The scatter factor/hepatocyte growth factor : c-met pathway in human embryonal central nervous system tumor malignancy

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 20; pp. 9355 - 9362
• Main Authors: YUNQING LI, LAL, Bachchu, KWON, Sherwin, XING FAN, SALDANHA, Usha, REZNIK, Thomas E, KUCHNER, Eric B, EBERHART, Charles, LATEMA, John, ABOUNADER, Roger
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.10.2005
• Subjects: Animals; Biological and medical sciences; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Adhesion - drug effects; Cell Adhesion - physiology; Cell Cycle - drug effects; Cell Cycle - physiology; Cell Growth Processes - drug effects; Cell Growth Processes - physiology; Cell Line, Tumor; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Hepatocyte Growth Factor - biosynthesis; Hepatocyte Growth Factor - pharmacology; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Medical sciences; Medulloblastoma - drug therapy; Medulloblastoma - metabolism; Medulloblastoma - pathology; Mice; Mitogen-Activated Protein Kinases - metabolism; Neoplasm Transplantation; Neurology; Phosphorylation; Prognosis; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-met - biosynthesis; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Transplantation, Heterologous; Tumors of the nervous system. Phacomatoses; Human; Nervous system diseases; Hepatocyte growth factor; C-Onc gene; Central nervous system disease; Malignancy; Malignant tumor; Intracranial tumor; Protooncogene; Cerebral disorder
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-1946

Embryonal central nervous system (CNS) tumors, which comprise medulloblastoma, are the most common malignant brain tumors in children. The role of the growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its tyrosine kinase receptor c-Met in these tumors has been until now completely unknown. In the present study, we show that human embryonal CNS tumor cell lines and surgical tumor specimens express SF/HGF and c-Met. Furthermore, c-Met mRNA expression levels statistically significantly correlate with poor clinical outcome. Treatment of medulloblastoma cells with SF/HGF activates c-Met and downstream signal transduction as evidenced by c-Met, mitogen-activated protein kinase, and Akt phosphorylation. SF/HGF induces tumor cell proliferation, anchorage-independent growth, and cell cycle progression beyond the G1-S checkpoint. Using dominant-negative Cdk2 and a degradation stable p27 mutant, we show that cell cycle progression induced by SF/HGF requires Cdk2 function and p27 inhibition. SF/HGF also protects medulloblastoma cells against apoptosis induced by chemotherapy. This cytoprotective effect is associated with reduction of proapoptotic cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 proteins and requires phosphoinositide 3-kinase activity. SF/HGF gene transfer to medulloblastoma cells strongly enhances the in vivo growth of s.c. and intracranial tumor xenografts. SF/HGF-overexpressing medulloblastoma xenografts exhibit increased invasion and morphologic changes that resemble human large cell anaplastic medulloblastoma. This first characterization establishes SF/HGF:c-Met as a new pathway of malignancy with multifunctional effects in human embryonal CNS tumors.