Cell Growth & Differentiation, Vol 7, Issue 2 263-270, Copyright © 1996 by American Association of Cancer Research

ARTICLES

Identification of a hepatocyte growth factor autocrine loop in a murine mammary carcinoma

N Rahimi, E Tremblay, L McAdam, M Park, R Schwall and B Elliott
Department of Pathology, Queens University, Kingston, Ontario, Canada.

Constitutive activation of growth factor receptors through autocrine/paracrine mechanisms occurs frequently in human cancers and is thought to play an important role in carcinogenesis. We have demonstrated previously that hepatocyte growth factor (HGF) is a potent mitogenic factor for murine mammary carcinoma (SP1) cells in vitro. We report here an autocrine HGF loop in SP1 cells. HGF receptor/Met is expressed in SP1 cells and is constitutively tyrosine phosphorylated. The phosphorylation of HGF receptor/Met is inhibited when cells are exposed to suramin or anti-HGF IgG. This finding suggests that constitutive tyrosine phosphorylation of HGF receptor/Met is sustained by an extracellular factor, most likely HGF. Using Northern blot and Western blot analysis, we detected expression of a 6-kb HGF mRNA in SP1 cells and a M(r) 85,000 HGF protein in SP1-conditioned medium, respectively. In vitro translation of mRNA from SP1 cells and metabolic labeling confirmed expression and synthesis of HGF by SP1 cells. SP1 cells also invade through Matrigel-coated transwell membranes in an in vitro invasion assay, and invasion of these cells was inhibited by neutralizing anti-HGF IgG. In addition, SP1-conditioned medium induced scatter activity of Madin-Darby canine kidney epithelial cells, and this activity was inhibited by neutralizing anti-HGF IgG. We have also shown that several signaling molecules including phosphatidylinositol 3-kinase, Src, focal adhesion kinase, and phospholipase C-gamma in SP1 cells are constitutively tyrosine phosphorylated, suggesting that coexpression of HGF and HGF receptor/Met may in part contribute to sustained tyrosine phosphorylation of these cytoplasmic proteins in SP1 cells. Our observations in the SP1 model suggest that HGF contributes to growth and invasive phenotypes of mammary carcinomas via both paracrine and autocrine mechanisms.

This article has been cited by other articles:

				N. Yamamoto, G. Mammadova, R. X.-D. Song, Y. Fukami, and K.-i. Sato Tyrosine phosphorylation of p145met mediated by EGFR and Src is required for serum-independent survival of human bladder carcinoma cells J. Cell Sci., November 15, 2006; 119(22): 4623 - 4633. [Abstract] [Full Text] [PDF]

				T. G. Wright, J. Tsai, Z. Jia, and B. E. Elliott Inhibition by Copper(II) Binding of Hepatocyte Growth Factor (HGF) Interaction with Its Receptor Met and Blockade of HGF/Met Function J. Biol. Chem., July 30, 2004; 279(31): 32499 - 32506. [Abstract] [Full Text] [PDF]

				K.-X. Zhang, K. R. Ward, and J. W. Schrader Multiple Aspects of the Phenotype of Mammary Epithelial Cells Transformed by Expression of Activated M-Ras Depend on an Autocrine Mechanism Mediated by Hepatocyte Growth Factor/Scatter Factor Mol. Cancer Res., April 1, 2004; 2(4): 242 - 255. [Abstract] [Full Text] [PDF]

				M. H. Herynk, O. Stoeltzing, N. Reinmuth, N. U. Parikh, R. Abounader, J. Laterra, R. Radinsky, L. M. Ellis, and G. E. Gallick Down-Regulation of c-Met Inhibits Growth in the Liver of Human Colorectal Carcinoma Cells Cancer Res., June 1, 2003; 63(11): 2990 - 2996. [Abstract] [Full Text] [PDF]

				A. Popsueva, D. Poteryaev, E. Arighi, X. Meng, A. Angers-Loustau, D. Kaplan, M. Saarma, and H. Sariola GDNF promotes tubulogenesis of GFR{alpha}1-expressing MDCK cells by Src-mediated phosphorylation of Met receptor tyrosine kinase J. Cell Biol., April 14, 2003; 161(1): 119 - 129. [Abstract] [Full Text] [PDF]

				J. Vadnais, G. Nault, Z. Daher, M. Amraei, Y. Dodier, I. R. Nabi, and J. Noel Autocrine Activation of the Hepatocyte Growth Factor Receptor/Met Tyrosine Kinase Induces Tumor Cell Motility by Regulating Pseudopodial Protrusion J. Biol. Chem., December 6, 2002; 277(50): 48342 - 48350. [Abstract] [Full Text] [PDF]

				G. A. Gmyrek, M. Walburg, C. P. Webb, H.-M. Yu, X. You, E. D. Vaughan, G. F. Vande Woude, and B. S. Knudsen Normal and Malignant Prostate Epithelial Cells Differ in Their Response to Hepatocyte Growth Factor/Scatter Factor Am. J. Pathol., August 1, 2001; 159(2): 579 - 590. [Abstract] [Full Text]

				J. Wang, P. Barbry, A. C. Maiyar, D. J. Rozansky, A. Bhargava, M. Leong, G. L. Firestone, and D. Pearce SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport Am J Physiol Renal Physiol, February 1, 2001; 280(2): F303 - F313. [Abstract] [Full Text] [PDF]

				N.N.C. Tam, S.S.M. Chung, D.T.W. Lee, and Y.C. Wong Aberrant expression of hepatocyte growth factor and its receptor, c-Met, during sex hormone-induced prostatic carcinogenesis in the Noble rat Carcinogenesis, December 1, 2000; 21(12): 2183 - 2191. [Abstract] [Full Text] [PDF]

				H. Qiao, R. Saulnier, A. Patryzkat, N. Rahimi, L. Raptis, J. Rossiter, E. Tremblay, and B. Elliott Cooperative Effect of Hepatocyte Growth Factor and Fibronectin in Anchorage-independent Survival of Mammary Carcinoma Cells: Requirement for Phosphatidylinositol 3-Kinase Activity Cell Growth Differ., February 1, 2000; 11(2): 123 - 133. [Abstract] [Full Text]

				T. Tamatani, K. Hattori, A. Iyer, K. Tamatani, and R. Oyasu Hepatocyte growth factor is an invasion/migration factor of rat urothelial carcinoma cells in vitro Carcinogenesis, June 1, 1999; 20(6): 957 - 962. [Abstract] [Full Text] [PDF]

				D. Ronen, R. T. Altstock, M. Firon, L. Mittelman, T. Sobe, J. H. Resau, G. F. Vande Woude, and I. Tsarfaty Met-HGF/SF Mediates Growth Arrest and Differentiation in T47D Breast Cancer Cells Cell Growth Differ., February 1, 1999; 10(2): 131 - 140. [Abstract] [Full Text]

				N. Rahimi, W. Hung, E. Tremblay, R. Saulnier, and B. Elliott c-Src Kinase Activity Is Required for Hepatocyte Growth Factor-induced Motility and Anchorage-independent Growth of Mammary Carcinoma Cells J. Biol. Chem., December 11, 1998; 273(50): 33714 - 33721. [Abstract] [Full Text] [PDF]

				M. Lail-Trecker, R. Gulati, and J. J. Peluso A Role for Hepatocyte Growth Factors/Scatter Factor in Regulating Normal and Neoplastic Cells of Reproductive Tissues Reproductive Sciences, May 1, 1998; 5(3): 114 - 121. [Abstract] [PDF]

				J. L. Jakubczak, W. J. Larochelle, and G. Merlino NK1, a Natural Splice Variant of Hepatocyte Growth Factor/Scatter Factor, Is a Partial Agonist In Vivo Mol. Cell. Biol., March 1, 1998; 18(3): 1275 - 1283. [Abstract] [Full Text]

				H. Takayama, W. J. LaRochelle, R. Sharp, T. Otsuka, P. Kriebel, M. Anver, S. A. Aaronson, and G. Merlino Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor PNAS, January 21, 1997; 94(2): 701 - 706. [Abstract] [Full Text] [PDF]

				N. Rahimi, E. Tremblay, and B. Elliott Phosphatidylinositol 3-Kinase Activity Is Required for Hepatocyte Growth Factor-induced Mitogenic Signals in Epithelial Cells J. Biol. Chem., October 4, 1996; 271(40): 24850 - 24855. [Abstract] [Full Text] [PDF]

				W. Hung and B. Elliott Co-operative Effect of c-Src Tyrosine Kinase and Stat3 in Activation of Hepatocyte Growth Factor Expression in Mammary Carcinoma Cells J. Biol. Chem., April 6, 2001; 276(15): 12395 - 12403. [Abstract] [Full Text] [PDF]