Elsevier

Neoplasia

Volume 11, Issue 5, May 2009, Pages 497-508
Neoplasia

Cancer-Stellate Cell Interactions Perpetuate the Hypoxia-Fibrosis Cycle in Pancreatic Ductal Adenocarcinoma1

https://doi.org/10.1593/neo.81618Get rights and content
Under a Creative Commons license
open access

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 α-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.

Abbreviations

CL
cell lysate
CP
chronic pancreatitis
ECM
extracellular matrix
PCC
pancreatic cancer cell
PDAC
pancreatic ductal adenocarcinoma
PSC
pancreatic stellate cell
SN
supernatant

Cited by (0)

1

This study was supported by a grant (Integrierten Verbunds der medizinischen Genomforschung, NGFN-Plus) from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung - BMBF) grant number: 016S08115. Competing interests: None declared.

2

These authors contributed equally to this manuscript.