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Molecular Oncology, Markers, Clinical Correlates |
Department of Visceral and Transplantation Surgery, University of Bern, Inselspital, CH-3010 Bern, Switzerland [Z-w. Z., H. F., L. W., J. K., M. W. B.], and Departments of Medicine, Biological Chemistry, and Pharmacology, University of California, Irvine, California 92697 [T. B., M. K.]
Nerve growth factor (NGF) exerts both stimulatory and inhibitory
effects on neuronal and certain nonneuronal tumors with the effect
based on the type of tumor. We investigated NGF and its receptors (TrkA
and p75) in pancreatic cancer cells (PANC-1, MIA-PaCa-2, CAPAN-1,
ASPC-1, and T3M4) by reverse transcription-PCR, Western blot analysis,
NGF ELISA, and growth assays. NGF mRNA was present at comparable levels
in all five pancreatic cancer cell lines. TrkA expression was
relatively high in PANC-1 and MIA-PaCa-2 cells and low in CAPAN-1,
ASPC-1, and T3M4 cells. p75 expression was high in PANC-1, MIA-PaCa-2,
and T3M4 cells, moderate in CAPAN-1, and low in ASPC-1 cells. By ELISA
assay, the intracellular NGF content in all cell lines was 
40
pg/106 cells. NGF content increased significantly in PANC-1
and MIA-PaCa-2 cells when these cells were cultured with serum-free
media, whereas there was no change in the other cancer cell lines.
PANC-1 and MIA-PaCa-2 cells but not the other cell lines released NGF
in the culture media. Exogenous NGF stimulated the growth of PANC-1 and
MIA-PaCa-2 cells, inhibited the growth of T3M4 and CAPAN-1 cells in a
dose- and time-dependent manner, and did not affect the growth of
ASPC-1 cells. NGF led to the phosphorylation of TrkA, mitogen-activated
protein kinase (MAPK), and p38 MAPK but not stress-activated protein
kinase/c-Jun NH2-terminal kinase in PANC-1 and MIA-PaCa-2
cells. In contrast, in the other pancreatic cancer cell lines none of
these kinases were phosphorylated by NGF. In conclusion, the effects of
NGF on pancreatic cancer cell growth are dependent on the expression
levels and the balance of its TrkA and p75 receptors. NGF-induced
pancreatic cancer cell growth seems to be mediated through the
phosphorylation of TrkA and subsequently via MAPK. These results point
to a previously unknown autocrine/paracrine pathway in pancreatic
cancer, suggesting that NGF-TrkA interactions are important factors
influencing cell growth and spread in this malignancy.
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