Uncontrolled activation of the Hedgehog (Hh) signaling pathway, operating through GLI transcription factors, plays a central role in the pathogenesis of cutaneous basal cell carcinoma and contributes to the development of several malignancies arising in extracutaneous sites. We now report that K5-tTA;tetO-Gli2 bitransgenic mice develop distinctive epithelial tumors within their jaws. These tumors consist of large masses of highly proliferative, monomorphous, basaloid cells with scattered foci of keratinization and central necrosis, mimicking human basaloid squamous cell carcinoma (BSCC), an aggressive upper aerodigestive tract tumor. Like human BSCC, these tumors express epidermal basal keratins and differentiation-specific keratins within squamous foci. Mouse BSCCs express high levels of Gli2 and Hh target genes, including Gli1 and Ptch1, which we show are also upregulated in a subset of human BSCCs. Mouse BSCCs appear to arise from distinct epithelial sites, including the gingival junctional epithelium and epithelial rests of Malassez, a proposed stem cell compartment. Although Gli2 transgene expression is restricted to epithelial cells, we also detect striking alterations in bone adjacent to BSCCs, with activated osteoblasts, osteoclasts and osteal macrophages, indicative of active bone remodeling. Gli2 transgene inactivation resulted in rapid BSCC regression and reversal of the bone remodeling phenotype. This first-reported mouse model of BSCC supports the concept that uncontrolled Hh signaling plays a central role in the pathogenesis of a subset of human BSCCs, points to Hh/GLI2 signaling as a potential therapeutic target and provides a powerful new tool for probing the mechanistic underpinnings of tumor-associated bone remodeling.

中文翻译：

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本构 Hedgehog/GLI2 信号传导驱动皮外基底样鳞状细胞癌的发展和骨重塑。

通过 GLI 转录因子发挥作用的 Hedgehog (Hh) 信号通路的不受控制的激活在皮肤基底细胞癌的发病机制中起核心作用，并有助于在皮外部位出现多种恶性肿瘤。我们现在报告 K5-tTA;tetO-Gli2 双转基因小鼠在它们的下巴内发展出独特的上皮肿瘤。这些肿瘤由大量高度增殖的单形基底样细胞组成，具有分散的角化病​​灶和中央坏死，类似于人类基底样鳞状细胞癌 (BSCC)，一种侵袭性上呼吸消化道肿瘤。与人类 BSCC 一样，这些肿瘤在鳞状灶内表达表皮基底角蛋白和分化特异性角蛋白。小鼠 BSCC 表达高水平的 Gli2 和 Hh 靶基因，包括 Gli1 和 Ptch1，我们展示的它也在人类 BSCC 的一个子集中上调。小鼠 BSCC 似乎起源于不同的上皮部位，包括牙龈交界上皮和 Malassez 的上皮残留物，这是一种建议的干细胞隔室。尽管 Gli2 转基因表达仅限于上皮细胞，但我们还检测到 BSCC 附近骨骼的显着变化，具有活化的成骨细胞、破骨细胞和骨巨噬细胞，表明活跃的骨重塑。Gli2 转基因失活导致快速 BSCC 消退和骨重塑表型的逆转。这种首次报道的 BSCC 小鼠模型支持不受控制的 Hh 信号传导在人类 BSCC 子集的发病机制中起核心作用的概念，