Cancer-Associated Fibroblasts in Mycosis Fungoides Promote Tumor Cell Migration and Drug Resistance through CXCL12/CXCR4
Cancer-Associated Fibroblasts in Mycosis Fungoides Promote Tumor Cell Migration and Drug Resistance through CXCL12/CXCR4
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DOI：
10.1016/j.jid.2020.06.034
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发表时间：
2021-02-19
影响因子：
6.5
通讯作者：
Hodak, Emmilia
中科院分区：
文献类型：
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作者：
Aronovich, Anna;Moyal, Lilach;Hodak, Emmilia
众所周知，癌细胞会将正常成纤维细胞重新编程为癌症相关成纤维细胞（CAF），以充当肿瘤支持者。 CAF 在蕈样肉芽肿 (MF)（最常见的皮肤 T 细胞淋巴瘤类型）中的存在和作用尚不清楚。本研究试图利用早期 MF 患者和健康受试者穿刺活检的原代成纤维细胞培养物来表征 MF 中的 CAF 及其与淋巴瘤细胞的交互作用。 MF 培养物中的 FAP α、CAF 标记物以及 CAF 相关基因和蛋白质的水平显着增加：CXCL12（MF 细胞上表达的 CXCR4 的配体）、胶原蛋白 XI 和基质金属蛋白酶 2。在离体实验中，培养的 MF 成纤维细胞比正常成纤维细胞显示出更大的增殖能力。与 MyLa 细胞（MF 细胞系）共培养可增加正常成纤维细胞的生长，降低 MyLa 细胞对阿霉素的敏感性，并增强其迁移。抑制 CXCL12/CXCR4 轴会增加阿霉素诱导的 MyLa 细胞凋亡并降低 MyLa 细胞运动性。我们的数据表明，MF 病变中的成纤维细胞比正常皮肤中的成纤维细胞更具增殖性，并且 CAF 可以保护 MF 细胞免受阿霉素诱导的细胞死亡，并通过分泌 CXCL12 增加其迁移。逆转 MF 中 CAF 介导的肿瘤微环境可能会提高抗癌治疗的效率。
Cancer cells are known to reprogram normal fibroblasts into cancer-associated fibroblasts (CAFs) to act as tumor supporters. The presence and role of CAFs in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, are unknown. This study sought to characterize CAFs in MF and their cross talk with the lymphoma cells using primary fibroblast cultures from punch biopsies of patients with early-stage MF and healthy subjects. MF cultures yielded significantly increased levels of FAP alpha, a CAF marker, and CAF-associated genes and proteins: CXCL12 (ligand of CXCR4 expressed on MF cells), collagen XI, and matrix metalloproteinase 2. Cultured MF fibroblasts showed greater proliferation than normal fibroblasts in ex vivo experiments. A coculture with MyLa cells (MF cell line) increased normal fibroblast growth, reduced the sensitivity of MyLa cells to doxorubicin, and enhanced their migration. Inhibiting the CXCL12/CXCR4 axis increased doxorubicin-induced apoptosis of MyLa cells and reduced MyLa cell motility. Our data suggest that the fibroblasts in MF lesions are more proliferative than fibroblasts in normal skin and that CAFs protect MF cells from doxorubicin-induced cell death and increase their migration through the secretion of CXCL12. Reversing the CAF-mediated tumor microenvironment in MF may improve the efficiency of anticancer therapy.