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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    • "There is accumulating evidence that chemokines play crucial roles during the establishment of primary cancerous lesions as well as metastases, and they are generally associated with a progressed state of cancer and poor prognosis123. Among inflammatory chemokines, CCL2 has been implicated in several crucial steps during cancer formation and metastasis including promotion of angiogenesis[4], recruitment of myeloid-derived suppressor cells567, regulation of invasiveness of cancer cells[8,9], and induction of prosurvival signaling in different cancer cells[7,10,11]. Furthermore, high levels of CCL2 in circulation were associated with poor outcome for breast, prostate, and colon cancer patients due to high incidence of metastasis (reviewed in[3]). Recent studies provided evidence that CCL2-CCR2 signaling represents a crucial axis for the formation of the metastatic microenvironment, which was largely dependent on recruitment of inflammatory monocytes in breast, colon, and lung cancer models1213141516. "
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    ABSTRACT: The CCL2-CCR2 chemokine axis has an important role in cancer progression where it contributes to metastatic dissemination of several cancer types (e.g., colon, breast, prostate). Tumor cell–derived CCL2 was shown to promote the recruitment of CCR2+/Ly6Chi monocytes and to induce vascular permeability of CCR2+ endothelial cells in the lungs. Here we describe a novel decoy protein consisting of a CCL2 mutant protein fused to human serum albumin (dnCCL2-HSA chimera) with enhanced binding affinity to glycosaminoglycans that was tested in vivo. The monocyte-mediated tumor cell transendothelial migration was strongly reduced upon unfused dnCCL2 mutant treatment in vitro. dnCCL2-HSA chimera had an extended serum half-life and thus a prolonged exposure in vivo compared with the dnCCL2 mutant. dnCCL2-HSA chimera bound to the lung vasculature but caused minimal alterations in the leukocyte recruitment to the lungs. However, dnCCL2-HSA chimera treatment strongly reduced both lung vascular permeability and tumor cell seeding. Metastasis of MC-38GFP, 3LL, and LLC1 cells was significantly attenuated upon dnCCL2-HSA chimera treatment. Tumor cell seeding to the lungs resulted in enhanced expression of a proteoglycan syndecan-4 by endothelial cells that correlated with accumulation of the dnCCL2-HSA chimera in the vicinity of tumor cells. These findings demonstrate that the CCL2-based decoy protein effectively binds to the activated endothelium in lungs and blocks tumor cell extravasation through inhibition of vascular permeability.
    Full-text · Article · Jan 2016 · Neoplasia (New York, N.Y.)
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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.
    Full-text · Article · Mar 2014 · Molecular Oncology
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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)
    Preview · Article · Sep 2013 · Journal of Molecular Modeling
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