Aberrant low expression of p85α in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b.
Aberrant low expression of p85α in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b.
复制标题
基质成纤维细胞中 p85α 的异常低表达通过外泌体介导的旁分泌 Wnt10b 促进乳腺癌细胞转移
作者：
Chen Y;Zeng C;Zhan Y;Wang H;Jiang X;Li W
P85α作为一种肿瘤抑制因子，经常被发现在多种人类癌症中表达下调。然而，p85α在肿瘤微环境中的作用尚不清楚。在此，我们报道乳腺癌间质中p85α异常低表达在临床上与乳腺癌疾病进展相关。由于p85α表达缺失，间质成纤维细胞可获得癌相关成纤维细胞（CAFs）的特征。来自p85α缺陷型成纤维细胞的旁分泌Wnt10b可通过经典Wnt通路诱导的上皮 - 间质转化（EMT）促进癌症进展。此外，外泌体在旁分泌Wnt10b从成纤维细胞到乳腺癌上皮细胞的运输中起关键作用。我们的研究结果表明，间质成纤维细胞中p85α的表达通过调节间质 - 上皮相互作用和重塑肿瘤微环境，在调控乳腺癌的发生和进展中起关键作用。因此，p85α可作为一种肿瘤抑制因子，是诊断、预后和靶向治疗的一个新的候选因子。
P85α, which acts as a tumour suppressor, is frequently found to be downregulated in various human cancers. However, the role of p85α in the tumour microenvironment is unknown. Here, we report that aberrantly low expression of p85α in breast cancer stroma is clinically relevant to breast cancer disease progression. Stromal fibroblasts can acquire the hallmarks of cancer-associated fibroblasts (CAFs) as a result of the loss of p85α expression. Paracrine Wnt10b from p85α-deficient fibroblasts can promote cancer progression via epithelial-to-mesenchymal transition (EMT) induced by the canonical Wnt pathway. Moreover, exosomes have a key role in paracrine Wnt10b transport from fibroblasts to breast cancer epithelial cells. Our results reveal that p85α expression in stromal fibroblasts haves a crucial role in regulating breast cancer tumourigenesis and progression by modifying stromal–epithelial crosstalk and remodelling the tumour microenvironment. Therefore, p85α can function as a tumour suppressor and represent a new candidate for diagnosis, prognosis and targeted therapy.
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