Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing, China.
Cancer Sci. 2022 Jul;113(7):2457-2471. doi: 10.1111/cas.15375. Epub 2022 May 2.
Our previous works have indicated that extracellular ATP is an important prometastasis factor. However, the molecular mechanism involved needs to be further studied. We demonstrated that extracellular ATP treatment could upregulate the expression of connective tissue growth factor (CTGF) in both triple-negative breast cancer (TNBC) cells and endothelial cells (ECs). Extracellular ATP stimulated the migration of TNBC cells and ECs, and angiogenesis of ECs via the P2Y2--YAP-CTGF axis. Furthermore, we demonstrated that adenosine triphosphate (ATP) stimulated TNBC cell adhesion to ECs and transmigration through the EC layer via CTGF by upregulation of integrin β1 on TNBC cells and VCAM-1 on ECs. Both apyrase (ATP-diphosphohydrolase) and CTGF shRNA treatments could inhibit the metastasis of inoculated tumors to lung and liver in a mouse model, and these treated tumors had fewer blood vessels. Collectively, our data indicated that extracellular ATP promotes tumor angiogenesis and the interactions between TNBC cells and ECs through upregulation of CTGF, thereby stimulating TNBC metastasis. The pleiotropic effects of ATP in angiogenesis and cell adhesion suggest that extracellular ATP or CTGF could be an effective target for TNBC therapy.
我们之前的研究表明，细胞外 ATP 是一种重要的促转移因子。然而，其涉及的分子机制仍需要进一步研究。我们发现，细胞外 ATP 处理可以上调三阴性乳腺癌（TNBC）细胞和内皮细胞（EC）中结缔组织生长因子（CTGF）的表达。细胞外 ATP 通过 P2Y2--YAP-CTGF 轴刺激 TNBC 细胞和 EC 的迁移以及 EC 的血管生成。此外，我们还证明，通过上调 TNBC 细胞上的整合素 β1 和 EC 上的 VCAM-1，三磷酸腺苷（ATP）通过 CTGF 刺激 TNBC 细胞与 EC 的黏附和穿过 EC 层的迁移。使用 ATP 二磷酸水解酶（apyrase）和 CTGF shRNA 处理均可抑制接种肿瘤在小鼠模型中向肺和肝的转移，并且这些处理过的肿瘤血管较少。总的来说，我们的数据表明，细胞外 ATP 通过上调 CTGF 促进肿瘤血管生成和 TNBC 细胞与 EC 之间的相互作用，从而刺激 TNBC 转移。ATP 在血管生成和细胞黏附中的多效性作用表明，细胞外 ATP 或 CTGF 可能是 TNBC 治疗的有效靶点。
