Targeting chemokine (C-C motif) ligand 2 (CCL2) as an example of translation of cancer molecular biology to the clinic

Abstract

Chemokines are a family of small and secreted proteins that play pleiotropic roles in inflammation-related pathological diseases, including cancer. Among the identified 50 human chemokines, chemokine (C-C motif) ligand 2 (CCL2) is of particular importance in cancer development since it serves as one of the key mediators of interactions between tumor and host cells. CCL2 is produced by cancer cells and multiple different host cells within the tumor microenvironment. CCL2 mediates tumorigenesis in many different cancer types. For example, CCL2 has been reported to promote prostate cancer cell proliferation, migration, invasion, and survival, via binding to its functional receptor CCR2. Furthermore, CCL2 induces the recruitment of macrophages and induces angiogenesis and matrix remodeling. Targeting CCL2 has been demonstrated as an effective therapeutic approach in preclinical prostate cancer models, and currently, neutralizing monoclonal antibody against CCL2 has entered into clinical trials in prostate cancer. In this chapter, targeting CCL2 in prostate cancer will be used as an example to show translation of laboratory findings from cancer molecular biology to the clinic.

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Proposed mechanism by which CCL2 and IL-6 potentiate tumor progression by protecting tumor infiltrating monocytes and inducing their differentiation toward M2-type macrophages.

Figure 3

Roles of chemokine (C-C motif) ligand 2 (CCL2) in prostate cancer cells and the bone microenvironment. The CCL2/CCR2 axis has been identified as an important contributor to prostate tumorigenesis. CCL2, by binding to its receptor CCR2, directly stimulates prostate cancer cell proliferation, survival, and migration. In addition, CCL2 contributes to the development of metastases in the bone microenvironment by stimulating macrophage recruitment and education, angiogenesis, and activation of osteoclastogenesis. Prostate cancer cells produce parathyroid hormone-related peptide (PTHrP), which stimulates CCL2 expression from osteoblasts. CCL2 appears to mediate the interactions between tumor-derived factors, such as PTHrP, and host-derived chemokines and cytokines, which act together to promote metastatic tumor growth in bone. IGF = insulin-like growth factor; IL-8 = interleukin 8; PCa = prostate cancer; RANKL = receptor activator of NF-κB ligand; TGF-β = transforming growth factor β; VEGF = vascular endothelial growth factor.