Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin.
Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin.
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DOI：
10.3389/fonc.2018.00337
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发表时间：
2018
影响因子：
4.7
通讯作者：
Brock A
中科院分区：
文献类型：
--
作者：
Joyce MH;Lu C;James ER;Hegab R;Allen SC;Suggs LJ;Brock A
化疗治疗后耐药细胞群的持续存在是癌症临床管理中的重大挑战。耐药亚群通过细胞内在和外在机制产生。微环境中的外在因素，包括邻近细胞、糖胺聚糖和纤维蛋白质，影响治疗反应。细胞外纤维蛋白水平升高与肿瘤进展相关，并通过细胞外基质（ECM）的结构和组成变化引起周围组织坏死。我们试图确定这种逐渐变硬的微环境如何影响乳腺癌细胞对化疗治疗的敏感性。MDA-MB-231三阴性乳腺癌细胞在3D藻酸盐基水凝胶系统中培养显示出对化疗阿霉素的刚度依赖性反应。在相同条件下培养的MCF 7乳腺癌细胞没有表现出这种刚度依赖性的耐药性。这种不同的治疗反应与间充质分化的标志物雅普的核转位相协调。当细胞从3D转移到单层培养时，刚度依赖性反应消失，表明终点ECM条件在很大程度上控制了对阿霉素的反应。为了进一步检查这种响应，我们利用能够动态ECM刚度调制的平台，以允许基质刚度随时间的变化。我们发现MDA-MB-231细胞对阿霉素具有刚度依赖性抗性，并且暴露于ECM刚度的持续时间足以调节这种反应。这些结果表明，需要额外的工具来整合机械刚度与治疗反应，并为临床上更有效地使用化疗药物提供决策信息。
The persistence of drug resistant cell populations following chemotherapeutic treatment is a significant challenge in the clinical management of cancer. Resistant subpopulations arise via both cell intrinsic and extrinsic mechanisms. Extrinsic factors in the microenvironment, including neighboring cells, glycosaminoglycans, and fibrous proteins impact therapy response. Elevated levels of extracellular fibrous proteins are associated with tumor progression and cause the surrounding tissue to stiffen through changes in structure and composition of the extracellular matrix (ECM). We sought to determine how this progressively stiffening microenvironment affects the sensitivity of breast cancer cells to chemotherapeutic treatment. MDA-MB-231 triple negative breast carcinoma cells cultured in a 3D alginate-based hydrogel system displayed a stiffness-dependent response to the chemotherapeutic doxorubicin. MCF7 breast carcinoma cells cultured in the same conditions did not exhibit this stiffness-dependent resistance to the drug. This differential therapeutic response was coordinated with nuclear translocation of YAP, a marker of mesenchymal differentiation. The stiffness-dependent response was lost when cells were transferred from 3D to monolayer cultures, suggesting that endpoint ECM conditions largely govern the response to doxorubicin. To further examine this response, we utilized a platform capable of dynamic ECM stiffness modulation to allow for a change in matrix stiffness over time. We found that MDA-MB-231 cells have a stiffness-dependent resistance to doxorubicin and that duration of exposure to ECM stiffness is sufficient to modulate this response. These results indicate the need for additional tools to integrate mechanical stiffness with therapeutic response and inform decisions for more effective use of chemotherapeutics in the clinic.
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影响因子：
21.3
作者：
Miroshnikova YA;Mouw JK;Barnes JM;Pickup MW;Lakins JN;Kim Y;Lobo K;Persson AI;Reis GF;McKnight TR;Holland EC;Phillips JJ;Weaver VM
通讯作者：
Weaver VM
影响因子：
82.9
作者：
通讯作者：
--
FOXM1-ABCC5 轴导致鼻咽癌细胞对紫杉醇产生耐药性。
影响因子：
9
作者：
Hou Y;Zhu Q;Li Z;Peng Y;Yu X;Yuan B;Liu Y;Liu Y;Yin L;Peng Y;Jiang Z;Li J;Xie B;Duan Y;Tan G;Gulina K;Gong Z;Sun L;Fan X;Li X
通讯作者：
Li X
影响因子：
3.8
作者：
Krause S;Maffini MV;Soto AM;Sonnenschein C
通讯作者：
Sonnenschein C
影响因子：
56.9
作者：
Hong, JH;Hwang, ES;Yaffe, MB
通讯作者：
Yaffe, MB