Department of Medicine, McGill University Health Centre, Glen Site, Montréal, QC, Canada.
Department of Orthopaedic Surgery, Faculty of Dentistry, Shriners Hospital, Montréal, QC, Canada.
Endocrinology. 2021 Jul 1;162(7). doi: 10.1210/endocr/bqab049.
Vitamin D deficiency is associated with poor cancer outcome in humans, and administration of vitamin D or its analogs decreases tumor progression and metastasis in animal models. Using the mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) model of mammary cancer, we previously demonstrated a significant acceleration of carcinogenesis in animals on a low vitamin D diet and a reduction in spontaneous lung metastases when mice received vitamin D through perfusion. We investigate here the action mechanism for vitamin D in lung metastasis in the same non-immunodeficient model and demonstrate that it involves the control of epithelial to mesenchymal transition as well as interactions between chemokine C-X-C motif chemokine 12 (CXCL12) and its receptor C-X-C chemokine receptor type 4 (CXCR4). In vitro, 10-9M vitamin D treatment modifies the phenotype of MMTV-PyMT primary mammary tumor cells and significantly decreases their invasiveness and mammosphere formation capacity by 40% and 50%, respectively. Vitamin D treatment also inhibits phospho-signal transducer and activator of transcription 3 (p-STAT3), zinc finger E-box-binding homeobox 1 (Zeb1), and vimentin by 52%, 75%, and 77%, respectively, and increases E-cadherin by 87%. In vivo, dietary vitamin D deficiency maintains high levels of Zeb1 and p-STAT3 in cells from primary mammary tumors and increases CXCL12 expression in lung stroma by 64%. In lung metastases, vitamin D deficiency increases CXCL12/CXCR4 co-localization by a factor of 2.5. These findings indicate an involvement of vitamin D in mammary cancer "seed" (primary tumor cell) and "soil" (metastatic site) and link vitamin D deficiency to epithelial-to-mesenchymal transition (EMT), CXCL12/CXCR4 signaling, and accelerated metastasis, suggesting vitamin D repleteness in breast cancer patients could enhance the efficacy of co-administered therapies in preventing spread to distant organs.
维生素 D 缺乏与人类癌症不良预后相关，而维生素 D 或其类似物的给药可减少动物模型中的肿瘤进展和转移。我们之前使用鼠乳腺肿瘤病毒-多瘤病毒中 T 抗原（MMTV-PyMT）乳腺癌模型证明，在低维生素 D 饮食的动物中，致癌作用明显加速，并且当小鼠通过灌注接受维生素 D 时，自发性肺转移减少。我们在这里研究了同一非免疫缺陷模型中维生素 D 在肺转移中的作用机制，并证明它涉及上皮间质转化的控制以及趋化因子 C-X-C 基序趋化因子 12（CXCL12）与其受体 C-X-C 趋化因子受体 4（CXCR4）之间的相互作用。在体外，10-9M 维生素 D 处理改变了 MMTV-PyMT 原发性乳腺肿瘤细胞的表型，并分别使侵袭性和乳腺球体形成能力降低 40%和 50%。维生素 D 处理还分别抑制磷酸信号转导和转录激活因子 3（p-STAT3）、锌指 E-框结合同源盒 1（Zeb1）和波形蛋白 52%、75%和 77%，并使 E-钙粘蛋白增加 87%。在体内，饮食中维生素 D 缺乏使原发性乳腺肿瘤细胞中的 Zeb1 和 p-STAT3 水平保持较高水平，并使肺基质中 CXCL12 的表达增加 64%。在肺转移中，维生素 D 缺乏使 CXCL12/CXCR4 共定位增加了 2.5 倍。这些发现表明维生素 D 参与乳腺癌“种子”（原发性肿瘤细胞）和“土壤”（转移部位），并将维生素 D 缺乏与上皮间质转化（EMT）、CXCL12/CXCR4 信号和加速转移联系起来，提示乳腺癌患者维生素 D 充足可能增强联合治疗预防扩散至远处器官的疗效。
