Zhang Rongsheng, Qi Fan, Shao Shengli, Li Geng, Feng Yongdong
1Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei China.
2Department of Otolaryngology-Head and Neck Surgery Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei China.
Cancer Cell Int. 2019 Jul 24;19:192. doi: 10.1186/s12935-019-0914-y. eCollection 2019.
Carcinoma-associated fibroblasts (CAFs) are dominant components of tumor microenvironment, which has been reported to promote development, progression, and metastasis of cancer. However, the role of CAFs during adhesion process remains unknown. It has been hypothesized that CAFs contribute to adhesion to endothelial cells of colorectal cancer (CRC) via HGF/c-Met pathway.
Clinical specimen and orthotopic liver metastasis model was used to investigate association between CD44 expression and propensity of metastasis in CRC. Human CRC derived cancer associated fibroblasts was isolated and its effect on migration and adhesion of CRC cells was investigated. We also confirm the conclusion on animal metastasis model.
In this study, clinical specimen and orthotopic liver metastatic model indicated that overexpression of CD44 is associated with CRC metastasis, and we found that colorectal cancer-derived CAFs (CC-CAFs) increased the adhesion and migration of CRC cells in vitro through up-regulation of CD44, we also found that CC-CAFs promoted adhesion and liver or lung metastasis in vivo. Mechanistically, we found that the expression of HGF increased tenfolds compared CC-CAFs with adjacent normal fibroblasts, and HGF promoted adhesion through up-regulation of CD44 via HGF/c-MET signal pathway.
These results indicated that CC-CAFs-derived HGF induced up-regulation of CD44 which mediated adhesion of CRC cells to endothelial cells, and subsequently resulted in enhancement of metastasis of CRC cells, it could provide a novel therapeutic or preventive target.
癌相关成纤维细胞（CAFs）是肿瘤微环境的主要组成部分，据报道其可促进癌症的发生、发展和转移。然而，CAFs在黏附过程中的作用尚不清楚。据推测，CAFs通过HGF/c-Met途径促进结直肠癌（CRC）与内皮细胞的黏附。
利用临床标本和原位肝转移模型研究CD44表达与CRC转移倾向之间的关联。分离出人CRC来源的癌相关成纤维细胞，并研究其对CRC细胞迁移和黏附的影响。我们还在动物转移模型上验证了这一结论。
在本研究中，临床标本和原位肝转移模型表明CD44的过表达与CRC转移相关，并且我们发现结直肠癌来源的CAFs（CC-CAFs）通过上调CD44在体外增加了CRC细胞的黏附和迁移，我们还发现CC-CAFs在体内促进了黏附和肝或肺转移。机制上，我们发现与相邻正常成纤维细胞相比，CC-CAFs中HGF的表达增加了10倍，并且HGF通过HGF/c-MET信号通路上调CD44促进黏附。
这些结果表明，CC-CAFs来源的HGF诱导CD44上调，介导CRC细胞与内皮细胞的黏附，随后导致CRC细胞转移增强，这可能提供一个新的治疗或预防靶点。
