The role of CCR5 polymorphism in colorectal cancer and liver metastasis in the Tunisian population

Authors

  • Marwa Weslati 1. Laboratory of Molecular Genetics Immunology and Biotechnology (LR99ES12), Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia; 2. Colorectal Cancer Research Laboratory UR12SP14, Mongi Slim Hospital, La Marsa, Tunisia https://orcid.org/0000-0001-5641-8754
  • Rahma Boughriba Laboratory of Genetics Immunology and Human Pathology (LR05ES05), Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia https://orcid.org/0000-0002-6824-8307
  • Donia Ounissi Laboratory of Neurophysiology, Cellular Physiopathology and Biomolecule Valorization (LR18ES03), Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia https://orcid.org/0000-0003-4585-271X
  • Meriam Hazgui Laboratory of Mycology, Pathologies and Biomarkers (LR16ES05), Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia https://orcid.org/0000-0003-2195-6469
  • Sonia Marghali Laboratory of Molecular Genetics Immunology and Biotechnology (LR99ES12), Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia https://orcid.org/0000-0002-3090-1454

DOI:

https://doi.org/10.2298/ABS210817044W

Keywords:

CCR5Δ32, colorectal cancer, liver metastasis, Tunisian cohort, chemokines

Abstract

Paper description:

  • Colorectal cancer results from the accumulation of genetic and epigenetic alterations and complex interactions between tumor cells and the tumor microenvironment. Understanding genetic differences in populations helps develop specific and more effective treatments.
  • Research targeting C-C chemokine receptor type 5 (CCR5) (rs333) in both colorectal cancer and colorectal cancer liver metastases are inconclusive. We investigated the impact of this mutation in different stages.
  • CCR5Δ32 reduced colorectal cancer risk; all metastases had wild type CCR5.
  • Having a dysfunctional/repressed CCR5 receptor is unfavorable to colorectal cancer and colorectal cancer liver metastases development, CCR5Δ32 might protect against CRC development and dissemination.

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 (CCR5Δ32) 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 “Δ32” 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 Δ32 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). CCR5Δ32 might be a protective factor against CRC development and dissemination.

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References

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209‑49.

https://doi.org/10.3322/caac.21660

Zang Y-W, Gu X-D, Xiang J-B, Chen Z-Y. Brain Metastases from Colorectal Cancer: Microenvironment and Molecular Mechanisms. Int J Mol Sci. 2012;13(12):15784‑800.

https://doi.org/10.3390/ijms131215784

Valderrama-Treviño AI, Barrera-Mera B, C Ceballos-Villalva J, Montalvo-Javé EE. Hepatic Metastasis from Colorectal Cancer. Euroasian J Hepatogastroenterol. 2017;7(2):166‑75.

https://doi.org/10.5005/jp-journals-10018-1241

Ounissi D, Weslati M, Boughriba R, Hazgui M, Bouraoui S. Clinicopathological characteristics and mutational profile of KRAS and NRAS in Tunisian patients with sporadic colorectal cancer. Turk J Med Sci. 2021;51(1):148‑58.

Morein D, Erlichman N, Ben-Baruch A. Beyond Cell Motility: The Expanding Roles of Chemokines and Their Receptors in Malignancy. Front Immunol. 2020;11:952.

https://doi.org/10.3389/fimmu.2020.00952

Mollica Poeta V, Massara M, Capucetti A, Bonecchi R. Chemokines and Chemokine Receptors: New Targets for Cancer Immunotherapy. Front Immunol. 2019;10:379.

https://doi.org/10.3389/fimmu.2019.00379

Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410(6824):50‑6.

https://doi.org/10.1038/35065016

Yang Q, Guo N, Zhou Y, Chen J, Wei Q, Han M. The role of tumor-associated macrophages (TAMs) in tumor progression and relevant advance in targeted therapy. Acta Pharm Sin B. 2020;10(11):2156‑70.

https://doi.org/10.1016/j.apsb.2020.04.004

Zhang S-Y, Song X-Y, Li Y, Ye L-L, Zhou Q, Yang W-B. Tumor-associated macrophages: A promising target for a cancer immunotherapeutic strategy. Pharmacol Res. 2020;161:105111.

https://doi.org/10.1016/j.phrs.2020.105111

Hsu C-J, Wu M-H, Chen C-Y, Tsai C-H, Hsu H-C, Tang C-H. AMP-activated protein kinase activation mediates CCL3-induced cell migration and matrix metalloproteinase-2 expression in human chondrosarcoma. Cell Commun Signal. 2013;11:68.

https://doi.org/10.1186/1478-811X-11-68

Mukaida N, Sasaki S-I, Baba T. CCL4 Signaling in the Tumor Microenvironment. Adv Exp Med Biol. 2020;1231:23‑32.

https://doi.org/10.1007/978-3-030-36667-4_3

Zlotnik A, Yoshie O. The Chemokine Superfamily Revisited. Immunity 2012;36(5):705‑16.

https://doi.org/10.1016/j.immuni.2012.05.008

Barmania F, Pepper MS. C-C chemokine receptor type five (CCR5): An emerging target for the control of HIV infection. Appl Transl Genom. 2013;2:3‑16.

https://doi.org/10.1016/j.atg.2013.05.004

Li L, Liu Y, Zhan Y, Zhu Y, Li Y, Xie D, Guan XY. High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma. Thorac Cancer. 2018;9(7):775‑84.

https://doi.org/10.1111/1759-7714.12643

De la Fuente López M, Landskron G, Parada D, Dubois-Camacho K, Simian D, Martinez M, Romero D, Roa JC, Chahuán I, Gutiérrez R, Lopez-K F, Alvarez K, Kronberg U, López S, Sanguinetti A, Moreno N, Abedrapo M, González MJ, Quera R, Hermoso-R MA. The relationship between chemokines CCL2, CCL3, and CCL4 with the tumor microenvironment and tumor-associated macrophage markers in colorectal cancer. Tumour Biol. 2018;40(11):1010428318810059.

https://doi.org/10.1177/1010428318810059

Aldinucci D, Borghese C, Casagrande N. The CCL5/CCR5 Axis in Cancer Progression. Cancers (Basel). 2020;12(7):1765.

https://doi.org/10.3390/cancers12071765

Pereira RW, Pires ER, Duarte APM, Moura RP de, Monteiro E, Torloni H, Proietti AB, Simpson AJG, Pena SDJ. Frequency of the CCRdelta32 allele in Brazilians: a study in colorectal cancer and in HTLV-I infection. Genet Mol Biol. 2000;23:523‑6.

https://doi.org/10.1590/S1415-47572000000300003

Ying H, Wang J, Gao X. CCL5-403, CCR5-59029, and Delta32 polymorphisms and cancer risk: a meta-analysis based on 20,625 subjects. Tumour Biol. 2014;35(6):5895‑904.

https://doi.org/10.1007/s13277-014-1780-9

Suarez-Carmona M, Chaorentong P, Kather JN, Rothenheber R, Ahmed A, Berthel A, Heinzelmann A, Moraleda R, Valous NA, Kosaloglu Z, Eurich R, Wolf J, Grauling-Halama S, Hundemer M, Lasitschka F, Klupp F, Kahlert C, Ulrich A, Schneider M, Falk C, Jäger D, Zoernig I, Halama N. CCR5 status and metastatic progression in colorectal cancer. Oncoimmunology. 2019;8(9):e1626193.

https://doi.org/10.1080/2162402X.2019.1626193

Deventer HW van, O'Connor W, Brickey WJ, Aris RM, Ting JPY, Serody JS. C-C Chemokine Receptor 5 on Stromal Cells Promotes Pulmonary Metastasis. Cancer Res. 2005;65(8):3374‑9.

https://doi.org/10.1158/0008-5472.CAN-04-2616

Pervaiz A, Ansari S, Berger MR, Adwan H. CCR5 blockage by maraviroc induces cytotoxic and apoptotic effects in colorectal cancer cells. Med Oncol. 2015;32(5):158.

https://doi.org/10.1007/s12032-015-0607-x

Halama N, Zoernig I, Berthel A, Kahlert C, Klupp F, Suarez-Carmona M, Suetterlin T, Brand K, Krauss J, Lasitschka F, Lerchl T, Luckner-Minden C, Ulrich A, Koch M, Weitz J, Schneider M, Buechler MW, Zitvogel L, Herrmann T, Benner A, Kunz C, Luecke S, Springfeld C, Grabe N, Falk CS, Jaeger D. Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients. Cancer Cell. 2016;29(4):587‑601.

https://doi.org/10.1016/j.ccell.2016.03.005

Tanabe Y, Sasaki S, Mukaida N, Baba T. Blockade of the chemokine receptor, CCR5, reduces the growth of orthotopically injected colon cancer cells via limiting cancerassociated fibroblast accumulation. Oncotarget. 2016;7(30):48335‑45.

https://doi.org/10.18632/oncotarget.10227

Mohan T, Zhu W, Wang Y, Wang B-Z. Applications of chemokines as adjuvants for vaccine immunotherapy. Immunobiology. 2018;223(6‑7):477‑85.

https://doi.org/10.1016/j.imbio.2017.12.001

Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system, vol. 3. 4th ed. Lyon: International Agency for Research on Cancer; 2010. 13 p.

Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, Meyer L, Gress DM, Byrd DR, Winchester DP. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more « personalized » approach to cancer staging. CA Cancer J Clin. 2017;67(2):93‑9.

https://doi.org/10.3322/caac.21388

Suarez‐Carmona M, Lesage J, Cataldo D, Gilles C. EMT and inflammation: inseparable actors of cancer progression. Mol Oncol. 2017;11(7):805‑23.

https://doi.org/10.1002/1878-0261.12095

Chow MT, Luster AD. Chemokines in Cancer. Cancer Immunol Res. 2014;2(12):1125‑31.

https://doi.org/10.1158/2326-6066.CIR-14-0160

Ntanasis-Stathopoulos I, Fotiou D, Terpos E. CCL3 Signaling in the Tumor Microenvironment. Adv Exp Med Biol. 2020;1231:13‑21.

https://doi.org/10.1007/978-3-030-36667-4_2

Korbecki J, Grochans S, Gutowska I, Barczak K, Baranowska-Bosiacka I. CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands. Int J Mol Sci. 2020;21(20):7619.

https://doi.org/10.3390/ijms21207619

Zimmermann T, Moehler M, Gockel I, Sgourakis GG, Biesterfeld S, Müller M, Berger MR, Lang H, Galle PR, Schimanski CC. Low expression of chemokine receptor CCR5 in human colorectal cancer correlates with lymphatic dissemination and reduced CD8+ T-cell infiltration. Int J Colorectal Dis. 2010;25(4):417‑24.

https://doi.org/10.1007/s00384-009-0868-y

Zumwalt TJ, Arnold M, Goel A, Richard Boland C. Active secretion of CXCL10 and CCL5 from colorectal cancer microenvironments associates with GranzymeB+ CD8+ T-cell infiltration. Oncotarget. 2014;6(5):2981‑91.

https://doi.org/10.18632/oncotarget.3205

Velasco-Velázquez M, Xolalpa W, Pestell RG. The potential to target CCL5/CCR5 in breast cancer. Expert Opin Ther Targets. 2014;18(11):1265‑75.

https://doi.org/10.1517/14728222.2014.949238

Pervaiz A, Zepp M, Mahmood S, Ali DM, Berger MR, Adwan H. CCR5 blockage by maraviroc: a potential therapeutic option for metastatic breast cancer. Cell Oncol (Dordr). 2019;42(1):93‑106.

https://doi.org/10.1007/s13402-018-0415-3

Wu Y, Li Y-Y, Matsushima K, Baba T, Mukaida N. CCL3-CCR5 Axis Regulates Intratumoral Accumulation of Leukocytes and Fibroblasts and Promotes Angiogenesis in Murine Lung Metastasis Process. The Journal of Immunology. 2008;181(9):6384‑93.

https://doi.org/10.4049/jimmunol.181.9.6384

Halvorsen EC, Hamilton MJ, Young A, Wadsworth BJ, LePard NE, Lee HN, Firmino N, Collier JL, Bennewith KL. Maraviroc decreases CCL8-mediated migration of CCR5+ regulatory T cells and reduces metastatic tumor growth in the lungs. Oncoimmunology. 2016;5(6):e1150398.

https://doi.org/10.1080/2162402X.2016.1150398

Nishikawa G, Kawada K, Nakagawa J, Toda K, Ogawa R, Inamoto S, Mizuno R, Itatani Y, Sakai Y. Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5. Cell Death Dis. 2019;10(4):1‑13.

https://doi.org/10.1038/s41419-019-1508-2

Pervaiz A, Zepp M, Georges R, Bergmann F, Mahmood S, Faiza S, Berger MR, Adwan H. Antineoplastic effects of targeting CCR5 and its therapeutic potential for colorectal cancer liver metastasis. J Cancer Res Clin Oncol. 2021;147(1):73‑91.

https://doi.org/10.1007/s00432-020-03382-9

Aoki MN, da Silva do Amaral Herrera AC, Amarante MK, do Val Carneiro JL, Fungaro MHP, Watanabe MAE. CCR5 and p53 codon 72 gene polymorphisms: implications in breast cancer development. Int J Mol Med. 2009;23(3):429‑35.

https://doi.org/10.3892/ijmm_00000148

Degerli N, Yilmaz E, Bardakci F. The delta32 allele distribution of the CCR5 gene and its relationship with certain cancers in a Turkish population. Clin Biochem. 2005;38(3):248‑52.

https://doi.org/10.1016/j.clinbiochem.2004.11.001

Duell EJ, Casella DP, Burk RD, Kelsey KT, Holly EA. Inflammation, Genetic Polymorphisms in Proinflammatory Genes TNF-A, RANTES, and CCR5, and Risk of Pancreatic Adenocarcinoma. Cancer Epidemiol Biomarkers Prev. 2006;15(4):726‑31.

https://doi.org/10.1158/1055-9965.EPI-05-0797

Singh H, Sachan R, Jain M, Mittal B. CCR5-Delta32 polymorphism and susceptibility to cervical cancer: association with early stage of cervical cancer. Oncol Res. 2008;17(2):87‑91.

https://doi.org/10.3727/096504008784523667

Petersen DC, Severi G, Hoang HN, Padilla EJD, Southey MC, English DR, Hopper JL, Giles GG, Hayes VM. No Association between Common Chemokine and Chemokine Receptor Gene Variants and Prostate Cancer Risk. Cancer Epidemiol Biomarkers Prev. 2008;17(12):3615‑7.

https://doi.org/10.1158/1055-9965.EPI-08-0896

Gawron AJ, Fought AJ, Lissowska J, Ye W, Zhang X, Chow W-H, Freeman LEB, Hou L. Polymorphisms in chemokine and receptor genes and gastric cancer risk and survival in a high risk Polish population. Scand J Gastroenterol. 2011;46(3):333‑40.

https://doi.org/10.3109/00365521.2010.537679

Kucukgergin C, Isman FK, Cakmakoglu B, Sanli O, Seckin S. Association of polymorphisms in MCP-1, CCR2, and CCR5 genes with the risk and clinicopathological characteristics of prostate cancer. DNA Cell Biol. 2012;31(8):1418‑24.

https://doi.org/10.1089/dna.2012.1716

Zhang Y, Meng FY, Li WL, Zhou CX, Guan Z, Fan HY. Association of chemotactic factor receptor 5 gene with breast cancer. Genet Mol Res. 2013;12(4):5289‑300.

https://doi.org/10.4238/2013.November.7.4

Eskandari-Nasab E, Hashemi M, Ebrahimi M, Amininia S, Bahari G, Mashhadi M-A, Taheri M. Evaluation of CCL5 -403 G>A and CCR5 Δ32 gene polymorphisms in patients with breast cancer. Cancer Biomarkers. 2014;14(5):343‑51.

https://doi.org/10.3233/CBM-140411

Stumbryte A, Gudleviciene Z, Kundrotas G, Dabkeviciene D, Kunickaite A, Cicenas S. Individual and combined effect of TP53, MDM2, MDM4, MTHFR, CCR5, and CASP8 gene polymorphisms in lung cancer. Oncotarget. 2017;9(3):3214‑29.

https://doi.org/10.18632/oncotarget.22756

Fatima F, Saleem S, Hameed A, Haider G, Ali Zaidi SA, Kanwal M, Zehra S, Azhar A. Association analysis and allelic distribution of deletion in CC chemokine receptor 5 gene (CCR5Δ32) among breast cancer patients of Pakistan. Mol Biol Rep. 2019;46(2):2387‑94.

https://doi.org/10.1007/s11033-019-04699-6

Mañes S, Mira E, Colomer R, Montero S, Real LM, Gómez-Moutón C, Jiménez-Baranda S, Garzón A, Lacalle RA, Harshman K, Ruíz A, Martínez. CCR5 Expression Influences the Progression of Human Breast Cancer in a p53-dependent Manner. J Exp Med. 2003;198(9):1381‑9.

https://doi.org/10.1084/jem.20030580

Srivastava A, Pandey SN, Choudhuri G, Mittal B. CCR5 Delta32 polymorphism: associated with gallbladder cancer susceptibility. Scand J Immunol. 2008;67(5):516‑22.

https://doi.org/10.1111/j.1365-3083.2008.02097.x

Zambra FMB, Biolchi V, Brum IS, Chies JAB. CCR2 and CCR5 genes polymorphisms in benign prostatic hyperplasia and prostate cancer. Hum Immunol. 2013;74(8):1003‑8.

https://doi.org/10.1016/j.humimm.2013.04.031

Jiao X, Nawab O, Patel T, Kossenkov AV, Halama N, Jaeger D, Pestell RG. Recent Advances targeting CCR5 for Cancer and its Role in Immuno-Oncology. Cancer Res. 2019;79(19):4801‑7.

https://doi.org/10.1158/0008-5472.CAN-19-1167

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2021-12-15

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Weslati M, Boughriba R, Ounissi D, Hazgui M, Marghali S. The role of CCR5 polymorphism in colorectal cancer and liver metastasis in the Tunisian population. Arch Biol Sci [Internet]. 2021Dec.15 [cited 2024Dec.22];73(4):503-12. Available from: https://serbiosoc.org.rs/arch/index.php/abs/article/view/6924

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