The relationship between chemokines CCL2, CCL3, and CCL4 with the tumor microenvironment and tumor-associated macrophage markers in colorectal cancer

Abstract

A complex network of chemokines can influence cancer progression with the recruitment and activation of hematopoietic cells, including macrophages to the supporting tumor stroma promoting carcinogenesis and metastasis. The aim of this study was to investigate the relation between tissue and plasma chemokine levels involved in macrophage recruitment with tumor-associated macrophage profile markers and clinicopathological features such as tumor-node-metastases stage, desmoplasia, tumor necrosis factor-a, and vascular endothelial growth factor plasma content. Plasma and tumor/healthy mucosa were obtained from Chilean patients undergoing colon cancer surgery. Chemokines were evaluated from tissue lysates (CCL2, CCL3, CCL4, CCL5, and CX3CL1) by Luminex. Statistical analysis was performed using Wilcoxon match-paired test (p \ 0.05). Macrophage markers (CD68, CD163, and iNOS) were evaluated by immunohistochemistry samples derived from colorectal cancer patients. Correlation analysis between chemokines and macrophage markers and clinicopathological features were performed using Spearman's test. Plasmatic levels of chemokines and inflammatory mediators' vascular endothelial growth factor and tumor necrosis factor-a were evaluated by Luminex. Tumor levels of CCL2 (mean 6 standard deviation = 530.1 6 613.9 pg/mg), CCL3 (102.7 6 106.0 pg/mg), and CCL4 (64.98 6 48.09 pg/mg) were higher than those found in healthy tissue (182.1 6 116.5, 26.79 6 22.40, and 27.06 6 23.69 pg/mg, respectively p \ 0.05). The tumor characterization allowed us to identify a positive correlation between CCL4 and the pro-tumor macrophages marker CD163 (p = 0.0443), and a negative correlation of iNOS with desmoplastic reaction (p = 0.0467). Moreover, we identified that tumors with immature desmoplasia have a higher CD163 density compared to those with a mature/intermediated stromal tissue (p = 0.0288). Plasmatic CCL4 has shown a positive correlation with inflammatory mediators (tumor necrosis factor-a and vascular endothelial growth factor) that Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).have previously been associated with poor prognosis in patients. In conclusion High expression of CCL4 in colon cancer could induce the infiltration of tumor-associated macrophages and specifically a pro-tumor macrophage profile (CD163 + cells). Moreover, plasmatic chemokines could be considered inflammatory mediators associated to CRC progression as well as tumor necrosis factor-a and vascular endothelial growth factor. These data reinforce the idea of chemokines as potential therapeutic targets or biomarker in CRC.

A combination of inhibitors of glycolysis, glutaminolysis and de�novo fatty acid synthesis decrease the expression of chemokines in human colon cancer cells

“…The expression levels of CCL4 are increased in tumor compared with healthy tissues. The higher levels of CCL4 in plasma are associated with poor prognosis (25). Although the expression levels of CCL2, CCL3, RANTES/CCL5 and CCL17 were not downregulated in the present study, these chemokines can also participate in colon cancer progression (25)(26)(27)(28)(29).…”

The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach

“…While MK2 was found to be significantly associated with a long list of cytokines and chemokines amongst gastric cancer patients including IL1-β, GM-CSF, TNFa, IL-6, Mip-1β, IFN-α2, MCP-1, G-CSF, and IL-2; it was only significantly associated, after the Sidak correction for multiple testing, with Mip-1β among those who metastasized, revealing a new link to gastric metastasis. Studies by other groups have suggested pro-metastatic activity of Mip-1β [22,23], but there has also been suggestions otherwise [24]. Thus, more in depth mechanistic studies are needed to assess the overall impact of this chemokine in cancer.…”

CCL2 promotes cell migration by inducing epithelial‐mesenchymal transition in oral squamous cell carcinoma

“…24 Excessive production of CCL2 has been demonstrated in multiple cancer or precancerous lesions including oral lesions. 25,26 Up to date, most studies have been focused on how CCL2 promotes cancer progression by recruiting inflammatory cells in lung cancer, 10 colorectal cancer, 11 breast cancer, 12 and oral cancer. 14 However, there is still a lack of evidence that the origin of local CCL2 in tumor microenvironment and its direct effect on tumor cells.…”

“…CCL2 and its main chemokine receptor CCR2 have been implicated in the pathogenesis of several different disease processes, including neurological disorders, autoimmune disease, obesity, atherosclerosis, and cancer. 9 Significantly high expression of CCL2 has been detected in the epithelial region of many tumor types, including lung cancer, 10 colorectal cancer, 11 and breast cancer. 12 CCL2 promotes tumor progression through multiple mechanisms including recruiting of CCR2-positive mononuclear macrophages to secret of a variety of inflammatory factors and to promote angiogenesis.…”