Loss of transforming growth factor-β type II receptor promotes metastatic head-and-neck squamous cell carcinoma

Abstract

The prognosis of head-and-neck squamous cell carcinoma (HNSCC) has not been improved in the past 20 years. Validation of HNSCC biomarkers for targeted therapy has been hindered by a lack of animal models mimicking human HNSCC at both the pathological and molecular levels. Here we report that overexpression of K-ras or H-ras and loss of transforming growth factor-β type II receptor (TGFβRII) are common events in human HNSCC. Activation of either K-ras or H-ras in combination with TGFβRII deletion from mouse head-and-neck epithelia caused HNSCC with complete penetrance, some of which progressed to metastases. These tumors displayed pathology indistinguishable from human HNSCCs and exhibited multiple molecular alterations commonly found in human HNSCCs. Additionally, elevated endogenous TGFβ1 in these lesions contributed to inflammation and angiogenesis. Our data suggest that targeting common oncogenic pathways in tumor epithelia together with blocking the effect of TGFβ1 on tumor stroma may provide a novel therapeutic strategy for HNSCC.

Keywords

• HNSCC
• head-and-neck-specific knockout
• metastasis
• Ras
• TGFβRII
• TGFβ1