Department of General Surgery, QiLu Hospital, Shandong University, Jinan, Shandong, China.
The Institute of Laparoscopic Minimally Invasive Surgery of Shandong University, Shandong University, Jinan, Shandong, China.
Biosci Rep. 2018 Dec 7;38(6). doi: 10.1042/BSR20180243. Print 2018 Dec 21.
Tumor microenvironment (TME) is the cellular environment in which tumor exists, and it contributes to tumor formation and progression. The TME is composed of tumor cells, stromal cells, cytokines, and chemotactic factors of which fibroblasts are the main cellular components. In our present study, we found that colorectal cancer (CRC) cells expressing integrin αvβ6 clearly could induce morphological changes in inactive fibroblasts and increased the expression of activated fibroblast markers such as α-smooth muscle actin (α-SMA) and fibroblast-activating protein (FAP). Those activated fibroblasts in the TME are called cancer-associated fibroblasts (CAFs). In order to investigate the mechanism by which CRC cells expressing integrin αvβ6 activated CAFs, a series of assays have been carried out in the follow-up. We found that CRC cells could secrete inactive transforming growth factor β (TGF-β); however, integrin αvβ6 activated TGF-β, which subsequently activated fibroblasts. This process was disrupted by knockdown of integrin αvβ6. In contrast, activated fibroblasts could promote CRC cell invasion. In particular, the strengthening effect on expression of integrin αvβ6 in colon cancer cells was obvious. Additionally, we found that CAFs could secrete stromal cell-derived factor-1 (SDF-1) and promote CRC cell metastasis in distant organs via the SDF-1/C-X-C chemokine receptor type 4 (CXCR4) axis. Taken together, we assumed that CRC cells and CAFs activated one another and worked together to promote cancer progression, with integrin αvβ6 playing a role in the bi-directional regulation of these cells. Hence, integrin αvβ6 may serve as a therapeutic target for the future CRC treatment.
肿瘤微环境（TME）是肿瘤存在的细胞环境，它有助于肿瘤的形成和发展。TME 由肿瘤细胞、基质细胞、细胞因子和趋化因子组成，其中成纤维细胞是主要的细胞成分。在我们目前的研究中，我们发现表达整合素αvβ6 的结直肠癌（CRC）细胞明显可以诱导无活性成纤维细胞的形态变化，并增加激活的成纤维细胞标志物的表达，如α-平滑肌肌动蛋白（α-SMA）和成纤维细胞激活蛋白（FAP）。TME 中的这些激活的成纤维细胞被称为癌相关成纤维细胞（CAFs）。为了研究表达整合素αvβ6 的 CRC 细胞激活 CAFs 的机制，我们在后续的一系列实验中进行了研究。我们发现 CRC 细胞可以分泌无活性的转化生长因子β（TGF-β）；然而，整合素αvβ6 激活了 TGF-β，进而激活了成纤维细胞。这个过程被整合素αvβ6 的敲低所破坏。相反，激活的成纤维细胞可以促进 CRC 细胞侵袭。特别是，对结肠癌细胞中整合素αvβ6 表达的增强作用更为明显。此外，我们发现 CAFs 可以分泌基质细胞衍生因子-1（SDF-1），并通过 SDF-1/C-X-C 趋化因子受体 4（CXCR4）轴促进 CRC 细胞向远处器官转移。综上所述，我们假设 CRC 细胞和 CAFs 相互激活，共同促进癌症进展，整合素αvβ6 在这些细胞的双向调节中发挥作用。因此，整合素αvβ6 可能成为未来 CRC 治疗的一个治疗靶点。
