Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations
Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations
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DOI：
10.1172/jci46307
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发表时间：
2011-05-01
影响因子：
15.9
通讯作者：
Dlugosz, Andrzej A.
中科院分区：
文献类型：
--
作者：
Grachtchouk, Marina;Pero, Joanna;Dlugosz, Andrzej A.
不受控制的Hedgehog（Hh）信号转导导致基底细胞癌（BCC）的发展，BCC是最常见的人类癌症，但BCC的起源细胞尚不清楚。虽然Hh途径失调对于基本上所有的BCC都是常见的，但存在多种组织学亚型，包括浅表和结节变体，这提高了形态学上不同的BCC可能来自皮肤中不同的细胞区室的可能性。在这里，我们已经表明，诱导Hh信号传导的主要介质，GLI 2激活剂（GLI 2AN），选择性地在小鼠静止毛囊的干细胞中，诱导结节性基底细胞癌的发展，从一个小的细胞亚群在较低的隆起和次级毛胚隔室。当在生长的毛囊中诱导GLI 2AN时，肿瘤发生显著加速。相反，表皮中GLI 2AN的诱导导致浅表BCC的形成。GLI 2AN在小鼠中以降低的水平表达产生类似基底细胞样滤泡性错构瘤的病变，其先前已在小鼠和人类中与低水平Hh信号传导相关联。我们的数据表明，细胞起源，组织环境（静止与生长的毛囊）和致癌信号的水平可以决定Hh/Gli驱动的皮肤肿瘤的表型，高水平的信号需要从毛囊间表皮和结节性BCC样肿瘤的毛囊干细胞的浅表BCC样肿瘤的发展。
Uncontrolled Hedgehog (Hh) signaling leads to the development of basal cell carcinoma (BCC), the most common human cancer, but the cell of origin for BCC is unclear. While Hh pathway dysregulation is common to essentially all BCCs, there exist multiple histological subtypes, including superficial and nodular variants, raising the possibility that morphologically distinct BCCs may arise from different cellular compartments in skin. Here we have shown that induction of a major mediator of Hh signaling, GLI2 activator (GLI2AN), selectively in stem cells of resting hair follicles in mice, induced nodular BCC development from a small subset of cells in the lower bulge and secondary hair germ compartments. Tumorigenesis was markedly accelerated when GLI2AN was induced in growing hair follicles. In contrast, induction of GLI2AN in epidermis led to the formation of superficial BCCs. Expression of GLI2AN at reduced levels in mice yielded lesions resembling basaloid follicular hamartomas, which have previously been linked to low-level Hh signaling in both mice and humans. Our data show that the cell of origin, tissue context (quiescent versus growing hair follicles), and level of oncogenic signaling can determine the phenotype of Hh/Gli-driven skin tumors, with high-level signaling required for development of superficial BCC-like tumors from interfollicular epidermis and nodular BCC-like tumors from hair follicle stem cells.