CCR2 signaling pathway in glioblastoma multiforme

Accepted Manuscript CCL2/CCR2 signaling pathway in glioblastoma multiforme Alireza Vakilian, Hossein Khorramdelazad, Parisa heidari, Zahra sheikh rezaei, Gholamhossein Hassanshahi PII:

S0197-0186(16)30417-X

DOI:

10.1016/j.neuint.2016.12.013

Reference:

NCI 3970

To appear in:

Neurochemistry International

Received Date: 1 November 2016 Accepted Date: 20 December 2016

Please cite this article as: Vakilian, A., Khorramdelazad, H., heidari, P., sheikh rezaei, Z., Hassanshahi, G., CCL2/CCR2 signaling pathway in glioblastoma multiforme, Neurochemistry International (2017), doi: 10.1016/j.neuint.2016.12.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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CCL2/CCR2 signaling pathway in glioblastoma multiforme Alireza Vakilian1, Hossein Khorramdelazad 2,

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Parisa heidari 3, Zahra sheikh rezaei3, Gholamhossein Hassanshahi 2*

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1- Geriatric Care Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran 2- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. 3- Department of Hematology and Medical Laboratory Sciences, School of Allied Medical Sciences, Kerman University of Medical Sciences, Kerman, Iran.

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*Correspond to: prof. Gholamhossein Hassanshahi, Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.

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E-mail: [email protected] Tel: 00983434339660

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Mobile: +989133933447

Running title: Role of CCL2 in the pathogenesis of GBM

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Abstract

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Glioblastoma multiform (GBM) is described as one of the most frequent primary brain tumors. These types of malignancies constitute only 15% of all primary brain tumors. Despite, extensive developments on effective therapeutic methods during

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the 20th century as well as the first decade of the present century (21th), the median

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survival rate for patients suffering from GBM is only approximately 15 months, even in response to multi-modal therapy. numerous types of reticuloendothelial system cells such as macrophages and microglial cells occupied within both GBM and also normal surrounding tissues. These immune cells acquire an otherwise

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activated phenotype with potent tumor-tropic functions that contribute to the glioma growth and invasion. The CC chemokine, CCL2 (previously named MCPinvolving in

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1) is of the most important CC chemokines family member

regulation of oriented migration and penetrative infiltration of mainly

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reticuloendothelial system cells specifically monocyte/macrophage phenotypes. Fundamental

parts are played by CCL2 and its related receptor (the CCR2) in

brain tumors and obviously in migration of monocytes from the bloodstream through the vascular endothelium. Therefore, CCL2/CCR2 axis is required for the routine immunological surveillance of tissues, in accordance with response to inflammation. Briefly, in this review, we have tried our best to collect the latest,

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straightened and summarize literature reports exist within data base regarding the interaction between microglia/macrophages and CCL2/CCR2 axis in GBM. We

for the expansion of future anti-glioma therapies as well.

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aimed to discuss potential application of this chemokine/receptor interaction axis

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Keywords: CCL2, MCP-1, GBM, Glioblastoma, CC chemokine Introduction

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Malignant gliomas are identified and fitted within the most proliferative and invasive tumors which extremely develop inside the central nerves system (CNS). Genetic variations, amplified signaling pathways, and their exploitation of surrounding non-transformed brain cells for molecules are essential for the glioma

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growth, invasiveness, and tumorigenicity (Huse and Holland 2010, Charles, Holland et al. 2011). In more recent investigations, especial attentions are paid to

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chemokine/receptor network functions in pathogenesis and pathophysiology of neuroinflammatory disorders (Vazirinejad, Ahmadi et al. 2014, Khorramdelazad,

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Bagheri et al. 2016, Kothur, Wienholt et al. 2016). Chemokines are members of a subfamily of the wider family of cytokines with pro-migratory properties and act as recruiters and/or chemo attractive factors for a broad spectrum of cell types for regulation of their oriented locomotion. Cells which are targeted by these mediators respond chemokine ligands and then express appropriate trans-

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membrane G protein chemokine receptors (Aminzadeh, Ghorashi et al. 2012, Derakhshan, Arababadi et al. 2012, Hassanshahi, Amin et al. 2013, Ahmadi,

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Hassanshahi et al. 2016, Khorramdelazad, Bagheri et al. 2016). According, on the basis of the position of conserved cysteine amino acid motifs within their biochemical structure, chemokines are further subdivided into C, CC, CX3C and

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CXC sub divisions(Aminzadeh, Ghorashi et al. 2012, Ahmadi, Arababadi et al. 2013, Ostadebrahimi, Jamali et al. 2013, Ahmadi, Hassanshahi et al. 2016).Several

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members of the CC and CXC chemokines including CCL2, CXCL8and CXCL12are generated by glioma cells (Oh, Schwiebert et al. 1999, Kielian, van Rooijen et al. 2002, Salmaggi, Gelati et al. 2004, Bajetto, Barbieri et al. 2006,

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Terasaki, Sugita et al. 2011). Glioma cells generate chemokines and express chemokine receptors and regardingly are involved in various biological aspects of glial tumors such as invasiveness, survival, angiogenesis, and proliferation

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(Proudfoot 2002, Sciumè, Santoni et al. 2010, Terasaki, Sugita et al. 2011). For

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instance, we have previously reported that CXCL12 was increasing patients suffering from glioblastoma (Moosavi, Khorramdelazad et al. 2013). however, there exist some evidences to report that expression of chemokines by glioma cells, the exact function(s) of these proteins in glioma biology and pathogenesis has yet to completely defined, (particularly their possible roles in the glioma microenvironment) (Rutar and Provis 2016).In addition to the stromal CNS-

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intrinsic cell types, such as astrocytes and microglia in the neighboring tissues of glioma cells, inflammatory cells including lymphocytes, macrophages and

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neutrophils (which are infiltrated into the tumor from the circulation)are also observed (Carvalho da Fonseca and Badie 2013). In spite of the fact that initially these infiltrated immune cells are responsible for the tumor growth and

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progression, much more evidences pointed to the fact that tumor also in turn capable of neutralizing the immune cells (von Hanwehr, Hofman et al. 1984,

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Hussain, Yang et al. 2006, Ben-Neriah and Karin 2011). Moreover, glioma recruit and attract neural and immune cell types into its microenvironment for growth progression, invasiveness and for facilitating of the phenomenon of angiogenesis

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(Le, Besson et al. 2003, Charles, Holland et al. 2011).Briefly, in this review, we collected a straightened and summarize the latest literature reports present within the database regarding the interaction between microglia/macrophages and

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CCL2/CCR2 axis in GBM. We also tried our best to discuss potential application

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of this chemokine/receptor interaction axis for the expansion of future anti glioma therapies.

Biostructure and biological functions of CCL2 The CCL2 fit within the C-C chemokine subfamily which is mainly involved in oriented locomotion of monocytes toward pathologic locations. The CCL gene locus exists on chromosome 17 (Chr. 17, q11. 2) (Feng, Flores-Villanueva et al.

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2012). The CCL2 in human is the mouse homologue of JE, a gene which shown to be up-regulated by platelet-derived growth factor (PDGF) in mouse fibroblasts

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(Cochran, Reffel et al. 1983). In other words, the human homologue that best characterized as CCL2 was originally purified from human cell lines with regard to its monocyte chemoattractant properties and was initially called Monocyte

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Chemoattractant Protein-1 (MCP-1) and is a protein with 13 kD in size and contains 76 amino acids (Van Coillie, Van Damme et al. 1999). The CC

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chemokine, branch of MCP proteins are accommodating at least four members, including MCP-1, 2, 3, and 4. There exist high levels of sequence homology between CCL2 and other MCP members, varying from71% for CCL7 to61% for

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CCL4 and CCL8 (Uguccioni, D'Apuzzo et al. 1995, Van Coillie, Van Damme et al. 1999). The main protein structure of human CCL2 was initially characterized

In response

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through employing purified natural material(Liu, Haelens et al. 1996). to the induction in by several stimuli and conditions such as

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cytokines, oxidative stress, or growth factors a wide variety of cell types including, endothelial, fibroblasts, epithelial cells, smooth muscle cells, mesangial cells, astrocytices, monocytices, and microglial cells generate CCL2. However, monocytes/macrophages are not the unique CCL2 producers but are considered as the major source of CCL2 (Deshmane, Kremlev et al. 2009). These cells are important during antiviral immune responses which occur in the peripheral

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circulation and within various tissues. Two different locates of the CCL2 primary structure are critical for its biological functions (Beall, Mahajan et al. 1996). The

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first region is consists of a sequence from Thr-10 to Tyr-13, and the second region which appears to be functionally important contains residues of 34 and 35. The CCL2 bio functions decrease following mutation in either residue 10 or 13

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(Ebisawa, Yamada et al. 1994). Two gene variations in the second region of the molecule are important, one of which introducing a proline between Ser-34 and

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Lys-35, and another one is a substitution of those two residues with the sequence Gly-Pro-His. Both of these mutations strictly reduce CCL2 activity. In addition to above polymorphisms , it has also been claimed that cell-type specificity of CCL2

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was affected by mutation of residues 28 and 30, but not by residue 30 alone (Beall, Mahajan et al. 1996). The activity of CCL2 can also be lost, when a deletion occurs within residues at its N-terminal domain (Gong and Clark-Lewis 1995) and

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some of these N-terminus deletion mutants serve as CCL2 antagonists (Gong,

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Ratkay et al. 1997).

Structural analysis by NMR techniques and asymmetrically labeling of CCL2, showed that the solution structure of the CCL2 is in dimer form (Handel and Domaille 1996).The secondary structure of CCL2 contains four regions of β-sheet. These regions consist of residues 9–11 (β0), 27–31 (β1), 40–45 (β2), and 51–54 (β3). In addition to the four strands of sheet, CCL2 also consists of two helical

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regions. A long helix extends from approximately residue 58 to residue 69, nonetheless, residues 6–16 are involved in the dimerization interface of CCL2

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(Zhang and Rollins 1995). The functional residues that involved in the interface include Asn6, Ala7, Val9, Cys11, Tyr13, Asn 14, Phe15, and Thr16 near by the Nterminus, and Glu 50, Ile51, and Cys 52. It is likely that the quaternary structures

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of CCL2 monomers and dimers resemble them macrophage inflammatory protein1β (MIP-1β) and CCL5 (Meunier, Bernassau et al. 1997). The protein complex

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appears to be extended with the two monomers and oriented to give an equally large pocket. Two crystal forms(I and P forms) are in structures of monomeric and dimeric CCL2 (Lubkowski, Bujacz et al. 1997). Antibody blocking studies and to

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determination of the structures of CCL2 (Reid, Rushe et al. 2006). Furthermore, CCL2 form a dimer with a nonfunctional mutated form which is possibly decreasing the function of CCL2. As an example, it has been well established

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that7ND as a dominant-negative inhibitor of CCL2 inhibits the CCL2/CCR2 signal

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pathway in vivo, via blocking the activation of N-terminal amino acids of 2 to 8 (Kitamoto and Egashira 2003). Additionally, it has been revealed that this CCL2 mutant (e.g7ND) in accompanying with wild-type CCL2 form a heterodimer, which binds to the CCL2 receptor (CCR2) and entirely constrains CCL2-mediated monocyte chemotaxis in vitro (Zhang and Rollins 1995). Consistent with these facts, in a study transgenic mice expressing 7ND gene were found to inhibit CCL2

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pathway and subsequently inhibit the formation of atherosclerotic lesions in parallel with affecting serum lipid concentrations (Ni, Egashira et al. 2001).

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CCL2 facilitates the process of both migration and infiltration of several cell systems such as monocytes, natural killer (NK) cells, T lymphocytes, and memory cells. CCL2 has also claimed to show a unique potential intervention ability to be

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employed as a therapeutic target for a broad spectrum of diseases with autoimmune

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nature, including multiple sclerosis (Sørensen, Ransohoff et al. 2004), rheumatoid arthritis (Hayashida, Nanki et al. 2001), atherosclerosis (Hernández-Aguilera, Cabré et al. 2015), and type-1 diabetes (Wieser, Moschen et al. 2013). All of the roles ascribed for CCL2 were primarily recognized by employing an in vitro assay

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via purified protein, which were reproduced and confirmed later in vivo (Fuentes, Durham et al. 1995, Gunn, Nelken et al. 1997). In further investigations, the

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CCL2/CCR2 axis signaling pathway has been confirmed using in vivo animal models, in which both CCL2 and CCR2 were knocked out (Kurihara, Warr et al.

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1997).

Migratory effects of CCL2/CCR2 axis on monocyte/macrophages

Van Furth and Diesselhoff-Den Dulk, in a study demonstrated that the half-life of circulating monocytes in human is approximately three folds longer than mice,

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and is estimated that around 340 millions of monocytes are leaving the circulation, daily (FURTH and DIESSELHOFF‐DEN DULK 1980). Additionally, under

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normal situations in mice around half of the circulating monocytes are cleared from the bloodstream daily (van Furth and Cohn 1968, Van Furth, Diesselhoff-den Dulk et al. 1973). A vast proportion of circulating monocytes are continuously

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differentiating into macrophages and then enter to the tissues (Sordet, Rébé et al.

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2002). Contrastly, immature dendritic cells (DCs) living within the tissues have the ability to leave via afferent lymphatic ducts into the draining lymph nodes, whereby they complete their maturation processes and serve as antigen presenter for T cells, and most often die following few days of arrival. Therefore, a

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considerable proportion of monocytes can potentially be cleared by molecular products of immune surveillance system. Although, CCL2 has been demonstrated to recruits monocytes into the foci of active inflammation (Ajuebor, Flower et al.

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1998) but it remained unclear whether monocytes utilize the same molecular

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signals to migrate into the tissues as a part of the constitutive or steady-state efflux from blood circulation. In order to recruit lymphocytes, the injected or secreted form of CCL2 enter into the skin in the draining lymph nodes where it can be presented on the surface of high endothelial venules (HEVs) (Palframan, Jung et al. 2001). Moreover, these findings are demonstrative for the fact that CCL2 is one of the pivotal chemokines involved in monocyte recruitment and tissue trans-

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migration and only approximately 2% of the circulating pool of monocytes are recruited to the lymph nodes (Palframan, Jung et al. 2001). In addition to CCL2,

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several other chemokine network members were also shown to play fundamental parts in the recruitment of monocytes. Especially, investigations provided enough evidences to confirm that the stimulation with the other critical members of CC

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chemokine family such as, CCL5 also leading to monocytes/macrophages chemo-

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attraction (Brown, Robson et al. 1996, Haberstroh, Stilo et al. 1998) (Diagram1). Role of CCL2/CCR2 axis in different pathologic states

Typically, CCL2 mediates its specific potential properties throughout its receptor (CCR2)which its expression is relatively limited to certain cell types (Feria and

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Díaz-González 2006). CCR2A and CCR2B are two spliced isoforms of CCR2 and they are only differed in their C-terminal tails (Charo, Myers et al. 1994). The

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CCR2A is the main isoform that is expressed by vascular smooth muscle cells and mononuclear cells (Bartoli, Civatte et al. 2001).However, monocytes and activated

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NK cells express the other isoform of CCR2 (e,g the CCR2B). It is not far from speculation that both CCR2A and CCR2B trigger diverse signaling pathways and utilize various fashion for their actions. For instance, chemotaxis activities mediated by CCL2/CCR2 axis in CCR2A-positive cells are occurred without Ca2+ mobilization, whilst inversely Ca2+ flux is induced in the CCR2B-positive cells (Sanders, Crean et al. 2000, Cho, Yoon et al. 2007). Evidences revealed that CCL2

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up-regulated and intensified the expression of CCR2A but not CCR2B on the surface member of synoviocytes of patients suffering from rheumatoid arthritis

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(Cho, Yoon et al. 2007). Interestingly, it appears valuable to pay attention to the issue that CCR2 has both pro-inflammatory and anti-inflammatory properties. The anti-inflammatory role of CCR2 mostly depends on the CCR2 expression on

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regulatory T cells and inversely its pro-inflammatory functions are due to its expression on antigen-presenting (APCs)and T cells (Yadav, Saini et al. 2010).

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Furthermore, several single nucleotide polymorphisms (SNPs) have been reported for the CCR2, to date, however, there exist only few evidences to confirm that every particular SNPs affecting clinical disease outcome in patients with acute

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idiopathic anterior uveitis (Yeo, Ahad et al. 2006).A study undertaken by Zhang and colleagues reported that the CX3CR1-/-CCR2-/- but not the single knockout of CX3Cr1 or CCR2 mice, showed decreased adipose macrophage activation. This

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investigation team demonstrated that CX3CR1 and CCR2 synergistically modulate

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inflammatory but not metabolic effects of high fat diet in obesity (Zhang, Hinkle et al. 2015).In another investigation, Wolf and co-workers reported that CCL2induced vascular permeability and metastasis was mediated by the members of JAK2-Stat5 and p38-MAPK signaling pathways. Results of this study defined a potential therapeutic property for the CCL2 in treating CCL2-dependent metastasis in colon carcinoma cells(Wolf, Hoos et al. 2012).Results of another study on

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osteoarthritis also indicated that infiltration of macrophage was not observed in Ccr2-null mice. Altogether, these remarks may suggest a critical role for the

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CCL2/CCR2 pathway in forming osteoarthritis pain(Miller, Tran et al. 2012).Studies by Mafuvadzeand co-workersrevealed that overexpression of CCR2 by cancerous cells in ductal cell carcinoma, improves intracellular signaling, and

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contributes to the development of invasive ductal carcinoma (IDC), hence, targeting the CCR2 pathway may serve as a useful strategy for the inhibition or

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treatment of IDC (Mafuvadze, Fang et al. 2015).Additionally, Jala and colleagues claimed that CCR2/CCL2 axis mediates recruitment of tumor-associated macrophages and Th17 cells modulate inflammation and microbiota in the tumor

2015).

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microenvironment to promote intestinal tumorigenesis (Jala, Bodduluri et al.

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Specific roles played by CCL2 in cancer

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Chemokines and their corresponding receptors are expressed by numerous tumor types (Moogooei, Shamaei et al. 2015, Rodero, Combadière et al. 2015). Chemokines are involved in a variety of normal host activities that influence cancer; thus, it is likely that these chemoattractive mediators play paramount roles in the pathogenesis of cancer (Mukaida and Baba 2012, Moogooei, Shamaei et al. 2015). According to the particular setting in which they are expressed, it may be

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speculated that chemokines emerge with both growth-promoting and growthinhibiting activities either in favor or against cancer cells, respectively. Regarding

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their specific potency to chemo-attract and activate lymphocytes, some chemokines are be expected to be involved and aid host antitumor responses. Additionally, some of the members of chemokine family claimed to have

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angiogenic activities, which in fact could potentially contribute to the processes of tumor growth and progression (Sarvaiya, Guo et al. 2013). For instance, the

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biological function of macrophage infiltration and macrophage-mediated angiogenesis is induced in response to changes in CCL2 and Vascular endothelial growth factor (VEGF) chemical gradient in breast cancer cells (Hu, Li et al. 2015).

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In particular the expression of CCL2 and VEGF in tumor cells is significantly associated with the number of infiltrated macrophages e.g tumor-associatedmacrophage (TAM) and angiogenesis in breast cancer (Valković, Dobrila et al.

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2002). Monocytes are essential for the initiation of tumor arteriogenesis, due to the

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adherence to and invade endothelium that is activated by the augmented stresses of shear forces which is caused by large pressure differences between perfused areas (Scholz, Cai et al. 2001). Angiogenic and arteriogenic properties of monocytes were initially described during 1976 to 1977 (Schaper, König et al. 1976, Polverini, Cotran et al. 1977). CCL2 attracts and promotes the adherence of monocytes by stimulation of these cells for up-regulation of MAC-1, the receptor

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for intracellular adhesion molecule-1 (ICAM-1) that is expressed by endothelial cells following activation (Scholz, Ito et al. 2000). Taken together, some studies

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stated that, due to the ability of CCL2 in induction of cytostatic activity against tumor cells, upon addition to macrophages in tissue culture (in parallel with its ability to induce expression of FAS ligand protein in cultured endometrial stromal apoptosis

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cells) proposed that CCL2 exert antitumor activity by facilitating

(Zachariae, Anderson et al. 1990). Contrastly , some other investigators reported

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that CCL2 might be associated with several tumors including glioma, colorectal, breast and acute myeloid leukemia (Ben-Baruch 2012, Chun, Lavoie et al. 2015, Kitamura, Qian et al. 2015, Lindemann, Marschall et al. 2015, Mishra, Kovalska et

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al. 2015, Yang, Lv et al. 2015). Role of CCL2 in glioma

glioma-associated

microglia

and

infiltrated

macrophages

in

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Altogether

combination constitute approximately 30% of tumor inflammatory cell types.

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These cells are actively chemo-recruited by gliomas in response to mediators generated by inflammatory cells such as cytokines, chemokines, and extra cellular matrix proteins (Badie, Schartner et al. 1999, Okada, Saio et al. 2009, Held-Feindt, Hattermann et al. 2010, Coniglio, Eugenin et al. 2012, Wang, Hong et al. 2012). CCL2 was primarily recognized in gliomas among chemokine pathways involved

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in TAM chemo-attraction (Desbaillets, Tada et al. 1994). In addition, CCL2 is defined as an influential chemoattractant that facilitate migration of monocytes

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(Carvalho da Fonseca and Badie 2013) and natural killer cells to neuroblastoma (Liu, Wu et al. 2013) and, mesenchymal stem cells into breast tumors (Tsuyada, Chow et al. 2012). CCL2 is expressed within human glial tumors exceedingly, and

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its expression has been indicated to be correlated with the tumor grade(Bowman and Joyce 2014). Additionally, expression of CCL2 is closed to TAM and

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astrocytes surrounding gliomas. The CCL2-dependent chemotactic effect of glioma culture supernatants suggest that glia-derived CCL2 can be implicated in the process leading to the plentiful tumor infiltration by macrophages/microglia and T

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regulatory cells (Platten, Kretz et al. 2003, Jordan, Sun et al. 2008). Therefore, CCL2-expression by glioma cells can be helpful for tumor growth by attraction of T regulatory cells which suppress lymphocyte anti-tumor effector functions, and

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microglial cells that were revealed to exhibit down-regulated anti-tumor functions

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and generation of pro-invasive metalloproteinases (Hussain, Yang et al. 2006). The relevant receptors for CCL2 are CCR2 on microglia and CCR4 on T regulatory cells. The ability of CCL2 to stimulate microglia attraction to tumor was also confirmed in an in vivo tumor model in which microglia infiltration in CCL2expressing against CCL2 negative tumor cells were compared (Platten, Kretz et al. 2003). Yoshimura et al., originally purified CCL2 from the tissue culture

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supernatant of a malignant glioma cell line (Yoshimura, Robinson et al. 1989). Several other studies also showed that CCL2 is highly elevated in glioblastomas,

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both at the mRNA and protein levels, where comparison was made with normal brain tissue (Takeshima, Kuratsu et al. 1994, Jordan, Sun et al. 2008, Semple, Kossmann et al. 2010, Zhang, Sarkar et al. 2011).Lilia et al., also claimed that

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glioma cells release low levels of CCL2 to recruit neighboring microglia and enhance the production of CCL2. This amplified secretion of CCL2bymicroglial

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cells recruits more microglial cells into the tumor in parallel with stimulation of glioma progression and development (Kucheryavykh, Rivera-Pagán et al. 2013). Again, Okada and colleagues reported a direct correlation between the percentage

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of GAMs and Monocyte chemotactic protein-3 (MCP3) expression levels in human gliomas, and this offers a mechanism that MCP-3 also can contribute in microglia/macrophages chemo attraction processes(Okada, Saio et al. 2009).In

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addition, glioma-derived CCL2 is able to induce monocyte migration in vitro

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(Desbaillets, Tada et al. 1994). Consistent with these remarks, cyst fluid and cerebrospinal fluid collected from patients with glioblastoma also contain elevated levels of CCL2 (Kuratsu, Yoshizato et al. 1993). Recently, Moogooei et al., reported that CCL2 and CCL5 are amplified in serum and tumor tissues of human glial tumor at both protein and mRNA levels. According to the findings of this study, it could be concluded that these chemokines are valuable predictive

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molecules for expecting tumor severity, metastasis, and response to treatment (Moogooei, Shamaei et al. 2015). Lindemann and co-workers demonstrated that

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CCL2 can initiates migration and invasion of GBM cells and exerts its paracrine effects on the GBM's microenvironment by motivating migration of astroglial cells (Lindemann, Marschall et al. 2015).A recent study found that CCL2

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expression by the majority of 16 human glioma lines and over-expression of CCL2 in U87 cells increase glioma invasiveness by interacting with CCR2-bearing

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microglia (Zhang, Sarkar et al. 2011). The antibody-mediated blocking techniques of CCL2 has also shown that prolonged the survival of mice bearing murine or human glioma cells (Zhu, Fujita et al. 2011),which propossing that CCL2 might

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be a useful therapy target."Furthermore, current non cytotoxic drugs including antibiotic-minocycline, antihypertensive drug-telmisartan, and a bisphosphonate – zoledronic acid, have ancillary attributed the MCP-1 synthesis inhibition and

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could be re-purposed, singly or in combination, inhibit or reverse MLC-mediated

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immunosuppression, angiogenesis, and other growth-enhancing aspects (Salacz, Kast et al. 2016). Thus, the CCL2/CCR2 signaling axis appears to play a dual role in mediating early tumor immunesurveillance and sustaining the growth and progression of established neoplasms. Compelling evidences support the application of anti-CCL2 therapies for the treatment of established breast

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carcinoma, although the complete abrogation of the CCL2 signaling cascade may

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also limit immune surveillance and support metastatic spread.

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Concluding Remarks

In an overall conclusion regarding our and others different studies, and on the growing evidences for understanding of the role of chemokines in the regulation of glioma cells functions and immune cell recruitment and according to the latest

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information available in the literature, considering roles played by CCL2 in the pathogenesis of glioma, authors of the current article suggest that the chemokine

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CCL2secreted by tumor cells and a variety of immune cells can trigger angiogenesis and tumor cell proliferation. Regardingly, these findings may propose

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that following evaluation of the clinical feasibility of different strategies targeting the chemokine system in human malignant gliomas, CCL2 can be a good selection in developing novel and promising therapies against malignant gliomas in near future.

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Conflict of interest The authors declare that they have not any conflict for interest.

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Acknowledgment

Present project was financially supported by a grant from the Rafsanjan University

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of Medical Sciences.

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Diagram I. depicts possible fundamental parts played by CCL2 in several biological aspects of glial tumors

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CCR2: Chemokine receptor2; BBB= Blood.brain.barrier

ACCEPTED MANUSCRIPT 1-CCL2 is amongst key chemokines involved in pathogenesis of glioblastoma multiforme

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2- CCL2 and it's receptor could aid producing and development of new drugs against glioblastoma multiforme