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Conversion of Stationary to Invasive Tumor Initiating Cells (TICs): Role of Hypoxia in Membrane Type 1-Matrix Metalloproteinase (MT1-MMP) Trafficking 1 2 1 1 3 3 Jian Li , Stanley Zucker *, Ashleigh Pulkoski-Gross , Cem Kuscu , Mihriban Karaayvaz , Jingfang Ju , 4 4 1,3 Herui Yao , Erwei Song , Jian Cao * 1 Department of Medicine/Cancer Prevention, Stony Brook University, Stony Brook, New York, United States of America, 2 Department of Research, Veterans Affair Medical Center, Northport, New York, United States of America, 3 Department of Pathology, Stony Brook University, Stony Brook, New York, United States of America, 4 Department of Breast Surgery, the Memorial Hospital of Sun-Yat-Sen University, Guangzhou, China Abstract Emerging evidence has implicated the role of tumor initiating cells (TICs) in the process of cancer metastasis. The mechanism underlying the conversion of TICs from stationary to invasive remains to be characterized. In this report, we employed less invasive breast cancer TICs, SK-3rd, that displays CD44high/CD24low with high mammosphere-forming and tumorigenic capacities, to investigate the mechanism by which stationary TICs are converted to invasive TICs. Invasive ability of SK-3rd TICs was markedly enhanced when the cells were cultured under hypoxic conditions. Given the role of membrane type 1-matrix metalloproteinase (MT1-MMP) in cancer invasion/metastasis, we explored a possible involvement of MT1-MMP in hypoxia-induced TIC invasion. Silencing of MT1-MMP by a shRNA approach resulted in diminution of hypoxia-induced cell invasion in vitro and metastasis in vivo. Under hypoxi