CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis

Departments of Medicine and Urology, Michigan Center for Translational Pathology and the University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, United States.
Cytokine & growth factor reviews (Impact Factor: 5.36). 12/2009; 21(1):41-8. DOI: 10.1016/j.cytogfr.2009.11.009
Source: PubMed


CCL2 is a chemokine known to recruit monocytes and macrophages to sites of inflammation. A growing body of research suggests CCL2 is progressively overexpressed in tumor beds and may play a role in the clinical progression of solid tumors. Cancer cells derived from several solid tumor types demonstrate functional receptors for CCL2, suggesting this chemokine may achieve tumorigenicity through direct effects on malignant cells; however, a variety of normal host cells that co-exist with cancer in the tumor microenvironment also respond to CCL2. These cells include macrophages, osteoclasts, endothelial cells, T-lymphocytes, and myeloid-derived immune suppressor cells (MDSCs). CCL2 mediated interactions between normal and malignant cells in the tumor microenvironment and plays a multi-faceted role in tumor progression.

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    • "Several molecular mechanisms are described to be involved in cellular resistance to paclitaxel and carboplatin: decreased drug accumulation , increased drug detoxification, elevated DNA repair, altered microtubule dynamicity, and enhanced expression of anti-apoptotic genes (Chen and Sikic, 2012; Gottesman, 2002). Chemokine (CeC motif) ligand 2 (CCL2) also known as monocyte chemotactic protein-1 (MCP-1) or small inducible cytokine A2, is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages which then become TAMs (Tumor Associated Macrophages) in the tumor microenvironment (Zhang et al., 2010). Both CCL2 and its receptor CeC chemokine receptor type 2 (CCR2) have been demonstrated to be induced and involved in various diseases (Deshmane et al., 2009). "
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    ABSTRACT: Ovarian cancer is strongly associated with a pro-inflammatory leukocyte infiltrate, and high levels of chemokines such as CCL2. CNTO 888, a neutralizing anti-human CCL2 antibody, can inhibit the pro-tumor inflammatory infiltrate and tumor growth. In the present study, we tested the hypothesis that CCL2 neutralization can inhibit tumor growth of ovarian cancer cell line pairs formed by a parental cell line and a non-multi-drug resistant (MDR) paclitaxel-resistant line. Furthermore, we investigated whether mouse stromal CCL2 plays a role in tumor growth promotion. Elevated CCL2 expression was determined by quantitative PCR in three non-MDR paclitaxel resistant (TP) ovarian cancer cell lines ES-2/TP, MES-OV/TP and OVCAR-3/TP, and compared to their related parental cells. Increased CCL2 protein expression levels in vitro and in vivo were confirmed in the drug resistant variants. In order to determine the role of CCL2 on tumor growth upon drug treatment, we established parental and non-MDR paclitaxel resistant cell lines expressing a GFP-luciferase fusion gene. These cells were implanted intraperitoneally (i.p.) and subcutaneously (s.c.) in nude mice. Mice were treated with the anti-human CCL2 antibody (CNTO 888) and the anti-mouse MCP-1 antibody (C1142), orthologous of human CCL2, with and without chemotherapy (paclitaxel or carboplatin). Tumor growth was evaluated by both bioluminescence and caliper measurements. Our results show a significant additive effect of CCL2 blockade on the efficacy of paclitaxel and carboplatin. The mechanism of this therapeutic effect was largely due to inhibition of mouse stromal CCL2. Our findings show that inhibition of CCL2 can enhance paclitaxel and carboplatin treatments of ovarian cancer.
    Molecular Oncology 03/2014; DOI:10.1016/j.molonc.2014.03.016 · 5.33 Impact Factor
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    • "MCP-1 may play a role in many diseases, including multiple sclerosis, rheumatoid arthritis, atherosclerosis, obesity and insulin-resistant diabetes [13]. It has a direct role in angiogenesis and tumor progression [14], promotes prostate cancer tumorigensis and metastasis [15]. The first studies on humans of a new drug CNTO888 (monoclonal antibody) blocking MCP-1 has been very recently published [16]. "
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    ABSTRACT: Monocyte-chemoattractant protein-1 (MCP-1), also known as CCL2, is a potent chemoattractant of T cells and monocytes, involved in inflammatory and angio-proliferative brain and retinal diseases. Higher expression of MCP-1 is observed in metastatic tumors. Unusual levels of MCP-1 in the brain may be correlated with autism. Immunochemistry where atomic force microscope (AFM) tips functionalized with appropriate antibodies against MCP-1 are used could in principle support medical diagnostics. Useful signals from single molecule experiments may be generated if interaction forces are large enough. The chemokine-antibody unbinding force depends on a relative motion of the interacting fragments of the complex. In this paper the stability of the medically important MCP-1- immunoglobulin G antibody Fab fragment complex has been studied using steered molecular dynamics (SMD) computer simulations with the aim to model possible arrangements of nano-diagnostics experiments. Using SMD we confirm that molecular recognition in MCP1-IgG is based mainly on six pairs of residues: Glu39A - Arg98H, Lys56A - Asp52H, Asp65A - Arg32L, Asp68A - Arg32L, Thr32A - Glu55L, Gln61A - Tyr33H. The minimum external force required for mechanical dissociation of the complex depends on a direction of the force. The pulling of the MCP-1 antigen in the directions parallel to the antigen-antibody contact plane requires forces about 20 %–40 % lower than in the perpendicular one. Fortunately, these values are large enough that the fast lateral force spectroscopy may be used for effective nano-diagnostics purposes. We show that molecular modeling is a useful tool in planning AFM force spectroscopy experiments. Figure Lateral SMD forces (green arrow) required for mechanical unbinding of MCP-1 chemokine (blue) from Ig G antibody (red/gray) are 20-40% lower than vertical ones (orange arrow)
    Journal of Molecular Modeling 09/2013; 19(11). DOI:10.1007/s00894-013-1972-z · 1.74 Impact Factor
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    • "We then determined whether AR silencing via siAR could also increase cell migration of PCa cells, since we observed increased CCL2 expression in AR silenced PCa cells and it has been shown that CCL2 controls PCa metastasis (Zhang et al, 2010b). We examined the cell migration of C4‐2 cells and found C4‐2 siAR cells have more migration capacity (Fig 2E, upper left). "
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    ABSTRACT: Increased CCL2 expression in prostate cancer (PCa) cells enhanced metastasis via macrophage recruitment. However, its linkage to androgen receptor (AR)-mediated PCa progression remains unclear. Here, we identified a previously unrecognized regulation: targeting AR with siRNA in PCa cells increased macrophage recruitment via CCL2 up-regulation, which might then result in enhancing PCa invasiveness. Molecular mechanism dissection revealed that targeting PCa AR with siRNA promoted PCa cell migration/invasion via CCL2-dependent STAT3 activation and epithelial-mesenchymal transition (EMT) pathways. Importantly, pharmacologic interruption of the CCL2/CCR2-STAT3 axis suppressed EMT and PCa cell migration, providing a new mechanism linking CCL2 and EMT. Simultaneously targeting PCa AR with siRNA and the CCL2/CCR2-STAT3 axis resulted in better suppression of PCa growth and metastasis in a xenograft PCa mouse model. Human PCa tissue microarray analysis suggests that increased CCL2 expression may be potentially associated with poor prognosis of PCa patients. Together, these results may provide a novel therapeutic approach to better battle PCa progression and metastasis at the castration resistant stage via the combination of targeting AR with siRNA and anti-CCL2/CCR2-STAT3 signalling.
    EMBO Molecular Medicine 09/2013; 5(9). DOI:10.1002/emmm.201202367 · 8.67 Impact Factor
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