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 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