The scatter factor/hepatocyte growth factor: c-met pathway in human embryonal central nervous system tumor malignancy.
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.
Li
Yunqing
Y
Department of Neurology, Johns Hopkins University School of Medicine, MD 21205, USA.
Lal
Bachchu
B
Kwon
Sherwin
S
Fan
Xing
X
Saldanha
Usha
U
Reznik
Thomas E
TE
Kuchner
Eric B
EB
Eberhart
Charles
C
Laterra
John
J
Abounader
Roger
R
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008527:Medulloblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014183:Transplantation, Heterologous
C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D051357:Cyclin-Dependent Kinase 2; D020928:Mitogen-Activated Protein Kinases