In Vivo c-Met Pathway Inhibition Depletes Human Glioma Xenografts of Tumor-Propagating Stem-Like Cells

被引:45
|
作者
Rath, Prakash [1 ,2 ]
Lal, Bachchu [1 ,2 ]
Ajala, Olutobi [1 ,2 ]
Li, Yunqing [1 ,2 ]
Xia, Shuli [1 ,2 ]
Kim, Jin [3 ]
Laterra, John [1 ,2 ]
机构
[1] Kennedy Krieger Inc, Hugo W Moser Res Inst, Dept Neurol, Baltimore, MD USA
[2] Johns Hopkins Univ, Sch Med, Baltimore, MD USA
[3] Galaxy Biotech LLC, Mountain View, CA USA
基金
美国国家卫生研究院;
关键词
HEPATOCYTE GROWTH-FACTOR; GLIOBLASTOMA; CANCER; TUMORIGENICITY; PHENOTYPE; RESPONSES; ONCOGENE;
D O I
10.1593/tlo.13127
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:104 / U160
页数:9
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