In addition to stimulating fibroblastic proliferation, fibroblast growth factors (FGFs) exert mitogenic and other important regulatory effects on a variety of epithelial, mesenchymal, and neuronal cells. FGFs are also angiogenic, and have been implicated in developmental regulation. Although FGFs modulate many biological processes, their potential role in the regulation of pancreatic exocrine function in normal and disease states is not known. It has been established, however, that basic fibroblast growth factor (bFGF) and acidic fibroblast growth factor (aFGF) bind to specific high-affinity receptors in the rat pancreatic acinar cell membranes. Furthermore, Northern blot analyses indicate that the rat and human pancreases express mRNA species encoding high-affinity FGF receptors. Both aFGF and bFGF enhance amylase secretion, raise cytosolic calcium levels, and induce inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] levels in rat pancreatic acini. In contrast to their relative potencies in other physiological systems, aFGF is more potent than bFGF in the case of all three biological actions in pancreatic acini. Both factors are found in the rat exocrine pancreas, and in the normal human pancreas. bFGF and aFGF enhance Ins(1,4,5)P3 levels in cultured human pancreatic cancer cells and stimulate their growth. These cancer cells are known to express FGFs, raising the possibility that FGFs may exert autocrine growth stimulatory actions in pancreatic cancer. Furthermore, in human pancreatic adenocarcinomas, the tumor cells are often surrounded by an extensive stroma which may act to protect the cancer cells from endogenous anti- neoplastic defense mechanisms and from chemotherapeutic agents. The mechanisms that confer a growth advantage to pancreatic cancer cells and that lead to the associated fibroblastic proliferation are not known. The possibility that FGFs may contribute to the aggressiveness of these cancers and to the genesis of the fibroblastic stroma has not been considered. Accordingly, in the present proposal we will define the potential role of fibroblast growth factors (FGFs) in the regulation of normal pancreatic exocrine function and test the hypothesis that altered expression and/or function of FGFs contributes to the growth advantage of human pancreatic cancer cells and to the associated fibroblastic stroma. We will study the biological effects of bFGF and aFGF in rat pancreatic acinar cells, assess their role in the growth of cancerous pancreatic cells, and use immunohistochemical methods to determine whether and in which cell type bFGF and aFGF are expressed in normal rat and human pancreatic tissues. We will also use molecular and in situ hybridization techniques to study the expression of both growth factors and their receptors in the normal human pancreas and in cancerous human pancreatic tissues, and determine whether the FGF receptors in the rat pancreas have unique features by comparison with the corresponding receptors in other tissues.
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