Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, 171 76 Stockholm, Sweden.
Department of Internal Medicine, Hypertension and Vascular Diseases, Medical University of Warsaw, 02 097 Warsaw, Poland.
Int J Mol Sci. 2019 Feb 5;20(3):686. doi: 10.3390/ijms20030686.
Colorectal cancer is the source of one of the most common cancer-related deaths worldwide, where the main cause of patient mortality remains metastasis. The aim of this study was to determine the role of CCL7 (chemokine (C-C motif) ligand 7) in tumor progression and finding whether it could predict survival of colorectal cancer patients. Initially, our study focused on the crosstalk between mesenchymal stem cells (MSCs) and CT26 colon carcinoma cells and resulted in identifying CCL7 as a chemokine upregulated in CT26 colon cancer cells cocultured with MSCs, compared with CT26 in monoculture in vitro. Moreover, we showed that MSCs enhance CT26 tumor cell proliferation and migration. We analyzed the effect of CCL7 overexpression on tumor progression in a murine CT26 model, where cells overexpressing CCL7 accelerated the early phase of tumor growth and caused higher lung metastasis rates compared with control mice. Microarray analysis revealed that tumors overexpressing CCL7 had lower expression of immunoglobulins produced by B lymphocytes. Additionally, using Jh mutant mice, we confirmed that in the CT26 model, CCL7 has an immunoglobulin-, and thereby, B-cell-dependent effect on metastasis formation. Finally, higher expression of CCL7 receptor CCR2 (C-C chemokine receptor type 2) was associated with shorter overall survival of colorectal cancer patients. Altogether, we showed that CCL7 is essentially involved in the progression of colorectal cancer in a CT26 mouse model and that the expression of its receptor CCR2 could be related to a different outcome pattern of patients with colorectal carcinoma.
结直肠癌是全球最常见的癌症相关死亡原因之一，患者死亡的主要原因仍然是转移。本研究旨在确定趋化因子（C-C 基序）配体 7（CCL7）在肿瘤进展中的作用，并研究其是否可以预测结直肠癌患者的生存情况。本研究最初专注于间充质干细胞（MSCs）与 CT26 结肠癌细胞之间的串扰，结果表明与 CT26 单培养相比，与 MSCs 共培养的 CT26 结肠癌细胞中 CCL7 是上调的趋化因子。此外，我们表明 MSCs 增强了 CT26 肿瘤细胞的增殖和迁移。我们分析了 CCL7 过表达对 CT26 小鼠模型中肿瘤进展的影响，结果显示过表达 CCL7 的细胞加速了肿瘤生长的早期阶段，并导致肺部转移率高于对照小鼠。微阵列分析显示，过表达 CCL7 的肿瘤中 B 淋巴细胞产生的免疫球蛋白表达降低。此外，使用 Jh 突变小鼠，我们证实 CCL7 在 CT26 模型中具有免疫球蛋白依赖性，从而对转移形成具有 B 细胞依赖性作用。最后，CCL7 受体 CCR2（C-C 趋化因子受体 2）的高表达与结直肠癌患者总生存时间缩短相关。总之，我们表明 CCL7 本质上参与了结直肠癌在 CT26 小鼠模型中的进展，其受体 CCR2 的表达可能与结直肠癌患者不同的预后模式相关。
