Chemokines and Lymphoproliferative Disorders

Chemokines are small proteins that regulate lymphocyte trafficking, the function of the immune system, the organisation of cells within the tissues and the formation of secondary lymphoid organs. Chemokines exert their biological effects on binding to chemokine receptors that are heterotrimeric, seven transmembrane, G-coupled receptors. Chemokines and chemokine receptors play a critical role in many pathophysiological processes such as allergic responses, infectious and autoimmune diseases, angiogenesis, inflammation and tumour growth.

In particular, lymphoproliferative disorders (LPD) develop a complex chemokine network that establishes an appropriate microenvironment for the tumour cells and allows cell growth, inhibition of apoptosis, migration and angiogenesis.

This article summarises the current information about chemokine/chemokine receptor expression and function in human LPD, stressing the specific role played in processes such as cell homing, tumour growth and progression. Finally, we discuss the potential value of chemokine receptors as novel therapeutic targets.

Key Concepts

  • Chemokines are small proteins involved in lymphocyte recruitment and trafficking to inflammatory sites.
  • Chemokines mediate their biological effects on binding to specific chemokine receptors that are heterotrimeric, seven-transmembrane, G-coupled receptors classified in four families, that is CXCR, CCR, CX3CR and CR.
  • Chemokines and chemokine receptors play a critical role in many pathophysiological processes such as allergic responses, infectious and autoimmune diseases, angiogenesis, inflammation and tumour growth.
  • Lymphoproliferative disorders are a set of disorders characterised by the abnormal proliferation of specific lymphocyte subsets that may be classified in: B-cell neoplasms, T-cell and NK-cell neoplasms and Hodgkin lymphoma.
  • Chemokines and chemokine receptors are largely expressed by malignant lymphocytes and play important roles in cell homing, tumour growth and progression.
  • Chemokine receptor antagonists hold promise for therapeutic targeting of some lymphoproliferative diseases.
  • B-chronic lymphocytic leukaemia progression is frequently accompanied by lymphoadenopathy, a process where the CCR7/CCL19/CCL21 axis represents an important contributor.
  • Multiple myeloma (MM) is a lymphoproliferative disease characterised by the expansion of plasma cells in the bone marrow, with high tendency to metastasise and cause osteolytic lesions. This latter process is regulated by osteoclast stimulating factors secreted by myeloma cells, marrow stromal cells or both. Among osteoclast stimulating factors, CCL3 has been identified as a pivotal molecule implicated in the development of MM and has been proposed as marker of poor prognosis.
  • T-cell acute lymphoblastic leukaemia (T-ALL) is a T-cell lymphoproliferative disease often characterised by central nervous system infiltration at relapse. CCR7 has been identified as a key receptor used by T-ALL cells to invade the CNS.
  • Hodgkin disease is characterised by the presence in the malignant lesions of low numbers of tumour cells known as Reed–Sternberg (R-S) cells embedded in a network of inflammatory cells. The recruitment of T lymphocytes into the involved tissue is regulated by specific chemokine/chemokine receptors axes, mainly CCL17 and CCL22 that attract T helper (TH2) cells and T regulatory cells (Tregs), respectively.

Keywords: chemokines; chemokine receptors; lymphoproliferative disorders

Figure 1. The role of chemokines/chemokine receptors in B-CLL. B-CLL cells express different chemokine receptors at high levels among which CXCR4 and CCR7 play important roles in tumour cell migration. CXCR4, the chemokine receptor for CXCL12, directs leukaemic cell chemotaxis and drives B-CLL cell infiltration into the bone marrow stroma. CXCL12 is produced not only by stromal cells but also by nurse-like cells (NLC), blood mononuclear cells that attract B-CLL cells and sustain their proliferation through the secretion of CXCL12. Also, CD40/CD40L interactions between B-CLL and T cells cooperate with B-cell receptor signalling to trigger survival of tumour B cells. CCR7 (the receptor for CCL19 and CCL21 chemokines) is highly expressed by B-CLL cells and is important for the migration of leukaemic cells into lymph nodes.
Figure 2. Model for the role of chemokines in multiple myeloma. Step 1: Stromal cells secrete different chemokines, such as CCL2, CCL3, CXCL8, CXCL12 and CCL20, among which CCL2 and CXCL12 attract multiple myeloma (MM) cells to the bone. Then, MM cells interact with stromal cells through 41/VCAM adhesion molecules. Step 2: After interaction between MM and stromal cells, the latter cells secrete different osteoclast-activating factors such as CXCL8, CCL2, IL-6 and RANKL. Moreover, MM cells upregulate production of CCL3 and IL-3 that stimulate their growth. Step 3: All the chemokines and cytokines depicted in the figure sustain MM cell survival and growth. Finally, the increased expression of RANKL, IL-3, CXCL8, CCL2, CCL3 and IL-6 induce osteoclast activation and bone resorption.
Figure 3. The role of chemokines in the formation of Hodgkin lymphoma microenvironment. Hodgkin lymphoma is characterised by the presence of Reed–Sternberg (R-S) cells and different inflammatory cells, such as T lymphocytes, T regulatory (Treg) cells, mast cells and eosinophils. R-S cells produce CCL17 and CCL22 that attract T helper (TH2) and Treg cells, both of which express CCR4. In addition, R-S cells secrete CCL5 and CCL28 which induce respectively mast cell and eosinophil migration. Eosinophil migration is also driven by CCL11 produced by R-S cells. Among the chemokine receptors, CCR7, CXCR4 and CCR5 are the most frequently expressed by R-S cells. CCR5, together with its ligands CCL3, CCL4 and CCL5, is involved in malignant cell growth and CD4+ T cell and eosinophil migration.
close
 References
    Aldinucci D, Lorenzon D, Cattaruzza L et al. (2008) Expression of CCR5 receptors on Reed-Sternberg cells and Hodgkin lymphoma cell lines: involvement of CCL5/Rantes in tumor cell growth and microenvironmental interactions. International Journal of Cancer 122: 769–776.
    Alfonso-Perez M, Lopez-Giral S, Quintana NE et al. (2006) Anti-CCR7 monoclonal antibodies as a novel tool for the treatment of chronic lymphocyte leukemia. Journal of Leukocyte Biology 79: 1157–1165.
    Alsayed Y, Ngo H, Runnels J et al. (2007) Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood 109: 2708–2717.
    Arendt BK, Velazquez-Dones A, Tschumper RC et al. (2002) Interleukin 6 induces monocyte chemoattractant protein-1 expression in myeloma cells. Leukemia 16: 2142–2147.
    Barone F, Bombardieri M, Rosado MM et al. (2008) CXCL13, CCL21, and CXCL12 expression in salivary glands of patients with Sjogren's syndrome and MALT lymphoma: association with reactive and malignant areas of lymphoid organization. Journal of Immunology 180: 5130–5140.
    Basso K, Liso A, Tiacci E et al. (2004) Gene expression profiling of hairy cell leukemia reveals a phenotype related to memory B cells with altered expression of chemokine and adhesion receptors. Journal of Experimental Medicine 199: 59–68.
    Bradstock KF, Makrynikola V, Bianchi A et al. (2000) Effects of the chemokine stromal cell-derived factor-1 on the migration and localization of precursor-B acute lymphoblastic leukemia cells within bone marrow stromal layers. Leukemia 14: 882–888.
    Buonamici S, Trimarchi T, Ruocco MG et al. (2009) CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature 459: 1000–1004.
    Burger JA, Burger M and Kipps TJ (1999) Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood 94: 3658–3667.
    Burger JA, Quiroga MP, Hartmann E et al. (2009) High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation. Blood 113: 3050–3058.
    Choi SJ, Cruz JC, Craig F et al. (2000) Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. Blood 96: 671–675.
    Choi SJ, Oba Y, Gazitt Y et al. (2001) Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease. Journal of Clinical Investigation 108: 1833–1841.
    Corcione A, Arduino N, Ferretti E et al. (2004) CCL19 and CXCL12 trigger in vitro chemotaxis of human mantle cell lymphoma B cells. Clinical Cancer Research 10: 964–971.
    Corcione A, Arduino N, Ferretti E et al. (2006) Chemokine receptor expression and function in childhood acute lymphoblastic leukemia of B-lineage. Leukemia Research 30: 365–372.
    Corcione A, Ottonello L, Tortolina G et al. (2000) Stromal cell-derived factor-1 as a chemoattractant for follicular center lymphoma B cells. Journal of the National Cancer Institute 92: 628–635.
    Fedyk ER, Ryyan DH, Ritterman I and Springer TA (1999) Maturation decreases responsiveness of human bone marrow B lineage cells to stromal-derived factor 1 (SDF-1). Journal of Leukocyte Biology 66: 667–673.
    Fischer M, Juremalm M, Olsson N et al. (2003) Expression of CCL5/RANTES by Hodgkin and Reed-Sternberg cells and its possible role in the recruitment of mast cells into lymphomatous tissue. International Journal of Cancer 107: 197–201.
    Fujii A, Ohshima K, Hamasaki M et al. (2004) Differential expression of chemokines, chemokine receptors, cytokines and cytokine receptors in diffuse large B cell malignant lymphoma. International Journal of Oncology 24: 529–538.
    Fujita Y, Abe R, Sasaki M et al. (2006) Presence of circulating CCR10+ T cells and elevated serum CTACK/CCL27 in the early stage of mycosis fungoides. Clinical Cancer Research 12: 2670–2675.
    Ghia P, Transidico P, Veiga JP et al. (2001) Chemoattractants MDC and TARC are secreted by malignant B-cell precursors following CD40 ligation and support the migration of leukemia-specific T cells. Blood 98: 533–540.
    Giuliani N, Bonomini S, Romagnani P et al. (2006) CXCR3 and its binding chemokines in myeloma cells: expression of isoforms and potential relationships with myeloma cell proliferation and survival. Haematologica 91: 1489–1497.
    Giuliani N, Lisignoli G, Colla S et al. (2008) CC-Chemokine ligand 20/macrophage inflammatory protein-3alpha and CC-chemokine receptor 6 are overexpressed in myeloma microenvironment related to osteolytic bone lesions. Cancer Research 68: 6840–6850.
    Hanamoto H, Nakayama T, Miyazato H et al. (2004) Expression of CCL28 by Reed-Sternberg cells defines a major subtype of classical Hodgkin's disease with frequent infiltration of eosinophils and/or plasma cells. American Journal of Pathology 164: 997–1006.
    Harris NL, Jaffe ES, Diebold J et al. (1999) World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. Journal of Clinical Oncology 17: 3835–3849.
    Hasegawa H, Nomura T, Kohno M et al. (2000) Increased chemokine receptor CCR7/EBI1 expression enhances the infiltration of lymphoid organs by adult T-cell leukemia cells. Blood 95: 30–38.
    Hopken UE, Foss HD, Meyer D et al. (2002) Up-regulation of the chemokine receptor CCR7 in classical but not in lymphocyte-predominant Hodgkin disease correlates with distinct dissemination of neoplastic cells in lymphoid organs. Blood 99: 1109–1116.
    Husson H, Freedman AS, Cardoso AA et al. (2002) CXCL13 (BCA-1) is produced by follicular lymphoma cells: role in the accumulation of malignant B cells. British Journal of Haematology 119: 492–495.
    Ishida T, Ishii T, Inagaki A et al. (2006) Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. Cancer Research 66: 5716–5722.
    Ishida T, Utsunomiya A, Iida S et al. (2003) Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clinical Cancer Research 9: 3625–3634.
    Jones D, Benjamin RJ, Shahsafaei A and Dorfman DM (2000) The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia. Blood 95: 627–632.
    Juarez J, Bradstock KF, Gottlieb DJ and Bendall LJ (2003) Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro. Leukemia 17: 1294–1300.
    Juarez J, Dela Pena A, Baraz R et al. (2007) CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment. Leukemia 21: 1249–1257.
    Kleinhans M, Tun-Kyi A, Gilliet M et al. (2003) Functional expression of the eotaxin receptor CCR3 in CD30+ cutaneous T-cell lymphoma. Blood 101: 1487–1493.
    Lentzsch S, Gries M, Janz M et al. (2003) Macrophage inflammatory protein 1-alpha (MIP-1 alpha ) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells. Blood 101: 3568–3573.
    Mazzucchelli L, Blaser A, Kappeler A et al. (1999) BCA-1 is highly expressed in Helicobacter pylori-induced mucosa-associated lymphoid tissue and gastric lymphoma. Journal of Clinical Investigation 104: R49–R54.
    Mohle R, Failenschmid C, Bautz F and Kanz L (1999) Overexpression of the chemokine receptor CXCR4 in B cell chronic lymphocytic leukemia is associated with increased functional response to stromal cell-derived factor-1 (SDF-1). Leukemia 13: 1954–1959.
    Mourad N, Mounier N, Briere J et al. (2008) Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials. Blood 111: 4463–4470.
    Narducci MG, Scala E, Bresin A et al. (2006) Skin homing of Sezary cells involves SDF-1-CXCR4 signaling and down-regulation of CD26/dipeptidylpeptidase IV. Blood 107: 1108–1115.
    Pellegrino A, Ria R, Di Pietro G et al. (2005) Bone marrow endothelial cells in multiple myeloma secrete CXC-chemokines that mediate interactions with plasma cells. British Journal of Haematology 129: 248–256.
    Qiuping Z, Jie X, Youxin J et al. (2005) Selectively frequent expression of CXCR5 enhances resistance to apoptosis in CD8(+)CD34(+) T cells from patients with T-cell-lineage acute lymphocytic leukemia. Oncogene 24: 573–584.
    Spiegel A, Kollet O, Peled A et al. (2004) Unique SDF-1-induced activation of human precursor-B ALL cells as a result of altered CXCR4 expression and signaling. Blood 103: 2900–2907.
    Suefuji H, Ohshima K, Karube K et al. (2005) CXCR3-positive B cells found at elevated frequency in the peripheral blood of patients with MALT lymphoma are attracted by MIG and belong to the lymphoma clone. International Journal of Cancer 114: 896–901.
    Tanaka Y, Mine S, Figdor CG et al. (1998) Constitutive chemokine production results in activation of leukocyte function-associated antigen-1 on adult T-cell leukemia cells. Blood 91: 3909–3919.
    Teruya-Feldstein J, Jaffe ES, Burd PR et al. (1999) Differential chemokine expression in tissues involved by Hodgkin's disease: direct correlation of eotaxin expression and tissue eosinophilia. Blood 93: 2463–2470.
    Till KJ, Lin K, Zuzel M and Cawley JC (2002) The chemokine receptor CCR7 and alpha4 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes. Blood 99: 2977–2984.
    Trentin L, Cabrelle A, Facco M et al. (2004) Homeostatic chemokines drive migration of malignant B cells in patients with non-Hodgkin lymphomas. Blood 104: 502–508.
    Vallet S, Raje N, Ishitsuka K et al. (2007) MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. Blood 110: 3744–3752.
    Weihrauch MR, Manzke O, Beyer M et al. (2005) Elevated serum levels of CC thymus and activation-related chemokine (TARC) in primary Hodgkin's disease: potential for a prognostic factor. Cancer Research 65: 5516–5519.
    Zambello R, Trentin L, Facco M et al. (2003) Upregulation of CXCR1 by proliferating cells in patients with lymphoproliferative disease of granular lymphocytes. British Journal of Haematology 120: 765–773.
    Zannettino AC, Farrugia AN, Kortesidis A et al. (2005) Elevated serum levels of stromal-derived factor-1alpha are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma patients. Cancer Research 65: 1700–1709.
 Further Reading
    Allen SJ, Crown SE and Handel TM (2007) Chemokine: receptor structure, interactions, and antagonism. Annual Review of Immunology 25: 787–820.
    Ribeiro S and Horuk R (2005) The clinical potential of chemokine receptor antagonists. Pharmacological Therapy 107: 44–58.
    Zlotnik A and Yoshie O (2000) Chemokines: a new classification system and their role in immunity. Immunity 12: 121–127.
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Raffaghello, Lizzia, Ferretti, Elisa, Corcione, Anna, and Pistoia, Vito(Apr 2010) Chemokines and Lymphoproliferative Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020457]