Targeting the CCL2-CCR2 signaling axis in cancer metastasis

Abstract

The CCL2-CCR2 signaling axis has generated increasing interest in recent years due to its association with the progression of cancer. Although first described as a chemotactic molecule with physiological roles in regulating inflammation, recent studies have revealed a pro-tumorigenic function for CCL2 in favoring cancer development and subsequent metastasis. CCL2 binds the cognate receptor CCR2, and together this signaling pair has been shown to have multiple pro-tumorigenic roles, from mediating tumor growth and angiogenesis to recruiting and usurping host stromal cells to support tumor progression. The importance of CCL2-CCR2 signaling has been further championed by the establishment of clinical trials targeting this signaling pair in solid and metastatic cancers. Here we review the roles of CCL2-CCR2 signaling in the development and progression of cancer metastasis. We further evaluate the outcome of several clinical trials targeting either CCL2 or CCR2, and discuss the prospects and challenges of manipulating CCL2-CCR2 interaction as a potential approach for combating metastatic disease.

Keywords: cancer metastasis; cancer therapy; chemokines; clinical trials.

Figure 1. The role of CCL2-CCR2 signaling during the metastatic process

CCL2 is expressed by cancer and stromal cells in the tumor microenvironment and, 1) induces tumor cell proliferation at the primary tumor site and 2) stimulates tumor cell migration and invasion into the surrounding extracellular matrix. CCL2 subsequently 3) promotes tumor cell intravasation into the circulation, likely by recruiting host myeloid cells to facilitate this process. Once in the circulation, CCL2 may 4) direct the dissemination of cancer cells along a chemotactic gradient towards the metastatic site. Trapping of tumor cells in small capillaries initiates 5) tumor cell extravasation, which is further supported by CCR2⁺ myeloid cells and the CCR2⁺ endothelium. Finally, CCL2 6) promotes tumor growth at the metastatic site, and tumor colonization by recruiting additional myeloid and endothelial cells.

Figure 2. Ribbon representation of CNTO888 in complex with CCL2

CCL2, represented in magenta, comprises an anti-parallel 3-stranded β-sheet and a C-terminal α helix. The light chain of the CNTO888 antibody is shown in cyan whilst the heavy chain is shown in green. The epitope (on CCL2) recognized by CNTO888 (residues 18-24 and 45-51) is shown in blue whilst those important in CCR2 binding (Tyr13, Arg24, Lys35 and Lys49) is shown in red. The CNTO888 and CCR2 receptor epitope both include Arg24 and Lys49, shown in yellow. Figure was generated with PyMoL [116] using crystal structure of CNTO888 and CCL2 complex (PDB ID: 4DN4).