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Targeting FAPα-expressing tumor-associated mesenchymal stromal cells inhibits triple-negative breast cancer pulmonary metastasis
Cancer Letters ( IF 9.1 ) Pub Date : 2021-01-19 , DOI: 10.1016/j.canlet.2021.01.013
Xiaobo Li 1 , Minfeng Chen 1 , Weijin Lu 1 , Jun Tang 2 , Lijuan Deng 3 , Qing Wen 1 , Maohua Huang 1 , Rong Deng 4 , Geni Ye 1 , Wencai Ye 1 , Dongmei Zhang 1
Affiliation  

Tumor metastasis is the main cause of death in patients with triple-negative breast cancer (TNBC). Bone marrow-derived mesenchymal stem cells (BM-MSCs) have tropism towards tumor tissues, and can be converted into tumor-associated mesenchymal stromal cells (TA-MSCs) to facilitate TNBC metastasis through interactions with tumor-associated macrophages (TAMs). However, the underlying molecular mechanisms are complex and unclear, and effective strategies to suppress tumor metastasis via eliminating TA-MSCs are still lacking. Here, we demonstrate that fibroblast activation protein alpha (FAPα) was overexpressed in TA-MSCs, which prompts TA-MSCs to secrete multiple C–C motif chemokine ligands, promoting C–C motif chemokine receptor 2 (CCR2)+ TAM recruitment and facilitating TAM polarization into the M2 phenotype, thereby promoting TNBC pulmonary metastasis. Z-GP-DAVLBH, an FAPα-activated vinblastine prodrug, induces FAPα+ TA-MSC apoptosis, which significantly suppresses CCR2+ TAM recruitment and polarization, thus inhibiting pulmonary metastasis of orthotopic TNBC cell-derived xenografts and patient-derived xenografts. This study provides insight into an important role of FAPα in mediating TA-MSC-induced TNBC metastasis and provides compelling evidence that targeting TA-MSCs with an FAPα-activated prodrug is a promising strategy for suppressing TNBC metastasis.



中文翻译:

靶向表达 FAPα 的肿瘤相关间充质基质细胞抑制三阴性乳腺癌肺转移

肿瘤转移是三阴性乳腺癌(TNBC)患者死亡的主要原因。骨髓间充质干细胞 (BM-MSCs) 对肿瘤组织具有趋向性,可以转化为肿瘤相关间充质基质细胞 (TA-MSCs),通过与肿瘤相关巨噬细胞 (TAMs) 的相互作用促进 TNBC 转移。然而,潜在的分子机制复杂且不清楚,仍然缺乏通过消除TA-MSC来抑制肿瘤转移的有效策略。在这里,我们证明成纤维细胞活化蛋白 α (FAPα) 在 TA-MSCs 中过度表达,这促使 TA-MSCs 分泌多个 C-C 基序趋化因子配体,促进 C-C 基序趋化因子受体 2 (CCR2) +TAM 募集并促进 TAM 极化进入 M2 表型,从而促进 TNBC 肺转移。Z-GP-DAVLBH 是一种 FAPα 激活的长春碱前药,可诱导 FAPα + TA-MSC 细胞凋亡,显着抑制 CCR2 + TAM 募集和极化,从而抑制原位 TNBC 细胞来源的异种移植物和患者来源的异种移植物的肺转移。这项研究提供了对 FAPα 在介导 TA-MSC 诱导的 TNBC 转移中的重要作用的见解,并提供了令人信服的证据,表明用 FAPα 激活的前药靶向 TA-MSC 是抑制 TNBC 转移的有前途的策略。

更新日期:2021-01-24
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