Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5

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.

CCR5 status and metastatic progression in colorectal cancer

“…13 Therefore, either prevention of the metastatic stage or expanded therapeuticespecially immunotherapeuticoptions, are in the focus of current research. 39 Our histological analysis of primary tumors showed an even distribution of CCR5 expression across the whole tissue sections, without predominance in invasive parts of the tumor, and is in accordance to previously published studies: CCR5 was expressed by cancer cells, 40,41 by tumor-infiltrating lymphocytes 32 as well as by macrophages. 18 We additionally illustrate that CCR5 expression levels increase during primary tumor growth and peak in liver metastases, corroborating the hypothesis that CCR5 promotes metastasis.…”

“…48 Finally, CCR5 expression in colorectal cancer primary tumors were recently found to be associated with a shorter overall survival. 41 Not a single colorectal cancer liver metastasis in our hand contained only CCR5-negative tumor cells in all our analyzed samples so far. However, liver metastases exhibited patchiness in CCR5 immunostainings, i.e.…”

“…If it appears that high CCR5 expression at the primary tumor is a poor prognosis indicator, 41 is this also the case on the metastatic site? In liver lesions, patchy/decreased CCR5 expression relates to a poor immune landscape characterized by an unfavorable CD8 + /FoxP3 + TIL ratio, elevated CTLA4 + , and PD1 + cell numbers and elevated markers of alternatively activated macrophages.…”

CCR5 and CCR5Δ32 in bacterial and parasitic infections: Thinking chemokine receptors outside the HIV box

“…On the other hand, the use of CCR5 blockers has been increasingly explored, and several studies support the use of this technology for the treatment of different diseases. For example, CCR5 blockers have a good potential for treating various types of cancer (Halama et al, 2016; Halvorsen et al, 2016; Mencarelli et al, 2013; Nishikawa et al, 2019; Pervaiz et al, 2019; Sicoli et al, 2014; Tanabe, Sasaki, Mukaida, & Baba, 2016; Velasco‐Velázquez et al, 2012), graft‐versus‐host disease (Moy et al, 2017; Reshef et al, 2019), inflammatory bowel disease (Mencarelli et al, 2016) and stroke (Joy et al, 2019). Therefore, the lack of CCR5 is deleterious in some situations, but blocking this receptor may be desirable in specific clinical contexts.…”

Oncogenic Linear Collagen VI of Invasive Breast Cancer Is Induced by CCL5

“…CCL5 (C-C motif chemokine ligand 5) is a member of the C-C chemokine family, and acts as a potent chemoattractant of T cells, basophils, eosinophils, and macrophages [6]. It has been shown that the main producer of tumor associated CCL5 is not the cancer cells, rather the local mesenchymal stem cell population [7,8]. The literature is unanimously agreed on the pro-oncogenic impact of CCL5 on invasive breast tumors [6,9].…”