Characterizing the Cells of Origin for Basal Cell Carcinoma

描述（由申请人提供）：基底细胞癌（BCC）是北美最常见的癌症。虽然bcc通常被认为是一种毛囊性肿瘤，但这种癌症的起源细胞——甚至这些细胞是否起源于毛囊——仍然是一个有争议的话题。由于干细胞具有长寿命和自我更新能力，它们是癌症潜在祖细胞的有吸引力的候选者；然而，在皮肤中，分散的干细胞群分布在几个隔室中，包括毛囊凸起、皮脂腺、毛囊间表皮和连接区（最近发现的上毛囊区域）。这些区室中的任何一种细胞都可能产生基底细胞癌。在人类中，bcc通常表现出上调的Hedgehog （Hh）信号，并且Hh通路组分如Smoothened和Gli2的皮肤特异性表达可以诱导小鼠bcc样病变的形成。使用多种体内方法，本研究旨在鉴定和表征两种Hh依赖的BCC小鼠模型中肿瘤的起源细胞。在此过程中，关于这种疾病的发病机制的长期问题将得到解决，包括：(1)不同的细胞类型是否会根据致癌起始事件引起bcc ？(2)毛囊间表皮细胞能否独立于毛囊生成bcc ？(3)来自滤泡膨出的细胞是否会导致基底细胞癌？(4)是否可以分离出具有不同致瘤能力的特定角化细胞亚群？这项研究的结果有望阐明BCC的发病机制，以及构成皮肤和毛囊的各种细胞类型的行为。

DESCRIPTION (provided by applicant): Basal cell carcinoma (BCC) is the most commonly diagnosed cancer in North America. Although BCCs are generally regarded as follicular tumors, the cells of origin for this cancer-and even whether these cells originate from the hair follicle-remain a subject of debate. Stem cells are attractive candidates as potential progenitor cells for cancer, given their long-lived nature and self renewal ability; however, in the skin, discrete stem cell populations reside in several compartments, including the follicular bulge, sebaceous glands, interfollicular epidermis, and the junctional zone, a recently identified domain of the upper hair follicle. Potentially, cells from any of these compartments can give rise to BCC. In humans, BCCs commonly display upregulated Hedgehog (Hh) signaling, and skin-specific expression of Hh pathway components such as Smoothened and Gli2 can induce the formation of BCC-like lesions in mice. Using a variety of in vivo approaches, this study seeks to identify and characterize the cells of origin for tumors arising from two Hh- dependent mouse models of BCC. In doing so, long-standing questions regarding the pathogenesis of this disease will be addressed, including, (1) Can different cell types give rise to BCCs depending on the oncogenic initiating event? (2) Can cells from the interfollicular epidermis generate BCCs independently of the hair follicle? (3) Can cells from the follicular bulge give rise to BCC? And (4), Can specific keratinocyte subpopulations with differing tumorigenic competency be isolated? The findings from this proposal will hopefully shed light on the pathogenesis of BCC, as well as on the behaviors of the various cell types that comprise the skin and hair follicle.