Inducible Activation of Oncogenic K- ras Results in Tumor Formation in the Oral Cavity

Abstract

Mouse models for cancer represent powerful tools to analyze the causal role of genetic alterations in cancer development. We have developed a novel mouse model that allows the focal activation of mutations in stratified epithelia. Using this system, we demonstrate that activation of an oncogenic K-rasG12D allele in the oral cavity of the mouse induces oral tumor formation. The lesions that develop in these mice are classified as benign squamous papillomas. Interestingly, these tumors exhibit changes in the expression pattern of keratins similar to those observed in human premalignant oral tumors, which are reflective of early stages of tumorigenesis. These results demonstrate a causal role for oncogenic K-ras in oral tumor development. The inducible nature of this model also makes it an ideal system to study cooperative interactions between mutations in oncogenes and/or tumor suppressor genes that are similar to those observed in human tumors. To our knowledge, this is the first reported inducible mouse model for oral cancer.

Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes

“…Hence, wounding recruits HF cells carrying a homozygous deletion of Ptch1 and thereby significantly increases the number of lesions in the wound area, and as shown in Lgr5-EGFP-IRES-creER T2 /Ptch1 fl/fl epidermis, HF cells with a homozygous Ptch1 deletion are intrinsically capable of inducing IFE-associated lesions in support of this hypothesis. The first two models also show different preferences for tumor initiation in the IFE vs. the HF, although the K5tTA and K5Cre*PR1 transgenes are driven by the same bovine K5 promoter sequence (14,15,28), and the different compartments of the HFs and the IFE are uniformly targeted (14). This and two recent studies argue for differential sensitivity of epidermal cell subpopulations to the activation of Hh signaling by targeting specific pathway components (29,30).…”

Defining the origins of Ras/p53-mediated squamous cell carcinoma

“…expressed in Cre-activated YFP + populations, we performed RT-PCR on YFP + and YFP − sorted cells to demonstrate that the HindIII restriction site introduced into the Kras allele by the G12D mutation was present (34). This Kras G12D -specific HindIII restriction site was enriched in the YFP + population but not found in the Kras G12D YFP − population or in wild-type Kras controls (Fig.…”

Chemical Carcinogenesis Models for Evaluating Molecular-Targeted Prevention and Treatment of Oral Cancer

“…Although some of the key molecular events contributing to HNSCC initiation and progression have been identified recently, translating these findings into the development of novel mechanism-based preventive and therapeutic approaches for HNSCC has been hampered by a paucity of appropriate animal models of oral carcinogenesis. To address this need, investigators have recently used genetically engineered mice to begin modeling HNSCC progression (6)(7)(8) and have initiated parallel efforts to recapitulate the tumor heterogeneity and complexity of the clinical setting by optimizing carcinogeninduced oral-specific carcinogenesis models in immunocompetent mice. As previously reviewed (9), the latter effort includes exposing experimental animals to chemical carcinogens such as coal tar, cigarette smoke, 20-methylcholanthrene, 9,10-dimethyl-1,2-benzanthracene, and 3,4-benzpyrene.…”