Nerve growth factor stimulates MMP-2 expression and activity and increases invasion by human pancreatic cancer cells.
Pancreatic cancer frequently invades and migrates along neural tissue. Although the exact mechanisms are unknown, perineural invasion negatively impacts prognosis for pancreatic cancer patients. Matrix metalloproteinases (MMPs) are overexpressed in pancreatic cancer and are associated with poor prognosis. We hypothesized that nerve growth factor (NGF) released from neural tissue increases the invasive properties of pancreatic cancer cells. In the present study we investigated the effect of NGF on the expression and activity of MMP-2 in human pancreatic cancer cells. NGF dose dependently increased MMP-2 protein in the culture medium and stimulated MMP-2 gelatinolytic activity. This effect was mediated by specific binding of NGF to its receptor trk A, which was detected on all pancreatic cancer cells, with subsequent activation of the p44/42 MAPK signaling pathway. The NGF-induced increase in MMP-2 expression and activity lead to an enhanced invasion in vitro. These findings support the hypothesis that neurotrophic factors, e.g., NGF, are critically involved in mediating perineural invasion of pancreatic cancer.
Okada
Yuji
Y
Section of Gastrointestinal Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-6904, USA.
Eibl
Guido
G
Guha
Sushovan
S
Duffy
John P
JP
Reber
Howard A
HA
Hines
Oscar J
OJ
D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D009361:Neoplasm Invasiveness; D020932:Nerve Growth Factor / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D020917:Receptor, trkA / Q000235:genetics
D020932:Nerve Growth Factor; D020917:Receptor, trkA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020778:Matrix Metalloproteinase 2