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

¹ Department of Otolaryngology, ² Department of Pathology, ³ Department of Dermatology ⁴ Department of Cell and Developmental Biology, OHSU Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239, USA

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- type II receptor (TGFRII) are common events in human HNSCC. Activation of either K-ras or H-ras in combination with TGFRII 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 TGF1 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 TGF1 on tumor stroma may provide a novel therapeutic strategy for HNSCC.

[Keywords: HNSCC; head-and-neck-specific knockout; metastasis; Ras; TGFRII; TGF1]

Received January 25, 2006; revised version accepted March 17, 2006.

E-MAIL wangxiao{at}ohsu.edu; FAX (503) 402-2817.

Supplemental material is available at http://www.genesdev.org.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1413306

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