Targeting FAPα-expressing tumor-associated mesenchymal stromal cells inhibits triple-negative breast cancer pulmonary metastasis
Targeting FAPα-expressing tumor-associated mesenchymal stromal cells inhibits triple-negative breast cancer pulmonary metastasis
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靶向表达 FAPα 的肿瘤相关间充质基质细胞可抑制三阴性乳腺癌肺转移。
DOI：
10.1016/j.canlet.2021.01.013
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发表时间：
2021-01-23
期刊：
影响因子：
9.7
通讯作者：
Zhang, Dongmei
中科院分区：
文献类型：
--
作者：
Li, Xiaobo;Chen, Minfeng;Zhang, Dongmei
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）具有肿瘤组织向性，可通过与肿瘤相关巨噬细胞（TAMs）相互作用转化为肿瘤相关间充质基质细胞（TA-MSCs），促进TNBC转移。然而，其分子机制复杂且不清楚，并且仍然缺乏通过消除TA-MSCs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（FAP α）在TA-MSC中过表达，这促使TA-MSC分泌多种C-C基序趋化因子配体，促进C-C基序趋化因子受体2（CCR 2）（+）TAM募集并促进TAM极化成M2表型，从而促进TNBC肺转移。Z-GP-DAVLBH是一种FAP α激活的长春碱前药，可诱导FAP α（+）TA-MSC凋亡，从而显著抑制CCR 2（+）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。该研究提供了FAPa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，即用FAPa活化的前药靶向TA-MSC是抑制TNBC转移的有希望的策略。
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 (FAP alpha) 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 FAP alpha-activated vinblastine prodrug, induces FAP alpha(+) 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 FAPa in mediating TA-MSC-induced TNBC metastasis and provides compelling evidence that targeting TA-MSCs with an FAP alpha-activated prodrug is a promising strategy for suppressing TNBC metastasis.