Targeting the c-Met/FZD8 signaling axis eliminates patient-derived cancer stem-like cells in head and neck squamous carcinomas.

Abstract

Cancer stem-like cells (CSC) thought to contribute to head and neck squamous carcinomas (HNSCC) may offer attractive therapeutic targets if a tractable approach can be developed. In this study, we report that silencing c-Met is sufficient to suppress sphere formation, tumor initiation, and metastatic properties of HN-CSC. Pharmacologic inhibition of c-Met with the selective inhibitor PF-2341066 preferentially targeted CSC and synergized with conventional chemotherapy to improve efficacy in a mouse xenograft model of HNSCC, impeding tumor growth and reducing metastasis. Mechanistic investigations showed that CSC elimination was due to downregulation of Wnt/β-catenin signaling in HN-CSC and that the Wnt pathway receptor FZD8 was essential for interactions of c-Met and Wnt/β-catenin signaling in HN-CSC. Notably, ectopic expression of FZD8 rescued the impaired phenotype of HN-CSC where c-Met was inhibited. Furthermore, c-Met upregulated FZD8 through the ERK/c-Fos cascade in HN-CSC. Taken together, our results offer a preclinical proof-of-concept for targeting the c-Met/FZD8 signaling axis as a CSC-directed therapy to improve HNSCC treatment.

• Authors: Shuyang Sun, Suling Liu, Sheng Zhong Duan, Lei Zhang, Henghua Zhou, Yongjie Hu, Xianghui Zhou, Chaoji Shi, Rong Zhou, Zhiyuan Zhang
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 24 Pg. 7546-59 (Dec 15 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 25320014 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Fzd8 protein, human
• Piperidines
• Pyrazoles
• Pyridines
• Receptors, Cell Surface
• Crizotinib
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Carcinoma, Squamous Cell (drug therapy, genetics, pathology)
• Crizotinib
• Gene Expression Regulation, Neoplastic (drug effects)
• Head and Neck Neoplasms (drug therapy, genetics, pathology)
• Humans
• Mice
• Neoplastic Stem Cells (drug effects)
• Piperidines (administration & dosage)
• Primary Cell Culture
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, genetics)
• Pyrazoles
• Pyridines (administration & dosage)
• Receptors, Cell Surface (antagonists & inhibitors, genetics)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays