The role of macrophage inhibitory factor in tumorigenesis and central nervous system tumors

Macrophage migration inhibitory factor (MIF) has been described as a protein that plays an important role in both innate and acquired immunity. Further research has shown that MIF plays a particularly critical part in cell cycle regulation and therefore in tumorigenesis as well. Over the past few years, the significance of the role of MIF in a variety of both solid and hematologic tumors has been established. More recently, interest has increased in the role of MIF in the development of central nervous system (CNS) tumors, in which it appears to influence cell cycle control. In addition, MIF has been identified as an essential actor in metastasis and angiogenesis. Vascular growth factor concentration raises because of increased levels of MIF in brain tumors. Recently, the MIF receptor complex has been described, and it appears that this may be a suitable drug target for treatment of brain tumors. In light of these findings, the authors chose to conduct a systematic search for information regarding MIF that has been published within the past 15 years using the terms “inflammation,” “glioblastoma,” “brain tumor,” “astrocytoma,” “microglia,” “glioblastoma,” “immune system and brain tumors,” “glioblastoma and MIF,” and “brain tumor and MIF.” The aim of this article was thus to present a detailed review of current knowledge regarding the role of MIF in CNS tumor pathophysiology. Cancer 2009. © 2009 American Cancer Society.     

Theoretical basis of paraneoplastic autoimmune disorders - (review)

The close correlation found between malignancies and autoimmune disorders suggests that a common pathogenetic mechanism plays a role in both disorders. Recent results obtained by analysis of V-H and V-L genes of autoreactive immunocytes reveal their oligo-clonality. They are essentially autoreactive with developmental antigens since these clones are prepared to recognize normal antigens without somatic mutations. Under the concept that immunity recognize developmental antigens as well as foreign antigens, it is conceivable that auto-reactivity is induced by an autonomy of immunocytes, when antigenic duality between self and non-self is an essential feature of immunity. In this process, autoimmunity due to malignancy is non-teleologic, since autoimmunity programmed a priori within immunocytes is expressed in an autonomic manner caused by cellular selfishness. On the other hand, paraneoplastic autoimmunity with non-immunocyte tumors suggests a mechanism differing from autonomic expansion of immunocytes. In order to explain this phenomenon, there are two possibilities: the first is that tumor cells secrete immune molecules including immunoglobulins and the second is that so-called antigen drive is related with curious MHC expression of tumor cells, with or without molecular mimicry due to somatic mutations. Both mechanisms are essentially non-teleological.     

Overexpression of macrophage migration inhibitory factor induces angiogenesis and deteriorates prognosis after radical resection for hepatocellular carcinoma

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pivotal cytokine that regulates inflammatory and immune responses. Recently, many investigators reported that MIF is expressed highly in several tumors, including hepatocellular carcinoma (HCC). However, the role of MIF in tumor angiogenesis and patient prognosis has not been examined in patients with HCC. METHODS: The authors evaluated MIF expression in 56 samples of HCC by Western blot analysis, and the results were correlated with clinicopathologic factors and patient prognosis. MIF localization was determined by immunohistochemical methods, and the results were compared with tumor microvessel density (MVD), as assessed by anti-CD34 antibody. Furthermore, to validate the role of MIF in angiogenesis, both MIF expression during culture of HCC cells (using the Hep3B, HepG2, and Huh7 cell lines) under hypoxic condition and the angiogenic potential of recombinant MIF in an in vitro angiogenic model were examined. RESULTS: Tumors with high MIF expression had high alpha-fetoprotein levels (P = 0.049) and frequent intrahepatic recurrence (P = 0.043). Immunohistochemical MIF scores had a significant correlation with MVD (P = 0.007). Patients who had tumors with high MIF expression levels had a significantly worse (P = 0.025) disease-free survival, and this finding remained significant as an independent prognostic factor in the multivariate analysis. Hep3B cells had high expression of MIF at 6 hours and 12 hours after hypoxic stress and exogenous MIF stimulated endothelial tube formation in in vitro angiogenesis. CONCLUSIONS: The current findings suggest that MIF expression may play a pivotal role in the dismal prognosis of patients with HCC that may be attributable to the modulation of angiogenesis.     

Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity

The majority of cancer antigens identified thus far have limited expression in normal tissues. It has been suggested that autoimmune disease is a necessary price for cancer immunity. This notion is supported by a recent clinical trial involving an anti-CTL antigen-4 (CTLA-4) antibody that showed significant clinical responses but severe autoimmune diseases in melanoma patients. To selectively modulate cancer immunity and autoimmunity, we used anti-CTLA-4 and anti-4-1BB antibodies to treat mice with a preexisting cancer, MC38. The combination of the two antibodies led to CD8 T-cell-mediated rejection of large established MC38 tumors and long-lasting immunity to the same tumor cells, although the same regimen was not effective for B16 melanoma. More importantly, whereas individual antibodies induced inflammation and autoimmune manifestations, combination therapy increased cancer immunity while reducing autoimmunity. The reduction of autoimmune effects correlates with an increased function of regulatory T cells. Our results suggest a novel approach to simultaneously enhance cancer immunity and reduce autoimmunity.     

巨噬细胞移动抑制因子与肿瘤

巨噬细胞移动抑制因子(MIF)是一种多功能细胞因子,因与多种炎症性疾病、自体免疫性疾病及肿瘤等密切相关而倍受关注。MIF通过多种信号传导通路,促进肿瘤细胞的增殖和浸润转移,参与肿瘤的发生演进过程。     

Altered immunity as a risk factor for non-Hodgkin lymphoma.

This review examines the association between disorders of immunity, including immune deficiency, atopy, and autoimmune disease, and non-Hodgkin lymphoma (NHL). Immune deficiency is one of the strongest known risk factors for NHL. Risk is increased whether the immune deficiency is congenital, iatrogenic, or acquired. Risk of NHL increases with degree of immune deficiency, and there is no evidence of a threshold. In the profoundly immune deficient, NHL is frequently caused by infection with the ubiquitous EBV. Whether mild, subclinical immune deficiency is related to increased NHL risk is unknown. There is inconsistent evidence that atopic conditions, such as asthma, hayfever, and eczema, characterized by an immune response that is skewed toward Th2, are associated with a decreased risk of NHL. These data come mainly from case-control studies. Concern has been expressed that the association may be due to reverse causality if early symptoms of NHL include a lessening of atopic manifestations. Case-control and cohort studies of people with autoimmune conditions have generally shown that rheumatoid arthritis, systemic lupus erythematosis, and Sjogren's disease are associated with increased NHL risk. It seems to be the intensity of the inflammatory disease rather than its treatment which is related to increased risk of NHL. The study of altered immunity as a cause of NHL in case-control studies is limited by the fact that development of NHL in itself leads to altered immunity. Cohort studies of the role of altered immunity should be a top priority in epidemiologic studies of NHL etiology.     

Autoimmune Manifestations in Patients With Waldenström Macroglobulinemia

Waldenström macroglobulinemia represents a lymphoplasmacytic lymphoma with an indolent clinical course. The existing literature associates this hematologic malignancy with various autoimmune disorders. Notwithstanding, these autoimmune conditions have not been comprehensively characterized or systematized to date. As a result, their clinical implications remain largely unknown. The authors offer a comprehensive review of the existing literature on various hematologic and nonhematologic autoimmune disorders documented in the course of Waldenström macroglobulinemia. Whereas some of them are thought to be secondary to a dysfunctional immune response associated with an underlying malignant process, others might be primary and might even play a role in its pathogenesis. Moreover, the observations that personal history and family history of certain autoimmune diseases were associated with an increased risk of subsequent Waldenström macroglobulinemia strengthen further the hypothesis that shared susceptibility genes and chronic antigenic stimulation might predispose individuals to both conditions.     

D‐dopachrome tautomerase is over‐expressed in pancreatic ductal adenocarcinoma and acts cooperatively with macrophage migration inhibitory factor to promote cancer growth

Previous studies have established the important role of MIF in the development of pancreatic ductal adenocarcinoma (PDAC) for both therapeutic and diagnostic perspectives, but little is known about the expression and function of D‐dopachrome tautomerase (DDT), a functional homolog of MIF, in PDAC. In the present study, we demonstrated that DDT was over‐expressed in PDAC tissues in a pattern correlated with MIF. In the pancreatic cancer cell lines, PANC‐1, BXPC‐3 and ASPC‐1, both DDT and MIF were expressed and co‐localized with each other in the endosomal compartments and plasma membrane. Knockdown of DDT and MIF in PANC‐1 cells cooperatively inhibited ERK1/2 and AKT phosphorylation, increased p53 expression, and reduced cell proliferation, invasion and tumor formation. These effects were rescued by the re‐expression of MIF or DDT, but not by the forced expression of the tautomerase‐deficient mutants of DDT and MIF, P1G‐DDT and P1G‐MIF. Finally, we observed that 4‐iodo‐6‐phenylpyrimidine (4‐IPP), a covalent tautomerase inhibitor of both DDT and MIF, attenuated PANC‐1 cell proliferation and colony formation in vitro and tumor growth in vivo. Thus, targeting the tautomerase sites of both MIF and DDT may offer more efficient therapeutic benefits to PDAC patients.     

Production of macrophage migration inhibitory factor by human and murine neuroblastoma.

Tumor cells avoid immune recognition by subverting the ability of the immune system to mount an inflammatory response that generates cytotoxic effector cells. This can be achieved through cytokine production by the tumor itself. Our objective was to determine the cytokine profile of neuroblastoma (NB) lesions in tumor vaccine models. We found that the murine NB cell line, Neuro2a, secretes macrophage migration inhibitory factor, MIF, a multifunctional cytokine with the potential to block effective immune responses to a tumor. Patient-derived NB cell lines were also found to produce MIF. MIF production by NB was documented at the level of RNA by RNAse protection, soluble cytokine production by ELISA, and in a macrophage migration assay. Our studies also confirmed reports of IL-6 production by human NB cell lines. NB culture-derived MIF was also shown to activate tumor cell migration. This supports the hypothesis that MIF is a tumor-derived cytokine that may play a role in NB aggressiveness and evasion of immune recognition.     

A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells

Although chemokine and growth factor receptors are attractive and popular targets for cancer therapeutic intervention, structure-based targeting of the ligands themselves is generally not considered practical. New evidence indicates that a notable exception to this is macrophage migration inhibitory factor (MIF). MIF, an autocrine- and paracrine-acting cytokine/growth factor, plays a pivotal role in both the initiation and maintenance of neoplastic diseases. MIF possesses a nonphysiologic enzymatic activity that is evolutionarily well-conserved. Although small molecule antagonists of MIFs enzymatic active site have been reported to inhibit biological activities of MIF, universally high IC(50)s have limited their clinical appeal. Using a computational virtual screening strategy, we have identified a unique small molecule inhibitor that serves as a suicide substrate for MIF, resulting in the covalent modification of the catalytically active NH(2)-terminal proline. Our studies further reveal that this compound, 4-iodo-6-phenylpyrimidine (4-IPP), is approximately 5x to 10x times more potent in blocking MIF-dependent catalysis and lung adenocarcinoma cell migration and anchorage-independent growth than the prototypical MIF inhibitor, ISO-1. Finally, using an in silico combinatorial optimization strategy, we have identified four unique congeners of 4-IPP that exhibit MIF inhibitory activity at concentrations 10x to 20x lower than that of parental 4-IPP.     

Autoimmune reactions in patients with various tumor localizations

Autoantibody levels in patients with malignancies of the oral cavity and lung and autoimmune disorders have been assayed. It was found that tumors initiated polymorphous autoimmune reactions to various tissue antigens. Autoantibody production rates in tumor patients were comparable with those in autoimmune disorders. The role of autoimmune reactions in cancer pathogenesis is discussed.     

Clinical utility of serum macrophage migration inhibitory factor in men with prostate cancer as a novel biomarker of detection and disease progression

Macrophage migration inhibitory factor (MIF) has been shown to play an important role in the growth and metastasis of prostate cancer. The objective of this study was to determine whether the serum level of MIF could be used as a diagnostic biomarker for prostate cancer as well as a predictor of disease progression. A total of 369 men who underwent systematic prostate biopsy from January 2000 to April 2004 and 30 healthy controls were included in this study. The serum MIF level was measured using an enzyme linked immunosorbent assay. Associations between the serum MIF level and several clinicopathological factors were analyzed. Among 359 patients, 137 were diagnosed as having prostate cancer. The mean values of serum MIF in the control, benign and cancer-groups were 2.1, 3.5 and 10.8 ng/ml, respectively. The MIF levels of patients with prostate cancer were significantly higher than those of the other two groups. A comparison of MIF and PSA values in all patients showed a positive correlation (correlation coefficient r(2)=0.56, p<0.0001). The MIF value in patients with prostate cancer was significantly associated with clinical T stage, Gleason score and percentage of positive biopsy core (PPBC). MIF levels in patients with metastasis were significantly elevated compared with those in patients without metastasis. Among patients undergoing radical prostatectomy, the level of MIF in those with pathologically confirmed extraprostatic disease was significantly higher than that in patients with organ-confined disease. Moreover, multivariate analysis showed that MIF values, PSA values and PPBC were independent predictors for extraprostatic disease. These findings suggest that an increased serum MIF level is closely associated with the progression of prostate cancer, and thus the serum MIF level could be useful as a novel biomarker for the detection of prostate cancer as well as a predictor of disease progression.     

Macrophage migration inhibitory factor promotes tumor invasion and metastasis via the Rho-dependent pathway.

PURPOSE: Macrophage migration inhibitory factor (MIF) plays an important role not only in the immune system but also in tumorigenesis. In this study, we investigated the potential role of MIF in association with tumor invasion and metastasis. METHODS: To assess the function of MIF, we knocked down the MIF mRNA using small interfering RNA (siRNA). Twenty-one base siRNA specific for the mRNA sequence of mouse MIF was introduced to a murine colon cancer cell line, colon 26. Tumor cell invasion was evaluated using a transwell method (8-microm pores) coated with Matrigel on the upperside membrane and with fibronectin on the underside membrane. Moreover, we investigated the signal transduction of lysophosphatidic acid (LPA) relevant to the Rho-dependent pathway and further examined the effect of MIF siRNA on this signal transduction system. In vivo, the tumor cells were pretreated with MIF siRNA and injected into the portal vein, and the effects on metastasis to the liver were evaluated. RESULTS: We found that MIF siRNA markedly reduced the invasion of the cells from the upperside to lowerside membranes. We revealed that the Rho-dependent pathway activated by LPA was suppressed by MIF siRNA. Next, we found that the tyrosine-phosphorylation of focal adhesion kinase and LPA-induced expressions of integrin beta1 were significantly suppressed by MIF siRNA. In vivo, metastasis to the liver was significantly inhibited by pretreatment of the cells with MIF siRNA. CONCLUSION: Taken together, these results suggest that MIF promotes tumor invasion and metastasis via the Rho-dependent pathway.     

New perspectives on the role of vitiligo in immune responses to melanoma

Melanoma-associated vitiligo is the best-studied example of the linkage between tumor immunity and autoimmunity. Although vitiligo is an independent positive prognostic factor for melanoma patients, the autoimmune destruction of melanocytes was long thought to be merely a side effect of robust anti-tumor immunity. However, new data reveal a key role for vitiligo in supporting T cell responses to melanoma. This research perspective reviews the history of melanoma-associated vitiligo in patients, the experimental studies that form the basis for understanding this relationship, and the unique characteristics of melanoma-specific CD8 T cells found in hosts with vitiligo. We also discuss the implications of our recent findings for the interpretation of patient responses, and the design of next-generation cancer immunotherapies.     

调节性B细胞在疾病免疫中的研究现状

B细胞在体液免疫中发挥重要作用,并通过分泌各种抗体促进细胞免疫。调节性B细胞是近年来发现的存在于B细胞中的一种新的细胞亚群,其主要通过分泌 IL-10、、IL-35 等来抑制过度炎症反应,研究表明其在自身免疫疾病、移植免疫、肿瘤免疫、感染免疫中发挥着重要的作用。本文就调节性B细胞的来源、功能、作用机制及相关研究进展作一综述。     

Expression of macrophage migration inhibitory factor in human breast cancer: association with nodal spread.

Macrophage migration inhibitory factor (MIF) is known to exert pleiotropic functions including inhibition of macrophage migration, anchoring, and counteraction of the anti-inflammatory and immunosuppressive activity of glucocorticoids. Ninety-three primary breast cancer tissues and 64 sera of primary breast cancer patients were analyzed for the expression of MIF. The clinico-pathological significance of MIF expression was evaluated. It was found that MIF was frequently over-expressed in primary breast cancer tissues. RT-PCR and western blotting analysis confirmed that wild-type MIF is expressed, and immunohistochemical analysis showed that MIF expression was localized at tumor cells as well as stromal cells, including tumor-associated macrophages. Intratumoral MIF protein concentrations detected by enzyme-linked immunosorbent assay (ELISA) varied with a median value of 1821 ng/mg protein (range: 8 - 8126 ng/mg protein), and correlated inversely with nodal involvement (P = 0.039). No significant correlation was observed with other clinico-pathological factors including tumor size, menopausal status and hormone receptors. The circulating level of MIF protein ranged up to 105.7 ng/ml (median: 17.3 ng/ml), and it was also found to correlate inversely with the number of involved nodes (P = 0.02). A comparative study with other soluble inflammatory mediators showed that intratumoral levels of MIF were significantly associated with those of interleukin-1 beta, suggesting that interactions between tumor cells and tumor-associated macrophages play an important role in the up-regulation of MIF. The multifunctional inflammatory/immune mediator MIF was frequently expressed in primary breast cancer, and its expression level was inversely associated with nodal spread. Thus, MIF seems to play a role in tumor-stroma interactions of primary breast cancers, particularly those with a phenotype of node-negative or minimal nodal spread.     

Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity

The phosphoinositide-3-kinase (PI3K)/Akt signaling pathway plays an important role in cell survival and the development of cancer. Macrophage migration inhibitory factor (MIF) is a critical inflammatory cytokine that was recently associated with tumorigenesis and that potently inhibits apoptosis. This may involve inhibition of p53-dependent genes, but the initiating molecular mechanism of how MIF controls survival/apoptosis is unknown. Here, we show that MIF prevents apoptosis and promotes tumor cell survival by directly activating the Akt pathway. MIF enhanced Akt activity in primary and immortalized fibroblasts (MEF and NIH/3T3), HeLa cervix carcinoma cells and various breast cancer cell lines. Activation was abolished by kinase inhibitors Ly294002 and PP2 and in Src/Yes/Fyn(SYF)(-/-) and CD74(-/-)(MEFs), while being enhanced in CD74-overexpressing MEFs, demonstrating that the MIF-induced Akt pathway encompasses signaling through the MIF receptor CD74 and the upstream kinases Src and PI3K. Akt was activated by exogenous rMIF and autocrine MIF action, as revealed by experiments in MIF(-/-)MEFs and antibody blockade. siRNA knockdown of CSN5/JAB1, a tumor marker and MIF-binding protein, showed that JAB1 controls autocrine MIF-mediated Akt signaling by inhibition of MIF secretion. Akt activation by MIF led to phosphorylation of the proapoptotic proteins BAD and Foxo3a. Apoptosis inhibition by MIF was functionally associated with Akt activation as it was abolished by overexpression of the Akt pathway inhibitor PTEN and occurred independently of p53. This was shown by studying DNA damage-induced apoptosis in fibroblasts, the Fas death pathway in HeLa cells that do not express functional p53, and etoposide-induced apoptosis in breast carcinoma cells expressing mutant p53. Importantly, dependence of breast cancer cell survival on MIF correlated with Akt activation and the PTEN status of these cells. Thus, MIF can directly promote cell survival through activation of the PI3K/Akt pathway and this effect is critical for tumor cell survival.     

Expression of Macrophage Migration Inhibitory Factor in Human Breast Cancer: Association with Nodal Spread

Macrophage migration inhibitory factor (MIF) is known to exert pleiotropic functions including inhibition of macrophage migration, anchoring, and counteraction of the anti-inflammatory and immunosuppressive activity of glucocorticoids. Ninety-three primary breast cancer tissues and 64 sera of primary breast cancer patients were analyzed for the expression of MIF. The clinico-pathological significance of MIF expression was evaluated. It was found that MIF was frequently over-expressed in primary breast cancer tissues. RT-PCR and western blotting analysis confirmed that wild-type MIF is expressed, and immunohistochemical analysis showed that MIF expression was localized at tumor cells as well as stromal cells, including tumor-associated macrophages. Intra-tumoral MIF protein concentrations detected by enzyme-linked immunosorbent assay (ELISA) varied with a median value of 1821 ng/mg protein (range: 8–8126 ng/mg protein), and correlated inversely with nodal involvement ( P =0.039). No significant correlation was observed with other clinico-pathological factors including tumor size, menopausal status and hormone receptors. The circulating level of MIF protein ranged up to 105.7 ng/ml (median: 17.3 ng/ml), and it was also found to correlate inversely with the number of involved nodes ( P =0.02). A comparative study with other soluble inflammatory mediators showed that intratumoral levels of MIF were significantly associated with those of interleukin-1β, suggesting that interactions between tumor cells and tumor-associated macrophages play an important role in the up-regulation of MIF. The multifunctional inflammatory/immune mediator MIF was frequently expressed in primary breast cancer, and its expression level was inversely associated with nodal spread. Thus, MIF seems to play a role in tumor-stroma interactions of primary breast cancers, particularly those with a phenotype of node-negative or minimal nodal spread.