Increased stiffness of the tumor microenvironment in colon cancer stimulates cancer associated fibroblast-mediated prometastatic activin A signaling
Increased stiffness of the tumor microenvironment in colon cancer stimulates cancer associated fibroblast-mediated prometastatic activin A signaling
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DOI：
10.1038/s41598-019-55687-6
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发表时间：
2020-01-09
影响因子：
4.6
通讯作者：
Jung, Barbara
中科院分区：
文献类型：
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作者：
Bauer, Jessica;Emon, Md Abdul Bashar;Jung, Barbara
结直肠癌（CRC）因其转移倾向而成为美国第二大致命癌症。基质细胞，尤其是癌症相关成纤维细胞（CAF）在癌症进展中发挥着关键的生物物理作用，但精确的促转移机制尚不清楚。激活素 A 是 TGF-β 家族成员，在 CRC 中是一种强效促转移细胞因子。在这里，我们通过测试 CAF 产生的机械力导致激活素 A 释放和相关下游效应的假设来评估生物物理力和促转移信号传导之间的联系。与我们的假设一致，我们首先确定基质激活素 A 分泌随着基质硬度的增加而增加。然后我们发现基质分泌的激活素 A 诱导配体依赖性 CRC 上皮细胞迁移和上皮间质转化 (EMT)。此外，转移性（IV 期）CRC 患者的血清激活素 A 水平显着升高（1.558 ng/ml 对比 0.4179 ng/ml，p < 0.05）。我们认为，肿瘤微环境硬度的增加会导致基质细胞介导的 TGF-β 家族信号传导依赖于激活素 A 信号传导的诱导和利用。
Colorectal cancer (CRC) is the second deadliest cancer in the US due to its propensity to metastasize. Stromal cells and especially cancer-associated fibroblasts (CAF) play a critical biophysical role in cancer progression, but the precise pro-metastatic mechanisms are not clear. Activin A, a TGF-beta family member, is a strong pro-metastatic cytokine in the context of CRC. Here, we assessed the link between biophysical forces and pro-metastatic signaling by testing the hypothesis that CAF-generated mechanical forces lead to activin A release and associated downstream effects. Consistent with our hypothesis, we first determined that stromal activin A secretion increased with increasing substrate stiffness. Then we found that stromally-secreted activin A induced ligand-dependent CRC epithelial cell migration and epithelial to mesenchymal transition (EMT). In addition, serum activin A levels are significantly increased in metastatic (stage IV) CRC patients (1.558 ng/ml versus 0.4179 ng/ml, p < 0.05). We propose that increased tumor microenvironment stiffness leads to stromal cell-mediated TGF-beta family signaling relying on the induction and utilization of activin A signaling.