Ishihara Seiichiro, Inman David R, Li Wan-Ju, Ponik Suzanne M, Keely Patricia J
Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin.
Departments of Orthopedics and Rehabilitation, and Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin.
Cancer Res. 2017 Nov 15;77(22):6179-6189. doi: 10.1158/0008-5472.CAN-17-0569. Epub 2017 Sep 28.
In response to chemical stimuli from cancer cells, mesenchymal stem cells (MSC) can differentiate into cancer-associated fibroblasts (CAF) and promote tumor progression. How mechanical stimuli such as stiffness of the extracellular matrix (ECM) contribute to MSC phenotype in cancer remains poorly understood. Here, we show that ECM stiffness leads to mechano-signal transduction in MSC, which promotes mammary tumor growth in part through secretion of the signaling protein prosaposin. On a stiff matrix, MSC cultured with conditioned media from mammary cancer cells expressed increased levels of α-smooth muscle actin, a marker of CAF, compared with MSC cultured on a soft matrix. By contrast, MSC cultured on a stiff matrix secreted prosaposin that promoted proliferation and survival of mammary carcinoma cells but inhibited metastasis. Our findings suggest that in addition to chemical stimuli, increased stiffness of the ECM in the tumor microenvironment induces differentiation of MSC to CAF, triggering enhanced proliferation and survival of mammary cancer cells. .
响应癌细胞的化学刺激，间充质干细胞（MSC）可分化为癌症相关成纤维细胞（CAF）并促进肿瘤进展。细胞外基质（ECM）硬度等机械刺激如何影响癌症中MSC的表型仍知之甚少。在此，我们表明ECM硬度导致MSC中的机械信号转导，这部分通过信号蛋白prosaposin的分泌促进乳腺肿瘤生长。在坚硬基质上，与在柔软基质上培养的MSC相比，用乳腺癌细胞条件培养基培养的MSC表达的α-平滑肌肌动蛋白（一种CAF标志物）水平增加。相比之下，在坚硬基质上培养的MSC分泌的prosaposin促进了乳腺癌细胞的增殖和存活，但抑制了转移。我们的研究结果表明，除了化学刺激外，肿瘤微环境中ECM硬度的增加诱导MSC向CAF分化，从而触发乳腺癌细胞增殖和存活增强。
