Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma.
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-beta type II receptor (TGFbetaRII) are common events in human HNSCC. Activation of either K-ras or H-ras in combination with TGFbetaRII 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 TGFbeta1 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 TGFbeta1 on tumor stroma may provide a novel therapeutic strategy for HNSCC.
Lu
Shi-Long
SL
Department of Otolaryngology, OHSU Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
Herrington
Heather
H
Reh
Douglas
D
Weber
Stephen
S
Bornstein
Sophia
S
Wang
Donna
D
Li
Allen G
AG
Tang
Chin-Fang
CF
Siddiqui
Yasmin
Y
Nord
Jo
J
Andersen
Peter
P
Corless
Christopher L
CL
Wang
Xiao-Jing
XJ
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000235:genetics / Q000556:secondary*; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009062:Mouth Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015533:Transcriptional Activation
D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D016283:Proto-Oncogene Proteins p21(ras)