Macrophage Colony-stimulating Factor and Cancer a Review

REVIEW

Macrophage colony-stimulating factor and cancer: a review

S. Chockalingam & Siddhartha Sankar Ghosh

Received: 21 July 2014 /Accepted: 10 September 2014# International Society of Oncology and BioMarkers (ISOBM) 2014

Abstract Tumor growth is influenced by a wide variety ofexternal and internal factors. One of the most important medi-ators of tumor development is our immune system. The non-stop surveillance of the immune system was originally expect-ed to clear the transformed cells from the body and guardagainst the development of tumor. But contradictory evidencesare reported to show the involvement of immune system insupporting the growth and spread of tumor. Tumor infiltratingimmune cells, in addition to harboring immunosuppressiveactivities, also promote angiogenesis and metastasis of tumor.Many growth factors and cytokines are involved in shaping thiscomplex immunemicroenvironment of the tumor. Macrophagecolony-stimulating factor (MCSF) is one such growth factorwhich is overexpressed in many tumors. In this review, wesummarize the basic biology of MCSF, its role in cancer anddiscuss the involvement of tumor-associated macrophages(TAMs) in tumor development.

Keywords Macrophage colony-stimulating factor .

Interleukins . Tumor-associatedmacrophages . Paraptosis .

Vascular endothelial growth factor . Angiogenesis . Drugresistance . Cancer stem cells

Introduction

The immune system is a complex and sophisticated machinerydesigned to distinguish between self, non-self materials,

and safe guard the body against invasion by foreign pathogensin addition to the routine clearance of aged and damaged cells.It is therefore surprising to see the magnitude of cancer devel-opment under the vigil of the immune system. Tumor tissuesare known to have heterogeneous populations of cells whichcan have distinct variations in characters such as cellularmorphology, growth rate, gene expression, tumor histology,expression of surface markers, and response to drug treatment[1]. In addition to the tumor cells and the surrounding stromalcells, tumor tissues are also infested with cells of both innateand adaptive immune system [24]. These cells are recruitedto the tumor sites depending on the type of cytokines and otherchemotactic factors secreted in the tumor microenvironment[3, 5].

The immune cell infiltration is known to have both pro-tumoral and anti-tumoral effects. While cells of innateimmune system promotes tumor progression by angiogen-esis, tissue remodeling, release of growth factors, and pro-tumoral cytokines, cells of adaptive immune system helpsin inhibition of tumor growth through efficient antigenpresentation and cytotoxic T cell activity [6]. However,the balance is disturbed in tumor tissues and the infiltratedimmune cells are driven more towards exhibiting tumor-supporting properties in tumor microenvironment. One ofthe most common type of immune cells found within tumoris TAMs [79]. Macrophages can have dual role with thepotential to exhibit both pro- and anti-tumor activities [10].However, within the tumor, macrophages are predominant-ly polarized towards a pro-tumor phenotype [11, 12].Overexpression of various chemotactic and growth factorssuch as macrophage colony-stimulating factor (MCSF),CC chemokine ligand 2 (CCL-2), vascular endothelialgrowth factor (VEGF), etc. have been associated withrecruitment of TAMs in different types of cancers [10, 7,13]. In this review, we will focus mainly on MCSF, its rolein cancer, and discuss the biology of TAMs.

S. Chockalingam (*) : S. S. GhoshDepartment of Biotechnology, Indian Institute of TechnologyGuwahati, Guwahati, Assam, Indiae-mail: [email protected]

S. S. GhoshCentre for Nanotechnology, Indian Institute of TechnologyGuwahati, Guwahati, Assam, India

Tumor Biol.DOI 10.1007/s13277-014-2627-0

Macrophage colony-stimulating factor

MCSF, also known as colony-stimulating factor-1 (CSF-1), isthe primary growth factor regulating the growth, proliferation,and differentiation of cells of hematopoietic lineages includ-ing monoblasts, promonocytes, monocytes, macrophages, andosteoclasts [1416]. MCSF is encoded by a unique gene;however, through alternative mRNA splicing and differentialpost-translational modification, three different forms ofMCSF, such as a secreted glycoprotein, a secreted proteogly-can, and a short membrane-bound isoform are found [14].MCSF is secreted by various types of cells like monocytes,fibroblasts, osteoblasts, stromal cells, endothelial cells, andtumor cells. All the biological effects of MCSF are mediatedthrough a type III receptor tyrosine kinase [17]. MCSF re-quires the synergistic action of IL-1 and IL-3 during differen-tiation of early myeloid bone marrow cells [18]. However, atlater stage, MCSF can be a self-regulator in controlling theproliferation and differentiation of cells of mononuclearphagocytic system.

In humans, MCSF gene is located at 1p21p13; in mice,it is located at chromosome 3, (51 cM) [19]. This singlegene produces a primary mRNA, from which five mRNAspecies of varying length arises through alternative splicing[20, 21]. The mRNA transcripts of length 1.6 and 3.1 kbgive rise to a shorter, membrane-bound MCSF, while thetranscripts of length 2.6, 3.7, and 4 kb are processed to formsecreted MCSF. Various proteases including a signal pepti-dase, MCSF -convertase, and MCSF -convertase areinvolved in the processing of nascent protein into differentforms of mature MCSF protein. The MCSF protein, ingeneral consists of five sections: an N-terminal signal pep-tide composed of 32 amino acids, a receptor binding do-main of 149 amino acids, a spacer region with varyinglength, a transmembrane domain with 24 amino acids anda cytoplasmic tail composed of 35 amino acids [19]. MCSFis processed to form a disulfide-linked homodimer [22]which can either stay attached to the membrane or proteo-lytically processed to form secreted forms of MCSF. Thesecreted MCSF can either be a proteoglycan or a glycopro-tein. All isoforms of MCSF are biologically active and canstimulate cell proliferation on target cells [23, 22].

MCSF receptor and signaling cascades

All the biological effects ofMCSF are mediated through CSF-1R, a receptor belonging to type III receptor tyrosine kinasefamily. It is encoded by the proto-oncogene c-fms [17]. CSF-1R belongs to a family of growth factor receptors which alsoincludes stem cell factor receptor (SCF), and receptors forplatelet-derived growth factor (PDGF-R) and Flt3/flk2 pro-teins [24, 25]. This family of receptors share similar structural

features and possess an extracellular N-terminal ligand-bind-ing domain, a hydrophobic transmembrane domain and thecytoplasmic tyrosine kinase domain [25]. Binding ofMCSF toCSF-1R initiates the signaling cascades, the first step of whichis the dimerization of receptor. It is followed by trans-phosphorylation of various tyrosine residues and binding ofsignaling proteins having SH2 domains to the phosphorylatedsites of the receptor.

Although there are 20 tyrosine residues found in the cyto-plasmic kinase domain of CSF-1R, phosphorylation of fourare shown to mediate the major downstream signaling cas-cades [17, 25]. In murine CSF-1R, these tyrosine phosphory-lation sites are Y697, Y706, Y721, and Y807, while in humanCSF-1R, the sites are Y699, Y708, Y723, and Y809. All ofthese auto-phosphorylation sites are located in the kinasedomain of CSF-1R [17]. The major signaling pathways acti-vated by binding of MCSF to CSF-1R are shown in Fig. 1.

Phosphorylation of tyrosine residue at position 697 (Y697)in CSF-1R binds Grb2 [26] and activates mitogen-activatedprotein (MAP) kinase pathway through SOS, Ras, and Raf[25], which can eventually lead to cell proliferation or celldifferentiation. Phosphorylated Y721 is shown to bind withphosphatidylinositol 3-kinase (PI3K) [27] and further activateprotein kinase B (PKB)/Akt-mediated signaling pathways.PI3K phosphorylates phosphatidylinositol 4, 5-bisphosphate(PIP2) to phosphatidylinositol (3, 4, 5)-triphosphate (PIP3).PIP3 then activates Akt, which further initiates the signalingpathways involved in cell proliferation. Activated Akt alsoplays an important role in the suppression of apoptosisthrough phosphorylation of Bcl-2-associated death promoter(BAD).

Besides PI3K-mediated signaling, phosphorylated Y721also recruits phospholipase C2 (PLC2) [28] which cleavesPIP2, into two products, namely diacylglycerol (DAG) andinositol 1, 3, 4 P3 (IP3). IP3 increases the concentration ofCa2+ in the cytoplasm by binding with IP3 receptors on thesmooth endoplasmic reticulum and releasing Ca2+ throughcalcium channels. Increasing concentrations of Ca2+ andDAG trigger the signaling pathways mediated through proteinkinase C (PKC). Activation of PI3K or PLC2 signalingcascades thus requires binding to the same phosphorylatedY721. Moreover, both PI3K and PLC2 share a commonsubstrate, PIP2. This represents that a fine balance in theactivation of these two distinct signaling pathways plays adecisive role in determining the outcome of cell differentia-tion. Although a protein binding to the phosphorylated Y706is yet to be determined [25], STAT1 activation in CSF-1stimulated cells is shown to require phosphorylation ofY706 [29]. Phosphorylation of the tyrosine residue, Y807situated in the main kinase domain of CSF-1R, does notinvolve directly in any of the signaling pathways, but isinstrumental in bringing about a conformational change thatcan relay all the proliferation and differentiation signals.

Tumor Biol.

Physiological functions of MCSF

Hematopoietic stem cells located in adult bone marrow,spleen, and fetal liver continuously give rise to lymphoidand myeloid progenitor cells. These progenitor cells furtherproliferate and differentiate to give rise to a variety of cellsbelonging to their respective lineages. One of the lineages ofmyeloid progenitor cells yield monoblasts, promonocytes,monocytes, and macrophages. Another class of specializedcells, the osteoclasts, also develops from monocyte/macrophages cell lineage. MCSF is the primary regulator ofcells of mononuclear phagocytic system. All these cells ex-press CSF-1R, the receptor for MCSF. All actions ofMCSF inthese target cells are by signaling through CSF-1R.

Under normal conditions, there is an abundance of MCSFin vivo, with the three different isoforms of MCSF playingdistinct yet overlapping roles. Most of the tissues and organsin the human body have resident macrophages. Monocytesand macrophage development in most of the tissues requireMCSF as a crucial factor. Although Langerhans cells, bonemarrow monocytes, and macrophages present in lymph nodesand thymus can develop independent ofMCSF, tissue-specificmacrophages present in other tissues like muscles, tendons,synovial membranes, etc. require MCSF for their develop-ment and maturation [30]. Further, MCSF stimulates macro-phage activation in response to infection with various

pathogenic organisms. In addition to macrophage develop-ment, MCSF stimulates the production of several other cyto-kines including IL-1, IL-1, IL-6, and granulocytemacro-phage colony-stimulating factor (GM-CSF) in murine perito-neal cells [31]. The regulation of monokine production byMCSF is dose dependent and also time dependent. Humanmonocytes, when incubated with MCSF, secrete interferon(IFN) and tumor necrosis factor (TNF), and also exhibitincreased myeloid colony-stimulating activity upon stimula-tion with other inducing agents such as lipopolysaccharide(LPS) and phorbol myristate acetate (PMA) [32]. However,the response of MCSF-activated monocytes is not uniformand it depends on the type of secondary priming signals.Generally, MCSF-activated monocytes produce pro-inflammatory cytokines when challenged with LPS. But whenthe activating stimulus is bacterial CpG-containing DNA, theresponse is anti-inflammatory and when the stimulus islipopeptide, no response is observed [33].

MCSF plays a crucial role in the regulation of bone phys-iology. Bone is a dynamic structure which undergoes contin-uous remodeling involving formation and resorption.Osteoblasts, which are cells of mesenchymal/stromal origin,regulate the formation of bones while osteoclasts, the cellsdifferentiated from mononuclear phagocytic precursors, con-trol bone resorption. For normal and healthy bone structure, afine balance between osteoblasts and osteoclasts is

Fig. 1 MCSF signalingpathways in murine CSF-1R.Binding of MCSF to CSF-1Rresults in dimerization of the re-ceptor and phosphorylation oftyrosine residues at variouspositions in the cytoplasmickinase domain of CSF-1R. Whilephosphorylation of Y697activates MAPK signalingpathway, phosphorylation oftyrosine residue at position 721can initiate PI3K or PLCsignaling pathways

Tumor Biol.

maintained.MCSF is required for the formation of osteoclasts.Mice having defective MCSF production were reported to besmall, toothless, suffering from low body weight, severe ab-normalities in skeletal structure and deficiency in macro-phages [34]. In 1990, Wiktor-Jedrzejczak et al. reported thata null mutation in MCSF gene in op/op mouse led to a severedeficiency of osteoclasts and subsequent development ofosteopetrosis. This defect was partially rectified when CSF-1producing L929 cells were implanted in op/op mouse [35].However, external administration ofMCSFwas not enough toovercome all the defects seen in op/op mouse.

Outside the hematopoietic system, MCSF has an importantrole in the development and regulation of placenta, mammarygland, and brain. Almost all functions of MCSF aredeciphered by using a mouse model where a homozygousnull mutation in the coding region of MCSF gene was gener-ated by a single basepair insertion (op/opmouse). These op/opmice completely lacking MCSF production have severemalfunctioning of central nervous system including visualand auditory defects and this abnormal shortcomings in func-tioning of brain can be rescued by daily postnatal administra-tion of MCSF [36]. Op/op mice also develop an aberrantmammary gland because of the failure to form lactating ductsduring pregnancy [37]. Further, MCSFwas also reported to bea crucial factor necessary for normal fertility [38].

Role of MCSF in cancer

In order to sustain incessant proliferation, many tumors ofnon-hematologic origin secrete different types of endocrineand other growth factors. MCSF is produced by differenttypes of cells including tumor cells. MCSF is overexpressedespecially in type II papillary renal cell carcinoma [39], breastcancers [40, 41], and tumors of female reproductive tract likeovarian [41, 42] and endometrial cancers [43]. High MCSFlevels are also seen in patients with colorectal cancer [44],pancreatic cancer [45], prostate cancer, and head and neckcancer [46]. The circulating level of MCSF is often used as amethod of estimating prognosis of patients. Overexpression ofMCSF and its receptor, CSF-1R, in tumors have been associ-ated with poor prognosis [47].

MCSF is known to infiltrate sites of injury and inflamma-tion with mononuclear phagocytes. Excess amount of MCSFsecreted by tumors acts as a chemo-attractant, infiltratingtumors with cells of mononuclear phagocytic system. In ad-dition to MCSF, tumor cells also produce other chemokinesand growth factors, like CCL3, CCL4, CCL5, CXCL12,transforming growth factor- (TGF-), transforming growthfactor- (TGF-), fibroblast growth factor (FGF) and VEGF[48, 12]. These tumor-derived factors (TDFs) are responsiblefor the bulk mobilization of cells of immune system intotumor. The immune infiltrate in tumor is comprised of

polymorphonuclear granulocytes, monocytes, immature den-dritic cells, and various types of T lymphocytes. The presenceof NK cells in tumor is very rare. The accumulation of im-mune cells in tumor has given rise to conflicting reports withsome reporting better prognosis and others, providing evi-dences for tumor growth and metastasis.

MCSF has been specifically implicated in the process ofmetastasis in breast cancer though the incidence and the initialgrowth of tumor are not affected in the absence of MCSF.Homozygous null mutation of MCSF gene in mice shows adepleted macrophage population in breast cancer, resulting inreduced malignancy and metastasis [49, 50]. Restoring thelocal concentrations of MCSF in this mouse model of mam-mary tumor by transgenic expression of MCSF gene resultedin the promotion of tumor development. The pro-tumoralactions of MCSF are exerted mainly through macrophages.Heavy infiltration of monocytes and macrophages into tumorare known to facilitate angiogenesis that caters to the contin-uous supply of nutrients necessary for tumor growth andprogression. Tumor cells and the surrounding stromal cellssecrete large quantities of angiogenic factors which enhancethe vascularisation of tumor. The excess vascularisation alsoprovides an entry point for tumor dissemination into bloodvessels moving to distant organs, thereby promotingmetastasis.

The presence of monocytes and macrophages in tumorpromotes angiogenesis by increasing the level of secretion ofvarious growth factors and chemokines including VEGF,FGF, transforming growth factor (TGF), thymidine phosphor-ylase (TP), and urokinase plasminogen activator (uPA). TAMsoften accumulate in the low oxygen and avascular regionswithin the tumor [51, 52]. This hypoxia condition of TAMsupregulates the expression of hypoxia-inducible factors(HIFs), which in turn drives the transcription of various mito-genic growth factors including VEGF [53]. VEGF is a well-known angiogenic growth factor which increases the prolifer-ation of endothelial cells and stimulates the formation of bloodvessels. Large quantities of VEGF are secreted by the tumorcells as well as by TAMs [5456]. Tumor growth and invasionresulting from the elevated production of VEGF and its re-ceptors have been documented in many tumors includingbreast cancer [57], prostate cancer [58], glioblastoma [59],ovarian cancer [60], colon cancer [61], and liver cancer [62].MCSF, apart from attracting monocytes into the tumor alsoacts as a transcriptional regulator of VEGF production inmonocytes [63, 64]. Further, the importance of MCSF in thedegradation of extracellular matrix through production ofurokinase, and augmentation of invasive properties is notedin ovarian cancer cells [65].

Nevertheless, MCSF has a potential role in eliciting anti-tumor response as well. Addition of purified MCSF to thehuman ovarian cancer cells has been documented to induceconcentration dependent growth inhibition in vitro [66]. RatT9 glioma cells transfected with the gene corresponding to

Tumor Biol.

membrane isoform of MCSF (mMCSF) is killed by macro-phages in a concentration dependent fashion [67]. This directkilling of mMCSF expressing tumor cells by macrophagein vitro occurs through phagocytosis [68, 69]. When injectedinto an immunodeficient mouse, the site of mMCSF-transduced human glioblastoma cells is reported to be heavilyinfiltrated by macrophages within 4 h and these infiltratingmacrophages are seen killing the tumor cells by paraptosis[68]. When monocytes or macrophages come into contactwith tumor cells expressing mMCSF, they release reactiveoxygen species (ROS). ROS then activates big potassiumchannels (BK channels) which in turn initiate paraptosis, aprocess where excessive swelling and vacuolization leads tocell death [70]. Glioblastoma cells transduced with mMCSFgene also conferred protective immunity in rat when chal-lenged with glioblastoma cells, suggesting the potential appli-cation of these mMCSF-expressing tumor cells as tumorvaccines [68]. The overall role played by MCSF within thetumor microenvironment is depicted in Fig. 2.

In addition to its role in promoting tumor developmentthrough involvement of macrophages, elevated quantities ofMCSF in tumor also lead to poor prognosis [47, 44].However, the exact mechanism leading to drug resistance inMCSF-overexpressing tumors is not known. Recently, wereported that MCSF can increase the resistance of glioma cellsto 5-fluorouracil treatment through formation of cancer stemcells (Fig. 3) [71]. In this study, expression of MCSF inU87MG cells induced epithelialmesenchymal transition(EMT). Numerous studies had shown the involvement of

EMT in inducing the formation of cancer stem cells andupregulation of multi-drug resistant genes in different typesof cancers [7274]. Our results demonstrated that MCSF caninduce EMTin solid tumors and promote drug resistance throughformation of cancer stem cells, leading to poor prognosis.

Tumor-associated macrophages

Monocytes are recruited to the site of tumor through thesecretion of various chemotactic molecules such as MCSF,MCP-1 (monocyte chemoattractant protein-1), MCP-2(Monocyte chemotactic protein 2), MIP-1 (macrophage in-flammatory protein-1), PIGF (placental growth factor),MIP-1 (macrophage inflammatory protein-1), RANTES,etc.[51]. These monocytes, depending on the stimulus and thetype of cytokines present in the tumor, get differentiatedlocally to form either M1 (classical) or M2 (alternate) polar-ized macrophages [12, 7, 11, 75]. M1- and M2-activatedmacrophages are involved in T-helper 1 (Th1) or T-helper 2(Th2) responses respectively. M1-polarized macrophages pos-sess high tumoricidal and anti-microbial activities [76] and areactivated in response to stimulation by LPS, IFN, and othermicrobial antigens and they mount a strong pro-inflammatoryresponse with high expression of IL-1, IL-12, IL-23, andTNF [77]. They are entrusted with high antigen-presentingcapacity and generate increased amount of ROI (reactiveoxygen intermediates) and RNI (reactive nitrogen intermedi-ates). On the other hand, M2-polarized macrophages are

Fig. 2 Scheme for the role ofMCSF in cancer. (a) The anti-tumor properties are elicited whenTAMs comes into contact withtumor cells expressing membranebound MCSF. (b) Pro-tumor roleof MCSF. Secretion of MCSF bytumor cells recruits TAMs intotumor which increasesangiogenesis and growth of tumor

Tumor Biol.

involved in post inflammatory processes such as scavengingdebris, tissue repair, and angiogenesis and are characterised bythe elevated productions of IL-10, IL-1 receptor antagonist(IL-1ra), and low IL-12. A brief summary of properties ofM1-and M2-activated macrophages is presented in Table 1.Macrophages found in tumor have been demonstrated toexpress primarily M2 phenotype with poor anti-cancer activ-ities [78, 39].

Macrophages exhibit enormous functional plasticity in re-sponse to the variety of signals that come from their localenvironment. No other pathological condition can demon-strate the yinyang properties of macrophages better thantumor. Although M1 and M2 phenotypes of macrophageshave distinct functions, they are in fact two extreme states inthe continuum of functional diversity which macrophagesexert in tumor [79]. Tumor cells are speculated to harbour aheterogeneous population of macrophages depending on the

region where the macrophages reside in tumor [49]. A recentstudy byMovahedi et al. provides evidence for the presence ofmacrophages with both M1-like properties and M2-like prop-erties in a mouse model of mammary tumor. Macrophagespresent in the normoxic areas of the tumor have high expres-sion of MHC II along with M1-associated markers whereasthe macrophages located in the hypoxic regions of the tumorhave low MHC II expression with high expression of M2-related markers. However, in spite of expressing markers ofM1-activated macrophages, MHC IIhigh macrophages seen innormoxic regions of tumor have poor antigen-presenting ca-pacity similar to MHC IIlow macrophages seen in hypoxicregions of the tumor [4]. Moreover, both MHC IIhigh andMHC IIlow macrophages exhibit immunosuppressive activity.

Cytokines including IL-4, IL-10, prostaglandin E2, andTGF- are produced by tumor cells as well as monocytes,TAMs, dendritic cells, and infiltrating CD4+ T cells at the

Fig. 3 Expression of MCSF in U87MG cells lead to increase in propor-tion of cancer stem cells and upregulation in the expression of multi-drugresistance (MDR)-associated genes. (A) Flow cytometry analysis for the

expression of CD24 and CD44 cancer stem cell markers in U87MG andU87-MCSF cells. (B) Real-time PCR analysis for the expression ofMDR-associated genes [71]

Table. 1 Summary of the role of M1- and M2-activated macrophages

M1 (classical activation) macrophages M2 (alternative activation) macrophages

Increased secretion of pro-inflammatory cytokinessuch as IL-1, IL-6, IL-12, IL-23, and TNF

Increased secretion of anti-inflammatory cytokines such as IL-10and low secretion of IL-12.

Characterized by high antigen-presenting capacityand generates ROI, RNI.

Characterized by high immunosuppressive properties and poorantigen-presenting capacity.

Responsible for mounting strong anti-microbialand tumoricidal actions.

Involved in scavenging debris, tissue repair, and promotingangiogenesis.

Tumor Biol.

site of tumor [12, 80, 49]. Exposure of the monocytes presentin tumor infiltrate to IL-4 and IL-10 drives them towards M2-like phenotypes [11]. Further, IL-10, an immunosuppressivecytokine secreted by tumor and the infiltrating monocytes,stimulates the expression of programmed death 1 ligand 1(PD-L1), a T-cell inhibitory molecule, in hepatocellular carci-noma [81]. The expression of PD-L1 is also reported in renalcancer [82], myeloma [83], and ovarian cancer [84]. PD-L1along with programmed death-1 (PD-1) receptor, suppressesthe tumor-specific T cell immunity by inhibiting CD8+ T cellmediated cytolytic activity [83, 85]. Moreover, IL-10-exposedmonocytes favour macrophage maturation to dendritic celldifferentiation [11] thereby, effectively curbing the availabilityof the premium antigen-presenting cells.

The M2-like properties of TAM which support tumor pro-gression [39, 13] are, however, reversible in many cancers.When NF-B activity is blocked in mouse macrophages bytargeting IB kinase (IKK) , these TAMs switch their phe-notype from M2- to M1-polarized macrophages [86]. Severalother researchers have also reported that by modulating thecytokine profile of the tumor environment, macrophages canbe reprogrammed from tumor supporting M2-like phenotypeto anti-tumor M1 phenotype [8789]. However, TAMs foundin tumor show predominantly M2-like polarized propertiessupporting tumor growth.

Concluding remarks

In the entire episode of macrophage-supported tumorgrowth, MCSF plays a vital role as one of the primarycytokines attracting monocytes into the tumor. Further,MCSF acts in synergy with macrophages in increasingthe concentrations of angiogenic growth factors likeVEGF in the tumor microenvironment. Although thereare some contradictory reports on the role played byMCSF in tumor, many of the tumor-supporting actions ofMCSF are well-known and hence it is classified as a pro-tumoral cytokine. Our recent study also demonstrated theinvolvement of MCSF in increasing the resistance of glio-ma cells to 5-FU through formation of cancer stem cells.However, the molecular pathways of MCSF-mediated drugresistance are not yet known. Understanding the signalingpathways for cancer stem cell formation in presence ofMCSF will give ample scope for development of therapeu-tic strategies aimed at targeting relevant signaling mole-cules. Further, how monocytes are triggered to undergodifferentiation into M2 macrophages, instead of the classi-cal antitumor M1 macrophages, is also largely unknown.Deciphering the mystery of monocyte differentiation intoTAMs will enable us to re-educate our immune systemand develop an efficient anti-cancer therapy.

Acknowledgments This research work was supported by Departmentof Biotechnology (no. BT/01/NE/PS/08) and Department of Electronicsand Information Technology, Government of India (no. 5 (9)/2012-n (vol.II)). Authors acknowledge assistance from the Centre for Nanotechnolo-gy, IIT Guwahati.

Conflict of interest None.

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Macrophage colony-stimulating factor and cancer: a reviewAbstractIntroductionMacrophage colony-stimulating factorMCSF receptor and signaling cascadesPhysiological functions of MCSFRole of MCSF in cancerTumor-associated macrophagesConcluding remarksReferences