Human colorectal cancer cells induce vascular smooth muscle cell apoptosis in an exocrine manner.
Human colorectal cancer cells induce vascular smooth muscle cell apoptosis in an exocrine manner.
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DOI：
10.18632/oncotarget.18893
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发表时间：
2017-09-22
期刊：
影响因子：
--
通讯作者：
Li BH
中科院分区：
文献类型：
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作者：
Li WW;Wang HY;Nie X;Liu YB;Han M;Li BH
肿瘤血管往往缺乏平滑肌层，这种不稳定性有利于肿瘤的侵袭和转移。肿瘤微环境对血管平滑肌细胞的影响有待进一步研究。在本研究中，我们检测了人结直肠癌组织中肿瘤血管的密度，并用人结直肠癌HT29细胞的肿瘤条件培养液模拟肿瘤微环境。我们发现结直肠癌组织中的血管密度增加，表现为与匹配的正常组织相比，血管平滑肌α-肌动蛋白的表达减少，血管平滑肌细胞层变薄或不连续。我们还发现，肿瘤条件培养液以浓度依赖的方式降低细胞存活率，并诱导血管平滑肌细胞凋亡。肿瘤条件培养液处理细胞后，原Caspase-3表达下调，裂解Caspase-3表达增加，提示Caspase-3被激活。在相同条件下，Bax的表达增加，而Bcl2/Bax的比值降低。此外，肿瘤条件培养液的处理导致血管平滑肌细胞线粒体膜电位的丧失。提示HT29细胞通过外分泌方式诱导血管平滑肌细胞凋亡，其机制可能与线粒体凋亡途径激活caspase-3有关。这可能是肿瘤血管结构异常的机制之一。
Tumor vessels often lack the smooth muscle layer, and the instability is conducive to tumor invasion and metastasis. The effect of tumor microenvironment on vascular smooth muscle cells needs to be explored. In the present study, we examined the density of the tumor vessels in human colorectal cancer tissues, and used the tumor conditioned medium of human colorectal cancer HT29 cells to mimic the tumor microenvironment. We showed that the vessel density in colorectal cancer tissues increased, which displayed a decreased expression of smooth muscle α-actin, a specific marker of vascular smooth muscle cells and an attenuated or a discontinuous layer of vascular smooth muscle cells compared with the matched normal tissues. We also showed that the tumor conditioned medium decreased the cell viability, and induced the apoptosis in vascular smooth muscle cells in a concentration-dependent manner. The expression of pro-Caspase-3 was down-regulated, accompanied by increasing of cleaved-Caspase-3 in the cells treated with the tumor conditioned medium, suggesting that Caspase-3 was activated. Moreover, the expression of Bax was increased, and the ratio of Bcl-2/Bax was decreased under the same conditions. Furthermore, the treatment with the tumor conditioned medium resulted in loss of mitochondrial membrane potential in vascular smooth muscle cells. These findings suggest that HT29 cells induce apoptosis of vascular smooth muscle cells in an exocrine manner, associated with activating caspase-3 via mitochondrial apoptotic pathway. This may be one of the mechanisms underlying tumor vascular structural abnormalities.