Macrophage migration inhibitory factor: A key cytokine and therapeutic target in colon cancer

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Macrophage migration inhibitory factor: A key cytokine and therapeutic target in colon cancer A.N. Gordon-Weeks *, S.Y. Lim, A.E. Yuzhalin, K. Jones, R. Muschel CRUK/MRC Gray Institute for Radiation Oncology & Biology, University of Oxford, UK

A R T I C L E I N F O

A B S T R A C T

Article history: Available online xxx

Macrophage migration inhibitory factor (MIF) was one of the first cytokines to be discovered, over 40 years ago. Since that time a burgeoning interest has developed in the role that MIF plays in both the regulation of normal physiology and the response to pathology. MIF is a pleotropic cytokine that functions to promote inflammation, drive cellular proliferation, inhibit apoptosis and regulate the migration and activation state of immune cells. These functions are particularly relevant for the development of cancer and it is notable that various solid tumours over express MIF. This includes tumours of the gastrointestinal tract and MIF appears to play a particularly prominent role in the development and progression of colonic adenocarcinoma. Here we review the role that MIF plays in colonic carcinogenesis through the promotion of colonic inflammation, as well as the progression of primary and metastatic colon cancer. The recent development of various antagonists and antibodies that inhibit MIF activity indicates that we may soon be able to classify MIF as a therapeutic target in colon cancer patients. ß 2015 Elsevier Ltd. All rights reserved.

Keywords: Colon cancer Inflammation MIF Macrophage migration inhibitory factor

1. Introduction Throughout Europe, colorectal cancer is the third most commonly diagnosed cancer in men and women combined [1], responsible for an estimated 150,000 cancer deaths in 2012 [1]. Chronic inflammation is recognised as an important contributing factor to the development of colorectal cancer. Patients with inflammatory bowel disease (IBD) have a significantly higher risk of colon cancer when compared with healthy populations [2–4]. Furthermore, the long-term administration of low-dose dextran sulphate sodium (DSS) to mice or rats results in chronic colonic inflammation which can progresses to colon cancer [5], indicating that colonic inflammation can pre-date malignancy within the colon. The carcinogenic effect of DSS is inhibited when mice are treated with various immunosuppressive agents [6,7], demonstrating the importance of the immune system in the promotion of colon cancer. Equally, patients with cardiovascular disease who are treated with low-dose anti-inflammatory medication have a reduced colon cancer risk [8,9]. In short, colonic inflammation and cancer are inextricably linked.

Cytokines are strongly implicated in the development of cancer within chronically inflamed tissues. Certain cytokines promote the development of a pro-tumourigenic microenvironment by orchestrating the recruitment of immune cells, as well as having direct effects on tumour, endothelial and stromal cells in order to promote cancer development and progression [10]. Of the cytokines displaying pro-tumourigenic activity, the pleiotropic molecule macrophage inhibitory factor (MIF) has received particular attention [11,12]. Indeed, the efficacy of MIF inhibition has been demonstrated in numerous pre-clinical models of both inflammatory and malignant disease (Table 1). This highly studied molecule displays an array of biological functions, many of which are capable of driving cancer progression. These functions have been studied in detail using in vitro and pre-clinical models of colon cancer. With this in mind, we review the current experimental and clinical data linking MIF expression to the development and progression of colon cancer and thus provide support for developing clinical trials of MIF inhibitors in colon cancer patients. 2. Biology of macrophage inhibitory factor 2.1. MIF gene and protein structure

* Corresponding author. Tel.: +44 7808030432. E-mail address: [email protected] (A.N. Gordon-Weeks).

MIF was one of the first cytokines to be discovered, when its production by T-lymphocytes was demonstrated to inhibit the

http://dx.doi.org/10.1016/j.cytogfr.2015.03.002 1359-6101/ß 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Gordon-Weeks AN, et al. Macrophage migration inhibitory factor: A key cytokine and therapeutic target in colon cancer. Cytokine Growth Factor Rev (2015), http://dx.doi.org/10.1016/j.cytogfr.2015.03.002

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Table 1 Effect of MIF inhibition in various pre-clinical disease models. Intraperitoneal [IP], oral [PO]. Condition

Murine model

MIF inhibitor [route]

Effect of MIF inhibition

References

Colon cancer

Caecal implantation

IBD

Reduced tumour weight and volume Reduced hepatic metastasis incidence Reduction in tumour burden Reduction in tumour growth Reduction in tumour angiogenesis Reduction in histological colitis score and disease activity Increased mouse weight Reduction in histological colitis score and disease activity Reduction in colonic myeloperoxidase activity and TNFa level Reduction in histological arthritis score Reduction in intra-codylar MMP13 Reduction in TNFa release by macrophages Increased survival Reduction in clinical signs Increased spinal cord regulatory T-cell count Reduction in histological severity score Reduction in central nervous system VCAM expression Improved alveolar architecture

[106]

Subcutaneous implantation of CT26 colon cancer cells DSS-induced colitis

ISO1 [IP] MIF neutralising antibody [IP] ISO-66 (ISO analogue) Anti-rat polyclonal MIF neutralising antibody ISO-F (fluorinated analogue of ISO-1) [PO]

DSS-induced colitis

Rheumatoid arthritis Sepsis

Multiple sclerosis

Bronchopulmonary dysplasia Diabetes

Polyclonal MIF neutralising antibody [IP] Monoclonal MIF neutralising antibody [IP] Polyclonal MIF neutralising antibody [IP] ISO-1 [IP]

Intrarectal 2,4,6 trinitrobenzenesulphonic acid Anti-type II collagen antibody/LPSinduced arthritis LPS administration Caecal ligation and puncture Experimental autoimmune encephalitis

Small molecule MIF inhibitors (CPSI-1306 and CPSI-2705) [PO]

Experimental autoimmune encephalitis

Monoclonal MIF neutralising antibody [IP]

Exposure of transgenic mouse demonstrating pulmonary MIF overexpression to hyperoxia Stroptazocin-induced diabetes

MIF 098 (small molecule inhibitor) [IP]

/

ISO-1 [IP] MIF neutralising antibody [IP]

Atherosclerosis

Apolipoprotein E-deficient (ApoE mice

Asthma

Ovalbumin-immunized rat asthma model

Polyclonal MIF neutralising antibody [IP]

Ovalbumin-immunized mouse asthma model

Anti-rat polyclonal MIF neutralising antibody [IP]

)

Monoclonal MIF neutralising antibody [IP]

random migration of guinea pig macrophages [13,14]. Despite this discovery almost 50 years ago, the MIF cDNA sequence – determined through functional expression cloning of a cDNA library prepared from activated T-cells – was not identified until 1989 [15]. The MIF gene resides on chromosome 22 and is highly conserved between mouse and human [16,17]. Interestingly, a homologue of the human MIF gene has also been identified in parasites [18,19], where the protein product is thought to serve a protective function [19]. Indeed, widespread MIF gene homology across various species of animal, parasite and plant suggests that the protein may serve a fundamental biological role [16]. Recombinant MIF was first produced in 1993 [20], a breakthrough that led to increased understanding of both its structure and function. The MIF protein is relatively small (12.5 kDa), lacking a conventional N-terminal leader sequence and is therefore released from the cell by a leaderless secretion pathway [17]. MIF shares considerable amino acid sequence homology with the enzyme D-dopachrometautomerase [21] and possesses similar catalytic activity [21]. The tertiary structure of the monomeric MIF protein was determined using X-ray crystallography in 1996 [22,23] (Fig. 1). A MIF monomer consists of two antiparallel a-helices, four b-strands forming a b-sheet and a further two singular b-strands [24]. MIF exists in dimeric and homotrimeric states under physiological conditions [24]. Trimeric MIF is arranged to produce an inner, hydrophobic pore [24] and this structure appears particularly important for maintenance of the proteins enzymatic function [25–27].

Reduction in circulating TNFa, INFg and nitric oxide concentration Reduction in hypoglycaemia Reduction in intimal macrophage count Reduction in plasma fibrinogen and IL6 concentrations Reduction in plaque volume Reduction in pulmonary eosinophil and neutrophil counts Reduction in airway pressure Reduction in pulmonary eosinophil and neutrophil counts Reduction in airway hyperresponsiveness

[125] [66] [126]

[75] [127] [128,129] [130]

[131]

[132]

[133]

[134]

[135]

[136]

[137,138]

Broadly speaking, amino acid residues at the C-terminus of the protein are important for enzymatic activity [28], whilst those at the N-terminus end appear to be involved in chemokine receptor binding [29]. Proline-1, found towards the C-terminus, in particular is important for maintaining the enzymatic activity of the protein [30]. Conversely, mutation at Aspartic acid-44 or Arginine-11 on adjacent MIF monomers within the trimeric protein reduces the proteins chemoattractant properties [31] (Fig. 1). 2.2. MIF function 2.2.1. Enzyme function MIFs catalytic activity includes both tautomerisation [32] and oxidoreduction [33]. The pathophysiological significance of such enzymatic activity is unclear, as the majority of identified MIF substrates are not present at physiologically relevant concentrations in vivo. Nonetheless, Mutational analyses and the use of specific MIF inhibitors indicate that MIF’s enzymatic site is required for many of the protein’s biological functions, including anti-gluocorticoid activity [26,30,34]. 2.2.2. Hormone function The first indication of MIFs hormone function came from the analysis of cultured pituitary cells, which were found to express high MIF levels following lipopolysaccharide (LPS) stimulation [20]. This was a surprising finding, given that cells of the anterior

Please cite this article in press as: Gordon-Weeks AN, et al. Macrophage migration inhibitory factor: A key cytokine and therapeutic target in colon cancer. Cytokine Growth Factor Rev (2015), http://dx.doi.org/10.1016/j.cytogfr.2015.03.002

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Fig. 1. MIF protein structure. Tertiary protein structure of monomeric and trimeric MIF (top and bottom respectively). For both monomeric and trimeric MIF, the 1st proline residue (yellow) is demonstrated. In the monomeric protein, the CXCR2 binding loop domain (red) and the catalytic site (blue) are also shown. In the trimeric form, the aspartic acid-44 residue (orange) and Arginine-11 (blue) can be seen. This view demonstrates the cooperation between these residues on adjacent monomers in order to form the pseudo-ELR motif. MIF monomers are demonstrated in green, purple and cyan in the timeric protein.

pituitary gland also produce adrenocorticotrophic hormone [35], a molecule responsible for the promotion of anti-inflammatory glucocorticoid release by the adrenal glands. The pituitary therefore produces two substances that have opposing effects in the regulation of the host response to inflammation. Nonetheless, analysis of serum from hypophysectomised mice revealed that the anterior pituitary gland makes a significant contribution to both basal circulating MIF levels and the elevation of MIF following challenge with endotoxin [20]. MIF expression was subsequently demonstrated in macrophages [36]. Furthermore, macrophages treated with low dose dexamethasone or hydrocortisone upregulated MIF expression, whereas at high glucocorticoid levels MIF secretion was inhibited [36], indicating a system of inbuilt negative feedback. Despite the fact that MIF expression is stimulated by glucocorticoids, low MIF concentrations are also

able to antagonise the anti-inflammatory [37] and cytokine suppressive effects of glucocorticoids in animal models [38]. The expression of MIF by the anterior pituitary and its ability to regulate the activity of glucocorticoids characterises MIF as both a hormone and a pro-inflammatory cytokine. These findings indicate an important role for MIF in the counter-regulation of antiinflammatory responses, where glucocorticoid action may be required. One such example of this is the role of MIF in exacerbating the inflammatory response to bacterial infection. Elevated serum MIF levels predicted early mortality in patients with sepsis [39–41]. Furthermore, MIF inhibition protects mice from lethal toxaemia induced by LPS, whilst MIF administration overrides the anti-inflammatory effect of glucocorticoids in septic mice [20,36]. These pieces of evidence indicate that therapeutic inhibition of MIF expression significantly limits the inflammatory

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cascade and may have a therapeutic role in diseases with an inflammatory component. 2.2.3. Chemokine function MIF further promotes the inflammatory process through its activity as a chemokine. Indeed, MIF acts as a chemoattractant to a number of different leucocyte subsets through various mechanisms. MIF is a non-cognate ligand to the chemokine receptors CXCR2 and CXCR4 [42]. In vivo models of atherosclerosis indicate that MIF is capable of promoting the recruitment of monocytes and T-lymphocytes to sites of atheroma, through CXCR2 and CXCR4 respectively [42]. MIF may also be responsible for the recruitment of neutrophils to head and neck cancers through CXCR2 [43], whilst work by our group has demonstrated a correlation between MIF expression and neutrophilk infiltration in the hepatic metastases from colon cancer patients (unpublished data). Interestingly, MIF displays striking structural similarities to members of the CXCL chemokine family, such as a pseudo-ELR motif and N-like loop [29,31] (Fig. 1), both features which are crucial for binding and activation of CXC receptors by their ligands. MIF is also capable of promoting cell migration indirectly by stimulating other cells to express chemotactic factors. This has been best demonstrated for endothelial cells, which expressed the monocyte chemoattractant CCL2 in response to MIF stimulation [44]. Interestingly, the MIF receptor human leucocyte antigen (HLA) Class II histocompatibility antigen gamma chain (CD74) may also be involved in the chemotactic response to MIF, as macrophages from CD74 / mice displayed limited chemotaxis to MIF relative to wild-type macrophages [45]. Also relevant to its role as a chemoattractant are findings demonstrating the ability of MIF to promote leucocyte-endothelial cell interactions in vivo, thereby promoting the movement of cells from the intravascular space into tissues [46,47]. For example, MIF stimulated Inter-Cellular Adhesion Molecule (ICAM-1) expression by endothelial cells [48], as well as both ICAM-1 and Vascular Cell Adhesion Molecule (VCAM-1) expression by monocytes [49]. Furthermore, inhibition of MIF expression in endothelial cells reduced their expression of E-selectin, VCAM1 and ICAM-1, inhibiting their ability to promote immune cell rolling and adhesion [50]. Interestingly, administration of exogenous MIF in the presence of TNF-a to cultured endothelial cells promoted leucocyte adhesion and rolling through expression of P-selectin rather than VCAM-1 or ICAM-1 [50], indicating that the mechanisms through which MIF promotes interactions between endothelia and leukocytes differs during inflammation and steady-state conditions. 2.2.4. Role for MIF in cellular proliferation and apoptosis Disruption of MIF expression significantly alters various aspects of cell growth kinetics. Fibroblasts taken from mice with homozygous MIF deficiency, for example, displayed induction of premature growth arrest dependent upon the activity of p53 [51]. Similarly, murine fibroblasts engineered to express MIF, are resistant to p53-mediated growth arrest and apoptosis [52]. These effects are likely to result from direct interaction between MIF and p53 resulting in the inhibition of p53 translocation from the cytoplasm to the nucleus [53]. MIF is also a ligand for the cell surface antigen CD74 [54] and this receptor may play a role in both chemotactic and cell kinetic MIF functions. When MIF binds to CD74, the cell surface receptor dimerises with to CD44 form a receptor complex, with CD44 crucial for signal transduction [55]. Following dimerisation, MAPK signalling is activated, resulting in an inhibition of apoptosis and promotion cell division [54,55]. It therefore appears that both exogenous and endogenous MIF are capable of affecting cell kinetics through various mechanisms. As such, it is likely that MIF

over-expression by tumour cells, as well as elevated exogenous MIF production by stromal cells, could promote tumour growth through favourable effects on cell kinetics. 2.2.5. MIF and hypoxia A number of reports demonstrate that MIF expression is regulated by hypoxia in normal cells. Endothelial and vascular smooth muscle cells, for example release MIF when grown under hypoxic conditions [56,57]. This effect is nullified by HIF-1a knockdown in smooth muscle cells [57] and MIF contains a hypoxia response element in its promoter region [58,59], indicating the involvement of HIF-1a mediated transcription in the regulation of MIF expression. As MIF in turn is a strong endothelial cell mitogen in vitro [60,61] and promotes endothelial cell migration and tubule formation in vivo [62], it is likely that elevated MIF expression is a mechanism through which hypoxia stimulates angiogenesis. This is supported by work demonstrating that MIF is expressed within healing wounds, inflamed tissue and cancer [63]; all settings typified by a low oxygen tension. 2.2.6. MIF function in the tumour microenvironment These broad-ranging functions indicate the potential contribution of MIF to tumour development and progression, through the promotion of inflammation, direct effects on tumour cell kinetics and effects on the tumour stroma [12]. Indeed, MIF may contribute to carcinogenesis by preventing cellular apoptosis in response to genotoxic stress, through interaction with p53, or by promoting chronic inflammation through the influx of inflammatory cells. MIF directly promotes tumour cell proliferation and invasion, as demonstrated in various cancer cell types including those of the bladder [64], breast [65] and colon [66–68]. Furthermore, MIF drives the proliferation of tumour stromal cells such as endothelia, with the resultant increase in angiogenesis capable of promoting tumour progression [69]. Although it remains to be formally demonstrated, hypoxia may be central to the regulation of MIF expression within the tumour microenvironment. Finally, in the setting of established malignancy, MIF is capable of recruiting protumourigenic immune cells [43,70], which upon arrival at the tumour microenvironment promote tumour progression through a broad range of mechanisms [71]. The proposed mechanisms through which MIF promotes tumour development and progression and thereby may be of significance for colon cancer are highlighted in Fig. 2. 3. Multiple roles for macrophage inhibitory factor in colon cancer 3.1. MIF promotes intestinal inflammation and colonic carcinogenesis Over the last decade, MIF has been shown to be a key mediator in the development of colonic inflammation. Given the etiological link between IBD and colon cancer, it is important to consider the significance of MIF in the pathogenesis of this disease. Interestingly, the MIF -173G/C gene single nucleotide polymorphism is associated with elevated MIF expression and increased risk of IBD [72], as well as being predictive of IBD extent [73]. Similarly, an identical MIF gene polymorphism is associated with colon cancer susceptibility [74]. MIF protein concentration is also higher in patients with IBD compared to healthy control subjects [75,76] and this finding is mimicked in murine IBD models [77]. Importantly, MIF is not simply a biomarker for IBD but plays an important part in the pathogenicity of this disease. Indeed, transgenic mice forced to over-express MIF developed colitis earlier and with greater severity than wild-type mice following low-dose DSS treatment [77], whilst treatment of mice with MIF neutralising antibodies reduced the severity of experimental colitis [75,76] (Table 1).

Please cite this article in press as: Gordon-Weeks AN, et al. Macrophage migration inhibitory factor: A key cytokine and therapeutic target in colon cancer. Cytokine Growth Factor Rev (2015), http://dx.doi.org/10.1016/j.cytogfr.2015.03.002

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Fig. 2. Potential mechanisms through which MIF promotes colon cancer development and progression. Macrophage inhibitory factor (MIF), tumour necrosis factor (TNF), vascular cell adhesion molecule (VCAM), intracellular adhesion molecule (ICAM), B-cell lymphoma 2 (Bcl-2), hypoxia inducible factor (HIF), hypoxia response element (hre), relevant single nucleotide polymorphism of the MIF promoter (173G/C).

These data indicate a direct link between MIF expression and colonic inflammation, as well as the potential for MIF inhibition in the treatment of IBD and therefore a reduction in the risk of colon cancer development. The cellular source of MIF within the inflamed colon has also been investigated in a land mark study demonstrating that MIF / Rag2 / transgenic mice developed limited colitis relative to Rag2 / mice in a T-lymphocyte-driven IBD model [76]. Fascinatingly, the transfer of myeloid-type bone marrow cells from MIF / mice to lethally irradiated Rag2 / mice protected against colitis, indicating that MIF expression by myeloid cells is required for the inflammatory phenotype. In support of this data, monocytic cells expressing MIF are found in abundance within the inflamed murine colon [75,76,78]. Although normal human colonic epithelial cells also express MIF [79], they do not appear to up-regulate MIF levels in response to inflammatory stimuli such as TNFa and INFg [79], suggesting that epithelial-derived MIF plays a lesser pathogenic role than that from intestinal inflammatory cells. More recently, research has begun to shine a light upon the mechanisms through which MIF promotes intestinal inflammation. High levels of the archetypal neutrophil enzyme myeloperoxidase have been demonstrated in the colons of MIF overexpressing [77] and wild-type [78] mice administered DSS, indicating extensive neutrophil activity in this model. This is supported by evidence documenting neutrophil accumulation in the colons of mice with DSS-induced colitis [80]. Given that MIF is a non-cognate ligand for CXCR2 [42] – a chemokine receptor expressed strongly by neutrophils, it is possible that following DSS administration MIF drives the recruitment of neutrophils, which are in turn responsible for inflammation through the

production of inflammatory mediators such as myeloperoxidase [81]. Whilst this mechanism for the development of IBD has not been demonstrated experimentally, significant evidence exists for MIF-driven neutrophil recruitment in other inflammatory disorders including pneumonitis [82] and arthritis [83]. Importantly, neutrophils are capable of promoting cancer development in vivo through the production of genotoxic reactive oxygen species [84]. With regards to intestinal tumourigenesis, antibody-mediated depletion of neutrophils [85], or loss of CXCR2 [86] delayed tumour formation in spontaneous colon cancer models, indicating that neutrophils promote intestinal carcinogenesis. Similarly, colonic tumourigenesis appears to be driven at least in part by MIF expression, as highlighted by analysis of adenomatous intestinal polyps which developed at a greater rate in APCMin/+ mice compared with those in APCMin/+ MIF / mice [87]. In humans, MIF signalling may also be important for colon cancer development, as increased MIF expression and adenoma dysplasia grade show significant correlation within colonic polyps [88]. Such lines of evidence demonstrate a role for aberrant MIF expression in the earliest stages of colon cancer development in both chronically inflamed and normal bowel. In normal bowel, specific gene polymorphisms may promote MIF expression. Alternatively, in the presence of IBD, recruited inflammatory cells may be the main source of MIF. Elevated MIF in the colonic microenvironment could then directly effect intestinal cell kinetics and lead to the development of a heightened inflammatory response, predisposing to malignant development. At present, it remains to be seen whether suppression of MIF in such potentially at-risk persons will reduce colon cancer occurrence. As such, larger

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prospective epidemiological studies are required before relevant clinical conclusions can be reached. 3.2. MIF receptor expression in colon cancer As MIF functions to promote cell migration and proliferation, as well as inhibit apoptosis, exogenous MIF – as well as that produced by cancer cells – could have direct growth-promoting effects. However, this is only possible if colon cancers express receptors for MIF. Interestingly, CXCR2 is expressed by various colon cancer cell lines [89]. Furthermore, antagonism of CXCR2 significantly inhibited the proliferation of CT26, CaCo2, KM12C and HCT-116 colon cancer cells [89–91]. Interestingly, antagonism of CXCR2 significantly impaired the growth of colon cancer xenografts in mice [91], although it is not clear whether this effect resulted from inhibition of CXCR2 on the surface of cancer cells, or other cells within the tumour microenvironment. The degree of CXCR2 expression by human colon cancer cells also correlates with metastatic potential [89], suggesting that expression of this receptor promotes an aggressive phenotype in colon cancer. To date, there have been no large studies analysing the relevance of CXCR2 protein or gene expression with regards to outcome in colon cancer patients. CXCR4 expression however, has been demonstrated in both colon cancer cells and tissues from colon cancer patients. CXCR4 is expressed by the colon cancer cell lines HT29, HCT-116, DLD-1, SW480, SW620 and LoVo [92–94]. CXCR4 antagonism has been shown to inhibit the proliferation and invasion of SW480 cells in culture [92,93]. CXCR4 antagonism is also capable of abrogating the anti-apoptotic and proliferative effects of recombinant MIF on SW480 cells [95], implicating MIF as a factor responsible for CXCR4-driven pro-tumourigenic effects. Interestingly, drug-resistant sub-clones of HT29 cells expressed elevated levels of CXCR4 relative to control HT29 cells [94], suggesting that MIF may have heightened activity on drug-resistant cancer cell populations. This is a particularly important finding given the significant clinical impact of drug resistance development in colon cancer and indicates that MIF inhibition may have a role to play in treating such resistant tumours. Inhibition of MIF signalling through the use of the small molecule MIF inhibitor (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1) reduced the invasive phenotype of CXCR4-expressing HT29 cells [94], whilst simultaneous CXCR4 and MIF inhibition did not further inhibit HT29 invasive capacity compared to inhibition of either molecule alone [94]. This data suggests that MIF is able to exert protumourigenic effects specifically through the CXCR4 receptor. Inhibition of CXCR4 expression in murine CT26 colon cancer cells also led to a reduction in both pulmonary and hepatic metastatic potential, as determined using intravenous and intrasplenic injection models respectively [96]. The reduction in liver metastasis appears to result from an impairment in metastatic outgrowth of CT26 cells expressing reduced CXCR4 compared to control CT26 cells [96]. This suggests that CXCR4 expression is required by colon cancer cells at metastatic sites for the promotion of cell proliferation or invasion. Although such mechanisms can be triggered by MIF activation of the CXCR4 receptor, the described study did not analyse ligands responsible for CXCR4 agonism. Similar results have been obtained in human colon cancer cell lines. Indeed, inhibition of CXCR4 in the highly metastatic colon cancer cell line SW620 led to a reduction in the development of spontaneous hepatic metastases following the development of rectal tumours in mice [93]. The importance of CXCR4 in colon cancer progression is also supported by clinical series, which demonstrate elevated expression of CXCR4 in the lymph node and hepatic metastases from colon cancer compared with matched primary tumours [93,97]. Finally, CXCR4 expression

in primary colorectal cancer is associated with a higher risk of recurrence following surgery, as well as the development of subsequent metastatic disease [98,99]. The evidence for CD74 expression in colon cancer has been less thoroughly studied. However, CD74 expression was detected in roughly 60% of colorectal tumours; the expression pattern of CD74 was more intense than that found in adenomas [100], suggesting a role for CD74 expression in colon cancer progression. CD74 is also expressed by the colon cancer cell lines HT29 [101] and CT26 [102]. CD74 expression by CT26 cells in particular has been demonstrated to promote cell survival through upregulation of the AKT pathway and expression of the anti-apoptotic protein Bcl-2 [102]. Activation of the CD74-CD44 receptor complex has also been shown to be responsible for the proliferation of colon cancer cells. Treatment of CaCo2 cells with recombinant MIF promoted proliferation; an effect that was in turn negated by the addition of a CD74 blocking antibody [103]. In summary, colon cancers and cultured colon cancer cell lines abundantly express MIF receptors. Furthermore, preliminary investigations have demonstrated that the expression of these receptors is important for promoting colon cancer cell survival and proliferation, as well as functions required for tumour progression such as cell invasion. In some studies MIF has been shown to be an important ligand for these receptors and this is particularly the case for CXCR4 and CD74. Nonetheless, MIF is only one of multiple ligands, with many alternative ligands having important effects on the colon cancer cell phenotype through these receptors. CXCL8 and CXCL12 for example are major ligands for CXCR2 and CXCR4 respectively and both ligands have been shown to play important roles in the progression of colon cancer by binding to these receptors [97,104]. Furthermore, in studies analysing the expression of MIF receptors in human colon cancer specimens, the cellular source of MIF receptors is typically not documented. Therefore, although pre-clinical models demonstrate that targeting MIF receptors may have therapeutic benefit, at the present stage, it is unclear whether tumour cells or other cells within the tumour microenvironment are the predominant expressers of such receptors. 3.3. The effect of MIF on colon cancer cell phenotype Various in vitro and in vivo experiments have been performed in order to determine the effect of MIF on colon cancer cell behaviour. These studies typically involve analysis of the effect of MIF inhibition through the use of si- or sh-RNA, or by the addition of small molecule MIF inhibitors or MIF neutralising antibodies to cells in culture. As previously discussed, MIF has a significant effect on cell kinetics, acting to promote proliferation and inhibit apoptosis. This too is the case for the action of MIF on colon cancer cells. Inhibition of endogenous MIF by way of antisense plasmid transfection significantly inhibited the proliferation of the human colon cancer cell lines DLD1 [67] and KM12SM [68], whilst having little effect on apoptosis. Similarly, MIF RNA interference in the murine colon cancer cell lines CT26 inhibited cell proliferation [105]. Pharmacological MIF inhibition in vitro using ISO-1 also caused a profound reduction in the proliferative fraction of LoVo human colon cancer cells [106]. This data is supported by in vivo work demonstrating a delay in the growth of subcutaneous murine colon cancers following administration of MIF neutralising antibodies [66]. Similar results were obtained with a caecal implantation model in mice. Here, MIF inhibition through administration of ISO-1 or a MIF neutralising antibody inhibited tumour growth [106]. As far as an effect on tumour cell apoptosis is concerned, the data appears somewhat more complex. MIF inhibition did not affect apoptosis of KM12SM cells [68]. However, in our

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unpublished data, inhibition of MIF expression through transfection of MIF sh-RNA significantly increased the apoptotic fraction in cultured LoVo and HCT116 human colon cancer cells but had little effect on the survival of HT29 cancer cells (manuscript in preparation). This finding is particularly interesting, as both LoVo and HCT116 express wild-type p53, whereas HT29 displays mutant p53. Given that MIF inhibits apoptosis through interaction with p53, it is possible that p53 wild-type cell lines rely heavily on MIF expression for apoptotic inhibition, whereas in the presence of p53 mutation, MIF expression is not required for apoptotic inhibition. This could be particularly relevant in the clinical setting, where therapies targeting MIF may be of significantly greater benefit for patients with p53 wild-type tumours. In contrast, tumours with p53 mutation may be somewhat resistant to MIF inhibition. This raises the possibility that MIF inhibition would need to be utilised on a case-by-case basis following assessment of tumour mutation status and circulating MIF level. As well as affecting cell kinetics, MIF plays a role in promoting other aspects of colon cancer cell behaviour. In vitro analysis demonstrates that MIF is capable of promoting epithelialmesenchymal transition (EMT) in normal gastrointestinal cells, directly implicating MIF in the development of colon cancer [103]. Similarly, addition of exogenous MIF to LoVo cells increased tumour cell invasion, potentially through the expression of matrix metalloproteinase-9 (MMP-9) [106], whilst MIF inhibition in CT26 cells reduced invasion and MMP-13 expression [107]. These findings in particular indicate that MIF may promote an invasive phenotype in colon cancer cells and may therefore be a target for the prevention of metastatic disease. This concept has been further supported in vivo, where CT26 cells transfected with MIF sh-RNA displayed reduced hepatic metastases following their injection into the portal vein [103]. 3.4. MIF in the colon cancer microenvironment Although the in vivo analysis of MIF inhibition provides more clinically relevant results than in vitro studies alone, global MIF inhibition in animal models makes it difficult to determine the precise biological mechanisms through which MIF affects colon cancer development and progression. As well as directly affecting colon cancer cell behaviour, MIF is capable of promoting protumourigenic activities in tumour stromal cells including the endothelia and tumour-associated immune cells. Both the MIF inhibitor ISO-1 and MIF neutralising antibodies significantly delayed the growth of primary orthotopic CT26 colon cancers and their hepatic metastases in BALB/c mice [106]. However, tumours from MIF-inhibited mice displayed a paucity of vasculature [106], indicating that in this model MIF promotes tumour growth through stimulation of angiogenesis. Similarly, following subcutaneous implantation of colon cancer cells in mice, MIF inhibition resulted in a significant reduction in peri-tumoural vasculature, whilst in vitro, MIF inhibition delayed endothelial cell proliferation [66]. This data supports that from other pre-clinical cancer models including those of melanoma [69] and bladder [64], both of which demonstrate a role for MIF in the promotion of tumour angiogenesis. As well as affecting endothelial cell behaviour, MIF is also able to promote the generation of regulatory T-cells (T-regs) within cutaneous colon cancers in mice [108]. Fascinatingly, the spleens and tumours from MIF / mice displayed an increase in cytotoxic CD8+ T-lymphocytes and a reduction in CD8+ T-reg cells [108], suggesting that MIF is responsible for the promotion of an immune-suppressive state within both the tumour and various immunological organs. In summary, MIF is capable of promoting tumour progression through effects on cells within the tumour

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microenvironment, indicating that even in settings where tumour cells are relatively resistant to MIF inhibition (for example those with p53 mutation–see above), MIF inhibition may be of therapeutic benefit. 4. Clinical relevance of MIF expression in colon cancer patients In order to determine the relevance of targeting MIF in colon cancer patients, it is important to first examine whether MIF is expressed at pathologically relevant levels in cancer patients. Assessment of various patient cohorts can determine whether MIF expression in serum or cancer tissue may have relevance for both the diagnosis and prognostication of colon cancer. Analysis of human colon cancer tissue demonstrated that MIF expression is up-regulated in the epithelium of colonic adenocarcinoma relative to normal colonic epithelium [106,109,110]. Furthermore, serum analyses indicate that MIF concentration is typically elevated in colon cancer patients and that its addition to prognostic scoring systems provides better sensitivity than measurement of classical tumour markers such as carcinoembryonic antigen alone [111– 113]. Nonetheless, the currently available data in this field must be interpreted with caution, as it is based solely on small case-control studies. Indeed, there is yet to be a comprehensive populationbased cohort study investigating the true predictive value of elevated MIF expression in relation to cancer diagnosis. It is therefore unlikely that clinicians will be able to routinely employ serum MIF measurement for the screening or prognostication of colon cancer in the near future. MIF expression levels in tissues could also give an indication of prognosis in colon cancer patients, however the literature here is both limited and contradictory. Analysis of human cancer tissue specimens demonstrated a correlation between MIF expression level and both tumour grade and the presence of hepatic metastases [106]. Conversely, in a detailed analysis of tissues taken from 33 patients with Dukes C or D colonic adenocarcinoma, MIF immunostaining intensity within the connective tissue compartment (but not the cancer epithelium) predicted longer survival in colon cancer patients [110]. Currently the significance of epithelial and connective tissue MIF expression is unclear and the paucity of data in this field makes it difficult to come to a conclusion as to the significance of tissue MIF expression with regard to prognosis in colon cancer. Finally, another area of clinical significance is the monitoring of tumour-specific factors following potentially curative treatment of colon cancer patients, in order to detect recurrent disease at a treatable stage. Given the proposed sensitivity of MIF for the diagnosis of colon cancer, it is reasonable to postulate that MIF expression may serve as an early indicator of recurrence, however at present there are no published studies confirming or disputing this theory. 5. Therapeutic strategies for targeting MIF MIF signalling be targeted by inhibition of the MIF protein or antagonism of MIF receptors. Targeting the MIF protein is likely to yield more specific results than targeting its receptors CXCR2 or CXCR4, as both receptors show promiscuity for multiple chemokines. However, prevention of MIFs interaction with CD74 through administration of partial MHC binding complexes does appear to provide MIF-specific inhibitory activity [114]. Currently, methods to target the MIF protein include the use of small molecule inhibitors and neutralising antibodies. Small molecule inhibitors are likely to provide significant cost benefits over the use of monoclonal antibodies and many such inhibitors have been identified that show biological anti-MIF activity in vitro [115]. It should be noted that as yet no small molecule MIF inhibitor has entered clinical trials, whereas a monoclonal MIF

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neutralising antibody is currently undergoing a phase 1 trial in patients with various solid tumours, including those of the colon (clinical trial identifier NCT01765790). 5.1. Small molecule MIF inhibitors The best characterised small molecule MIF inhibitor is ISO-1 [116]. This isoxazoline binds to MIF monomers without disrupting the proteins 3 dimensional structure. It is a competitive inhibitor of tautomerase activity and demonstrates significant biological activity in various pre-clinical models of inflammatory disease and cancer (Table 1). ISO-1 has been used as a template for the design of further small molecule MIF inhibitors with significant success. Indeed, most small molecule MIF inhibitors are designed on the basis of their predicted ability to bind to the protein’s enzymatically active site [115]. In silico approaches have also enabled the screening of vast chemical libraries for potential MIF inhibitors based upon the shape and flexibility of the MIF tautomerase region [117]. This has resulted in the discovery of several chemicals that act as potent inhibitors of the MIF tautomerase, and have the ability to inhibit some of the biological functions of MIF, including its function with regards to cell kinetics [115]. Nonetheless, whilst screens based on targeting MIFs catalytic site have been productive, as not all of MIFs functions are dependent on amino acids within the proteins enzymatic region, such screens may not identify drugs capable of inhibiting the chemoattractant activity of MIF. As yet, the degree to which MIF inhibitors show selectivity for specific functions of the protein is somewhat unclear. Recent high-throughput screening has, however, identified various mechanisms through which MIF is inhibited, including covalent modification, disruption of the trimeric MIF structure [118] and allosteric protein modification [119]. Intriguingly, Ebselen – a compound identified in one such screening process – demonstrated an ability to override glucocorticoid-mediated inhibition of cytokine production by macrophages, inhibit MIF tautomerase activity and inhibit MIFmediated AKT phosphorylation, however it exhibited a hyperagonist effect with regards chemoattraction of endothelial progenitor cells [118]. This finding suggests that it is possible to selectively inhibit singular MIF functions. Furthermore, it highlights the importance of thorough biological testing of screened compounds, preferably in relevant pre-clinical disease models, as there may be clinical circumstances in which inhibition of singular MIF functions is desirable. Although screening techniques have identified novel chemicals with anti-MIF activity, drugs are yet to be designed based on such chemicals and most literature in this field has tested the pharmacological properties of such chemicals in culture, rather than in pre-clinical disease models. Intriguingly, there are various drugs currently in clinical use that demonstrate MIF inhibitory activity, raising the possibility that trials of certain agents for MIF inhibition could be fast-tracked. The iminoquinone metabolite of acetaminophen (paracetamol) for example inhibits both the catalytic and biological activities of MIF [34], whilst phosphodiesterase inhibitors such as ibudilast also inhibit the tautomerase activity of MIF [120]. Libraries of drugs currently in clinical use should be further screened to predict MIF-inhibitor activity in order to identify potential MIF inhibitors. 5.2. MIF monoclonal antibodies The generation of MIF neutralising antibodies offers a highly specific way of inhibiting MIF function. Targeting cytokines such as TNFa using monoclonal antibodies has been shown to be of significant benefit to patients with IBD [121], highlighting the

clinical applicability of monoclonal antibody therapy as an emerging treatment modality in such patient groups. Various humanised MIF monoclonal antibodies have been developed and tested using in vivo models [122,123]. These antibodies bind to various regions throughout the MIF amino acid sequence and interestingly, their degree of activity does not appear to correlate with MIF catalytic function as has been demonstrated for most of the small molecule inhibitors. These antibodies appear to protect mice against sepsis [122] as well as contact hypersensitivity [123], however they are yet to be examined in the settings of IBD or colon cancer. 6. Conclusions There is currently significant research evidence linking the over-expression of MIF to both IBD and colon cancer. Given the highlighted functions of MIF, it is unsurprising that significant in vitro and in vivo evidence demonstrates a pro-tumourigenic effect for this cytokine in colon cancer and that conversely, MIF inhibition inhibits colon cancer progression. Significant advances are being made in the development of novel therapeutics with which to target the MIF protein, however, the benefit of MIF inhibition for colon cancer patients may only be realised once further rigorous epidemiological studies have been undertaken. Future research should aim to determine the significance of MIF expression within subsets of colon cancer patients in order to determine the proportion of patients that may benefit from MIF inhibition. The relationship between p53 mutation status and MIF expression in colon cancer cell lines and specimens should be analysed. Research evidence to date indicates that MIF inhibition may be of significantly less benefit to patients with colon cancer harbouring p53 mutation (accounting for roughly 50% of all colon cancer patients [124]). As such, future targeting of the MIF protein may eventually form part of a personalised therapeutic approach, whereby a decision to treat is based on a prior knowledge of tumour mutation status and MIF expression level. References [1] Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JWW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013;49(April (6)):1374–403. [2] Gyde SN, Prior P, Allan RN, Stevens A, Jewell DP, Truelove SC, et al. Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centres. Gut 1988;29(February (2)):206–17. [3] Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 1990;323(November (18)):1228–33. [4] Gillen CD, Walmsley RS, Prior P, Andrews HA, Allan RN. Ulcerative colitis and Crohn’s disease: a comparison of the colorectal cancer risk in extensive colitis. Gut 1994;35(November (11)):1590–2. [5] Okayasu I, Ohkusa T, Kajiura K, Kanno J, Sakamoto S. Promotion of colorectal neoplasia in experimental murine ulcerative colitis. Gut 1996;39(July (1)):87–92. [6] Kohno H, Suzuki R, Yasui Y, Miyamoto S, Wakabayashi K, Tanaka T. Ursodeoxycholic acid versus sulfasalazine in colitis-related colon carcinogenesis in mice. Clin Cancer Res 2007;13(April (8)):2519–25. [7] Clapper ML, Gary MA, Coudry RA, Litwin S, Chang W.-C.L., Devarajan K, et al. 5-Aminosalicylic acid inhibits colitis-associated colorectal dysplasias in the mouse model of azoxymethane/dextran sulfate sodium-induced colitis. Inflamm Bowel Dis 2008;14(October (10)):1341–7. [8] Flossmann E, Rothwell PM. British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 2007;369(May (9573)):1603–13. [9] Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol 2012;13(May (5)):518–27. [10] Balkwill F. Cancer and the chemokine network. Nat Rev Cancer 2004;4(July (7)):540–50. [11] Conroy H, Mawhinney L, Donnelly SC. Inflammation and cancer: macrophage migration inhibitory factor (MIF) – the potential missing link. Q J Med 2010;103(November (11)):831–6.

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atherosclerosis by blockade of macrophage migration inhibitory factor (MIF). Atherosclerosis 2006;184(January (1)):28–38. [136] Kobayashi M, Nasuhara Y, Kamachi A, Tanino Y, Betsuyaku T, Yamaguchi E, et al. Role of macrophage migration inhibitory factor in ovalbumin-induced airway inflammation in rats. Eur Respir J 2006;27(April (4)):726–34. [137] Amano T, Nishihira J, Miki I. Blockade of macrophage migration inhibitory factor (MIF) prevents the antigen-induced response in a murine model of allergic airway inflammation. Inflamm Res 2007;56(January (1)):24–31. [138] Chen P-F, Luo Y, Wang W, Wang J, Lai W, Hu S, et al. ISO-1, a macrophage migration inhibitory factor antagonist, inhibits airway remodeling in a murine model of chronic asthma. Mol Med 2010;16(October (9–10)):400–8. Mr. Alex Gordon-Weeks is a general surgical trainee and Academic Clinical Lecturer at the University of Oxford. He completed his undergraduate medical degree and BSc at the University of Leicester and Warwick (2006) and his DPhil at the University of Oxford (2014) under the supervision of Prof. Ruth Muschel. His research interests include the cellular and molecular mechanisms underpinning the development and progression of liver metastasis and his career interest is hepatobiliary surgery.

Dr. Su Yin Lim obtained her PhD in Pathology in 2010 from the University of New South Wales in Sydney, Australia. She is currently a postdoctoral scientist at the University of Oxford. Her current research is focused on investigating the roles of myeloid immune cells in metastatic colorectal cancer.

Mr. Arseniy E. Yuzhalin obtained his bachelor’s degree in Genetics at Kemerovo State University, Russia. Afterwards he earned his Master by Research degree under the supervision of Prof. Ruth Muschel at the Department of Oncology, University of Oxford, England. His research interests are elucidating the role of the extracellular matrix in tumour progression and metastasis.

Keaton Jones completed his medical undergraduate training and BMedSci at the University of Nottingham (2011) has recently completed a Post-graduate diploma in medical education. He is currently working towards a DPhil in Oncology at the University go Oxford. His work focuses on the role of myeloid cells in liver metastasis.

Prof. Ruth Muschel completed an MD PhD at the Albert Einstein College of Medicine, New York in 1978. She is currently a Professor in the Department of Oncology and deputy director of the Cancer Research UK/Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford. Her research interests include elucidation of the effects of the tumour microenvironment on mechanisms governing metastasis and response to radiation therapy. She currently heads a group of 17 research scientists and students. To date, Ruth has contributed over 190 peer-reviewed publications to the field of cancer biology.

Please cite this article in press as: Gordon-Weeks AN, et al. Macrophage migration inhibitory factor: A key cytokine and therapeutic target in colon cancer. Cytokine Growth Factor Rev (2015), http://dx.doi.org/10.1016/j.cytogfr.2015.03.002