c-Met pathway promotes self-renewal and tumorigenecity of head and neck squamous cell carcinoma stem-like cell

Objectives: Increasing evidence indicates that a rare subpopulation of cancer cells, namely, cancer stem cells (CSCs), is the primary cause of tumorigenesis in some tumor types, including head and neck squamous cell carcinoma (HNSCC). Hepatocyte growth factor (HGF) and its receptor, c-Met, are involved in tongue development and carcinogenesis of HNSCC. Here, we investigated whether activation of HGF/c-Met signaling influences the stem cell traits of HNSCC CSC. Materials and methods: After HGF treatment, we assessed the sphere-forming capacity and stem cell marker expression in HNSCC stem-like cells compared with the respective control cells in vitro. In addition, we evaluated the effect of c-Met knockdown on the sphere-forming capacity, stem cell marker expression, and cisplatin chemosensitivity of HNSCC stem-like cells in vitro. Furthermore, we evaluated the inhibitory effect of c-Met knockdown on the capacity of HNSCC stem-like cells to initiate tumor growth in the orthotopic mouse model. Results: HGF treatment promoted the sphere-forming capacity of HNSCC stem-like cells and increased the expression of stem cell markers such as Oct4, Sox2, and CD44. Transcriptional levels of c-Met was increased in cells with high aldehyde dehydrogenase (ALDH) 1 activity, a putative marker for HNSCC stem-like cells, compared to cells with low activity. In contrast, knockdown of c-Met attenuated the sphere-forming capacity and stem cell markers expression in HNSCC stem-like cells, and augmented cisplatin chemosensitivity by decreased side population cells and suppression of an ABCG2 transporter gene. Furthermore, knockdown of c-Met in HNSCC stem-like cells inhibits tumor formation of mice in a xenograft model and increases mice survival. Conclusion: Our results suggest that inhibition of the c-Met pathway could serve as a potent therapeutic strategy to target HNSCC stem-like cells. (C) 2014 Elsevier Ltd. All rights reserved.