FIBROBLAST GROWTH FACTORS AND THE PANCREAS

  • Korc, Murray, (PI)

Project: Research project

Description

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.
StatusFinished
Effective start/end date8/15/937/31/97

Funding

  • National Institutes of Health
  • National Institutes of Health: $153,535.00
  • National Institutes of Health

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Fibroblast Growth Factors
Pancreas
Fibroblasts
Fibroblast Growth Factor 1
Pancreatic Neoplasms
Growth
Pancreatic Function Tests
Biological Phenomena
Exocrine Pancreas
Neoplasms
Inositol 1,4,5-Trisphosphate
Acinar Cells
Amylases
Northern Blotting
Intercellular Signaling Peptides and Proteins

Keywords

  • Medicine(all)