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      A MCP1 fusokine with CCR2-specific tumoricidal activity

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          Abstract

          Background

          The CCL2 chemokine is involved in promoting cancer angiogenesis, proliferation and metastasis by malignancies that express CCR2 receptor. Thus the CCL2/CCR2 axis is an attractive molecular target for anticancer drug development.

          Methods

          We have generated a novel fusion protein using GMCSF and an N-terminal truncated version of MCP1/CCL2 (6-76) [hereafter GMME1] and investigated its utility as a CCR2-specific tumoricidal agent.

          Results

          We found that distinct to full length CCL2 or its N-truncated derivative (CCL2 5-76), GMME1 bound to CCR2 on mouse lymphoma EG7, human multiple myeloma cell line U266, or murine and human medulloblastoma cell lines, and led to their death by apoptosis. We demonstrated that GMME1 specifically blocked CCR2-associated STAT3 phosphorylation and up-regulated pro-apoptotic BAX. Furthermore, GMME1 significantly inhibited EG7 tumor growth in C57BL/6 mice, and induced apoptosis of primary myeloma cells from patients.

          Conclusion

          Our data demonstrate that GMME1 is a fusokine with a potent, CCR2 receptor-mediated pro-apoptotic effect on tumor cells and could be exploited as a novel biological therapy for CCR2 + malignancies including lymphoid and central nervous system malignancies.

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          Most cited references21

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          Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner.

          Yoon Kow Young, Philippe M Campeau, Marie-Noëlle Boivin … (2009)
          The administration of ex vivo culture-expanded mesenchymal stromal cells (MSCs) has been shown to reverse symptomatic neuroinflammation observed in experimental autoimmune encephalomyelitis (EAE). The mechanism by which this therapeutic effect occurs remains unknown. In an effort to decipher MSC mode of action, we found that MSC conditioned medium inhibits EAE-derived CD4 T cell activation by suppressing STAT3 phosphorylation via MSC-derived CCL2. Further analysis demonstrates that the effect is dependent on MSC-driven matrix metalloproteinase proteolytic processing of CCL2 to an antagonistic derivative. We also show that antagonistic CCL2 suppresses phosphorylation of AKT and leads to a reciprocal increased phosphorylation of ERK associated with an up-regulation of B7.H1 in CD4 T cells derived from EAE mice. CD4 T cell infiltration of the spinal cord of MSC-treated group was robustly decreased along with reduced plasma levels of IL-17 and TNF-alpha levels and in vitro from restimulated splenocytes. The key role of MSC-derived CCL2 was confirmed by the observed loss of function of CCL2(-/-) MSCs in EAE mice. In summary, this is the first report of MSCs modulating EAE biology via the paracrine conversion of CCL2 from agonist to antagonist of CD4 Th17 cell function.
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            Activation of stat3 in human melanoma promotes brain metastasis.

            K Aldape, Tong Xie, Suyun Huang … (2006)
            Brain metastasis is a major cause of morbidity and mortality in patients with melanoma. The molecular changes that lead to brain metastasis remain poorly understood. In this study, we developed a model to study human melanoma brain metastasis and found that Stat3 activity was increased in human brain metastatic melanoma cells when compared with that in cutaneous melanoma cells. The expression of activated Stat3 is also increased in human brain metastasis specimens when compared with that in the primary melanoma specimens. Increased Stat3 activation by transfection with a constitutively activated Stat3 enhanced brain metastasis, whereas blockade of Stat3 activation by transfection with a dominant-negative Stat3 suppressed brain metastasis of human melanoma cells in animal models. Furthermore, altered Stat3 activity profoundly affected melanoma angiogenesis in vivo and melanoma cell invasion in vitro and significantly affected the expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-2 (MMP-2) in vivo and in vitro. Finally, Stat3 activity transcriptionally regulated the promoter activity of bFGF in addition to VEGF and MMP-2 in human melanoma cells. These results indicated that Stat3 activation plays an important role in dysregulated expression of bFGF, VEGF, and MMP-2 as well as angiogenesis and invasion of melanoma cells and contributes to brain metastasis of melanoma. Therefore, Stat3 activation might be a new potential target for therapy of human melanoma brain metastases.
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              Chemokines and cancer: migration, intracellular signalling and intercellular communication in the microenvironment.

              Morgan O'Hayre, Catherina L. Salanga, Tracy M Handel … (2008)
              Inappropriate chemokine/receptor expression or regulation is linked to many diseases, especially those characterized by an excessive cellular infiltrate, such as rheumatoid arthritis and other inflammatory disorders. There is now overwhelming evidence that chemokines are also involved in the progression of cancer, where they function in several capacities. First, specific chemokine-receptor pairs are involved in tumour metastasis. This is not surprising, in view of their role as chemoattractants in cell migration. Secondly, chemokines help to shape the tumour microenvironment, often in favour of tumour growth and metastasis, by recruitment of leucocytes and activation of pro-inflammatory mediators. Emerging evidence suggests that chemokine receptor signalling also contributes to survival and proliferation, which may be particularly important for metastasized cells to adapt to foreign environments. However, there is considerable diversity and complexity in the chemokine network, both at the chemokine/receptor level and in the downstream signalling pathways they couple into, which may be key to a better understanding of how and why particular chemokines contribute to cancer growth and metastasis. Further investigation into these areas may identify targets that, if inhibited, could render cancer cells more susceptible to chemotherapy.
              Article 0 comments Cited 97 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central
                ISSN (Electronic): 1476-4598
                Publication date Collection: 2011
                Publication date (Electronic): 24 September 2011
                Volume: 10
                Page: 121
                Affiliations
                [1 ]The Montreal Center for Experimental Therapeutics in Cancer, McGill University, Montreal, Canada
                [2 ]The Institute for Research in Immunology and Cancer, Montreal University, Montreal, Canada
                [3 ]Department of Hematology and Oncology, Emory University, 1365B Clifton Road, Clinic B, Atlanta, GA 30322, USA
                [4 ]Department of Pediatrics, Winship Cancer Institute, Emory University, 1365B Clifton Road, Atlanta, GA, 30322, USA
                Article
                Publisher ID: 1476-4598-10-121
                DOI: 10.1186/1476-4598-10-121
                PMC ID: 3189909
                PubMed ID: 21943176
                SO-VID: 018c288a-90b3-491d-b0df-c5b5bbee961d
                Copyright © Copyright ©2011 Rafei et al; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 20 February 2011
                Date accepted : 24 September 2011
                Categories
                Subject: Research

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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