Oxygen-dependent contraction and degradation of the extracellular matrix mediated by interaction between tumor and endothelial cells
Oxygen-dependent contraction and degradation of the extracellular matrix mediated by interaction between tumor and endothelial cells
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DOI：
10.1063/1.5089772
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发表时间：
2019-04
期刊：
影响因子：
1.6
通讯作者：
D. Yoshino;Kenichi Funamoto
中科院分区：
文献类型：
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作者：
D. Yoshino;Kenichi Funamoto
理解癌症发展和转移的机制需要全面分析正常和肿瘤细胞与缺氧肿瘤微环境中的细胞外基质（ECM）之间的相互作用。然而，许多肿瘤微环境研究的范围仅限于验证产生微环境的细胞培养平台的开发和性能。本研究描述了共培养和缺氧对ECM的收缩和降解的影响。将I型胶原凝胶置于氧分压可控微流控装置的凝胶通道中作为肿瘤组织基底。MDA-MB-231人乳腺癌细胞和/或人脐静脉内皮细胞（HUVEC）分别在凝胶内或相邻培养基通道上培养。通过改变气体混合物的供应产生常氧（21%O2）或低氧（1%O2）条件来评价胶原凝胶的变化。HUVECs诱导的胶原凝胶收缩和降解比MDA-MB-231细胞更强烈。虽然共培养的MDA-MB-231细胞和HUVECs之间的相互作用促进了凝胶收缩和降解，但缺氧减弱了这种作用。免疫荧光染色显示低氧条件下胶原凝胶内分泌型基质金属蛋白酶-7（MMP-7）的表达减少，但未观察到细胞形态学变化。使用在细胞培养皿上培养的细胞进行的单独的蛋白质印迹分析证实了缺氧暴露的HUVEC中内源性MMP表达降低。这些结果表明，缺氧条件下影响胶原凝胶的收缩和降解，通过改变MMP-7的表达在共培养的MDA-MB-231细胞和HUVECs.Understanding肿瘤的发展和转移的机制，需要全面分析正常和肿瘤细胞之间的相互作用和细胞外基质（ECM）在缺氧肿瘤微环境。然而，许多肿瘤微环境研究的范围仅限于验证产生微环境的细胞培养平台的开发和性能。本研究描述了共培养和缺氧对ECM的收缩和降解的影响。将I型胶原凝胶置于氧分压可控微流控装置的凝胶通道中作为肿瘤组织基底。MDA-MB-231人乳腺癌细胞和/或人脐静脉内皮细胞（HUVEC）分别在凝胶内或相邻培养基通道上培养。通过改变气体混合物的供应产生常氧（21%O2）或低氧（1%O2）条件来评价胶原凝胶的变化。HUVECs诱导的胶原凝胶收缩和降解作用强于MDA-MB-1。
Understanding the mechanisms of cancer development and metastasis requires comprehensive analyses of interactions between normal and tumor cells and the extracellular matrix (ECM) in hypoxic tumor microenvironments. However, the scope of many tumor microenvironment studies is limited to verifying the development and performance of microenvironment-producing cell culture platforms. This study describes the effects of co-culture and hypoxia on contraction and degradation of the ECM. Collagen type I gel was placed in the gel channel of an oxygen tension–controllable microfluidic device as a tumor tissue substrate. MDA-MB-231 human breast cancer cells and/or human umbilical vein endothelial cells (HUVECs) were cultured inside the gel or on the adjacent media channels, respectively. Changes in the collagen gel were evaluated by generating normoxic (21% O2) or hypoxic (1% O2) conditions via variation of the supply of gas mixture. HUVECs induced collagen gel contraction and degradation more strongly than MDA-MB-231 cells. Although interaction between co-cultured MDA-MB-231 cells and HUVECs promoted gel contraction and degradation, hypoxia attenuated the effect. Immunofluorescence staining indicated decreased expression of secretory matrix metalloproteinase-7 (MMP-7) inside the collagen gel under hypoxic conditions, but no morphologic changes in cells were observed. Separate Western blot analyses using cells cultured on cell culture dishes confirmed reduced endogenous MMP expression in hypoxia-exposed HUVECs. These results demonstrate that hypoxic conditions affect collagen gel contraction and degradation by altering the expression of MMP-7 in co-cultured MDA-MB-231 cells and HUVECs.Understanding the mechanisms of cancer development and metastasis requires comprehensive analyses of interactions between normal and tumor cells and the extracellular matrix (ECM) in hypoxic tumor microenvironments. However, the scope of many tumor microenvironment studies is limited to verifying the development and performance of microenvironment-producing cell culture platforms. This study describes the effects of co-culture and hypoxia on contraction and degradation of the ECM. Collagen type I gel was placed in the gel channel of an oxygen tension–controllable microfluidic device as a tumor tissue substrate. MDA-MB-231 human breast cancer cells and/or human umbilical vein endothelial cells (HUVECs) were cultured inside the gel or on the adjacent media channels, respectively. Changes in the collagen gel were evaluated by generating normoxic (21% O2) or hypoxic (1% O2) conditions via variation of the supply of gas mixture. HUVECs induced collagen gel contraction and degradation more strongly than MDA-MB-...