The Department of Pathology, University Medical Center Utrecht, The Netherlands.
Experimental Animal Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Neoplasia. 2023 Jan;35:100844. doi: 10.1016/j.neo.2022.100844. Epub 2022 Nov 10.
Tissue-specific inactivation of E-cadherin combined with tumor suppressor loss leads to invasive and metastatic cancers in mice. While epidermal E-cadherin loss in mice induces squamous cell carcinomas, inactivation of E-cadherin in the mammary gland leads to invasive lobular carcinoma. To further explore the carcinogenic consequences of cell-cell adhesion loss in these compartments, we developed a new conditional mouse model inactivating E-cadherin (Cdh1) and p53 (Trp53) simultaneously in cells expressing the leucine-rich repeat-containing G-protein coupled receptor 6 (Lgr6), a putative epithelial stem cell marker in the skin and alveolar progenitor marker in the mammary gland. Compound Lgr6-CreERT2;Cdh1;Trp53 female mice containing either heterozygous or homozygous Cdh1 alleles were bred, and Lgr6-driven Cre expression was activated in pre-puberal mice using tamoxifen. We observed that 41% of the mice (16/39) developed mostly invasive squamous-type skin carcinomas, but also a non-lobular mammary tumor was formed. In contrast to previous K14cre or WAPcre E-cadherin and p53 compound models, no significant differences were detected in the tumor-free survival of Lgr6-CreERT2 heterozygous Cdh1;Trp53 versus homozygous Cdh1;Trp53 mice (778 versus 754 days, p=0.5). One Cdh1 homozygous mouse presented with lung metastasis that originated from a non-lobular and ERα negative invasive mammary gland carcinoma with squamous metaplasia. In total, 2/8 (25%) Cdh1 heterozygous and 3/12 (25%) Cdh1 homozygous mice developed metastases to lungs, liver, lymph nodes, or the gastro-intestinal tract. In conclusion, we show that inducible and conditional Lgr6-driven inactivation of E-cadherin and p53 in mice causes squamous cell carcinomas of the skin in approximately 40% of the mice and an occasional ductal-type mammary carcinoma after long latency periods.
组织特异性 E-钙黏蛋白失活与肿瘤抑制因子缺失导致小鼠发生侵袭性和转移性癌症。虽然小鼠表皮 E-钙黏蛋白的缺失会诱导鳞状细胞癌，但乳腺中 E-钙黏蛋白的失活会导致浸润性小叶癌。为了进一步探讨这些部位细胞间黏附丧失的致癌后果，我们在表达富含亮氨酸重复的 G 蛋白偶联受体 6（Lgr6）的细胞中构建了一种新的条件性小鼠模型，使 E-钙黏蛋白（Cdh1）和 p53（Trp53）同时失活，Lgr6 是皮肤中的上皮干细胞标志物和乳腺中的肺泡祖细胞标志物。含有杂合或纯合 Cdh1 等位基因的复合 Lgr6-CreERT2；Cdh1；Trp53 雌性小鼠被繁殖，并且在青春期前的小鼠中使用他莫昔芬激活 Lgr6 驱动的 Cre 表达。我们观察到，41%的小鼠（16/39）主要形成侵袭性鳞状皮肤癌，但也形成了非小叶型乳腺肿瘤。与之前的 K14cre 或 WAPcre E-钙黏蛋白和 p53 复合模型不同，Lgr6-CreERT2 杂合 Cdh1；Trp53 与纯合 Cdh1；Trp53 小鼠的无肿瘤生存时间没有显著差异（778 天与 754 天，p=0.5）。一只 Cdh1 纯合子小鼠出现了来自非小叶型和 ERα 阴性侵袭性乳腺腺癌的肺转移，伴有鳞状化生。总共有 2/8（25%）的 Cdh1 杂合子和 3/12（25%）的 Cdh1 纯合子小鼠发生肺、肝、淋巴结或胃肠道转移。总之，我们表明，在小鼠中诱导和条件性 Lgr6 驱动的 E-钙黏蛋白和 p53 失活会导致大约 40%的小鼠出现皮肤鳞状细胞癌，并在长时间潜伏期后偶尔出现导管型乳腺癌。
