nach oben

Journal of Cancer Research and Clinical Oncology

Erschienen in:

13.10.2023 | Research

CCR5/CCL5 axis is linked to a poor outcome, and inhibition reduces metastasis in oral squamous cell carcinoma

verfasst von: Wilfredo Alejandro González-Arriagada, Ricardo D. Coletta, Carlo Lozano-Burgos, Cynthia García, Jaime Maripillán, Francisca Alcayaga-Miranda, Bastián Godínez-Pacheco, Sebastián Oyarce-Pezoa, René Martínez-Flores, Isaac E. García

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 19/2023

Einloggen, um Zugang zu erhalten

Abstract

Purpose

The CCR5/CCL5 axis is essential for interactions between malignant cells and microenvironment components, promoting tumor progression in oral squamous cell carcinoma (OSCC). This study aims to evaluate the association of CCL5 and CCR5 with the behavior of oral cancer and assess the therapeutic potential of a CCR5 antagonist.

Methods

A retrospective study to analyze CCR5 and CCL5 expression on paraffin-embedded tissues was performed. In cell lines, rhCCL5 was added to induce CCR5-related pathways, and Maraviroc and shRNA against CCR5 were used to neutralize the receptor. Finally, an in vivo murine orthotopic xenograft model of tongue cancer was used to evaluate Maraviroc as an oncologic therapy. After 15 days, the mice were killed, and the primary tumors and cervical lymph nodes were analyzed.

Results

The expression of CCR5 was associated with clinical stage and metastasis, and CCL5 was related to overall survival. Adding rhCCL5 induced cell proliferation, while shRNA and Maraviroc reduced it in a dose-dependent manner. Maraviroc treatment also increased apoptosis and modified cytoskeletal organization. In vivo, Maraviroc reduced neck metastasis.

Conclusions

The effects of CCR5 antagonists in OSCC have been poorly studied, and this study reports in vitro and in vivo evidence for the effects of Maraviroc in OSCC. Our results suggest that the CCR5/CCL5 axis plays a role in oral cancer behavior, and that its inhibition is a promising new therapy alternative.

Nur mit Berechtigung zugänglich

Baba A, Okuyama Y, Ikeda K, Kozakai A, Suzuki T, Saito H, Ogane S, Yamazoe S, Yamauchi H, Ogino N, Seto Y, Kobashi Y, Mogami T, Ojiri H (2019) Undetectability of oral tongue cancer on magnetic resonance imaging; clinical significance as a predictor to avoid unnecessary elective neck dissection in node negative patients. Dentomaxillofac Radiol 48(3):20180272. https://doi.org/10.1259/dmfr.20180272CrossRefPubMed

Bai S, Wu Y, Yan Y, Kang H, Zhang J, Ma W, Gao Y, Hui B, Zhang X, Ren J (2020) The effect of CCL5 on the immune cells infiltration and the prognosis of patients with kidney renal clear cell carcinoma. Int J Med Sci 17(18):2917–2925. https://doi.org/10.7150/ijms.51126CrossRefPubMedPubMedCentral

Borges GA, Elias ST, Amorim B, de Lima CL, Coletta RD, Castilho RM, Squarize CH, Silva EN (2020) Curcumin downregulates the PI3K-AKT-mTOR pathway and inhibits growth and progression in head and neck cancer cells. Phytother Res 34(12):3311–3324. https://doi.org/10.1002/ptr.6780CrossRefPubMed

Cao Z, Xu X, Luo X, Li L, Huang B, Li X, Tao D, Hu J, Gong J (2011) Role of RANTES and its receptor in gastric cancer metastasis. J Huazhong Univ Sci Technolog Med Sci 31(3):342–347. https://doi.org/10.1007/s11596-011-0378-3CrossRefPubMed

Capote-Moreno A, Brabyn P, Muñoz-Guerra MF, Sastre-Perez J, Escorial-Hernandez V, Rodríguez-Campo FJ, García T, Naval-Gías L (2020) Oral squamous cell carcinoma: epidemiological study and risk factor assessment based on a 39-year series. Int J Oral Maxillofac Surg 49(12):1525–1534. https://doi.org/10.1016/j.ijom.2020.03.009CrossRefPubMed

Chen M, Yang X, Yang M, Zhang W, Li L, Sun Q (2019) Identification of a novel biomarker-CCL5 using antibody microarray for colorectal cancer. Pathol Res Pract 215(5):1033–1037. https://doi.org/10.1016/j.prp.2019.02.011CrossRefPubMed

Chuang JY, Yang WH, Chen HT, Huang CY, Tan TW, Lin YT, Hsu CJ, Fong YC, Tang CH (2009) CCL5/CCR5 axis promotes the motility of human oral cancer cells. J Cell Physiol 220(2):418–426. https://doi.org/10.1002/jcp.21783CrossRefPubMed

da Silva JM, Soave DF, Moreira TP, Batista AC, Russo RC, Teixeira MM, da Silva TA (2016) Significance of chemokine and chemokine receptors in head and neck squamous cell carcinoma: a critical review. Oral Oncol 56:8–16. https://doi.org/10.1016/j.oraloncology.2016.02.016CrossRefPubMed

Dantas TS, de Barros PG, Sousa EF, da Cunha MDP, de Aguiar ASW, Costa FWG, Mota MRL, Alves AP, Sousa FB (2016) Influence of educational level, stage, and histological type on survival of oral cancer in a Brazilian population: a retrospective study of 10 years observation. Med 95(3):e2314. https://doi.org/10.1097/MD.0000000000002314CrossRef

Deo SV, Shukla NK, Jha D, Khanna P, Pandit A, Thulkar S (2012) Are We over-treating neck in buccal & alveolo-buccal cancers: experience from a tertiary cancer care center. Indian J Surg Oncol 3(4):272–275. https://doi.org/10.1007/s13193-012-0173-zCrossRefPubMedPubMedCentral

Domingueti CB, Janini JBM, Paranaíba RLM, Lozano-Burgos C, Olivero P, González-Arriagada WA (2019) Prognostic value of immunoexpression of CCR4, CCR5, CCR7 and CXCR4 in squamous cell carcinoma of tongue and floor of the mouth. Med Oral Patol Oral Cir Bucal 24(3):e354–e363. https://doi.org/10.4317/medoral.22904CrossRefPubMedPubMedCentral

Dourado MR, Elseragy A, da Costa BC, Téo FH, Guimarães GN, Machado RA, Risteli M, Wahbi W, Gurgel CA, Ribeiro LM, González-Arriagada WA, da Silva SD, Carrinho AL, Rocha M, Rossa C, Salo T, Coletta RD (2022) Stress induced phosphoprotein 1 overexpression controls proliferation, migration and invasion and is associated with poor survival in oral squamous cell carcinoma. Front Oncol 12:1085917. https://doi.org/10.3389/fonc.2022.1085917CrossRefPubMed

Gao T, Shen Z, Ma C, Li Y, Kang X, Sun M (2018) The CCL5/CCR5 chemotactic pathway promotes perineural invasion in salivary adenoid cystic carcinoma. J Oral Maxillofac Surg 76(8):1708–1718. https://doi.org/10.1016/j.joms.2018.02.009CrossRefPubMed

Gong R, Ren H (2020) Targeting chemokines/chemokine receptors: a promising strategy for enhancing the immunotherapy of pancreatic ductal adenocarcinoma. Signal Transduct Target Ther 5:149. https://doi.org/10.1038/s41392-020-00267-8CrossRefPubMedPubMedCentral

Gonzalez-Arriagada WA, Lozano-Burgos C, Zuniga-Moreta R, Gonzalez-Diaz P, Coletta RD (2018) Clinicopathological significance of chemokine receptor (CCR1, CCR3, CCR4, CCR5, CCR7 and CXCR4) expression in head and neck squamous cell carcinomas. J Oral Pathol Med 47(8):755–763. https://doi.org/10.1111/jop.12736CrossRefPubMed

Gonzalez-Arriagada WA, Garcia IE, Martinez-Flores R, Morales-Pison S, Coletta RD (2022) Therapeutic perspectives of HIV-associated chemokine receptor (CCR5 and CXCR4) antagonists in carcinomas. Int J Mol Sci 24(1):478. https://doi.org/10.3390/ijms24010478CrossRefPubMedPubMedCentral

Guan B, Li H, Yao J, Guo J, Yu F, Li G, Wan B, Ma J, Huang D, Sun L, Chen Y (2023) CCL3-CCR5 axis promotes cell migration and invasion of colon adenocarcinoma via Akt signaling pathway. Environ Toxicol 38(1):172–184. https://doi.org/10.1002/tox.23675ADSCrossRefPubMed

Gulick RM, Fatkenheuer G, Burnside R, Hardy WD, Nelson MR, Goodrich J, Mukwaya G, Portsmouth S, Heera JR (2014) Five-year safety evaluation of maraviroc in HIV-1-infected treatment-experienced patients. J Acquir Immune Defic Syndr 65(1):78–81. https://doi.org/10.1097/QAI.0b013e3182a7a97aCrossRefPubMedPubMedCentral

Haag GM, Springfeld C, Grün B, Apostolidis L, Zschäbitz S, Dietrich M, Berger AK, Weber TF, Zoernig I, Schaaf M, Waberer L, Müller DW, Al-Batran SE, Niels H, Jaeger D (2022) Pembrolizumab and maraviroc in refractory mismatch repair proficient/microsatellite-stable metastatic colorectal cancer—the PICCASSO phase I trial. Eur J Cancer 167:112–122. https://doi.org/10.1016/j.ejca.2022.03.017CrossRefPubMed

Halvorsen EC, Hamilton MJ, Young A, Wadsworth BJ, LePard NE, Lee HN, Firmino N, Collier JL, Bennewith KL (2016) Maraviroc decreases CCL8-mediated migration of CCR5(+) regulatory T cells and reduces metastatic tumor growth in the lungs. Oncoimmunology 5(6):e1150398. https://doi.org/10.1080/2162402X.2016.1150398CrossRefPubMedPubMedCentral

Hemmatazad H, Berger MD (2021) CCR5 is a potential therapeutic target for cancer. Expert Opin Ther Targets 25(4):311–327. https://doi.org/10.1080/14728222.2021.1902505CrossRefPubMed

Huang H, Zepp M, Georges RB, Jarahian M, Kazemi M, Eyol E, Berger MR (2020) The CCR5 antagonist maraviroc causes remission of pancreatic cancer liver metastasis in nude rats based on cell cycle inhibition and apoptosis induction. Cancer Lett 474:82–93. https://doi.org/10.1016/j.canlet.2020.01.009CrossRefPubMed

Huang R, Guo L, Gao M, Li J, Xiang S (2021) Research trends and regulation of CCL5 in prostate cancer. Onco Targets Ther 14:1417–1427. https://doi.org/10.2147/OTT.S279189CrossRefPubMedPubMedCentral

Hunt PW, Shulman NS, Hayes TL, Dahl V, Somsouk M, Funderburg NT, McLaughlin B, Landay AL, Adeyemi O, Gilman LE, Clagett B, Rodriguez B, Martin JN, Schacker TW, Shacklett BL, Palmer S, Lederman MM, Deeks SG (2013) The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial. Blood 121(23):4635–4646. https://doi.org/10.1182/blood-2012-06-436345CrossRefPubMedPubMedCentral

Jin K, Pandey NB, Popel AS (2018) Simultaneous blockade of IL-6 and CCL5 signaling for synergistic inhibition of triple-negative breast cancer growth and metastasis. Breast Cancer Res 20:54. https://doi.org/10.1186/s13058-018-0981-3CrossRefPubMedPubMedCentral

Kalpana G, Figy C, Yeung M, Yeung KC (2019) Reduced RhoA expression enhances breast cancer metastasis with a concomitant increase in CCR5 and CXCR4 chemokines signaling. Sci Rep 9:16351. https://doi.org/10.1038/s41598-019-52746-wADSCrossRefPubMedPubMedCentral

Kodama T, Koma YI, Arai N, Kido A, Urakawa N, Nishio M, Shigeoka M, Yokozaki H (2020) CCL3-CCR5 axis contributes to progression of esophageal squamous cell carcinoma by promoting cell migration and invasion via Akt and ERK pathways. Lab Invest 100:1140–1157. https://doi.org/10.1038/s41374-020-0441-4CrossRefPubMedPubMedCentral

Kolegova ES, Patysheva MR, Larionova IV, Fedorova IK, Kulbakin DE, Choinzonov EL, Denisov EV (2022) Early-onset oral cancer as a clinical entity: aetiology and pathogenesis. Int J Oral Maxillofac Surg 51(12):1497–1509. https://doi.org/10.1016/j.ijom.2022.04.005CrossRefPubMed

Li C, Chen S, Liu C, Mo C, Gong W, Hu J, He M, Xie L, Hou X, Tang J, Ou M (2022a) CCR5 as a prognostic biomarker correlated with immune infiltrates in head and neck squamous cell carcinoma by bioinformatic study. Hereditas 159:37. https://doi.org/10.1186/s41065-022-00251-yCrossRefPubMedPubMedCentral

Li H, Wu M, Zhao X (2022b) Role of chemokine systems in cancer and inflammatory diseases. MedComm 3(2):e147. https://doi.org/10.1002/mco2.147ADSCrossRefPubMedPubMedCentral

Lin NC, Hsien SI, Hsu JT, Chen MYC (2020) Impact on patients with oral squamous cell carcinoma in different anatomical subsites: a single-center study in Taiwan. Sci Rep 11:15446. https://doi.org/10.1038/s41598-021-95007-5CrossRef

Ling Z, Cheng B, Tao X (2021) Epithelial-to-mesenchymal transition in oral squamous cell carcinoma: challenges and opportunities. Int J Cancer 148(7):1548–1561. https://doi.org/10.1002/ijc.33352CrossRefPubMed

Madera MV, Franco JV, Merchan-Galvis AM, Gallardo CR, Bonfill X (2018) Quality assessment of clinical practice guidelines on treatments for oral cancer. Cancer Treat Rev 65:47–53. https://doi.org/10.1016/j.ctrv.2018.03.001CrossRef

Manfroi B, De Grandis M, Moreaux J, Tabruyn S, Mayol JF, Quintero M, Righini C, Sturm N, Aurrand-Lions M, Huard B (2021) The microenvironment of DLBCL is characterized by noncanonical macrophages recruited by tumor-derived CCL5. Blood Adv 5(21):4338–4351. https://doi.org/10.1182/bloodadvances.2021004203CrossRefPubMedPubMedCentral

Mencarelli A, Graziosi L, Renga B, Cipriani S, D’Amore C, Francisci D, Bruno A, Baldelli F, Donini A, Fiorucci S (2013) CCR5 antagonism by maraviroc reduces the potential for gastric cancer cell dissemination. Transl Oncol 6(6):784–793. https://doi.org/10.1593/tlo.13499CrossRefPubMedPubMedCentral

Neckel N, Michael M, Troeltzsch D, Wüster J, Koerdt S, Doll C, Jöhrens K, Neumann K, Heiland M, Raguse JD (2020) Rediscussing the role of traditional risk factors in young adults with oral squamous cell carcinoma. Anticancer Res 40(12):6987–6995. https://doi.org/10.21873/anticanres.14723CrossRefPubMed

Onyeisi JOS, Pernambuco PCA, Mesquita APS, Azevedo LC, Nader HB, Lopes CC (2020) Effects of syndecan-4 gene silencing by micro RNA interference in anoikis resistant endothelial cells: Syndecan-4 silencing and anoikis resistance. Int J Biochem Cell Biol 128:105848. https://doi.org/10.1016/j.biocel.2020.105848CrossRefPubMed

Pervaiz A, Ansari S, Berger MR, Adwan H (2015) CCR5 blockage by maraviroc induces cytotoxic and apoptotic effects in colorectal cancer cells. Med Oncol 32(5):158. https://doi.org/10.1007/s12032-015-0607-xCrossRefPubMed

Pervaiz A, Zepp M, Mahmood S, Ali DM, Berger MR, Adwan H (2019) CCR5 blockage by maraviroc: a potential therapeutic option for metastatic breast cancer. Cell Oncol (dordr) 42(1):93–106. https://doi.org/10.1007/s13402-018-0415-3CrossRefPubMed

Piconi S, Foschi A, Malagoli A, Carli F, Zona S, Milic J, Ricci ED, Rizzardini G, Guaraldi G (2019) Impact of prolonged maraviroc treatment on non-AIDS-related comorbidities in HIV-positive patients: a retrospective cohort study. J Antimicrob Chemother 74(9):2723–2731. https://doi.org/10.1093/jac/dkz227CrossRefPubMed

Qiu J, Xu L, Zeng X, Wu H, Liang F, Lv Q, Du Z (2022) CCL5 mediates breast cancer metastasis and prognosis through CCR5/Treg cells. Front Oncol 12:972383. https://doi.org/10.3389/fonc.2022.972383CrossRefPubMedPubMedCentral

Satgunaseelan L, Allanson BM, Asher R, Reddy R, Low HTH, Veness M, Iyer NG, Smee RI, Palme CE, Gupta R, Clark JR (2020) The incidence of squamous cell carcinoma of the oral tongue is rising in young non-smoking women: an international multi-institutional analysis. Oral Oncol 110:104875. https://doi.org/10.1016/j.oraloncology.2020.104875CrossRefPubMed

Singh SK, Mishra MK, Eltoum IA, Bae S, Lillard JW Jr, Singh R (2018) CCR5/CCL5 axis interaction promotes migratory and invasiveness of pancreatic cancer cells. Sci Rep 8(1):1323. https://doi.org/10.1038/s41598-018-19643-0ADSCrossRefPubMedPubMedCentral

Singh SK, Mishra MK, Rivers BM, Gordetsky JB, Bae S, Singh R (2020) Biological and clinical significance of the CCR5/CCL5 axis in hepatocellular carcinoma. Cancers (basel) 12(4):883. https://doi.org/10.3390/cancers12040883CrossRefPubMed

Sobral LM, Bufalino A, Lopes MA, Graner E, Salo T, Coletta RD (2011) Myofibroblasts in the stroma of oral cancer promote tumorigenesis via secretion of activin A. Oral Oncol 47(9):840–846. https://doi.org/10.1016/j.oraloncology.2011.06.011CrossRefPubMed

Somaida A, Tariq I, Ambreen G, Abdelsalam AM, Ayoub AM, Wojcik M, Dzoyem JP, Bakowsky U (2020) Potent cytotoxicity of four cameroonian plant extracts on different cancer cell lines. Pharm 13(11):357. https://doi.org/10.3390/ph13110357CrossRef

Stepan KO, Mazul AL, Larson J, Shah P, Jackson RS, Pipkorn P, Kang SY, Puram SV (2023) Changing epidemiology of oral cavity cancer in the United States. Otolaryngol Head Neck Surg 168(4):761–768. https://doi.org/10.1177/01945998221098011CrossRefPubMed

Sugasawa H, Ichikura T, Tsujimoto H, Kinoshita M, Morita D, Ono S, Chochi K, Tsuda H, Seki S, Mochizuki H (2008) Prognostic significance of expression of CCL5/RANTES receptors in patients with gastric cancer. J Surg Oncol 97(5):445–450. https://doi.org/10.1002/jso.20984CrossRefPubMed

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249. https://doi.org/10.3322/caac.21660CrossRefPubMed

Szturz P, Vermorken JB (2020) Management of recurrent and metastatic oral cavity cancer: raising the bar a step higher. Oral Oncol 101:104492. https://doi.org/10.1016/j.oraloncology.2019.104492CrossRefPubMed

Ucuncu M, Serilmez M, Sari M, Bademler S, Karabulut S (2019) The diagnostic significance of PDGF, EphA7, CCR5, and CCL5 levels in colorectal cancer. Biomol 9(9):464. https://doi.org/10.3390/biom9090464CrossRef

Velasco-Velazquez M, Jiao X, De La Fuente M, Pestell TG, Ertel A, Lisanti MP, Pestell RG (2012) CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res 72(15):3839–3850. https://doi.org/10.1158/0008-5472.CAN-11-3917CrossRefPubMed

Wang T, Wei Y, Tian L, Song H, Ma Y, Yao Q, Feng M, Wang Y, Gao M, Xue Y (2016) C-C motif chemokine ligand 5 (CCL5) levels in gastric cancer patient sera predict occult peritoneal metastasis and a poorer prognosis. Int J Surg 32:136–142. https://doi.org/10.1016/j.ijsu.2016.07.008CrossRefPubMed

Wang L, Li L, Zhu G (2021) Role of extracellular vesicles on cancer lymphangiogenesis and lymph node metastasis. Front Oncol 11:721785. https://doi.org/10.3389/fonc.2021.721785CrossRefPubMedPubMedCentral

Wang F, Tao Z, Tian Z, Jin J, Dong J, Dai Y, Yu W, Tang B, Hu S (2022) CCR5 as a prognostic factor in lower-grade glioma is involved in the remodeling of the tumor microenvironment. Front Genet 13:874896. https://doi.org/10.3389/fgene.2022.874896CrossRefPubMedPubMedCentral

Weng CJ, Chien MH, Lin CW, Chung TT, Zavras AI, Tsai CM, Mk C, Yang SF (2010) Effect of CC chemokine ligand 5 and CC chemokine receptor 5 genes polymorphisms on the risk and clinicopathological development of oral cancer. Oral Oncol 46(10):767–772. https://doi.org/10.1016/j.oraloncology.2010.07.011CrossRefPubMed

Willenbrock F, Cox CM, Parkes EE, Wilhelm-Benartzi CS, Abraham AG, Owens R, Sabbagh A, Jones CM, Hughes DLI, Maughan T, Hurt CN, O’Neill EE, Mukherjee S (2021) Circulating biomarkers and outcomes from a randomised phase 2 trial of gemcitabine versus capecitabine-based chemoradiotherapy for pancreatic cancer. Br J Cancer 124(3):581–586. https://doi.org/10.1038/s41416-020-01120-zCrossRefPubMed

Xu L, Wu W, Cheng G, Qian M, Hu K, Yin G, Wang S (2017) Enhancement of proliferation and invasion of gastric cancer cell by KDM5C via decrease in p53 expression. Technol Cancer Res Treat 16(2):141–149. https://doi.org/10.1177/1533034616629261CrossRefPubMed

Yang H, Son NH, Lee SH, Kim D, Kim HJ, Cha IH, Nam W (2021) Predictive modelling of level IIb lymph node metastasis in oral squamous cell carcinoma. Sci Rep 11(1):17562. https://doi.org/10.1038/s41598-021-96827-1ADSCrossRefPubMedPubMedCentral

Zeng Z, Lan T, Wei Y, Wei X (2022) CCL5/CCR5 axis in human diseases and related treatments. Genes Dis 9(1):12–27. https://doi.org/10.1016/j.gendis.2021.08.004CrossRefPubMed

Titel: CCR5/CCL5 axis is linked to a poor outcome, and inhibition reduces metastasis in oral squamous cell carcinoma
verfasst von: Wilfredo Alejandro González-Arriagada
Ricardo D. Coletta
Carlo Lozano-Burgos
Cynthia García
Jaime Maripillán
Francisca Alcayaga-Miranda
Bastián Godínez-Pacheco
Sebastián Oyarce-Pezoa
René Martínez-Flores
Isaac E. García
Publikationsdatum: 13.10.2023
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 19/2023
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-023-05443-1

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

CCR5/CCL5 axis is linked to a poor outcome, and inhibition reduces metastasis in oral squamous cell carcinoma