Pancreatic carcinoma cells stimulate proliferation and matrix synthesis of hepatic stellate cells

Abstract

Pancreatic ductal carcinoma cells induce fibrosis by stimulating pancreatic stellate cells to proliferate and synthesize matrix. Desmoplastic reaction has also been observed in liver metastases of pancreatic carcinoma. Hepatic stellate cells are similar to pancreatic stellate cells and may contribute to the desmoplasia associated with liver metastases of pancreatic cancer. The aim of this study was to determine the role of hepatic stellate cells in metastasis. Markers of the desmoplastic reaction in tumors induced in nude mice (n=6) by subcutaneously injecting pancreatic carcinoma cells with and without hepatic stellate cells were monitored immunohistochemically. Paracrine stimulation was studied by measuring matrix synthesis (collagen type I and c-fibronectin protein) and cell proliferation. Supernatants of pancreatic carcinoma cells stimulated proliferation of cultured hepatic stellate cells and synthesis of collagen I and c-fibronectin. Preincubation of the supernatants with neutralizing antibodies against fibroblast growth factor 2, transforming growth factor-beta1, and platelet-derived growth factor significantly reduced these stimulatory effects. Subcutaneous injection of hepatic stellate cells induced earlier onset and faster-growth of subcutaneous fibrotic pancreatic tumors in nude mice. Hepatic stellate cells enhance tumor growth in nude mouse and may play an important role in metastasis formation.