Pancreatic cancer – Influence of Tumour Microenvironment

Abstract: Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths, with a 5-year survival less than 6%. It does not show any symptoms in its early stages, hence most (>85%) of the patients are diagnosed at late stage. At the time of diagnosis, metastases are frequently observed which make most patients unsuitable for curative surgical treatment and chemotherapy remains the only choice for them. In addition, PC is resistant to chemotherapy and currently available treatments provide only marginal survival benefits. PC is characterized by a dense desmoplastic (stromal) reaction surrounding the tumour cells, which is believed to promote tumour survival and chemoresistance. Although being a central pathological feature of pancreatic cancer, the cellular and molecular interactions underlying the stromal reaction remain incompletely understood. The aim of the thesis was to investigate the role of the tumour microenvironment in pancreatic cancer progression. To address the role of the stroma, we have managed to generate the first conditionally immortalized human nontumour (NPSC) and tumour-derived pancreatic stellate cells (TPSC). PSCs are believed to be the principal source of the stromal reaction in PC. In our study, we have found that insulin-like growth factor-I stimulated the proliferation of both PSCs. Both basal and IGF-I stimulated motility was significantly enhanced in TPSC compared to NPSC. Further we have found that curcumin and L49H37 effectively inhibited proliferation and induced apoptosis in TPSC. TPSC were retained in the G0/G1 phase of the cell cycle through the down-regulation of p21WAF1/Cip1. L49H37 significantly decreased the phosphorylation of ERK1/2. L49H37 was found to be more potent at a lower concentration than curcumin. It has been stated that secreted protein acidic and rich in cysteine (SPARC) is involved in the tumour-stroma interaction. We have evaluated SPARC expression in normal pancreas, invasive adenocarcinoma and lymph node metastasis. Our data revealed that SPARC expression was absent in normal pancreas but expressed in invasive adenocarcinoma and its expression was maintained in subsequent metastases. SPARC expression was exclusively found in stromal cells. The survival of patients with high stromal SPARC expression was significantly worse than that of the patients with low stromal SPARC expression (11.5 vs 25.3 months; p = 0.020). We observed that combined treatment of sorafenib and celecoxib synergistically induced growth inhibition and apoptosis in pancreatic cancer cells (PCC) through a process involving p21WAF1/Cip1 suppression. This thesis provides insights into interactions and mechanisms within the pancreatic tumour microenvironment, with potential implications for targeted interventions.