Extracellular ATP promotes angiogenesis and adhesion of TNBC cells to endothelial cells via upregulation of CTGF.
Extracellular ATP promotes angiogenesis and adhesion of TNBC cells to endothelial cells via upregulation of CTGF.
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细胞外 ATP 通过上调 CTGF 促进血管生成以及 TNBC 细胞与内皮细胞的粘附
作者：
我们的前期工作表明细胞外ATP是一个重要的促转移因子。但其分子机制还有待进一步研究。我们证明了细胞外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P2 Y2-雅普-CTGF轴刺激TNBC细胞和EC的迁移以及EC的血管生成。此外，我们证明了三磷酸腺苷（ATP）通过上调TNBC细胞上的整合素β1和EC上的VCAM-1，刺激TNBC细胞粘附于EC，并通过CTGF穿过EC层迁移。腺苷三磷酸双磷酸酶（ATP-二磷酸水解酶）和CTGF shRNA治疗都可以抑制小鼠模型中接种肿瘤向肺和肝的转移，并且这些治疗的肿瘤具有较少的血管。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在血管生成和细胞粘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。所提出的TNBC侵袭和转移中ATP-CTGF轴的模型。ATP上调TNBC细胞和EC中CTGF的表达和分泌。对于TNBC细胞，分泌的CTGF增强其迁移和整合素β1表达。对于EC细胞，分泌的CTGF增强其迁移和血管生成以及VCAM-1表达。上调的整合素β1和VCAM-1促进TNBC细胞与EC的粘附并穿过EC层迁移。
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. The proposed model for the ATP–CTGF axis in TNBC invasion and metastasis. ATP upregulates CTGF expression and secretion in TNBC cells and ECs. For TNBC cells, secreted CTGF enhanced their migration and integrin β1 expression. For EC cells, secreted CTGF enhanced their migration and angiogenesis, as well as VCAM‐1 expression. The upregulated integrin β1 and VCAM‐1 promoted TNBC cell adhesion to ECs and transmigration through the ECs layer.
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