Cancer associated fibroblasts modulate the cytotoxicity of anti-cancer drugs in breast cancer: An in vitro study.

Breast disease Pub Date : 2024-01-01 DOI:10.3233/BD-230011

Dharambir Kashyap, Shalmoli Bhattacharya, Santosh Irinike, Siddhant Khare, Ashim Das, Gurpreet Singh, Amanjit Bal

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Abstract

Background: Tumour microenvironment (TME) contributes to resistance to anti-cancer drugs through multiple mechanisms including secretion of pro-survival factors by cancer associated fibroblasts (CAFs). In this study, we determined the chemotherapy resistance producing potential of CAFs in molecular subtypes of breast cancer.

Methods: The CAFs were isolated from fresh lumpectomy/mastectomy specimens of different molecular subtypes of breast cancer. The CAFs were cultured and secretome was collected from each breast cancer subtype. Breast cancer cell lines MCF-7, SK-BR3, MDA-MB-231, and MDA-MB-468 were treated with different doses of tamoxifen, trastuzumab, cisplatin, and doxorubicin alone respectively and in combination with secretome of CAFs from respective subtypes. MTT assay was done to check cell death after drug treatment. Liquid chromatography-mass spectrometry (LCMS) analysis of CAF secretome was also done.

Results: MTT assay showed that anti-cancer drugs alone had growth inhibitory effect on the cancer cells however, presence of CAF secretome reduced the anti-cancer effect of the drugs. Resistant to drugs in the presence of secretome, was determined by increased cell viability i.e., MCF-7, 51.02% to 63.02%; SK-BR-3, 34.22% to 44.88%; MDA-MB-231, 52.59% to 78.63%; and MDA-MB-468, 48.92% to 55.08%. LCMS analysis of the secretome showed the differential abundance of CAFs secreted proteins across breast cancer subtypes.

Conclusions: The treatment of breast cancer cell lines with anti-cancer drugs in combination with secretome isolated from molecular subtype specific CAFs, reduced the cytotoxic effect of the drugs. In addition, LCMS data also highlighted different composition of secreted proteins from different breast cancer associated fibroblasts. Thus, TME has heterogenous population of CAFs across the breast cancer subtypes and in vitro experiments highlight their contribution to chemotherapy resistance which needs further validation.

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癌症相关成纤维细胞调节乳腺癌抗癌药物的细胞毒性：体外研究

背景：肿瘤微环境（TME）通过癌症相关成纤维细胞（CAFs）分泌促生存因子等多种机制导致抗癌药物的耐药性。本研究测定了乳腺癌分子亚型中 CAFs 产生化疗耐药性的潜力：方法：从不同分子亚型乳腺癌的新鲜肿块切除术/乳房切除术标本中分离出 CAFs。培养 CAFs 并收集各亚型乳腺癌的分泌物。乳腺癌细胞系 MCF-7、SK-BR3、MDA-MB-231 和 MDA-MB-468，分别单独使用不同剂量的他莫昔芬、曲妥珠单抗、顺铂和多柔比星，以及与各亚型的 CAFs 分泌物联合使用。MTT 试验用于检测药物治疗后的细胞死亡情况。还对 CAF 分泌组进行了液相色谱-质谱（LCMS）分析：MTT 试验表明，单独使用抗癌药物对癌细胞有生长抑制作用，但 CAF 分泌组的存在降低了药物的抗癌效果。在有分泌物存在的情况下，细胞存活率的增加决定了对药物的耐药性，即 MCF-7，51.02% 至 63.02%；SK-BR-3，34.22% 至 44.88%；MDA-MB-231，52.59% 至 78.63%；MDA-MB-468，48.92% 至 55.08%。分泌组的 LCMS 分析表明，不同亚型乳腺癌的 CAFs 分泌蛋白丰度不同：结论：使用抗癌药物治疗乳腺癌细胞系时，结合使用从分子亚型特异性 CAFs 中分离出的分泌物组，可降低药物的细胞毒性作用。此外，LCMS 数据还突显了不同乳腺癌相关成纤维细胞分泌蛋白的不同组成。因此，TME 在乳腺癌亚型中具有异质性的 CAFs 群体，体外实验强调了它们对化疗耐药性的贡献，这需要进一步验证。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Breast disease Medicine-Oncology

CiteScore

1.80

自引率

0.00%

发文量

期刊介绍： The recent expansion of work in the field of breast cancer inevitably will hasten discoveries that will have impact on patient outcome. The breadth of this research that spans basic science, clinical medicine, epidemiology, and public policy poses difficulties for investigators. Not only is it necessary to be facile in comprehending ideas from many disciplines, but also important to understand the public implications of these discoveries. Breast Disease publishes review issues devoted to an in-depth analysis of the scientific and public implications of recent research on a specific problem in breast cancer. Thus, the reviews will not only discuss recent discoveries but will also reflect on their impact in breast cancer research or clinical management.