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Breast Cancer Research
Published in: Breast Cancer Research 1/2018

Open Access 01-12-2018 | Research article

Simultaneous blockade of IL-6 and CCL5 signaling for synergistic inhibition of triple-negative breast cancer growth and metastasis

Authors: Kideok Jin, Niranjan B. Pandey, Aleksander S. Popel

Published in: Breast Cancer Research | Issue 1/2018

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Abstract

Background

Metastatic triple-negative breast cancer (TNBC) is a heterogeneous and incurable disease. Numerous studies have been conducted to seek molecular targets to treat TNBC effectively, but chemotherapy is still the main choice for patients with TNBC. We have previously presented evidence of the important roles of interleukin-6 (IL-6) and chemokine (C-C motif) ligand 5 (CCL5) in TNBC tumor growth and metastasis. These experiments highlighted the importance of the crosstalk between cancer cells and stromal lymphatic endothelial cells (LECs) in tumor growth and metastasis.

Methods

We examined the viability and migration of MDA-MB-231-LN, SUM149, and SUM159 cells co-cultured with LECs when treated with maraviroc (CCR5 inhibitor) and tocilizumab (anti-IL-6 receptor antibody). To assess the anti-tumor effects of the combination of these two drugs in an athymic nude mouse model, MDA-MB-231-LN cells were implanted in the mammary fat pad and maraviroc (8 mg/kg, orally daily) and cMR16-1 (murine surrogate of the anti-IL-6R antibody, 10 mg/kg, IP, 3 days a week) were administrated for 5 weeks and effects on tumor growth and thoracic metastasis were measured.

Results

In this study, we used maraviroc and tocilizumab to confirm that IL-6 and CCL5 signaling are key pathways promoting TNBC cell proliferation and migration. Further, in a xenograft mouse model, we showed that tumor growth was dramatically inhibited by cMR16-1, the mouse version of the anti-IL6R antibody. The combination of maraviroc and cMR16-1 caused significant reduction of TNBC tumor growth compared to the single agents. Significantly, the combination of maraviroc and cMR16-1 abrogated thoracic metastasis.

Conclusion

Taken together, these findings show that IL-6 and CCL5 signaling, which promote crosstalk between TNBC and lymphatic vessels, are key enhancers of TNBC tumor growth and metastasis. Furthermore, these results demonstrate that a drug combination inhibiting these pathways may be a promising therapy for TNBC patients.
Appendix
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Literature
1.
Lee E, Pandey NB, Popel AS. Crosstalk between cancer cells and blood endothelial and lymphatic endothelial cells in tumour and organ microenvironment. Expert Rev Mol Med. 2015;17:e3.CrossRefPubMedPubMedCentral
2.
Karnezis T, Shayan R, Caesar C, Roufail S, Harris NC, Ardipradja K, Zhang YF, Williams SP, Farnsworth RH, Chai MG, et al. VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell. 2012;21(2):181–95.CrossRefPubMed
3.
Wakisaka N, Hasegawa Y, Yoshimoto S, Miura K, Shiotani A, Yokoyama J, Sugasawa M, Moriyama-Kita M, Endo K, Yoshizaki T. Primary tumor-secreted lymphangiogenic factors induce pre-metastatic lymphvascular niche formation at sentinel lymph nodes in oral squamous cell carcinoma. PLoS One. 2015;10(12):e0144056.CrossRefPubMedPubMedCentral
4.
Cao Y. Opinion: emerging mechanisms of tumour lymphangiogenesis and lymphatic metastasis. Nat Rev Cancer. 2005;5(9):735–43.CrossRefPubMed
5.
Von Marschall Z, Scholz A, Stacker SA, Achen MG, Jackson DG, Alves F, Schirner M, Haberey M, Thierauch KH, Wiedenmann B, et al. Vascular endothelial growth factor-D induces lymphangiogenesis and lymphatic metastasis in models of ductal pancreatic cancer. Int J Oncol. 2005;27(3):669–79.PubMed
6.
Kesler CT, Liao S, Munn LL, Padera TP. Lymphatic vessels in health and disease. Wiley Interdiscip Rev Syst Biol Med. 2013;5(1):111–24.CrossRefPubMed
7.
Sleeman JP. The lymph node pre-metastatic niche. J Mol Med (Berl). 2015;93(11):1173–84.CrossRef
8.
Lee E, Fertig EJ, Jin K, Sukumar S, Pandey NB, Popel AS. Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis. Nat Commun. 2014;5:4715.CrossRefPubMedPubMedCentral
9.
Lee E, Rosca EV, Pandey NB, Popel AS. Small peptides derived from somatotropin domain-containing proteins inhibit blood and lymphatic endothelial cell proliferation, migration, adhesion and tube formation. Int J Biochem Cell Biol. 2011;43(12):1812–21.CrossRefPubMedPubMedCentral
10.
Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul. 1984;22:27–55.CrossRef
11.
Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70(2):440–6.CrossRefPubMed
12.
Koskimaki JE, Lee E, Chen W, Rivera CG, Rosca EV, Pandey NB, Popel AS. Synergy between a collagen IV mimetic peptide and a somatotropin-domain derived peptide as angiogenesis and lymphangiogenesis inhibitors. Angiogenesis. 2013;16(1):159–70.CrossRefPubMed
13.
14.
Lee E, Pandey NB, Popel AS. Pre-treatment of mice with tumor-conditioned media accelerates metastasis to lymph nodes and lungs: a new spontaneous breast cancer metastasis model. Clin Exp Metastasis. 2014;31(1):67–79.CrossRefPubMed
15.
Achen MG, Stacker SA. Tumor lymphangiogenesis and metastatic spread-new players begin to emerge. Int J Cancer. 2006;119(8):1755–60.CrossRefPubMed
16.
Dieterich LC, Detmar M. Tumor lymphangiogenesis and new drug development. Adv Drug Deliv Rev. 2016;99(Pt B):148–60.CrossRefPubMed
17.
Steinskog ES, Sagstad SJ, Wagner M, Karlsen TV, Yang N, Markhus CE, Yndestad S, Wiig H, Eikesdal HP. Impaired lymphatic function accelerates cancer growth. Oncotarget. 2016;7(29):45789–802.CrossRefPubMedPubMedCentral
18.
Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 1997;16(13):3898–911.CrossRefPubMedPubMedCentral
19.
Stacker SA, Stenvers K, Caesar C, Vitali A, Domagala T, Nice E, Roufail S, Simpson RJ, Moritz R, Karpanen T, et al. Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. J Biol Chem. 1999;274(45):32127–36.CrossRefPubMed
20.
Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med. 2005;201(7):1089–99.CrossRefPubMedPubMedCentral
21.
Bjorndahl MA, Cao R, Burton JB, Brakenhielm E, Religa P, Galter D, Wu L, Cao Y. Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res. 2005;65(20):9261–8.CrossRefPubMed
22.
Schulz P, Fischer C, Detjen KM, Rieke S, Hilfenhaus G, von Marschall Z, Bohmig M, Koch I, Kehrberger J, Hauff P, et al. Angiopoietin-2 drives lymphatic metastasis of pancreatic cancer. FASEB J. 2011;25(10):3325–35.CrossRefPubMed
23.
Fagiani E, Lorentz P, Kopfstein L, Christofori G. Angiopoietin-1 and -2 exert antagonistic functions in tumor angiogenesis, yet both induce lymphangiogenesis. Cancer Res. 2011;71(17):5717–27.CrossRefPubMed
24.
Kajiya K, Hirakawa S, Ma B, Drinnenberg I, Detmar M. Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J. 2005;24(16):2885–95.CrossRefPubMedPubMedCentral
25.
Jiang WG, Davies G, Martin TA, Parr C, Watkins G, Mansel RE, Mason MD. The potential lymphangiogenic effects of hepatocyte growth factor/scatter factor in vitro and in vivo. Int J Mol Med. 2005;16(4):723–8.PubMed
26.
Cao R, Bjorndahl MA, Gallego MI, Chen S, Religa P, Hansen AJ, Cao Y. Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action. Blood. 2006;107(9):3531–6.CrossRefPubMed
27.
Platonova N, Miquel G, Regenfuss B, Taouji S, Cursiefen C, Chevet E, Bikfalvi A. Evidence for the interaction of fibroblast growth factor-2 with the lymphatic endothelial cell marker LYVE-1. Blood. 2013;121(7):1229–37.CrossRefPubMed
28.
Marino D, Angehrn Y, Klein S, Riccardi S, Baenziger-Tobler N, Otto VI, Pittelkow M, Detmar M. Activation of the epidermal growth factor receptor promotes lymphangiogenesis in the skin. J Dermatol Sci. 2013;71(3):184–94.CrossRefPubMedPubMedCentral
29.
Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D, Meister B, Ikomi F, Tritsaris K, Dissing S, et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell. 2004;6(4):333–45.CrossRefPubMed
30.
Li ZJ, Ying XJ, Chen HL, Ye PJ, Chen ZL, Li G, Jiang HF, Liu J, Zhou SZ. Insulin-like growth factor-1 induces lymphangiogenesis and facilitates lymphatic metastasis in colorectal cancer. World J Gastroenterol. 2013;19(43):7788–94.CrossRefPubMedPubMedCentral
31.
Velasco-Velazquez M, Jiao X, De La Fuente M, Pestell TG, Ertel A, Lisanti MP, Pestell RG. CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res. 2012;72(15):3839–50.CrossRefPubMed
32.
Velasco-Velazquez M, Xolalpa W, Pestell RG. The potential to target CCL5/CCR5 in breast cancer. Expert Opin Ther Targets. 2014;18(11):1265–75.CrossRefPubMed
33.
34.
Hartman ZC, Poage GM, den Hollander P, Tsimelzon A, Hill J, Panupinthu N, Zhang Y, Mazumdar A, Hilsenbeck SG, Mills GB, et al. Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8. Cancer Res. 2013;73(11):3470–80.CrossRefPubMed
35.
Lin C, Liao W, Jian Y, Peng Y, Zhang X, Ye L, Cui Y, Wang B, Wu X, Xiong Z, et al. CGI-99 promotes breast cancer metastasis via autocrine interleukin-6 signaling. Oncogene. 2017;36(26):3695-705.
Metadata
Title
Simultaneous blockade of IL-6 and CCL5 signaling for synergistic inhibition of triple-negative breast cancer growth and metastasis
Authors
Kideok Jin
Niranjan B. Pandey
Aleksander S. Popel
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2018
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-018-0981-3

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