Department of Anatomy and Cell Biology, Western University, London, ON, Canada.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
Neoplasia. 2021 Apr;23(4):375-390. doi: 10.1016/j.neo.2021.02.004. Epub 2021 Mar 27.
The tumor microenvironment (TME) is an important mediator of breast cancer progression. Cancer-associated fibroblasts constitute a major component of the TME and may originate from tissue-associated fibroblasts or infiltrating mesenchymal stromal cells (MSCs). The mechanisms by which cancer cells activate fibroblasts and recruit MSCs to the TME are largely unknown, but likely include deposition of a pro-tumorigenic secretome. The secreted embryonic protein NODAL is clinically associated with breast cancer stage and promotes tumor growth, metastasis, and vascularization. Herein, we show that NODAL expression correlates with the presence of activated fibroblasts in human triple-negative breast cancers and that it directly induces Cancer-associated fibroblasts phenotypes. We further show that NODAL reprograms cancer cell secretomes by simultaneously altering levels of chemokines (e.g., CXCL1), cytokines (e.g., IL-6) and growth factors (e.g., PDGFRA), leading to alterations in MSC chemotaxis. We therefore demonstrate a hitherto unappreciated mechanism underlying the dynamic regulation of the TME.
肿瘤微环境（TME）是乳腺癌进展的重要介质。癌相关成纤维细胞构成 TME 的主要组成部分，可能来源于组织相关成纤维细胞或浸润的间质基质细胞（MSCs）。癌细胞激活成纤维细胞并招募 MSCs 进入 TME 的机制在很大程度上尚不清楚，但可能包括分泌促肿瘤的分泌组。分泌的胚胎蛋白 NODAL 与乳腺癌分期临床相关，并促进肿瘤生长、转移和血管生成。在此，我们表明 NODAL 的表达与人三阴性乳腺癌中成纤维细胞的激活有关，并且它直接诱导癌相关成纤维细胞表型。我们进一步表明，NODAL 通过同时改变趋化因子（例如，CXCL1）、细胞因子（例如，IL-6）和生长因子（例如，PDGFRA）的水平来重新编程癌细胞分泌组，导致 MSC 趋化性的改变。因此，我们证明了 TME 动态调节的一种迄今未被认识的机制。
