Abstract
Mesenchymal stem cells (MSCs) are recruited from BM to the stroma of developing tumors, where they serve as critical components of the tumor microenvironment by secreting growth factors, cytokines, and chemokines. The role of MSCs in colorectal cancer (CRC) progression was controversial. In this study, we found that C-C chemokine receptor type 5 (CCR5) ligands (i.e., C-C motif chemokine ligand 3 (CCL3), CCL4, and CCL5) were highly produced from MSCs using a chemokine array screening with conditioned media from the cultured human MSCs. A relatively strong CCR5 expression could be detected within the cytoplasm of several CRC cell lines. Regarding the effect of MSC, we found that the xenografts in which CCR5-overexpressing HCT116 cells were inoculated into immunocompromised mice were highly promoted in vivo by a mixture with MSCs. Notably, the CCR5 inhibitor, maraviroc, significantly abolished the MSC-induced tumor growth in vivo. In human clinical specimens (n = 89), 20 cases (29%) were high for CCR5, whereas 69 cases (71%) were low. Statistical analyses indicated that CCR5 expression in primary CRC was associated with CRC patients’ prognosis. Especially, stage III/IV patients with CCR5-high CRCs exhibited a significantly poorer prognosis than those with CCR5-low CRCs. Furthermore, we investigated the effects of preoperative serum CCR5 ligands on patients’ prognosis (n = 114), and found that CRC patients with high serum levels of CCL3 and CCL4 exhibited a poorer prognosis compared to those with low levels of CCL3 and CCL4, while there was no association between CCL5 and prognosis. These results suggest that the inhibition of MSC–CRC interaction by a CCR5 inhibitor could provide the possibility of a novel therapeutic strategy for CRC, and that serum levels of CCL3 and CCL4 could be predictive biomarkers for the prognosis of CRC patients.
Highlights
Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer death worldwide, accounting for about 1.36 million deaths every year[1]
We demonstrated that human Mesenchymal stem cells (MSCs) secreted high levels of chemokine receptor type 5 (CCR5) ligands (i.e., CCL3, CCL4, and C motif chemokine ligand 5 (CCL5)), and that MSCs promoted colorectal cancer (CRC) tumor growth in vivo via CCR5 signaling
These results suggest that a CCR5 inhibitor may provide the possibility of a novel therapeutic strategy for CRC, and that serum levels of CCL3 and CCL4 could be predictive biomarkers for the prognosis of CRC patients
Summary
CCL3/4/5–CCR5 axis is a candidate that functions between MSCs and CRC cells, which resulted in tumor growth in vivo. In the HCT116-CCR5 + MSCs tumors, maraviroc significantly reduced tumor size (P = 0.042) These results suggest that CCR5 signaling is important for the interaction between CRC cells and MSCs, and that an inhibitor of CCR5 could suppress CRC progression. Statistical analysis indicated that the cases with high CCL3 levels exhibited a significantly shorter OS and CSS compared to those with low CCL3 levels (P = 0.02 and 0.02, respectively), such a correlation was not observed in RFS (Fig. 5a). The cases with high CCL4 levels exhibited a significantly shorter OS compared to those with low CCL4 levels (P = 0.04), and a similar correlation was observed in CSS and RFS (P = 0.06 and 0.07, respectively) (Fig. 5b). To evaluate the clinical relevance of the abovementioned results, we examined CCR5 expression in CRC
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