Characterizing the Cells of Origin for Basal Cell Carcinoma

描述（由申请人提供）：基底细胞癌（BCC）是北美最常诊断的癌症。虽然基底细胞癌通常被认为是滤泡性肿瘤，但这种癌症的起源细胞，甚至这些细胞是否起源于毛囊，仍然是一个争论的主题。干细胞是有吸引力的候选人作为潜在的癌症祖细胞，因为它们的长寿的性质和自我更新能力;然而，在皮肤中，离散的干细胞群体驻留在几个区室中，包括毛囊隆起，皮脂腺，毛囊间表皮和交界区，最近确定的上毛囊的域。潜在地，来自任何这些隔室的细胞可以引起BCC。在人类中，BCC通常显示上调的Hedgehog（Hh）信号传导，并且Hh途径组分（例如Smoothened和Gli 2）的皮肤特异性表达可以诱导小鼠中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依赖性BCC小鼠模型产生的肿瘤的起源细胞。在这样做的过程中，长期存在的问题，关于这种疾病的发病机制将得到解决，包括：（1）不同的细胞类型可以引起基底细胞癌取决于致癌起始事件？(2)毛囊间表皮细胞能独立于毛囊产生基底细胞癌吗？(3)来自毛囊隆突的细胞会引起BCC吗？能否分离出具有不同致瘤能力的特定角质形成细胞亚群？这项提案的发现将有望阐明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.