Cancer-associated fibroblasts support vascular growth through mechanical force.
Cancer-associated fibroblasts support vascular growth through mechanical force.
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DOI：
10.1038/s41598-017-13006-x
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发表时间：
2017-10-03
影响因子：
4.6
通讯作者：
George SC
中科院分区：
文献类型：
--
作者：
Sewell-Loftin MK;Bayer SVH;Crist E;Hughes T;Joison SM;Longmore GD;George SC
肿瘤相关成纤维细胞(CAF)作为肿瘤进展的调节因子，特别是血管生长的调节作用，直到最近才被描述。CAF被认为在机械上更活跃，但这一特征如何改变肿瘤微环境却知之甚少。我们假设，受Rho/ROCK途径调控的CAF机械活性增强有助于血管生长。使用血管生成的3D体外组织模型，我们观察到与正常乳腺成纤维细胞相比，乳腺癌CAF存在时血管生成增加。进一步的研究表明，这种现象不仅仅是包括血管内皮生长因子(VEGF)在内的可溶性信号因子增强的结果，而且与正常成纤维细胞相比，CAF在3D凝胶中产生的变形明显更大。机械传导通路的抑制消除了CAF使基质变形的能力，并抑制了血管形成。最后，利用磁性微珠对机械抑制的CAF进行机械刺激，显示了部分血管形成的恢复。我们的研究表明，增强的CAF的机械活性可能在肿瘤相关血管的形成中发挥关键的、以前未被认识的作用，这可能为未来的抗癌治疗提供潜在的新靶点。
The role of cancer-associated fibroblasts (CAFs) as regulators of tumor progression, specifically vascular growth, has only recently been described. CAFs are thought to be more mechanically active but how this trait may alter the tumor microenvironment is poorly understood. We hypothesized that enhanced mechanical activity of CAFs, as regulated by the Rho/ROCK pathway, contributes to increased blood vessel growth. Using a 3D in vitro tissue model of vasculogenesis, we observed increased vascularization in the presence of breast cancer CAFs compared to normal breast fibroblasts. Further studies indicated this phenomenon was not simply a result of enhanced soluble signaling factors, including vascular endothelial growth factor (VEGF), and that CAFs generated significantly larger deformations in 3D gels compared to normal fibroblasts. Inhibition of the mechanotransductive pathways abrogated the ability of CAFs to deform the matrix and suppressed vascularization. Finally, utilizing magnetic microbeads to mechanically stimulate mechanically-inhibited CAFs showed partial rescue of vascularization. Our studies demonstrate enhanced mechanical activity of CAFs may play a crucial and previously unappreciated role in the formation of tumor-associated vasculature which could possibly offer potential novel targets in future anti-cancer therapies.
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DOI：
10.1039/c3ib40170g
发表时间：
2014-06
期刊：
Integrative biology : quantitative biosciences from nano to macro
影响因子：
--
作者：
Ehsan SM;Welch-Reardon KM;Waterman ML;Hughes CC;George SC
通讯作者：
George SC
影响因子：
3.2
作者：
Cohen, M;Joester, D;Addadi, L
通讯作者：
Addadi, L
DOI：
10.1083/jcb.201408103
发表时间：
2015-03-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Coon BG;Baeyens N;Han J;Budatha M;Ross TD;Fang JS;Yun S;Thomas JL;Schwartz MA
通讯作者：
Schwartz MA
影响因子：
15.9
作者：
Elkabets, Moshe;Gifford, Ann M.;McAllister, Sandra S.
通讯作者：
McAllister, Sandra S.
影响因子：
3
作者：
Buchanan, Cara F.;Voigt, Elizabeth E.;Rylander, Marissa Nichole
通讯作者：
Rylander, Marissa Nichole