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

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

Neoplasia 11, 497-508 (2009)
Verlagsversion Volltext DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter ENDOTHELIAL GROWTH-FACTOR; TUMOR ANGIOGENESIS; PROGNOSTIC MARKER; INDUCE FIBROSIS; EXPRESSION; ENDOSTATIN; PERIOSTIN; FIBROBLASTS; PROGRESSION; CARCINOMA
ISSN (print) / ISBN 1522-8002
e-ISSN 1476-5586
Zeitschrift Neoplasia : An International Journal for Oncology Research
Quellenangaben Band: 11, Heft: 5, Seiten: 497-508 Artikelnummer: , Supplement: ,
Verlag Neoplasia Press
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pathology (PATH)