Basal cell carcinomas: p53-dependent mechanisms of resistance

描述(申请人提供)：这个项目的目标是更好地了解内在的肿瘤抑制机制，这种机制抑制携带癌基因突变的细胞发展成具有临床意义的癌症。这种抑制在预防基底细胞癌方面的效果有限，因为它是迄今为止最常见的人类癌症。尽管如此，小鼠模型显示存在非常强的依赖于p53的抗基底细胞癌效应，而人类基底细胞癌通常携带p53突变。我们(I)将研究突变驱动激活的Hedgehog信号--基底细胞癌发生中的关键异常--激活P53‘S抗癌效应的联系；(Ii)我们将阐明P53功能缺失突变(如在PTCH1/基底细胞痣综合征患者中发生在人BCC中)和P53功能突变获得(如零星发生在人BCC中)的促癌作用之间的差异；以及(Iii)将比较携带Hedgehog信号突变的毛囊组织干细胞和携带突变的等位基因激活致癌途径的毛囊组织干细胞之间的差异，后者通常是其他组织而不是皮肤癌的潜在致癌途径。该项目的成功开展将有助于阐明为什么这种“异常值”癌症如此常见，为什么不同的遗传背景会影响所发现的p53突变的类型，以及为什么特定的组织和细胞会通过独特的致癌途径转化。 公共卫生相关性：在一些人群中，基底细胞癌与所有其他癌症的总和一样常见，但这种高发病率的原因仍然不明，其他类型的癌症相对较少发生在同一来源的组织细胞中也是如此。我们的项目将利用对内在肿瘤抑制机制的新理解来解决这些临床特征，内在肿瘤抑制机制可以防止携带癌基因突变的细胞发展成具有临床意义的癌症。因此，对这种常见癌症的耐药性研究不仅可以指出预防这些皮肤癌的新方法，还可以预防潜在的内脏癌。

DESCRIPTION (provided by applicant): The goal of this project is to understand better the mechanisms of intrinsic tumor suppression that inhibit cells carrying oncogenic mutations from developing into clinically significant cancers. This suppression is of limited efficacy in preventing basal cell carcinogenesis, as it is by far the most common human cancer. Nonetheless mouse modeling indicates the presence of very strong p53-dependent anti-BCC effects, and human BCCs routinely carry p53 mutations. We (i) will investigate the connections by which mutation-driven activated hedgehog signaling, the pivotal abnormality in BCC carcinogenesis, activates p53's anti-cancer effects (ii) will elucidate the differences between the pro-carcinogenic effects of p53 loss of function mutations (as occur in human BCCs in PTCH1/basal cell nevus syndrome patients) and p53 gain of function mutations (as occur in human BCCs occurring sporadically) and (iii) will compare the effects of p53-dependent tumor suppression on the hair follicle tissue stem cells carrying mutations of hedgehog signaling vs. carrying mutant alleles activating oncogenic pathways that commonly underlie cancers of other tissues but not of skin. Successful prosecution of this Project will help elucidate why this "outlier" cancer is so common, why different genetic backgrounds can influence the type of p53 mutation found, and why specific tissues and cells are transformed by characteristic oncogenic pathways. PUBLIC HEALTH RELEVANCE: Basal cell carcinomas in some populations are as common as all other cancers combined but the reasons for this high frequency remain cryptic, as does the relative lack of other types of cancers arising from the same tissue cell of origin. Our project will address these clinical characteristics using newer understandings of mechanisms of intrinsic tumor suppression that prevent cells carrying oncogenic mutations from developing into clinically significant cancers. Hence study of resistance to this common cancer can point to new ways for prevention not only these skin cancers but potentially of visceral cancers as well.