Chemokines and Lymphoproliferative Disorders

Abstract

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 upon 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 upon binding to specific chemokine receptors, which 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.
  • Lymphadenopathy is an abnormal enlargement of lymph nodes that may acute and self‐resolving or chronic. One of the major causes of chronic lymphadenopathy is cancer, either primary (as in the case of lymphomas) or metastatic.
  • 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's lymphoma.
  • Malignant lymphocytes largely express chemokines and chemokine receptors which 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 characterised by lymph node enlargement due to malignant cell infiltration. The CCR7/CCL19/CCL21 axis represents an important contributor to the development of lymphadenopathy.
  • Multiple myeloma (MM) is a lymphoproliferative disease characterised by the expansion of plasma cells in the bone marrow, with high tendency to metastasize 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's lymphoma (HL) 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 (T regs), respectively.

Keywords: chemokines; chemokine receptors; lymphoproliferative disorders; chemokine and chemokine receptor therapeutic targeting; malignant lymphoid cell migration and survival

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 NLCs, blood‐derived mononuclear cells that attract B‐CLL cells and sustain their proliferation through the secretion of CXCL12. In addition, 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 α4β1/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 up‐regulate 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 reabsorption.
Figure 3. The role of chemokines in the formation of Hodgkin's lymphoma microenvironment. Hodgkin's lymphoma is characterised by the presence of Reed–Sternberg (R–S) cells and different inflammatory cells, such as T lymphocytes, T regulatory (T reg) cells, mast cells, and eosinophils. R–S cells produce CCL17 and CCL22, which attract T helper (Th2) and T reg 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.
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Further Reading

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Jöhrer K, Hofbauer SW, Zelle‐Rieser C, Greil R and Hartmann TN (2012) Chemokine‐dependent B cell‐T cell interactions in chronic lymphocytic leukemia and multiple myeloma – targets for therapeutic intervention? Expert Opinion on Biological Therapy 12 (4): 425–441. DOI: 10.1517/14712598.2012.664128 Epub 2012 Feb 15. PMID: 22332909.

Liu Y, Sattarzadeh A, Diepstra A, Visser L and van den Berg A (2014) The microenvironment in classical Hodgkin lymphoma: an actively shaped and essential tumor component. Seminars in Cancer Biology 24: 15–22. DOI: 10.1016/j.semcancer.2013.07.002 Epub 2013 Jul 15. PMID: 23867303.

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Raffaghello, Lizzia, Ferretti, Elisa, Corcione, Anna, and Pistoia, Vito(Nov 2015) Chemokines and Lymphoproliferative Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020457.pub2]