today there is a great debate about the role of inflammation in control and regulation of tumor microenvironment directly influencing the development of neoplasms . inflammation plays a fundamental role in tumor dynamic and is accepted as one of the hallmarks of cancer [ 1 , 2 ] . currently there are two marked ways by which inflammation is associated with cancer development , an intrinsic pathway characterized by the gene expression and an extrinsic pathway , characterized by the formation of an inflammatory microenvironment . within this microenvironment , macrophages are the major cell populations involved in the inflammatory process associated with the development of neoplasms . considered highly plastic cells , they are able to respond to stimuli and produce numerous pro- and anti - inflammatory factors and when related to cancer , they are termed tumor - associated macrophages ( tams ) . it is believed that tams play a key role in promoting and coordination phenomena of tumor growth due to their ability to modulate the angiogenesis and lymphangiogenesis that are processes involved in the progression of neoplasms . tams are activated by different stimuli , such as growth factors , nutrients , and cytokines , produced in the tumor microenvironment that are responsible for inducing differentiation in functionally distinct populations . in populations of classically activated macrophages ( m1 ) , there is a high production of proinflammatory cytokines displaying an immune - stimulatory function . on the other hand , the alternative activation of macrophages ( m2 ) is based on the release of anti - inflammatory cytokines supporting an immunosuppressive environment [ 79 ] . this environment , formed by cells , extracellular matrix , growth factors , nutrients , and cytokines , may be responsible for the macrophages differentiation and behavior of tumor cells . however , like a feedback loop , these cells alter the environment in reply to stimuli . , the role of tams polarization in m1 and m2 profiles might have clinical and pathological importance and appears to be associated with angiogenesis , proliferation , aggressiveness of tumor , and apoptosis . moreover , the debate appears to be controversial about the relation between inhibitory or promoter ability of m1 or m2 on tumor . recently , one of the ways suggested for activation of macrophages subpopulations involves the signaling akt / mtor pathway . a change in regulation of this metabolic pathway plays a crucial role in activation controlling and acquisition of macrophages effector activity , depending on the context in which they are , as well as the tumor microenvironment . with this view of the tumor stroma and its influence on the progression of neoplasms , the study about the role of macrophage polarization in the tumor pathogenesis may emerge as a new therapeutic approach . in this review , we discuss the role of tumor microenvironment and macrophages in cancer ; m1 and m2 differentiation and the role of mtor pathway ; and m1 and m2 macrophages as possible tumor markers . the monocyte - derived macrophages are cells of the myeloid lineage that have functional plasticity [ 12 , 13 ] . they are important cells of the innate immune system and can act in different tissues as phagocytes , antigen presenting cells , and tissue remodeling [ 14 , 15 ] . the functional plasticity associated with phenotypic and metabolic differences led to the characterization of two macrophage subtypes , m1 and m2 . these macrophages subtypes were primarily defined in murine models , but actually the m1 and m2 terms are widely used for humans and others mammalians . however , clearly , there are not only two functional subtypes of macrophages and the polarization process has a large spectrum of subpopulations with phenotypic differences showing the plasticity of macrophages [ 15 , 16 ] . m1 macrophages are always related to the inflammatory response by presenting a large phagocytic and microbicidal capacity , increased expression of mhc ii molecules , cd80 , and cd86 and also secreting cytokines such as tnf - alpha . this m1 profile is induced by the presence of pamps that bind mainly to tlr2 and tlr4 and th1 cytokines such as ifn - gamma that activate the transcription factors stat1 and irf5 [ 12 , 14 , 15 ] . m2 macrophages , in turn , are typically activated in the presence of th2 cytokines such as il-4 and il-13 that improve the stat6 and irf4 interaction . the m2 profile is characterized by low phagocytic and microbicidal activity , and it is linked to the presence of helminthes or to the tissue remodeling processes . these m2 macrophages , unlike the m1 , do not activate inos and therefore do not produce nitric oxide ( no ) ; however , they have great arginase activity that is important in wound healing and tissue remodeling process [ 14 , 16 ] . the differences between these profiles are also observed in their metabolism , m1 have preferably glycolytic pathways while m2 has increased beta - oxidation [ 11 , 12 ] . tams are a major stromal component and exhibit , mostly , m2 similar profile . however , according to sica and mantovani ( 2012 ) macrophages change during tumor development . tams show m1-like phenotype characterized by high il-12 releases that cause tumor cell disruption , when in tumoral early - stage . despite this , in late - stage of tumor progression , tams exhibit an m2-like phenotype accompanied to reduced antitumoral activity . the antitumoral m1-dependent response is related to inflammatory response and the activation of specific lymphocytes in an attempt to eliminate tumor cells . on the other hand , m2 participation in tumor environment provides angiogenesis and survival , supporting metastasis and tumor growth [ 11 , 18 ] . thus , tams play a crucial role in the modulation of tumor microenvironment producing a large amount of growth factors and inflammatory mediators that stimulate proliferation , angiogenesis , deposition , or degradation of extracellular matrix [ 19 , 20 ] the tumor cells present an unusual metabolic activity and consume a large amount of nutrients and oxygen ; in addition , these cells need to remove the waste metabolic products such as carbon dioxide . thus , the new vascularization associated with tumor , generated by the angiogenesis process , allows these conditions . thus , without a pathological neovascularization the tumors grow slower decreasing their capacity to promote metastasis . at the same time , ineffective blood supply does not allow the action of anticancer drugs in effective amounts in tumor regions . in some cancers the first occurs directly by oncogenes such as ras and myc that can increase the expression of angiogenic factors in cancer cells , while , in second , the angiogenic signals are indirectly produced by inflammatory cells , specially tams   that play a crucial role in tumor promotion and progression , contributing to neovascularization and tumor cell proliferation and metastasis [ 2427 ] . the epidermal growth factor ( egf ) ; family members of fibroblast growth factor ( fgf ) ; vegf ; matrix metalloproteinases ( mmps ) ; heparanase ; plasmin , activator of the urokinase - type plasminogen ( upa ) ; the upa receptor ; and cytokines and chemokines as tgf- , which enlarge the inflammatory state , are among the key related factors secreted by tams in the tumor microenvironment [ 21 , 25 , 28 ] . proangiogenic factors produced by tams are critical to regulate tumor development and have ability to maintain a favorable environment to encourage and maintain the remodeling and a complex vascular network within the lesion . vegf   and matrix metalloproteinase-9 zymogen ( prommp-9 )   are considered key factors involved in this increased organization of tumor vasculature . 2013 , demonstrated that the angiogenic capacity of m2 macrophages critically depends on production of the readily activatable proenzyme prommp-9 and only m2 macrophages approach the high angiogenic capability of neutrophils . in addition to angiogenesis researchers have also studied a new approach in vascular biology  the lymphangiogenesis . lymphangiogenesis is described as the development of a new lymphatic vessels , which in normal condition occurs in embryonic development being absent in adults . however , this process can be induced by pathological condition such as chronic inflammation , wound healing , and several neoplastic lesions [ 31 , 32 ] . as angiogenesis , the process of lymphangiogenesis can be stimulated by cytokines and growth factors ; the vascular endothelial growth factor family ( vegfs ) plays a pivotal role in this mechanism . related to lymphangiogenesis , vegf - c and vegf - d present an exclusive involvement and recent data has also described vegf - a , a well known angiogenic growth factor , as an important lymphangiogenic growth factor [ 33 , 34 ] . the expression of lymphangiogenic growth factor and related protein was revised by ran and montgomery ( 2012 ) and , together with vegf , the authors listed pdgf , adrenomedullin , hgf , cox-2 , fgf , tnf - alpha , mmps , heparanase , and angiopoietin-2 as factors that can also provide lymphangiogenesis . ( 2012 ) describes the vegf production not only by tumor cells but also by tams   and this starts the lymphangiogenic process through vegf - c and vegf - d via vegfr3   results presented on cancers of the cervix postulate the hypothesis of peritumoral lymphangiogenesis process mediated by tams . in first step , thus , activated tams serve as a major producer of vegf - c and vegf - d that cause proliferation of lymphatic microvessels and this new dense vessel network could favor the lymphatic metastases formation . once recruited into neoplastic microenvironment tams may also disrupt lymphangiogenesis and lymphatic tumoral spread in pancreatic cancer ; kurahara and colleagues ( 2011 ) reported that this tumor presented a high density of tams correlated with lymph node metastasis . additionally , these authors also analyzed the correlation between cd163 + densities with clinic - pathological data , and , as a result , the the evidences that macrophages can cooperate with lymphangiogenesis also came from studies on bladder cancer , breast , lungs , and melanoma . the research data presented above suggest that macrophages induce the formation of both angiogenic and lymphangiogenic microenvironment . in contrast , these cells can also express antiangiogenic molecules and damage the integrity of the blood vessels . this paradoxical role of m1 and m2 in cancer is explained by their functional plasticity , which results in the expression of pro- or antitumor functions [ 24 , 42 , 43 ] . the treatment induced an antitumor effect by subsequent reduction of m2 cd206 + macrophages and a simultaneous increase in m1 macrophages expressing class ii mhc and cd86 + . this change was preceded by an increase in il-12 production within the tumor and a reduction in its neovascularization . takeuchi et al . ( 2016 ) to correlate the prevalence of m2 macrophages , angiogenesis , and clinic - pathological features in bladder cancer showed higher density of m2 macrophages in invasive bladder cancer in relation to non - muscle invasive cancers . moreover , the higher the distribution of microvessels , the greater the degree of severity of cancer , and the predominance of m2 macrophage correlated to the amount of microvessels in bladder cancer and can have prognostic value for this type of cancer . although high concentration of m2 promotes tumor angiogenesis , the mechanism that promotes the differentiation of monocytes in tams and their phenotypes is still unclear . thus , it was proposed that the mtor pathway could be a critical element in the regulation of tams differentiation . the molecular control of polarization and activation of m1 and m2 has been the subject of many investigations and has well established the participation of stat1 and stat6 , respectively [ 13 , 16 ] . in addition to these canonical pathways , molecules of other routes are also being related to differentiation of macrophages [ 11 , 46 ] . mammalian target of rapamycin ( mtor ) , a serine - threonine kinase that is highly conserved , is a component of the pathway cell survival phosphatidylinositol 3-kinase ( pi3k ) that monitors the availability of nutrients , mitogenic signals , cellular energy , and oxygen levels and is therefore insignificant in the regulation of cell growth and proliferation [ 11 , 47 , 48 ] . mtor is regulated by nutrients and growth factor and regulates cell growth by controlling many biological process such as autophagia , mrna translation , and energetic metabolism [ guertin and sabatini , 2007 ] . the mtor acts both upstream and downstream of the akt , operating as a connection with pi3k pathway and forming two different multiprotein complexes , mtorc1 ( mtor complex 1 ) and mtorc2 ( mtor complex 2 ) , which regulate protein synthesis required for cell growth and proliferation [ 48 , 50 ] . the stimulation of tlrs by pamps leads to the recruitment of pi3k that activates mtorc1 and mtorc2 in macrophages . the mtorc1 may be inhibited physiologically by the action of tsc1 ( tuberous sclerosis complex 1 ) and tsc2 ( tuberous sclerosis complex 2 ) and by rapamycin due to the presence of raptor ( regulatory associated protein of mtor ) that is sensitive to the action of rapamycin [ 48 , 5053 ] . mutations in tsc1 or tsc2 genes lead to tuberous sclerosis syndrome with the appearance of various benign tumors in skin , kidney , brain , heart , and lung [ 48 , 50 , 54 ] . mtorc1 is described as a regulator of the inflammatory activity of macrophages and other innate cells because its activation is related to reduction of the nfb activity and increase of il-10 , tgf- , and pdl1 expression . mtorc2 , on the other hand , is insensitive to rapamycin and rictor ( rapamycin insensitive companion of mtor ) and sin1 are two specific proteins for this complex . moreover , the mtorc2 can be activated by specific growth factors in macrophages and phosphorylates akt . the specific mtorc2 function in macrophages remains unclear , but recent studies showed that since the lack mtorc2 , the inflammatory response is augmented in dendritic cells   and macrophages . in this study with murine macrophages lacking rictor , the authors demonstrated the overresponse to tlrs ligands and the increase of the levels of m1 related - genes and lower expression of m2 markers . these data suggest that mtorc2 plays key roles in the macrophage polarization and in the regulation of the inflammatory response . in 2013 , a group of researchers using rapamycin in human monocytes showed that monocytes had a cytokine profile after stimulation similar to that expected for m1 . in the same year , byles and colleagues showed that the tsc1-mtor pathway regulated the polarization of human macrophages . they showed that , in the absence of tsc1 , the macrophages did not differ to m2 even in the presence of il-4 and suggested that activation of mtorc1 would lead to downregulation of akt interfering with the expression of characteristic m2 genes . in addition , recently , huang and collaborators ( 2015 ) observed that glycolytic metabolism , specific of m2 profile , requires both mtorc2 and stat6 pathway activation in il-4 and csf1-stimulated macrophages . lin et al . ( 2002 ) highlighted the csf-1 as one of the major regulators to mononuclear cells and its expression in breast carcinomas is correlated with poor prognosis . in 2014 , zhu and colleagues also related the macrophages polarization to tsc1 and mtor . in this case , the authors used tsc1 knockout mice and observed resistance to m2 profile polarization and m1 macrophages increased . however , they concluded that m2 inhibition occurred in mtor - dependent manner and the m1 increase was mtor - independent and erk - dependent . additionally , mtor pathway is also responsible for the control of cellular metabolism , which appears differently between the poles . in the tumor context chen et al . ( 2012 ) demonstrated that , in human peripheral monocytes stimulated by lipopolysaccharide , the mtor was inhibited by rapamycin or activated by rna interference - mediated knockdown of the mtor repressor tuberous sclerosis complex 2 ( tsc2 ) . thus , rapamycin took to differentiation of monocytes into macrophages m1 releasing more il-12 and less il-10 while tsc2 knockdown led to the differentiation of monocytes into macrophages m2 releasing less il-12 and more il-10 . moreover , angiogenic properties were stimulated from endothelial cells from human umbilical vein cocultured with tsc2 deficient monocytes or reduced in the group treated with rapamycin . the tumor angiogenesis and growth in murine xenografts were held after infusion of tsc2 deficient monocytes or reduced with monocytes overexpressing tsc2 . finally , in vivo depletion of macrophages was sufficient to block the antiangiogenic effects of rapamycin in tumors . these results define the tsc2-mtor pathway as a determinant in the differentiation of monocytes in tam m2 phenotype that promote angiogenesis . . ( 2016 ) demonstrated that macrophages , associated with the microenvironment of the renal cell carcinoma , favor tumor metastasis by activation of akt / mtor pathway . in addition , as for the mtor signaling to be related to macrophages differentiation and consequently in angiogenesis , studies show its role in proliferation , migration and cell survival [ 59 , 61 , 62 ] . these data together reinforce that the mtor pathway can be used as a therapeutic target in an attempt to modulate macrophage response in the tumor environment or the raised immune response so that there is an antitumor effect . not only macrophages but also cancer cells present mtor pathway activation that modulates different molecules that contribute to the tumoral microenvironment . in turn , this environment can induce the tam polarization , demonstrating the close and complex relationship between cancer cell , macrophages , and tumor progression . gene mutations such as oncogenes and tumor suppressor genes confer constitutive activation of the mtor pathway in conditions of nutrient depletion increasing its expression in various types of cancer , such as akt in breast and ovarian cancer , pi3k in ovarian , gastrointestinal , breast , and prostate cancer , tsc1/tsc2 in the hamartomas formation and lymphangioleiomyomatosis development . however , the inhibition by rapamycin or nutrient depletion induces the activation of autophagy by pi3 kinase , akt , and mtor pathways , which allows the cancerous cells survival under conditions of a microenvironment with low amount of nutrients [ 59 , 63 ] . in autophagy , the release of amino acids arising from autophagic degradation generates reactivation of mtorc1 and the restoration of lysosomal cell population and promotes cell growth . mtor pathway plays a critical role in the tumoral neovascularization providing an environment where cells grow . initially , tumor microenvironment modifications can induce mtor to increase the translation of hypoxia - inducible factor 1 ( hif-1)/hypoxia - inducible factor 2 ( hif-2 ) , which drive the expression of genes for hypoxic stress response , including angiogenic growth factors such as vegf , pdgf- , and tgf- . interestingly , vegf has also presented the direct capability to activate the mammalian target of rapamycin complex 1 ( mtorc1 ) pathway through the cross talk with phospholipase c gamma ( plc ) . as mtorc1 is a metabolic sensor , metabolic signals may be integrated with signals from vegf in the regulation of angiogenesis leading to a positive feedback loop to enhance angiogenic responses . furthermore , the lymphangiogenesis can be also controlled by mtor pathway modulation . to illustrate the relation between mtor and lymphangiogenesis ekshyyan et al . the authors observed that rapamycin ( mtor inhibitor ) significantly inhibited tumor progression and lymphangiogenesis when compared to control , and in conclusion ekshyyan et al . ( 2013 ) describes mtor inhibitor impairing the autocrine and paracrine vegf - c / vegfr-3 axis . ( 2013 ) conclusion could be linked to tmas population ; mtor inhibitor can affect macrophages changing their expression profile . in last decades significant improvement of overall survival has been observed in patients with neoplastic disease . some factors ( locoregional recurrences , distant metastases , and a second primary tumor ) may influence the prognosis reducing overall survival rates . in recent years , a better understanding of tumor - associated macrophages associated with these tumors microenvironment might help to find adjuvant therapies to improve patients ' overall survival . we need to remember that tams may present an m2-like ( immunosuppressive ) phenotype that leads to enhancing the tumor development . therefore , the tams phenotype may play a dual role in tumoral progression and disease overall survival . an animal model of lung cancer demonstrated that the immunomodulation of m2 tams population was able to reduce the tams population and tumor size and enhances overall survival rates . ( 2011 ) aimed at analyzing the impact of tumoral microenvironment on survival outcomes showed that patients diagnosed with human gastric cancer that have high level of tams presented a significantly lower overall survival when compared to patients presenting low level of tams . in a retrospective study comparing tams population in pancreatic ductal adenocarcinoma chen et al . ( 2015 ) described that tumor presenting a high level of tams infiltration has a significantly worse relation to prognostic factors and lower survival rates . as a first analysis the authors observed distribution of cd68 and cd163 ( m2-like macrophages ) , and focused on m2 phenotype the authors observed a positive relation to histological grade and n stage . 2015 ) have also demonstrated the relation between tams and survival ; neoplasm with high m2-like macrophage infiltration presented a worse survival rate when compared to lesion presenting a low m2-like infiltration . corroborating the idea of worse prognoses of m2-infiltrating tams a study evaluating the correlation between cd163 + macrophages and survival rates in melanomas showed that lesions presenting a high population of cd163 + macrophages have significantly poor overall and melanoma - specific survival . in the same way , breast cancer has also demonstrated a worse prognosis related to tams infiltration , and tsutsui et al . ( 2005 ) described that patients with high tams population have a reduced disease - free survival . however , this behavior ( relation between tams and worse prognoses ) is not rule for all neoplastic entities . to exemplify the correlation between tams infiltration and better prognosis , edin et al . ( 2012 ) studying colorectal cancer demonstrated a significant association between improved prognosis and cd163 + tams . to explain this relation the authors demonstrate the parallel existence of a nos2 + tams population ( m1-like macrophage ) , and edin et al . ( 2012 ) believe that patient 's outcome was determined by m1 and m2 phenotypes balance . the tumor - associated macrophages have emerged as a main component effector and regulator of the innate immune response to neoplasms . biologically , the cancer microenvironment has provided important signals to macrophages plasticity . in this context , the mtor signaling pathway , a key factor in m1 and m2 polarization , can be , in the near future , considered as possible target in anticancer therapy .