Head neck squamous cell carcinoma c‐Met⁺ cells display cancer stem cell properties and are responsible for cisplatin‐resistance and metastasis

Abstract

c-Met, the tyrosine kinase receptor for hepatocyte growth factor, is overexpressed in a variety of tumors in which it plays a central role in malignant transformation. Although c-Met has also been determined to be a critical signaling molecule in normal stem cell function, the potential role of c-Met as a single marker for cancer stem cells (CSCs) has not been previously examined. In our study, we reported that human head neck squamous cell carcinoma (HNSCC) cells expressing c-Met were capable of self-renewal and of generating tumors that recapitulate the heterogeneity of the parental tumors, and isolation of HNSCC cells using a second marker CD44 could further enhance upon the in-vivo tumorigenicity. We also reported that c-Met 1 HNSCC cells could readily make spherical colonies in nonadherent culture conditions, in contrast, c-Met 2 population did not; these spherical colonies could be passaged multiple times without loss of colony-forming capability. Furthermore, we showed that c-Met 1 HNSCC cells have increased expression of self-renewal pathways are spared by cisplatin treatment and are responsible for mediating metastasis. These results indicated that c-Met could serve as a novel marker for CSCs at least in HNSCC, and the highly chemoresistant and metastatic capabilities of c-Met 1 HNSCC population make them an important cell type to better define and understand their function.

Inhibition of Tumor Growth and Metastasis in Pancreatic Cancer Models by Interference With CD44v6 Signaling

“…High Met-expression was also detected on populations of cancer stem cells, e.g. in head and neck squamous cell carcinoma 15 . Particularly interesting is the finding that Met and CD44 are stem cell markers on pancreatic carcinoma 16 suggesting that the co-receptor function of CD44 for Met might be of functional importance in these cells.…”

Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: A Review

“…Sun and Wang looked at CMET+ cells compared to CMET− and found increased tumorigenicity in a flank injections and found higher percentage of implantation in CMET+ cells compared to CD44+ cells and slightly lower than ALDH+ cells (Sun et al, 2011). In addition, Zhang et al looked at HNSCC cell lines and oral cavity primary tumors identified the presence of SP cells.…”

“…Davies et al has shown that HNSCC CD44high cells have greater migration, invasion and metastatic potential compared to CD44low cells (Davis et al, 2010). Gene expression studies comparing ALDH+ cells and ALDH− cells demonstrated elevated levels of the metastatic and epithelial-mesenchymal transition (EMT) biomarkers CMET, TWIST, and SNAIL (Chen et al, 2011;Sun et al, 2011). Zhang et al demonstrated that Side population cells have also been associated with metastasis .…”

Cancer Stem Cells and Stemness Markers in Oral Squamous Cell Carcinomas

“…In HNSCC, c-Met+ cells demonstrated self renewal and were able to generate heterogeneous tumours with more tumourigenic potential than by CD44+ marker. Also, c-Met+ /CD44+ combination yielded tumours in 80% of cases, while c-Met+/ALDH1+ displayed tumour formation in 66% cases (Sun and Wang, 2011). Thus c-Met has been proposed as a potent CSC marker in OSCC but further investigation with a greater number of samples and a comparison of c-Met+ with other CSC and stemness markers could give a clear depiction (Sun and Wang, 2011).…”

“…The resistance to current modalities of treatment such as chemotherapy and radiotherapy is owed to the CSC subpopulation's ability to orchestrate recurrence and facilitate metastasis, which has significant treatment implications (Bradletz et al, 2005;Davis et al, 2010;Sun and Wang, 2011). Hence, CSC hypothesis demands modifications in therapeutic applications & measurement of treatment success.…”