Lu Shi-Long, Herrington Heather, Reh Douglas, Weber Stephen, Bornstein Sophia, Wang Donna, Li Allen G, Tang Chin-Fang, Siddiqui Yasmin, Nord Jo, Andersen Peter, Corless Christopher L, Wang Xiao-Jing
Department of Otolaryngology, OHSU Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
Genes Dev. 2006 May 15;20(10):1331-42. doi: 10.1101/gad.1413306.
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.
在过去20年中，头颈部鳞状细胞癌（HNSCC）的预后并未得到改善。由于缺乏在病理和分子水平上模拟人类HNSCC的动物模型，HNSCC生物标志物用于靶向治疗的验证受到了阻碍。在此我们报告，K-ras或H-ras的过表达以及II型转化生长因子-β受体（TGFbetaRII）的缺失是人类HNSCC中的常见事件。从小鼠头颈部上皮细胞中激活K-ras或H-ras并同时缺失TGFbetaRII会导致HNSCC完全发生，其中一些会进展为转移。这些肿瘤表现出与人类HNSCC难以区分的病理学特征，并表现出人类HNSCC中常见的多种分子改变。此外，这些病变中内源性TGFbeta1的升高促进了炎症和血管生成。我们的数据表明，靶向肿瘤上皮细胞中的常见致癌途径并同时阻断TGFbeta1对肿瘤基质的作用可能为HNSCC提供一种新的治疗策略。
