title: In Vivo c-Met Pathway Inhibition Depletes Human Glioma Xenografts of Tumor-Propagating Stem-Like Cells.
abstract: Solid malignancies contain sphere-forming stem-like cells that are particularly efficient in propagating tumors. Identifying agents that target these cells will advance the development of more effective therapies. Recent converging evidence shows that c-Met expression marks tumor-initiating stem-like cells and that c-Met signaling drives human glioblastoma multiforme (GBM) cell stemness in vitro. However, the degree to which tumor-propagating stem-like cells depend on c-Met signaling in histologically complex cancers remains unknown. We examined the effects of in vivo c-Met pathway inhibitor therapy on tumor-propagating stem-like cells in human GBM xenografts. Animals bearing pre-established tumor xenografts expressing activated c-Met were treated with either neutralizing anti- hepatocyte growth factor (HGF) monoclonal antibody L2G7 or with the c-Met kinase inhibitor PF2341066 (Crizotinib). c-Met pathway inhibition inhibited tumor growth, depleted tumors of sphere-forming cells, and inhibited tumor expression of stem cell markers CD133, Sox2, Nanog, and Musashi. Withdrawing c-Met pathway inhibitor therapy resulted in a substantial rebound in stem cell marker expression concurrent with tumor recurrence. Cells derived from xenografts treated with anti-HGF in vivo were depleted of tumor-propagating potential as determined by in vivo serial dilution tumor-propagating assay. Furthermore, daughter xenografts that did form were 12-fold smaller than controls. These findings show that stem-like tumor-initiating cells are dynamically regulated by c-Met signaling in vivo and that c-Met pathway inhibitors can deplete tumors of their tumor-propagating stem-like cells.
authors.affiliation: Department of Neurology, The Hugo W. Moser Research Institute at Kennedy Krieger Inc and The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Prakash
authors.initials: P
authors.lastname: Rath
authors.forename: Bachchu
authors.initials: B
authors.lastname: Lal
authors.forename: Olutobi
authors.initials: O
authors.lastname: Ajala
authors.forename: Yunqing
authors.initials: Y
authors.lastname: Li
authors.forename: Shuli
authors.initials: S
authors.lastname: Xia
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.forename: John
authors.initials: J
authors.lastname: Laterra
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