Abstract
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.
Highlights
Colorectal cancer is the third most common type of cancer, causing 694,000 deaths in 2012 and accounting for about 10% of all cancer cases [1]
In the case of mesenchymal stem cells (MSCs) cocultured with CT26 in a transwell system, CCL7 concentration was significantly higher when compared to MSCs in monoculture (255 ± 7 vs. 155 ± 15, p = 0.002)
We report that MSCs enhanced CT26 tumor cell proliferation and migration
Summary
Colorectal cancer is the third most common type of cancer, causing 694,000 deaths in 2012 and accounting for about 10% of all cancer cases [1]. The main cause of mortality in colorectal cancer patients is liver metastasis, either present already at the cancer diagnosis stage, or developing after resecting the primary tumor. A substantial effort needs to be made in order to identify proteins controlling the metastatic cascade as they have crucial clinical significance in future patient treatments. Mesenchymal stem cells and the chemokines released by them are a crucial part of the tumor microenvironment and play a role in determining the growth and metastasis of colorectal cancer [3,4]. Identified from osteosarcoma supernatant [5], it was found to be expressed by different cell types: monocytes, fibroblasts, platelets, colon epithelial cells, and some tumor cell lines [6,7,8]. Due to its capacity to bind to multiple leukocyte receptors, CCL7 affects immune cells and activates monocytes and granulocytes [9]
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