CTHRC1 promotes liver metastasis by reshaping infiltrated macrophages through physical interactions with TGF-β receptors in colorectal cancer
CTHRC1 promotes liver metastasis by reshaping infiltrated macrophages through physical interactions with TGF-β receptors in colorectal cancer
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CTHRC1 通过与结直肠癌中 TGF-β 受体的物理相互作用重塑浸润的巨噬细胞，从而促进肝转移
DOI：
10.1038/s41388-021-01827-0
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发表时间：
2021-05-13
期刊：
影响因子：
8
通讯作者：
Jiang, Shu-Heng
中科院分区：
文献类型：
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作者：
Zhang, Xue-Li;Hu, Li-Peng;Jiang, Shu-Heng
转移是癌症相关死亡的主要原因。肿瘤的内在特性可以决定肿瘤是否发生转移。在这里，通过比较原发性结直肠癌（CRC）患者的基因表达模式，有或没有转移，我们发现，胶原蛋白三重受阻重复序列1（CTHRC 1）在原发性CRC作为转移相关基因。动物实验证实，CRC细胞分泌的CTHRC 1促进肝转移，与巨噬细胞浸润密切相关。氯膦酸二钠脂质体对巨噬细胞的消耗在很大程度上消除了CTHRC 1对CRC肝转移的促进作用。此外，我们证明了CTHRC 1通过TGF-β信号传导调节巨噬细胞向M2表型的极化。一项机制研究表明，CTHRC 1直接结合TGF-β受体II和TGF-β受体III，稳定TGF-β受体复合物，并激活TGF-β信号传导。CTHRC 1单克隆抗体和抗PD-1阻断抗体联合治疗可有效抑制CRC肝转移。综上所述，我们的数据表明CTHRC 1是CRC转移的内在标志物，并进一步揭示了CTHRC 1通过TGF-β信号重塑浸润的巨噬细胞来促进CRC肝转移，这表明CTHRC 1可能是CRC肝转移的早期预测和治疗靶点的潜在生物标志物。
Metastasis is a major cause of cancer-related deaths. Tumor-intrinsic properties can determine whether tumor metastasis occurs or not. Here, by comparing the gene expression patterns in primary colorectal cancer (CRC) patients with or without metastasis, we found that Collagen Triple Helix Repeat Containing 1 (CTHRC1) in primary CRC served as a metastasis-associated gene. Animal experiments verified that CTHRC1 secreted by CRC cells promoted hepatic metastasis, which was closely correlated with macrophage infiltration. Depletion of macrophages by liposomal clodronate largely abolished the promoting effect of CTHRC1 on CRC liver metastasis. Furthermore, we demonstrated that CTHRC1 modulated macrophage polarization to M2 phenotypes through TGF-beta signaling. A mechanistic study revealed that CTHRC1 bound directly to TGF-beta receptor II and TGF-beta receptor III, stabilized the TGF-beta receptor complex, and activated TGF-beta signaling. The combination treatment of CTHRC1 monoclonal antibody and anti-PD-1 blocking antibody effectively suppressed CRC hepatic metastasis. Taken together, our data demonstrated that CTHRC1 is an intrinsic marker of CRC metastasis and further revealed that CTHRC1 promoted CRC liver metastasis by reshaping infiltrated macrophages through TGF-beta signaling, suggesting that CTHRC1 could be a potential biomarker for the early prediction of and a therapeutic target of CRC hepatic metastasis.