Skip to main content
SpringerLink
Log in

CCL4 Signaling in the Tumor Microenvironment

  • Chapter
  • First Online:
Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1231))

Abstract

CCL4, a CC chemokine, previously known as macrophage inflammatory protein (MIP)-1β, has diverse effects on various types of immune and nonimmune cells by the virtue of its interaction with its specific receptor, CCR5, in collaboration with related but distinct CC chemokines such as CCL3 and CCL5, which can also bind CCR5. Several lines of evidence indicate that CCL4 can promote tumor development and progression by recruiting regulatory T cells and pro-tumorigenic macrophages, and acting on other resident cells present in the tumor microenvironment, such as fibroblasts and endothelial cells, to facilitate their pro-tumorigenic capacities. These observations suggest the potential efficacy of CCR5 antagonists for cancer treatment. On the contrary, under some situations, CCL4 can enhance tumor immunity by recruiting cytolytic lymphocytes and macrophages with phagocytic ability. Thus, presently, the clinical application of CCR5 antagonists warrants more detailed analysis of the role of CCL4 and other CCR5-binding chemokines in the tumor microenvironment.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Griffith JW, Sokol CL, Luster AD (2014) Chemokines and chemokine receptors: positioning cells for host defense and immunity. Ann Rev Immunol 32:659–702

    CAS  Google Scholar 

  2. Miller MC, Mayo KH (2017) Chemokines from a structural perspective. Int J Mol Sci 18:10

    Google Scholar 

  3. Mukaida N, Baba T (2012) Chemokines in tumor development and progression. Exp Cell Res 318(2):95–102

    CAS  PubMed  Google Scholar 

  4. Wolpe SD, Davatelis G, Sherry B, Beutler B, Hesse DG, Nguyen HT et al (1988) Macrophages secrete a novel heparin-binding protein with inflammatory and neutrophil chemokinetic properties. J Exp Med 167(2):570–581

    CAS  PubMed  Google Scholar 

  5. Sherry B, Tekamp-Olson P, Gallegos C, Bauer D, Davatelis G, Wolpe SD et al (1988) Resolution of the two components of macrophage inflammatory protein 1, and cloning and characterization of one of those components, macrophage inflammatory protein 1 beta. J Exp Med 168(6):2251–2259

    CAS  PubMed  Google Scholar 

  6. Obaru K, Fukuda M, Maeda S, Shimada KA (1986) cDNA clone used to study mRNA inducible in human tonsillar lymphocytes by a tumor promoter. J Biochem 99(3):885–894

    CAS  PubMed  Google Scholar 

  7. Lipes MA, Napolitano M, Jeang KT, Chang NT, Leonard WJ (1988) Identification, cloning, and characterization of an immune activation gene. Proc Natl Acad Sci U S A 85(24):9704–9708

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Zipfel PF, Balke J, Irving SG, Kelly K, Siebenlist U (1989) Mitogenic activation of human T cells induces two closely related genes which share structural similarities with a new family of secreted factors. J Immunol 142(5):1582–1590

    CAS  PubMed  Google Scholar 

  9. Chang HC, Reinherz EL (1989) Isolation and characterization of a cDNA encoding a putative cytokine which is induced by stimulation via the CD2 structure on human T lymphocytes. Eur J Immunol 19(6):1045–1051

    CAS  PubMed  Google Scholar 

  10. Bachelerie F, Ben-Baruch A, Burkhardt AM, Combadiere C, Farber JM, Graham GJ et al (2014) International union of basic and clinical pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev 66(1):1–79

    PubMed  PubMed Central  Google Scholar 

  11. Irving SG, Zipfel PF, Balke J, McBride OW, Morton CC, Burd PR et al (1990) Two inflammatory mediator cytokine genes are closely linked and variably amplified on chromosome 17q. Nucleic Acids Res 18(11):3261–3270

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Colobran R, Adreani P, Ashhab Y, Llano A, Este JA, Dominguez O et al (2005) Multiple products derived from two CCL4 loci: high incidence of a new polymorphism in HIV+ patients. J Immunol 174(9):5655–5664

    CAS  PubMed  Google Scholar 

  13. Townson JR, Barcellos LF, Nibbs RJ (2002) Gene copy number regulates the production of the human chemokine CCL3-L1. Eur J Immunol 32(10):3016–3026

    CAS  PubMed  Google Scholar 

  14. Lodi PJ, Garrett DS, Kuszewski J, Tsang ML, Weatherbee JA, Leonard WJ et al (1994) High-resolution solution structure of the beta chemokine hMIP-1 beta by multidimensional NMR. Science 263(5154):1762–1767

    CAS  PubMed  Google Scholar 

  15. Ren M, Guo Q, Guo L, Lenz M, Qian F, Koenen RR et al (2010) Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulin-degrading enzyme. Embo J 29(23):3952–3966

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lortat-Jacob H, Grosdidier A, Imberty A (2002) Structural diversity of heparan sulfate binding domains in chemokines. Proc Natl Acad Sci U S A 99(3):1229–1234

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Koopmann W, Ediriwickrema C, Krangel MS (1999) Structure and function of the glycosaminoglycan binding site of chemokine macrophage-inflammatory protein-1 beta. J Immunol 163(4):2120–2127

    CAS  PubMed  Google Scholar 

  18. Menten P, Wuyts A, Van Damme J (2002) Macrophage inflammatory protein-1. Cytokine Growth Factor Rev 13(6):455–481

    CAS  PubMed  Google Scholar 

  19. Ziegler SF, Tough TW, Franklin TL, Armitage RJ, Alderson MR (1991) Induction of macrophage inflammatory protein-1 beta gene expression in human monocytes by lipopolysaccharide and IL-7. J Immunol 147(7):2234–2239

    CAS  PubMed  Google Scholar 

  20. Oliva A, Kinter AL, Vaccarezza M, Rubbert A, Catanzaro A, Moir S et al (1998) Natural killer cells from human immunodeficiency virus (HIV)-infected individuals are an important source of CC-chemokines and suppress HIV-1 entry and replication in vitro. J Clin Invest 102(1):223–231

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P (1995) Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 270(5243):1811–1815

    CAS  PubMed  Google Scholar 

  22. Zaitseva M, King LR, Manischewitz J, Dougan M, Stevan L, Golding H et al (2001) Human peripheral blood T cells, monocytes, and macrophages secrete macrophage inflammatory proteins 1alpha and 1beta following stimulation with heat-inactivated Brucella abortus. Infect Immun 69(6):3817–3826

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Krzysiek R, Lefevre EA, Zou W, Foussat A, Bernard J, Portier A et al (1999) Antigen receptor engagement selectively induces macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta chemokine production in human B cells. J Immunol 162(8):4455–4463

    CAS  PubMed  Google Scholar 

  24. Sallusto F, Palermo B, Lenig D, Miettinen M, Matikainen S, Julkunen I et al (1999) Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur J Immunol 29(5):1617–1625

    CAS  PubMed  Google Scholar 

  25. Lapinet JA, Scapini P, Calzetti F, Perez O, Cassatella MA (2000) Gene expression and production of tumor necrosis factor alpha, interleukin-1beta (IL-1beta), IL-8, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and gamma interferon-inducible protein 10 by human neutrophils stimulated with group B meningococcal outer membrane vesicles. Infect Immun 68(12):6917–6923

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Lukacs NW, Kunkel SL, Allen R, Evanoff HL, Shaklee CL, Sherman JS et al (1995) Stimulus and cell-specific expression of C-X-C and C-C chemokines by pulmonary stromal cell populations. Am J Physiol 268(5 Pt 1):L856–L861

    CAS  PubMed  Google Scholar 

  27. Shukaliak JA, Dorovini-Zis K (2000) Expression of the beta-chemokines RANTES and MIP-1 beta by human brain microvessel endothelial cells in primary culture. J Neuropathol Exp Neurol 59(5):339–352

    CAS  PubMed  Google Scholar 

  28. Samson M, Labbe O, Mollereau C, Vassart G, Parmentier M (1996) Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry 35(11):3362–3367

    CAS  PubMed  Google Scholar 

  29. Neote K, DiGregorio D, Mak JY, Horuk R, Schall TJ (1993) Molecular cloning, functional expression, and signaling characteristics of a C-C chemokine receptor. Cell 72(3):415–425

    CAS  PubMed  Google Scholar 

  30. Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R et al (1996) Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273(5283):1856–1862

    CAS  PubMed  Google Scholar 

  31. Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM et al (1996) Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382(6593):722–725

    CAS  PubMed  Google Scholar 

  32. Scurci I, Martins E, Hartley O (2018) CCR5: Established paradigms and new frontiers for a ‘celebrity’ chemokine receptor. Cytokine 109:81–93

    CAS  PubMed  Google Scholar 

  33. Oppermann M, Mack M, Proudfoot AE, Olbrich H (1999) Differential effects of CC chemokines on CC chemokine receptor 5 (CCR5) phosphorylation and identification of phosphorylation sites on the CCR5 carboxyl terminus. J Biol Chem 274(13):8875–8885

    CAS  PubMed  Google Scholar 

  34. Shukla AK, Xiao K, Lefkowitz RJ (2011) Emerging paradigms of beta-arrestin-dependent seven transmembrane receptor signaling. Trends Biochem Sci 36(9):457–469

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Escola JM, Kuenzi G, Gaertner H, Foti M, Hartley O (2010) CC chemokine receptor 5 (CCR5) desensitization: cycling receptors accumulate in the trans-Golgi network. J Biol Chem 285(53):41772–41780

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Rottman JB, Ganley KP, Williams K, Wu L, Mackay CR, Ringler DJ (1997) Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection. Am J Pathol 151(5):1341–1351

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Sallusto F, Lenig D, Mackay CR, Lanzavecchia A (1998) Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med 187(6):875–883

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Schlecker E, Stojanovic A, Eisen C, Quack C, Falk CS, Umansky V et al (2012) Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent recruitment of regulatory T cells favoring tumor growth. J Immunol 189(12):5602–5611

    CAS  PubMed  Google Scholar 

  39. Taub DD, Sayers TJ, Carter CR, Ortaldo JR (1995) Alpha and beta chemokines induce NK cell migration and enhance NK-mediated cytolysis. J Immunol 155(8):3877–3888

    CAS  PubMed  Google Scholar 

  40. Taub DD, Conlon K, Lloyd AR, Oppenheim JJ, Kelvin DJ (1993) Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1 alpha and MIP-1 beta. Science 260(5106):355–358

    CAS  PubMed  Google Scholar 

  41. Tanaka Y, Adams DH, Hubscher S, Hirano H, Siebenlist U, Shaw S (1993) T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1 beta. Nature 361(6407):79–82

    CAS  PubMed  Google Scholar 

  42. Sozzani S, Allavena P, D’Amico G, Luini W, Bianchi G, Kataura M et al (1998) Differential regulation of chemokine receptors during dendritic cell maturation: a model for their trafficking properties. J Immunol 161(3):1083–1086

    CAS  PubMed  Google Scholar 

  43. Uguccioni M, D’Apuzzo M, Loetscher M, Dewald B, Baggiolini M (1995) Actions of the chemotactic cytokines MCP-1, MCP-2, MCP-3, RANTES, MIP-1 alpha and MIP-1 beta on human monocytes. Eur J Immunol 25(1):64–68

    CAS  PubMed  Google Scholar 

  44. Broxmeyer HE, Sherry B, Cooper S, Lu L, Maze R, Beckmann MP et al (1993) Comparative analysis of the human macrophage inflammatory protein family of cytokines (chemokines) on proliferation of human myeloid progenitor cells. Interacting effects involving suppression, synergistic suppression, and blocking of suppression. J Immunol 150(8 Pt 1):3448–3458

    CAS  PubMed  Google Scholar 

  45. Schecter AD, Calderon TM, Berman AB, McManus CM, Fallon JT, Rossikhina M et al (2000) Human vascular smooth muscle cells possess functional CCR5. J Biol Chem 275(8):5466–5471

    CAS  PubMed  Google Scholar 

  46. Berger O, Gan X, Gujuluva C, Burns AR, Sulur G, Stins M et al (1999) CXC and CC chemokine receptors on coronary and brain endothelia. Mol Med 5(12):795–805

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Maguire JJ, Jones KL, Kuc RE, Clarke MC, Bennett MR, Davenport AP (2014) The CCR5 chemokine receptor mediates vasoconstriction and stimulates intimal hyperplasia in human vessels in vitro. Cardiovasc Res 101(3):513–521

    CAS  PubMed  Google Scholar 

  48. Sasaki S, Baba T, Nishimura T, Hayakawa Y, Hashimoto S, Gotoh N et al (2016) Essential roles of the interaction between cancer cell-derived chemokine, CCL4, and intra-bone CCR5-expressing fibroblasts in breast cancer bone metastasis. Cancer Lett 378(1):23–32

    CAS  PubMed  Google Scholar 

  49. Wang B, Chou YE, Lien MY, Su CM, Yang SF, Tang CH (2017) Impacts of CCL4 gene polymorphisms on hepatocellular carcinoma susceptibility and development. Int J Med Sci 14(9):880–884

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Lien MY, Lin CW, Tsai HC, Chen YT, Tsai MH, Hua CH et al (2017) Impact of CCL4 gene polymorphisms and environmental factors on oral cancer development and clinical characteristics. Oncotarget 8(19):31424–31434

    PubMed  PubMed Central  Google Scholar 

  51. Hu GN, Tzeng HE, Chen PC, Wang CQ, Zhao YM, Wang Y et al (2018) Correlation between CCL4 gene polymorphisms and clinical aspects of breast cancer. Int J Med Sci 15(11):1179–1186

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Erreni M, Bianchi P, Laghi L, Mirolo M, Fabbri M, Locati M et al (2009) Expression of chemokines and chemokine receptors in human colon cancer. Methods Enzymol 460:105–121

    CAS  PubMed  Google Scholar 

  53. Nishikawa G, Kawada K, Nakagawa J, Toda K, Ogawa R, Inamoto S et al (2019) Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5. Cell Death Dis 10(4):264

    PubMed  PubMed Central  Google Scholar 

  54. De la Fuente Lopez M, Landskron G, Parada D, Dubois-Camacho K, Simian D, Martinez M et al (2018) The relationship between chemokines CCL2, CCL3, and CCL4 with the tumor microenvironment and tumor-associated macrophage markers in colorectal cancer. Tumour Biol 40(11):1010428318810059

    PubMed  Google Scholar 

  55. Fujimoto H, Saito Y, Ohuchida K, Kawakami E, Fujiki S, Watanabe T et al (2018) Deregulated mucosal immune surveillance through gut-associated regulatory T cells and PD-1(+) T cells in human colorectal cancer. J Immunol 200(9):3291–3303

    CAS  PubMed  Google Scholar 

  56. Xue J, Yu X, Xue L, Ge X, Zhao W, Peng W (2019) Intrinsic beta-catenin signaling suppresses CD8(+) T-cell infiltration in colorectal cancer. Biomed Pharmacother 108921:115

    Google Scholar 

  57. Vayrynen JP, Kantola T, Vayrynen SA, Klintrup K, Bloigu R, Karhu T et al (2016) The relationships between serum cytokine levels and tumor infiltrating immune cells and their clinical significance in colorectal cancer. Int J Cancer 139(1):112–121

    PubMed  Google Scholar 

  58. Li L, Liu YD, Zhan YT, Zhu YH, Li Y, Xie D et al (2018) High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma. Thoracic Cancer 9(7):775–784

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Chen S, Jiao J, Jiang D, Wan Z, Li L, Li K et al (2015) T-box transcription factor Brachyury in lung cancer cells inhibits macrophage infiltration by suppressing CCL2 and CCL4 chemokines. Tumour Biol 36(8):5881–5890

    CAS  PubMed  Google Scholar 

  60. Scaiewicz V, Nahmias A, Chung RT, Mueller T, Tirosh B, Shibolet OCCAAT (2013) enhancer-binding protein homologous (CHOP) protein promotes carcinogenesis in the DEN-induced hepatocellular carcinoma model. PLoS One 8(12):e81065

    PubMed  PubMed Central  Google Scholar 

  61. Trellakis S, Bruderek K, Dumitru CA, Gholaman H, Gu X, Bankfalvi A et al (2011) Polymorphonuclear granulocytes in human head and neck cancer: enhanced inflammatory activity, modulation by cancer cells and expansion in advanced disease. Int J Cancer 129(9):2183–2193

    CAS  PubMed  Google Scholar 

  62. Wang Y, Liu T, Yang N, Xu S, Li X, Wang D (2016) Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis. Oncol Rep 36(6):3522–3528

    CAS  PubMed  Google Scholar 

  63. Xiao L, Harrell JC, Perou CM, Dudley AC (2014) Identification of a stable molecular signature in mammary tumor endothelial cells that persists in vitro. Angiogenesis 17(3):511–518

    CAS  PubMed  Google Scholar 

  64. Pitarresi JR, Liu X, Sharma SM, Cuitino MC, Kladney RD, Mace TA et al (2016) Stromal ETS2 regulates chemokine production and immune cell recruitment during acinar-to-ductal metaplasia. Neoplasia 18(9):541–552

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lien MY, Tsai HC, Chang AC, Tsai MH, Hua CH, Wang SW et al (2018) Chemokine CCL4 induces vascular endothelial growth factor C expression and lymphangiogenesis by miR-195-3p in oral squamous cell carcinoma. Front Immunol 9:412

    PubMed  PubMed Central  Google Scholar 

  66. 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. Cellular Oncol 42(1):93–106

    CAS  Google Scholar 

  67. Liu JY, Li F, Wang LP, Chen XF, Wang D, Cao L et al (2015) CTL- vs Treg lymphocyte-attracting chemokines, CCL4 and CCL20, are strong reciprocal predictive markers for survival of patients with oesophageal squamous cell carcinoma. Br J Cancer 113(5):747–755

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Pallasch CP, Leskov I, Braun CJ, Vorholt D, Drake A, Soto-Feliciano YM et al (2014) Sensitizing protective tumor microenvironments to antibody-mediated therapy. Cell 156(3):590–602

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Sektioglu IM, Carretero R, Bulbuc N, Bald T, Tuting T, Rudensky AY et al (2017) Basophils promote tumor rejection via chemotaxis and infiltration of CD8+ T cells. Cancer Res 77(2):291–302

    CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported partly by the Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS) KAKEHI grant number 17K07159.

Author information

Authors and Affiliations

  1. Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan

    Naofumi Mukaida, So-ichiro Sasaki & Tomohisa Baba

Authors
  1. Naofumi Mukaida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. So-ichiro Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomohisa Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naofumi Mukaida .

Editor information

Editors and Affiliations

  1. Department of Radiology, Columbia University Medical Center, New York, NY, USA

    Alexander Birbrair

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mukaida, N., Sasaki, Si., Baba, T. (2020). CCL4 Signaling in the Tumor Microenvironment. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1231. Springer, Cham. https://doi.org/10.1007/978-3-030-36667-4_3

Download citation

Publish with us

Policies and ethics

Search

Navigation