Abstract
Chemokines and their receptors are involved in cancer initiation and progression, including colorectal cancer (CRC) and liver metastasis formation. Our aim was to elucidate C-C chemokine receptor type 5 (CCR5) gene polymorphism (CCR5?32) impact on CRC and colorectal cancer liver metastases (CRLM) occurrence risk. We analyzed the CCR5 gene mutational status in 108 primary CRC cases, 35 CRLM and 248 healthy individuals, and evaluated CCR5 expression in healthy tissue and tumors. Rare allele ??32? was more frequent in controls (7.2% vs 2.8% in CRC). All 35 metastases had wild-type CCR5. Our analysis showed that CCR5 wild type has a significant risk of 2.73-fold (95% CI=1.22-7.31) to cause CRC while ?32 reduced the risks 0.36-fold (95% CI=0.13-0.82). For CRC, CCR5 correlated with left-sided tumors and liver metastases (P=0.040 and P= 0.039 respectively). As for CRLM, no correlation was found. Immunohistochemical profile analysis of CCR5 revealed a significant association with the male gender (P=0.049) and non-mucinous carcinomas (P< 0.001) in primary CRC. CCR5 expression revealed an association with the degree of tumor differentiation for both CRC and CRLM (P < 0.001). CCR5?32 might be a protective factor against CRC development and dissemination.
Highlights
colorectal cancer (CRC) is the third most common cancer in the world and second in terms of mortality; it is responsible for 935000 deaths and 1.9 million new cases in 2020, and is growing steadily, affecting both genders [1]
Several reports associate chemokine receptor type 5 (CCR5)/CCL5 intermediate or strong expression to extended CRC patient survival as well as tumor regression [31,32], but other studies show that this chemokine receptor significantly contributes to tumor growth through its main actors CCL5, CCL4 and CCL3 [11,16,19,29], and that neutralization of this receptor’s chemokines can reduce tumor invasion in colorectal [21,23], breast [33,34] and lung cancers [35,36]
For CRC treatment, CCR5 is widely studied, given its involvement in cancer progression and metastasis, and is a frequently inhibited using specific molecules to hinder the interaction between mesenchymal stem cells (MSC)/CRC cells and to effectively treat CRC advanced stages [37,38]
Summary
CRC is the third most common cancer in the world and second in terms of mortality; it is responsible for 935000 deaths and 1.9 million new cases in 2020, and is growing steadily, affecting both genders [1]. Numerous deaths caused by solid malignant tumors are due to disseminated metastases in secondary organs. In this context, 40-50 % of patients with CRC mainly develop liver metastasis, less frequently in the lungs and more rarely in the brain [2,3]. The cancer process depends on a series of acquired or transmitted genetic alterations targeting oncogenes, tumor suppressor and repair genes [4]. The persistence of an initiated tumor cell, its in situ proliferation and metastatic dissemination requires its escape from the antitumor immunity surveillance system [5]. The CRC carcinogenesis model follows a multistep sequence, and the interactions between tumor cells and stromal components (especially immune cells) represent a very promising area of research to improve its prognosis and establish more effective personalized therapies [6].The protumor microenvironment is developed when the mesenchymal, immune cells and their precursors are recruited to the primary and/or secondary tumor site and undergo a phenotypic change to promote tumor growth and migration
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