Hypoxia stimulates pancreatic stellate cells to induce fibrosis and angiogenesis in pancreatic cancer

Abstract

Pancreatic cancer is characterized by excessive desmoplastic reaction and by a hypoxic microenvironment within the solid tumor mass. Chronic pancreatitis is also characterized by fibrosis and hypoxia. Fibroblasts in the area of fibrosis in these pathological settings are now recognized as activated pancreatic stellate cells (PSCs). Recent studies have suggested that a hypoxic environment concomitantly exists not only in pancreatic cancer cells but also in surrounding PSCs. This study aimed to clarify whether hypoxia affected the cell functions in PSCs. Human PSCs were isolated and cultured under normoxia (21% O(2)) or hypoxia (1% O(2)). We examined the effects of hypoxia and conditioned media of hypoxia-treated PSCs on cell functions in PSCs and in human umbilical vein endothelial cells. Hypoxia induced migration, type I collagen expression, and vascular endothelial growth factor (VEGF) production in PSCs. Conditioned media of hypoxia-treated PSCs induced migration of PSCs, which was inhibited by anti-VEGF antibody but not by antibody against hepatocyte growth factor. Conditioned media of hypoxia-treated PSCs induced endothelial cell proliferation, migration, and angiogenesis in vitro and in vivo. PSCs expressed several angiogenesis-regulating molecules including VEGF receptors, angiopoietin-1, and Tie-2. In conclusion, hypoxia induced profibrogenic and proangiogenic responses in PSCs. In addition to their established profibrogenic roles, PSCs might play proangiogenic roles during the development of pancreatic fibrosis, where they are subjected to hypoxia.

DKK3 blocked translocation of β‐catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc‐3 cell

“…Severe intratumoural hypoxia is present in pancreatic cancer 25, 37, suggesting that hypoxia plays a role in the accumulation and activation of β‐catenin in pancreatic cancer cells. As a Wnt antagonists, it is reported that DKK3 overexpression does not affect nuclear/cytoplasmic accumulation of β‐catenin 11.…”

Hypoxia induces Wee1 expression and attenuates hydrogen peroxide-induced endothelial damage in MS1 cells

“…Many genes involved in tumor biology are regulated by levels of oxygen. In some human tumor types, hypoxia inducible factor-1α (HIF-1α) is overexpressed compared with corresponding normal tissues (Zhong et al, 1999;Furlan et al, 2007;Fan et al, 2008;Hamaguchi et al, 2008;Liang et al, 2008;Masamune et al, 2008;Sayed et al, 2008;Simiantonaki et al, 2008).…”

Impact by pancreatic stellate cells on epithelial-mesenchymal transition and pancreatic cancer cell invasion: Adding a third dimension in vitro

“…The major non-malignant cellular components of the tumour microenvironment, the pancreatic stellate cells and tumour-associated macrophages, have been suggested to be involved in the progression of pancreatic cancer by creating a favourable tumour microenvironment and stimulate invasion, tumour growth, and development of metastases (Hwang et al, 2008, Masamune et al, 2008, Neyen et al, 2013, Green et al, 2009 TPSCs such as uPA, FGF and PDGF may likely also be involved (Rosendahl et al, 2015).…”

“…It is now widely accepted that the pancreatic stellate cells, myofibroblast-like cells in the pancreatic microenvironment, are responsible for this stromal reaction due to their ability to produce large quantities of ECM and influence the composition and turnover of ECM proteins (Yen et al, 2002, Erkan et al, 2009, Apte et al, 2004. In addition, they may promote the pathogenesis of pancreatic cancer by creating a favourable tumour microenvironment through secretion of growth-and angiogenic factors as well as stimulating cancer cell migration (Tod et al, 2013, Hwang et al, 2008, Masamune et al, 2008. Although pancreatic stellate cells have an established role in the desmoplastic stroma, further investigations are needed to elucidate the influence by paracrine communication and cell-cell interactions with the tumour microenvironment on invasive properties of the cancer cells.…”