Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an, China.
FASEB J. 2020 Aug;34(8):10860-10870. doi: 10.1096/fj.202000951RR. Epub 2020 Jun 27.
The tumor microenvironment (TME) is a crucial factor in cancer progression. In breast cancer, cancer-associated fibroblasts (CAFs) and the derived stromal components have been recognized as comprising the majority of the pathological structure of the TME. In this study, we show that metformin (Met), a diabetes drug, transforms CAFs in the TME. Met disrupts tumor-stromal cross talk by preventing breast cancer cell transforming growth factor-β (TGF-β) signaling and the production of stromal-derived factor-1 (SDF-1) and interleukin-8 (IL-8) by CAFs. The suppression of bidirectional signaling between tumor cells and CAFs by Met is attributed to increased phospho-AMP kinase (p-AMPK) levels. By upregulating p-AMPK in CAFs, Met induces prolyl hydroxylases (PHDs), leading to the degradation of hypoxia-inducible factor-1α (HIF-1α) in CAFs. Moreover, interruption of HIF-1α-driven SDF-1 signaling in CAFs by Met leads to decreased breast cancer cell invasion. These findings suggest that Met may be used to target tumor-promoting signaling between CAFs and breast cancer cells in the TME.
肿瘤微环境（TME）是癌症进展的关键因素。在乳腺癌中，癌相关成纤维细胞（CAFs）和衍生的基质成分已被认为构成了 TME 的大部分病理结构。在这项研究中，我们表明，糖尿病药物二甲双胍（Met）可转化 TME 中的 CAFs。Met 通过阻止乳腺癌细胞转化生长因子-β（TGF-β）信号转导以及 CAFs 产生基质衍生因子-1（SDF-1）和白细胞介素-8（IL-8）来破坏肿瘤-基质间的相互作用。Met 对肿瘤细胞和 CAFs 之间双向信号的抑制归因于磷酸化 AMP 激酶（p-AMPK）水平的增加。通过在 CAFs 中上调 p-AMPK，Met 诱导脯氨酰羟化酶（PHDs），导致 CAFs 中缺氧诱导因子-1α（HIF-1α）的降解。此外，Met 中断 HIF-1α 驱动的 SDF-1 信号转导可导致 CAFs 中乳腺癌细胞侵袭减少。这些发现表明，Met 可用于靶向 TME 中 CAFs 和乳腺癌细胞之间促进肿瘤的信号转导。
