Suppression of Ras-mediated tumorigenicity and metastasis through inhibition of the Met receptor tyrosine kinase

Mutations in the Ras family of GTP binding proteins represent one of the most frequently observed genetic alterations in human cancers. We and others have recently demonstrated that expression of Met, the tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF), is significantly up-regulated in Ras-transformed cells. Because HGF/SF-Met signaling is proposed to play a prominent role in tumor development and progression, we assessed the possible requirement for Met during Ras-mediated tumor growth and metastasis. To disrupt endogenous Met signaling, we constructed dominant-negative mutants of both human and murine Met and showed that these can inhibit HGF/SF-mediated Met signaling and cell invasion of ras-transformed cells in vitro. Moreover, ectopic expression of dominant-negative Met mutants reduced the s.c. tumor growth of ras-transformed cells and dramatically suppressed their ability to form lung metastases in vivo. Our data demonstrate that Met plays a prominent role during Ras-mediated tumor growth and metastasis, and further suggest that agents that inhibit HGF/SF-Met signaling may represent an important therapeutic avenue for the treatment of a variety of malignant tumors.

[1]  G. V. Vande Woude,et al.  Met-HGF/SF: tumorigenesis, invasion and metastasis. , 2007, Ciba Foundation symposium.

[2]  K. Furge,et al.  Met receptor tyrosine kinase: enhanced signaling through adapter proteins , 2000, Oncogene.

[3]  B. Westermark,et al.  Epidermal growth factor receptor signaling activates met in human anaplastic thyroid carcinoma cells. , 2000, Experimental cell research.

[4]  I. Tsarfaty,et al.  Dominant negative Met reduces tumorigenicity-metastasis and increases tubule formation in mammary cells , 2000, Oncogene.

[5]  I. Macdonald,et al.  Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. , 2000, Cancer research.

[6]  D. Seol,et al.  Transcriptional activation of the Hepatocyte Growth Factor receptor (c-met) gene by its ligand (Hepatocyte Growth Factor) is mediated through AP-1 , 2000, Oncogene.

[7]  P. Traxler,et al.  ATP site‐directed competitive and irreversible inhibitors of protein kinases , 2000, Medicinal research reviews.

[8]  A. Bardelli,et al.  A Peptide Representing the Carboxyl-terminal Tail of the Met Receptor Inhibits Kinase Activity and Invasive Growth* , 1999, The Journal of Biological Chemistry.

[9]  H. Friess,et al.  Molecular Aspects of Pancreatic Cancer and Future Perspectives , 1999, Digestive Surgery.

[10]  M. Fiscella,et al.  Evidence for a role of Met-HGF/SF during Ras-mediated tumorigenesis/metastasis , 1998, Oncogene.

[11]  C. Birchmeier,et al.  Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. , 1998, Trends in cell biology.

[12]  M. Tsao,et al.  The roles of hepatocyte growth factor/scatter factor and met receptor in human cancers (Review). , 1998, Oncology reports.

[13]  M. Wigler,et al.  Signaling pathways in Ras-mediated tumorigenicity and metastasis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Y. Liu,et al.  The human hepatocyte growth factor receptor gene: complete structural organization and promoter characterization. , 1998, Gene.

[15]  M. Ivan,et al.  Activated ras and ret oncogenes induce over-expression of c-met (hepatocyte growth factor receptor) in human thyroid epithelial cells , 1997, Oncogene.

[16]  M. Stella,et al.  Ets up-regulates MET transcription. , 1996, Oncogene.

[17]  J. Thompson,et al.  Expression of a truncated FGF receptor results in defective lens development in transgenic mice. , 1995, Development.

[18]  W. Birchmeier,et al.  Mutation of juxtamembrane tyrosine residue 1001 suppresses loss-of-function mutations of the met receptor in epithelial cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[19]  T. Nakamura,et al.  Tumorigenicity of the met proto-oncogene and the gene for hepatocyte growth factor , 1992, Molecular and cellular biology.

[20]  M. Kirschner,et al.  Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in xenopus embryos , 1991, Cell.

[21]  J. Rubin,et al.  Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. , 1991, Science.

[22]  G. V. Vande Woude,et al.  Structure, tissue-specific expression, and transforming activity of the mouse met protooncogene. , 1990, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[23]  J. L. Bos,et al.  ras oncogenes in human cancer: a review. , 1989, Cancer research.

[24]  C. Cooper,et al.  Mechanism of met oncogene activation , 1986, Cell.

[25]  Taylor Murray,et al.  Cancer statistics, 2000 , 2000, CA: a cancer journal for clinicians.

[26]  F. Vittimberga,et al.  The molecular and cellular biology of pancreatic cancer. , 1998, Critical reviews in eukaryotic gene expression.

[27]  C. Cooper,et al.  Molecular genetics of soft tissue sarcomas. , 1997, Cancer treatment and research.

[28]  G. V. Vande Woude,et al.  The Met-HGF/SF autocrine signaling mechanism is involved in sarcomagenesis. , 1995, EXS.

[29]  A. Chambers,et al.  Ras-responsive genes and tumor metastasis. , 1993, Critical reviews in oncogenesis.

[30]  R. Zarnegar,et al.  Expression of HGF-SF in normal and malignant human tissues. , 1993, EXS.

[31]  John G. Collard,et al.  Genetic analysis of invasion and metastasis. , 1988, Cancer surveys.

[32]  D. C. Sheehan,et al.  Theory and Practice of Histotechnology , 1980 .