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

Erkan, M; Reiser-Erkan, C; Michalski, CW; Deucker, S; Sauliunaite, D; Streit, S; Esposito, I; Friess, H; Kleeff, J

Benutzer: Gast

journal article

Titel:: Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma.
Dokumenttyp:: Journal Article; Research Support, Non-U.S. Gov't; Article
Autor(en):: Erkan, M; Reiser-Erkan, C; Michalski, CW; Deucker, S; Sauliunaite, D; Streit, S; Esposito, I; Friess, H; Kleeff, J
Abstract:: BACKGROUND AND AIMS: Although both cancer and stellate cells (PSCs) secrete proangiogenic factors, pancreatic cancer is a scirrhous and hypoxic tumor. The impact of cancer-PSCs interactions on angiogenesis was analyzed. METHODS: Expression of periostin, CD31, and alpha-smooth muscle actin was assessed by immunohistochemistry. Human PSCs and cancer cells were cultivated under normoxia and hypoxia alone, or in coculture, to analyze the changes in their angiogenic and fibrogenic attributes, using enzyme-linked immunosorbent assay, immunoblot, and quantitative polymerase chain reaction analyses and growth of cultured endothelial cells in vitro. RESULTS: On the invasive front of the activated stroma, PSCs deposited a periostin-rich matrix around the capillaries in the periacinar spaces. Compared with the normal pancreas, there was a significant reduction in the microvessel density in chronic pancreatitis (five-fold, P < .001) and pancreatic cancer (four-fold, P < .01) tissues. In vitro, hypoxia increased PSCs' activity and doubled the secretion of periostin, type I collagen, fibronectin, and vascular endothelial growth factor (VEGF). Cancer cells induced VEGF secretion of PSCs (390 +/- 60%, P < .001), whereas PSCs increased the endostatin production of cancer cells (210 +/- 14%, P < .001) by matrix metalloproteinase-dependent cleavage. In vitro, PSCs increased the endothelial cell growth, whereas cancer cells alone, or their coculture with PSCs, suppressed it. CONCLUSIONS: Although PSCs are the dominant producers of VEGF and increase endothelial cell growth in vitro, in the peritumoral stroma, they contribute to the fibrotic/hypoxic milieu through abnormal extracellular matrix deposition and by amplifying endostatin production of cancer cells.
Zeitschriftentitel:: Neoplasia
Jahr:: 2009
Band / Volume:: 11
Heft / Issue:: 5
Seitenangaben Beitrag:: 497-508
Sprache:: eng
PubMed:: http://view.ncbi.nlm.nih.gov/pubmed/19412434
Print-ISSN:: 1522-8002
TUM Einrichtung:: Chirurgische Klinik und Poliklinik; Institut für Allgemeine Pathologie und Pathologische Anatomie
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