Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive stroma being

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive stroma being also present in chronic pancreatitis (CP). poorly differentiated tumors significantly differed from CP tissues. Analysis of 27 parameters within each pancreatic disease revealed a significant correlation of i) CD4+ and FoxP3+CD4+ T cells with FoxP3 expression in PDAC cells, ii) -SMA+ fibroblasts with L1CAM expression and proliferation in PDAC cells, iii) CD3 and CD8 expression with -TCR expression in both pancreatic diseases and 143457-40-3 iv) CD68+ and CD163+ macrophages with vimentin expression in PDAC cells. High expression of FoxP3, vimentin and L1CAM in PDAC cells as well as a tumor-related localization of macrophages each tended to correlate with higher tumor grade. Multivariate survival analysis revealed a younger age at time of surgery as a positive prognostic marker for PDAC patients with the most frequently operated disease stage T3N1M0. Overall this study identified several interrelationships between stroma and epithelial/carcinoma cells in PDACs but also in CP, which in light of previous experimental data strongly support the view that the inflammatory stroma contributes to malignancy-associated alterations already in precursor cells during CP. Introduction Pancreatic ductal adenocarcinoma (PDAC) is the 4th most lethal tumor disease with an overall 5-year-survival rate of 2% [1]. It is commonly diagnosed in an advanced stage, limiting curative therapeutic options to <20% of the patients. In addition, most of the PDAC patients do not respond to radio- or chemotherapy further worsening patient prognosis [2]. Thus, improving the diagnosis at an early disease stage as well as therapeutic options are both still 143457-40-3 urgently needed. For both, the identification of reliable biomarkers is of pivotal importance allowing the discrimination of PDAC from other benign pancreatic diseases on the one hand and prediction/improvement of therapeutic responses on the other hand. Different precursor lesions have been identified which can give rise to PDAC. Besides intraductal papillary mucinous neoplasias (IPMN), mucinous cystic neoplasias (MCN) and atypical flat lesions (AFL), pancreatic intraepithelial neoplasias (PanIN) are the most frequent and best characterized precursor lesions of PDAC [3]. PanINs exhibit a ductal phenotype underscoring the view that 143457-40-3 PDAC originates from the ductal epithelium. Since PDAC is characterized by an extensive desmoplastic reaction accounting for up to 80% of the whole tumor mass, the tumor microenvironment has been regarded as a promising target to improve diagnosis and therapy of PDAC. The PDAC stroma is composed of extracellular matrix, fibroblasts, myofibroblasts and diverse immune cells [4], [5]. Interestingly, chronic pancreatitis (CP), which is regarded as high risk factor for the development 143457-40-3 of PDAC, also exhibits an extensive stromal response [4], [5]. Previous reports have demonstrated that the tumor-specific, non-neoplastic stromal cell population is highly variable and creates an immunosuppressive and tumor-promoting environment for the tumor cells of PDAC [4], [5]. High numbers of myofibroblasts (determined by -SMA), M2-macrophages (determined by CD163 or CD204), regulatory T cells (T-regs determined by FoxP3 or CD25) and Th2 cells (determined by GATA-3+) have been generally found to correlate with tumor progression, reduced patient survival and worse prognosis [6]C[13]. Moreover, a recent study revealed that a stromal composition of CD4+ T cellshigh/CD8+ T cellshigh/T-reglow and M1-macrophageshigh/M2-macrophageslow correlates with longer survival [13]. Beside the antigen-restricted T cell populations, -T cells represent a promising T cell population in cancer therapy because of their ability of potently killing tumor cells in an non-HLA-restricted manner [14], [15]. However, little can be known about their existence and part during PDAC advancement. Upregulation of Rabbit Polyclonal to SLC25A11 the adhesion molecule L1CAM (CD171) is associated with epithelial-mesenchymal-transition (EMT) which is also characterized by the upregulation of mesenchymal proteins such as vimentin [16]C[18]. L1CAM expression increases during PDAC progression in the ductal epithelium [16], [19], [20] and correlates with poor prognosis of PDAC patients [21]. Underscoring its protumorigenic function, L1CAM induces tumorigenicity of human pancreatic ductal epithelial (HPDE) cells, migration, apoptosis resistance and metastasis of HPDE and PDAC cells and and underscores the role of stromal cells in the initiation and progression of PDAC [22], [28]C[30]. Using an endogenous PDAC mouse model, Rhim et al. showed that inflammation can induce the epithelial-mesenchymal-transition (EMT) of pancreatic ductal epithelial cells thereby promoting cell invasion and 143457-40-3 dissemination already prior to the formation of primary tumors [31]. In accordance, our own studies demonstrated a role of myofibroblasts in the upregulation of L1CAM (as component of the EMT) not really.