Basal cell carcinomas: p53-dependent mechanisms of resistance

基底细胞癌：p53 依赖性耐药机制

• 批准号: 8219815
• 负责人: Ervin HAROLD Epstein
• 金额: $ 33.62万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8219815
• 关键词: Accounting; Address; Alleles; Automobile Driving; Basal Cell; Basal Cell Nevus Syndrome; Basal cell carcinoma; Cells; Characteristics; Clinical; DNA Damage; Development; Frequencies; Genetic; Goals; Hair follicle structure; Human; Malignant Neoplasms; Mediating; Missense Mutation; Modeling; Molecular Abnormality; Mus; Mutation; Nevus; Oncogenic; Pathway interactions; Patients; Population; Prevention; Relative (related person); Reporter; Resistance; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Squamous cell carcinoma; Stem cells; Tissues; Tumor Suppression; Tumor-Derived; Visceral; cancer type; carcinogenesis; cell transformation; clinically significant; gain of function mutation; keratinocyte; loss of function; loss of function mutation; mouse model; mutant; prevent; resistance mechanism; response; smoothened signaling pathway; tumor; tumorigenesis; tumorigenic

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.

描述（由申请人提供）：该项目的目的是更好地了解内在肿瘤抑制的机制，这些机制抑制携带致癌突变的细胞，从发育成临床意义的癌症。这种抑制在防止基底细胞致癌作用方面具有有限的功效，因为它是迄今为止最常见的人类癌症。尽管如此，小鼠的建模表明存在非常强的p53依赖性抗BCC效应，而人BCC通常携带p53突变。我们（i）将研究突变驱动的激活的刺猬信号传导，BCC癌变中的关键异常，激活p53的抗癌作用（II）将阐明功能突变p53损失突变（p53损失）的差异（II）如PTCH1/基底细胞尿综合征患者中的人类BCC所发生的那样）和p53功能突变的增益（如偶发发生的人BCC中发生的那样），（iii）将比较依赖p53依赖性肿瘤对毛卵泡组织干细胞的影响。刺猬信号传导与携带突变等位基因的突变激活了通常是其他组织癌的基础但不是皮肤的致癌途径。成功起诉该项目将有助于阐明为什么这种“异常”癌症如此普遍，为什么不同的遗传背景会影响发现的p53突变的类型，以及为什么特定的组织和细胞会被特征性的致癌途径转化。 公共卫生相关性：某些人群中的基底细胞癌与所有其他癌症的总和一样普遍，但是这种高频的原因仍然隐秘，而相对缺乏由同一起源组织细胞引起的其他类型的癌症也是如此。我们的项目将通过对内在肿瘤抑制机制的新理解来解决这些临床特征，这些机制可以防止携带致癌突变的细胞发展成具有临床意义的癌症。因此，研究对这种常见癌症的耐药性不仅可以指出预防这些皮肤癌的新方法，而且还可能对内脏癌症进行预防。