The intricate role of CXCR4 in cancer

Abstract

Chemokines mediate numerous physiological and pathological processes related primarily to cell homing and migration. The chemokine CXCL12, also known as stromal cell-derived factor-1, binds the G-protein-coupled receptor CXCR4, which, through multiple divergent pathways, leads to chemotaxis, enhanced intracellular calcium, cell adhesion, survival, proliferation, and gene transcription. CXCR4, initially discovered for its involvement in HIV entry and leukocytes trafficking, is overexpressed in more than 23 human cancers. Cancer cell CXCR4 overexpression contributes to tumor growth, invasion, angiogenesis, metastasis, relapse, and therapeutic resistance. CXCR4 antagonism has been shown to disrupt tumor-stromal interactions, sensitize cancer cells to cytotoxic drugs, and reduce tumor growth and metastatic burden. As such, CXCR4 is a target not only for therapeutic intervention but also for noninvasive monitoring of disease progression and therapeutic guidance. This review provides a comprehensive overview of the biological involvement of CXCR4 in human cancers, the current status of CXCR4-based therapeutic approaches, as well as recent advances in noninvasive imaging of CXCR4 expression.

Keywords: CXCL12; CXCR4 inhibitor; CXCR4 tracers; Cancer therapy; Chemokine receptor; Chemotaxis; Metastasis; Molecular imaging; PET–CT; Therapeutic intervention.

Figure 2.1

(A) CXCL12 is highly expressed in tissues like lungs, liver, and bone marrow and is also secreted by tumor and stromal cells. CXCR4/CXCL12 interaction results in increased proliferative, migratory, and invasive properties of tumor cells that enable them to escape from primary tumors. CXCR4-expressing tumor cells migrate toward CXCL12 gradient and home to organs that release CXCL12. (B) Schematic diagram of CXCR4/CXCL12 signaling pathway.

Figure 2.2

Representative structures of CXCR4-targeted tracers employed in in vivo imaging applications.

Figure 2.3

Volume rendered whole body PET/CT images of CXCR4 expression in subcutaneous NOD–SCID mice bearing U87-stb-CXCR4 (yellow arrow) and U87 control (white arrow) tumors (A) and MDA-MB-231-derived lung metastases (B) following injection of 300 µCi of ⁶⁴Cu-AMD3100; U87-stb-CXCR4 (yellow arrow) and U87 control (white arrow) tumors following administration of 250 µCi of ⁶⁴Cu-AMD3465 or a 25-mg/kg AMD3465 blocking dose followed by 250 µCi of ⁶⁴Cu-AMD3465 (C). Images (A,B) were recreated from Nimmagadda et al. (2010) and (C) from De Silva et al. (2011).