Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma

Mert M Erkan, Carolin Reiser-Erkan, Christoph W Michalski, Stefanie Deucker, Danguole Sauliunaite, Sylvia Streit, Irene Esposito, Helmut Friess and Jorg Kleeff

Year 2009, Volume 11, Issue 5

Abstract

Background & Aims: Although both pancreatic cancer and stellate cells (PSC) secrete proangiogenic factors, pancreatic ductal adenocarcinoma is a scirrhous and hypoxic tumor. The aim of this study is to analyze the impact of the cancer-PSC interactions on angiogensis. Methods: In pancreatic tissues, expression of periostin, CD31 and alpha smooth-muscle actin was assessed by immunohistochemistry. Human PSC and cancer cells were cultivated under normoxia and hypoxia alone, or in co-culture, to analyze the changes in their angiogenic and fibrogenic attributes, using ELISA, immunoblot, and quantitative-PCR analyses and growth of cultured endothelial cells in vitro. Results: On the invasive front of the activated stroma, PSC deposited a periostin-rich matrix around the capillaries in the periacinar spaces. Compared to the normal pancreas there was a significant reduction in the microvessel density in chronic pancreatitis (5-fold, p<0.001) and pancreatic ductal adenocarcinoma (4-fold, p<0.01) tissues. In vitro, hypoxia increased PSC activity and doubled the secretion of periostin, collagen type-I, fibronectin and VEGF. Cancer cells induced VEGF secretion of PSC (390±60%, p<0.001), which in return induced the endostatin production of cancer cells (210±14%, p<0.001) that could be blocked by MMP inhibition. In vitro, PSC increased the endothelial cell growth, whereas cancer cells alone, or their co-culture with PSC suppressed it. Conclusions: Although PSC are the dominant producers of VEGF and increase endothelial growth in vitro, in the peritumoral stroma they contribute to the fibrotic/hypoxic milieu through abnormal extracellular matrix deposition, and by amplifying the antiangiogenic attributes of cancer cells by inducing their endostatin production.

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