CXCL12-CXCR4 Axis in Angiogenesis, Metastasis and Stem Cell Mobilization

S.      Liekens; D.      Schols; S.      Hatse

Abstract

Chemokines are key players in the attraction and activation of leukocytes and are thus implicated in the recruitment of immune cells at sites of infection and/or inflammation. They exert their action by binding to seven-transmembrane G protein-coupled receptors. The chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 represents the single natural ligand for the chemokine receptor CXCR4. CXCL12 possesses angiogenic properties and is involved in the outgrowth and metastasis of CXCR4-expressing tumors and in certain inflammatory autoimmune disorders, such as rheumatoid arthritis. CXCR4 expression on tumor cells is upregulated by hypoxia and angiogenic factors, such as vascular endothelial growth factor (VEGF). CXCR4 also acts as a co-receptor for entry of human immunodeficiency virus (HIV) in CD4+ T cells. Finally, CXCL12/CXCR4 interactions were shown to play an important role in the migration of hematopoietic stem cells and their progenitors from, and their retention within, the bone marrow, a site characterized by high CXCL12 expression. As such, CXCR4 inhibitors may be utilized to inhibit HIV-1 infection, tumor growth and metastasis and to mobilize hematopoietic stem cells from the bone marrow in the circulation, where they can be collected for autologous stem cell transplantation. Here, we discuss the different aspects of CXCL12/CXCR4 biology as well as the development and anti-cancer/stem cell mobilizing activity of CXCR4 antagonists.

Keywords: Angiogenesis, CXCL12, CXCR4, metastasis, progenitor cells, SDF-1, small molecule inhibitors, ELR, multiple myeloma, HUVEC, FGF-2, KR158, GL261, rheumatoid synovium, AMD3100, SCLC, Asp262, Glu288, non-Hodgkin's lymphoma, cholangiocarcinoma, acute lymphoblastic, acute myelogenous leukemia, bortezomib, melphalan, doxorubicin, dexamethasone, sorafenib, TN14003, MDA-MB-231, AMD070, WZ811, KRH-1636, KRH-3955, PRO2000, ALX40-4C, CTCE-9908, Plerixafor, BKT140, POL6326, TG-0054