Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
University of Colorado Cancer Center Young Women's Breast Cancer Translational Program, Aurora, Colorado.
Cancer Res. 2018 Nov 15;78(22):6473-6485. doi: 10.1158/0008-5472.CAN-18-1642. Epub 2018 Sep 25.
Postpartum mammary gland involution is a tissue remodeling event that occurs in all mammals in the absence of nursing or after weaning to return the gland to the pre-pregnant state. The tissue microenvironment created by involution has proven to be tumor promotional. Here we report that the GPI-linked protein semaphorin 7A (SEMA7A) is expressed on mammary epithelial cells during involution and use preclinical models to demonstrate that tumors induced during involution express high levels of SEMA7A. Overexpression of SEMA7A promoted the presence of myeloid-derived podoplanin (PDPN)-expressing cells in the tumor microenvironment and during involution. SEMA7A drove the expression of PDPN in macrophages, which led to integrin- and PDPN-dependent motility and adherence to lymphatic endothelial cells to promote lymphangiogenesis. In support of this mechanism, mammary tissue from SEMA7A-knockout mice exhibited decreased myeloid-derived PDPN-expressing cells, PDPN-expressing endothelial cells, and lymphatic vessel density. Furthermore, coexpression of , and macrophage marker predicted for decreased distant metastasis-free survival in a cohort of over 600 cases of breast cancer as well as in ovarian, lung, and gastric cancers. Together, our results indicate that SEMA7A may orchestrate macrophage-mediated lymphatic vessel remodeling, which in turn drives metastasis in breast cancer. SEMA7A, which is expressed on mammary cells during glandular involution, alters macrophage biology and lymphangiogenesis to drive breast cancer metastasis. .
产后乳腺退化是一个组织重塑事件，发生在所有哺乳动物中，无论是在没有哺乳的情况下，还是在断奶后，以使腺体恢复到怀孕前的状态。退化过程中形成的组织微环境已被证明具有促进肿瘤的作用。在这里，我们报告 GPI 连接蛋白信号素 7A（SEMA7A）在乳腺上皮细胞中在退化过程中表达，并使用临床前模型证明在退化过程中诱导的肿瘤表达高水平的 SEMA7A。SEMA7A 的过表达促进了肿瘤微环境和退化过程中骨髓源性 podoplanin（PDPN）表达细胞的存在。SEMA7A 驱动巨噬细胞中 PDPN 的表达，导致整合素和 PDPN 依赖性运动以及与淋巴管内皮细胞的黏附，从而促进淋巴管生成。支持这一机制，SEMA7A 敲除小鼠的乳腺组织表现出骨髓源性 PDPN 表达细胞、PDPN 表达内皮细胞和淋巴管密度减少。此外，在超过 600 例乳腺癌以及卵巢癌、肺癌和胃癌的队列中，和巨噬细胞标志物的共表达预测了远处无转移生存时间的减少。总之，我们的结果表明 SEMA7A 可能协调巨噬细胞介导的淋巴管重塑，从而驱动乳腺癌的转移。在乳腺腺退化过程中表达于乳腺细胞上的 SEMA7A 改变了巨噬细胞生物学和淋巴管生成，从而驱动乳腺癌转移。
