The Epithelial-Mesenchymal Transition Mediator S100A4 Maintains Cancer-Initiating Cells in Head and Neck Cancers

Abstract

Cancer-initiating cells (CIC) comprise a rare subpopulation of cells in tumors that are proposed to be responsible for tumor growth. Starting from CICs identified in head and neck squamous cell carcinomas (HNSCC), termed head and neck cancer-initiating cells (HN-CIC), we determined as a candidate stemnessmaintaining molecule for HN-CICs the proinflammatory mediator S100A4, which is also known to be an inducer of epithelial-mesenchymal transition. S100A4 knockdown in HN-CICs reduced their self-renewal capability and their stemness and tumorigenic properties, both in vitro and in vivo. Conversely, S100A4 overexpression in HNSCC cells enhanced their stem cell properties. Mechanistic investigations indicated that attenuation of endogenous S100A4 levels in HNSCC cells caused downregulation of Notch2 and PI3K (phosphoinositide 3-kinase)/pAKT along with upregulation of PTEN, consistent with biological findings. Immunohistochemical analysis of HNSCC clinical specimens showed that S100A4 expression was positively correlated with clinical grading, stemness markers, and poorer patient survival. Together, our findings reveal a crucial role for S100A4 signaling pathways in maintaining the stemness properties and tumorigenicity of HN-CICs. Furthermore, our findings suggest that targeting S100A4 signaling may offer a new targeted strategy for HNSCC treatment by eliminating HN-CICs. Cancer Res; 71(5); 1912-23. Ó2010 AACR.

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

“…Recently, inhibition of poly ADP ribose polymerase [81] and S100A4 signaling pathways have also been suggested as possible new target strategies for SCCHN [82]. Thus, PI3K inhibition in combination with targeted inhibition of other intracellular signaling pathways may provide a promising therapeutic strategy in SCCHN.…”

Epidermal differentiation complex (locus 1q21) gene expression in head and neck cancer and normal mucosa

“…S100A4 was confirmed to regulate E-cadherin expression in oral SCC cell lines [30], and its expression was correlated with invasion and metastasis [31]. It was shown to mediate epithelial-mesenchymal transition in HNSCC and was associated with stem-cell like phenotype (S100A4 knockdown reduced self-renewal and stemness of cells, while S100A4 over-expression enhanced their stem cell properties) [32].…”

Prognostic and Predictive Protein Biomarkers in Laryngeal Squamous Cell Carcinoma—A Systematic Review

“…There is current evidence to suggest the role of S100 proteins in cancer cell differentiation [38], cell proliferation [39] [40], cell apoptosis [41] [42] and tumor metastasis [43] [44]. Members of the S100 family have been implicated in various types of cancers.…”