophagy have been proposed as possible antican-cer treatments. Studies on the molecular controls of autophagy are ongoing and are expected to generate novel therapeutic strategies. Chloroquin is an antimalarial drug that acts as an autophagic inhibitor by blocking the autophagosome and has been tested for its anticancer properties.Cancer InvasionA feature of malignant cells is their ability to invade the sur-rounding normal tissue. Tumors in which the malignant cells appear to lie exclusively above the basement membrane are referred to as in situ cancer, whereas tumors in which the malig-nant cells are demonstrated to breach the basement membrane, penetrating into surrounding stroma, are


Surgery_Schwartz

Surgery_Schwartz. above the basement membrane are referred to as in situ cancer, whereas tumors in which the malig-nant cells are demonstrated to breach the basement membrane, penetrating into surrounding stroma, are termed invasive cancer. The ability to invade involves changes in adhesion, initiation of motility, and proteolysis of the extracellular matrix (ECM).Cell-to-cell adhesion in normal cells involves interactions between cell-surface proteins. Calcium adhesion molecules of the cadherin family (E-cadherin, P-cadherin, and N-cadherin) are thought to enhance the cells’ ability to bind to one another and suppress invasion. Migration occurs when cancer cells pen-etrate and attach to the basal matrix of the tissue being invaded; this allows the cancer cell to pull itself forward within the tissue. Attachment to glycoproteins of the ECM such as fibronectin, laminin, and collagen is mediated by tumor cell integrin recep-tors. Integrins are a family of glycoproteins that form heterodi-meric receptors


Surgery_Schwartz

Surgery_Schwartz. to glycoproteins of the ECM such as fibronectin, laminin, and collagen is mediated by tumor cell integrin recep-tors. Integrins are a family of glycoproteins that form heterodi-meric receptors for ECM molecules. The integrins can form at least 25 distinct pairings of their α and β subunits, and each pairing is specific for a unique set of ligands. In addition to regulating cell adhesion to the ECM, integrins relay molecular signals regarding the cellular environment that influence shape, survival, proliferation, gene transcription, and migration.Factors that are thought to play a role in cancer cell motil-ity include autocrine motility factor, autotaxin, scatter factor (also known as hepatocyte growth factor), TGFα, EGF, and insulin-like growth factors. Also, serine, cysteine, and aspar-tic proteinases and MMPs have all been implicated in cancer invasion. Urokinase and tissue plasminogen activators (uPA and tPA) are serine proteases that convert plasminogen into plasmin. Plasmin, in


Surgery_Schwartz

Surgery_Schwartz. proteinases and MMPs have all been implicated in cancer invasion. Urokinase and tissue plasminogen activators (uPA and tPA) are serine proteases that convert plasminogen into plasmin. Plasmin, in return, can degrade several ECM components. Plas-min also may activate MMPs. uPA has been more closely corre-lated with tissue invasion and metastasis than tPA. Plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2) are produced in tissues and counteract the activity of plasminogen activators.MMPs comprise a family of metal-dependent endopepti-dases. Upon activation, MMPs degrade a variety of ECM com-ponents. Although MMPs often are referred to by their common names, which reflect the ECM component for which they have specificity, a sequential numbering system has been adopted for standardization. For example, collagenase-1 is now referred to as MMP-1. The MMPs are further classified as secreted and membrane-type MMPs. Most of the MMPs are synthesized as inactive zymogens (pro-MMP) and


Surgery_Schwartz

Surgery_Schwartz. For example, collagenase-1 is now referred to as MMP-1. The MMPs are further classified as secreted and membrane-type MMPs. Most of the MMPs are synthesized as inactive zymogens (pro-MMP) and are activated by proteolytic removal of the propeptide domain outside the cell by other active MMPs or serine proteinases.MMPs are upregulated in almost every type of cancer. Some of the MMPs are expressed by cancer cells, whereas others are expressed by the tumor stromal cells. Experimental models have demonstrated that MMPs promote cancer progression by Brunicardi_Ch10_p0305-p0354.indd 31522/02/19 2:14 PM 316BASIC CONSIDERATIONSPART Iincreasing cancer cell growth, migration, invasion, angiogenesis, and metastasis. MMPs exert these effects by cleaving not only structural components of the ECM but also growth factor–binding proteins, growth factor precursors, cell adhesion molecules, and other proteinases to provide a growth advantage. The activity of MMPs is regulated by their endogenous


Surgery_Schwartz

Surgery_Schwartz. but also growth factor–binding proteins, growth factor precursors, cell adhesion molecules, and other proteinases to provide a growth advantage. The activity of MMPs is regulated by their endogenous inhibitors and tissue inhibitors of MMPs (TIMP-1, TIMP-2, TIMP-3, and TIMP-4).AngiogenesisAngiogenesis is the establishment of new blood vessels from a preexisting vascular bed. This neovascularization is essential for tumor growth and metastasis. Tumors develop an angiogenic phenotype as a result of accumulated genetic alterations and in response to local selection pressures such as hypoxia. Many of the common oncogenes and tumor-suppressor genes have been shown to play a role in the induction of angiogenesis.In response to the angiogenic switch, pericytes retract and the endothelium secretes several growth factors such as basic fibroblast growth factor, platelet-derived growth fac-tor (PDGF), and insulin-like growth factor. The basement membrane and stroma around the capillary are


Surgery_Schwartz

Surgery_Schwartz. several growth factors such as basic fibroblast growth factor, platelet-derived growth fac-tor (PDGF), and insulin-like growth factor. The basement membrane and stroma around the capillary are proteolytically degraded, a process that is mediated in most part by uPA. The endothelium then migrates through the degraded matrix, ini-tially as a solid cord and later forming lumina. Finally, sprout-ing tips anastomose to form a vascular network surrounded by a basement membrane.Angiogenesis is mediated by factors produced by various cells, including tumor cells, endothelial cells, stromal cells, and inflammatory cells. The first proangiogenic factor was identi-fied by Folkman and colleagues in 1971.22 Since then, several other factors have been shown to be proangiogenic or antian-giogenic. Of the angiogenic stimulators, the best studied are the vascular endothelial growth factors (VEGFs). The VEGF fam-ily consists of six growth factors (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental


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Surgery_Schwartz. angiogenic stimulators, the best studied are the vascular endothelial growth factors (VEGFs). The VEGF fam-ily consists of six growth factors (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor) and three receptors (VEGFR1 or Flt-1, VEGFR2 or KDR/FLK-1, and VEGFR3 or Flt-4).23 Neuropilin 1 and 2 also may act as recep-tors for VEGF.24 VEGF is induced by hypoxia and by different growth factors and cytokines, including EGF, PDGF, TNF-α, TGFβ, and interleukin-1β. VEGF has various functions, includ-ing increasing vascular permeability, inducing endothelial cell proliferation and tube formation, and inducing endothelial cell synthesis of proteolytic enzymes such as uPA, PAI-1, uroki-nase plasminogen activator receptor, and MMP-1. Furthermore, VEGF may mediate blood flow by its effects on the vasodila-tor nitric oxide and act as an endothelial survival factor, thus protecting the integrity of the vasculature. The proliferation of new lymphatic vessels, lymphangiogenesis, is


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Surgery_Schwartz. effects on the vasodila-tor nitric oxide and act as an endothelial survival factor, thus protecting the integrity of the vasculature. The proliferation of new lymphatic vessels, lymphangiogenesis, is also thought to be controlled by the VEGF family. Signaling in lymphatic cells is thought to be modulated by VEGFR3.25 Experimental studies with VEGF-C and VEGF-D have shown that they can induce tumor lymphangiogenesis and direct metastasis via the lymphatic vessels and lymph nodes.25,26PDGFs A, B, C, and D also play important roles in angio-genesis. PDGFs are produced by tumor cells as well as support-ing cells in the tumor microenvironment. PDGFs can enhance endothelial cell proliferation directly, and they can also upreg-ulate VEGF expression in vascular smooth muscle cells, pro-moting endothelial cell survival via a paracrine effect.23 The angiopoietins, angiopoietin-1 and angiopoietin-2 (Ang-1 and Ang-2), are thought to regulate blood vessel maturation. Ang-1 and Ang-2 both bind to


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Surgery_Schwartz. cell survival via a paracrine effect.23 The angiopoietins, angiopoietin-1 and angiopoietin-2 (Ang-1 and Ang-2), are thought to regulate blood vessel maturation. Ang-1 and Ang-2 both bind to the angiopoietin-1 receptor (also known as tyrosine-protein kinase receptor TIE-2), but only the binding of Ang-1 activates signal transduction; thus Ang-2 is an Ang-1 antagonist. Ang-1, via the Tie-2 receptor, induces remodel-ing and stabilization of blood vessels. Therefore, the balance between these factors determines the angiogenetic capacity of a tumor.Tumor angiogenesis is regulated by several factors in a coordinated fashion. In addition to upregulation of proangiogenic molecules, angiogenesis also can be encouraged by suppression of naturally occurring inhibitors. Such inhibitors of angiogen-esis include thrombospondin 1 and angiostatin. Angiogenesis is a prerequisite not only for primary tumor growth but also for metastasis. Angiogenesis in the primary tumor, as determined by microvessel


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Surgery_Schwartz. include thrombospondin 1 and angiostatin. Angiogenesis is a prerequisite not only for primary tumor growth but also for metastasis. Angiogenesis in the primary tumor, as determined by microvessel density, has been demonstrated to be an inde-pendent predictor of distant metastatic disease and survival in several cancers. Expression of angiogenic factors such as VEGFs has had prognostic value in many studies. These findings further emphasize the importance of angiogenesis in cancer biology.MetastasisMetastases arise from the spread of cancer cells from the pri-mary site and the formation of new tumors in distant sites. The metastatic process consists of a series of steps that need to be completed successfully (Fig. 10-8).27 First, the primary cancer must develop access to the circulation through either the blood circulatory system or the lymphatic system. After the cancer cells are shed into the circulation, they must survive. Next, the circulating cells lodge in a new organ and


Surgery_Schwartz

Surgery_Schwartz. through either the blood circulatory system or the lymphatic system. After the cancer cells are shed into the circulation, they must survive. Next, the circulating cells lodge in a new organ and extravasate into the new tissue. Next, the cells need to initiate growth in the new tis-sue and eventually establish vascularization to sustain the new tumor. Overall, metastasis is an inefficient process, although the initial steps of hematogenous metastasis (the arrest of tumor cells in the organ and extravasation) are believed to be per-formed efficiently. Only a small subset of cancer cells is then able to initiate micrometastases, and an even smaller portion goes on to grow into macrometastases.Metastases can sometimes arise several years after the treatment of primary tumors. For example, although most breast cancer recurrences occur within the first 10 years after the initial treatment and recurrences are rare after 20 years, breast cancer recurrences have been reported decades after


Surgery_Schwartz

Surgery_Schwartz. although most breast cancer recurrences occur within the first 10 years after the initial treatment and recurrences are rare after 20 years, breast cancer recurrences have been reported decades after the original tumor. This phenomenon is referred to as dormancy, and it remains one of the biggest challenges in cancer biology. Persistence of solitary cancer cells in a secondary site such as the liver or bone marrow is one possible contributor to dormancy.28 Another explanation of dormancy is that cells remain viable in a qui-escent state and then become reactivated by a physiologically perturbing event. Interestingly, primary tumor removal has been proposed to be a potentially perturbing factor.29 An alternate explanation is that cells establish preangiogenic metastases in which they continue to proliferate but that the proliferative rate is balanced by the apoptotic rate. Therefore, when these small metastases acquire the ability to become vascularized, substan-tial tumor growth can


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Surgery_Schwartz. to proliferate but that the proliferative rate is balanced by the apoptotic rate. Therefore, when these small metastases acquire the ability to become vascularized, substan-tial tumor growth can be achieved at the metastatic site, leading to clinical detection. More recently, it has been proposed that dormancy may be the result of the host losing immunologic con-trol of subclinical metastatic foci of disease either through loss of immune cell populations with antigen-specific capabilities or via the mutation of tumor cells such that their immunogenicity is altered.30Several types of tumors metastasize in an organ-specific pattern. One explanation for this is mechanical and is based on Brunicardi_Ch10_p0305-p0354.indd 31622/02/19 2:14 PM 317ONCOLOGYCHAPTER 10the different circulatory drainage patterns of the tumors. When different tumor types and their preferred metastasis sites were compared, 66% of organ-specific metastases were explained on the basis of blood flow alone. The


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Surgery_Schwartz. drainage patterns of the tumors. When different tumor types and their preferred metastasis sites were compared, 66% of organ-specific metastases were explained on the basis of blood flow alone. The other explanation for pref-erential metastasis is what is referred to as the “seed and soil” theory, the dependence of the seed (the cancer cell) on the soil (the secondary organ). According to this theory, once cells have reached a secondary organ, their growth efficiency in that organ is based on the compatibility of the cancer cell’s biology with its new microenvironment. For example, breast cancer cells may grow more efficiently in bone than in some other organs because of favorable molecular interactions that occur in the bone microenvironment. The ability of cancer cells to grow in a specific site likely depends on features inherent to the cancer cell, features inherent to the organ, and the interplay between the cancer cell and its microenvironment.31Many of the oncogenes discovered


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Surgery_Schwartz. site likely depends on features inherent to the cancer cell, features inherent to the organ, and the interplay between the cancer cell and its microenvironment.31Many of the oncogenes discovered to date, such as HER2 and ras, are thought to potentiate not only malignant transforma-tion but also one or more of the steps required in the metastatic process. Experimental models have suggested a role for several molecules, including RhoC, osteopontin and interleukin-11, and Twist, in tumor metastasis. Metastasis also may involve the loss of metastasis-suppressor genes. Laboratory work involving cancer cell lines that have been selected to have a higher meta-static potential have led to the realization that these more highly metastatic cells have a different gene expression profile than their less metastatic parental counterparts. This in turn has led to the currently held belief that the ability of a primary tumor to metastasize may be predictable by analysis of its gene expres-sion


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Surgery_Schwartz. less metastatic parental counterparts. This in turn has led to the currently held belief that the ability of a primary tumor to metastasize may be predictable by analysis of its gene expres-sion profile. Indeed, several studies have focused on identify-ing a gene expression profile or a molecular signature that is associated with metastasis. It has been shown that such a gene expression profile can be used to predict the probability that the patient will remain free of distant metastasis.32 This suggests that the metastatic potential of a tumor is already predetermined by the genetic alterations that the cancer cells acquire early in tumorigenesis. Notably, this hypothesis differs from the mul-tistep tumorigenesis theory in that the ability to metastasize is considered an inherent quality of the tumor from the beginning. It is assumed that metastasis develops not from a few rare cells in the primary tumor that acquire the ability to metastasize but that all cells in tumors with such


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Surgery_Schwartz. of the tumor from the beginning. It is assumed that metastasis develops not from a few rare cells in the primary tumor that acquire the ability to metastasize but that all cells in tumors with such molecular signatures develop the ability to metastasize. The reality probably lies in between since some early genetic changes detectable in the entire tumor can give tumors an advantage in the metastatic process, whereas additional genetic changes can give a clone of cells additional advantages, thus allowing them to succeed in metastasis.Epithelial-Mesenchymal TransitionA regulatory program referred to as epithelial-mesenchymal transition (EMT) is a fundamental event in morphogenesis. During EMT, epithelial cells are converted to migratory and Figure 10-8. A schematic representation of the metastatic process. A. The metastatic process begins with an in situ cancer surrounded by an intact basement membrane. B. Invasion requires reversible changes in cell-cell and cell-extracellular matrix


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Surgery_Schwartz. process. A. The metastatic process begins with an in situ cancer surrounded by an intact basement membrane. B. Invasion requires reversible changes in cell-cell and cell-extracellular matrix adherence, destruction of proteins in the matrix and stroma, and motility. C. Metastasizing cells can enter the circulation via the lymphatics. D. They can also directly enter the circulation. E. Intravascular survival of the tumor cells and extravasation of the circulatory system follow. F. Metastatic single cells can colonize sites and remain dormant for years as occult micrometastases. G. Subsequent progression and neovascularization leads to clinically detectable metastases and progressively growing, angiogenic metastases. (Reproduced with permission Steeg PS. Metastasis suppressors alter the signal transduction of cancer cells, Nat Rev Cancer. 2003 Jan;3(1):55-63.)Brunicardi_Ch10_p0305-p0354.indd 31722/02/19 2:14 PM 318BASIC CONSIDERATIONSPART Iinvasive mesenchymal cells.33 EMT has also


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Surgery_Schwartz. transduction of cancer cells, Nat Rev Cancer. 2003 Jan;3(1):55-63.)Brunicardi_Ch10_p0305-p0354.indd 31722/02/19 2:14 PM 318BASIC CONSIDERATIONSPART Iinvasive mesenchymal cells.33 EMT has also been implicated as the mechanism through which epithelial cells acquire the abil-ity to migrate, invade, resist apoptosis, and metastasize in the setting of cancer. EMT is a developmental process, and a set of pleiotropically acting transcriptional factors, including Snail, Twist, Slug, and Zeb1/2 orchestrate EMT. Several of these tran-scription factors can directly repress E-cadherin gene expression reducing levels of this key suppressor of motility and invasive-ness in cancer cells. This process also entails the induction of mesenchymal markers such as vimentin. It has been proposed that the process of invasion and metastases requires significant plasticity, suggesting that EMT is required for invasion, intrava-sation, and extravasation. Thus, suppression of EMT regulators (and consequently


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Surgery_Schwartz. of invasion and metastases requires significant plasticity, suggesting that EMT is required for invasion, intrava-sation, and extravasation. Thus, suppression of EMT regulators (and consequently EMT reversion, or MET) can be important for metastatic outgrowth.34-36Cancer Stem CellsStem cells are cells that have the ability to perpetuate them-selves through self-renewal and to generate mature cells of a particular tissue through differentiation.37 It has been proposed that stem cells themselves may be the target of transformation. It was first documented for leukemia and multiple myeloma that only a small subset of cancer cells is capable of extensive prolif-eration. It has subsequently also been shown for many solid can-cers that only a small proportion of cells is clonogenic in culture and in vivo. Similarly, in many solid tumor types only a small proportion of cells is clonogenic in culture and in vivo. If indeed tumor growth and metastasis are driven by a small population of


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Surgery_Schwartz. and in vivo. Similarly, in many solid tumor types only a small proportion of cells is clonogenic in culture and in vivo. If indeed tumor growth and metastasis are driven by a small population of cancer stem cells, this may alter our current approaches to cancer therapy. Currently available drugs can shrink metastatic tumors but often cannot eradicate them. The failure of these treatments usually is attributed to the acquisition of drug resistance by the cancer cells; however, the cancer stem cell hypothesis raises the possibility that existing therapies may simply fail to kill cancer stem cells effectively. Therapeutic approaches targeting stem cells specifically are under study.CANCER ETIOLOGYCancer GenomicsOne widely held opinion is that cancer is a genetic disease that arises from an accumulation of genomic alterations that leads to the selection of cells with increasingly aggressive behavior. These alterations may lead either to a gain of function by onco-genes or to a loss of


Surgery_Schwartz

Surgery_Schwartz. accumulation of genomic alterations that leads to the selection of cells with increasingly aggressive behavior. These alterations may lead either to a gain of function by onco-genes or to a loss of function by tumor-suppressor genes. These acquired gene alterations present within the tumor are termed somatic mutations to distinguish them from germline mutations that are inherited from parents and transmitted to offspring. Somatic mutations in a cancer genome may consist of several classes of DNA sequence changes. These include substitutions of one base by another; insertions or deletions of small or large segments of DNA; rearrangements, in which the DNA sequence has been broken and then rejoined to another DNA segment; copy number losses that may result in complete absence of a DNA sequence; and copy number gains over and above the two copies present in the normal diploid genome.Somatic mutations in a cancer cell genome have accumu-lated over the lifetime of the patient (Fig.


Surgery_Schwartz

Surgery_Schwartz. sequence; and copy number gains over and above the two copies present in the normal diploid genome.Somatic mutations in a cancer cell genome have accumu-lated over the lifetime of the patient (Fig. 10-9).38 DNA in normal cells is continuously damaged by internal and external mutagens. Most of this damage is repaired; however, a small fraction may remain as fixed mutations. Mutation rates increase in the pres-ence of substantial exogenous mutagenic exposures, such as tobacco carcinogens or various forms of radiation, including ultraviolet light. These exposures are associated with increased rates of lung and skin cancer, respectively, and somatic muta-tions within such cancers often exhibit the distinctive mutational signatures known to be associated with the mutagen.39 The rates of somatic mutations are also increased in several rare inher-ited diseases, such as Fanconi anemia, ataxia telangiectasia, and xeroderma pigmentosum, which are associated with increased risks of cancer.40,41