Up-Regulation of Macrophage Migration Inhibitory Factor Gene and Protein Expression in Glial Tumor Cells during Hypoxic and Hypoglycemic Stress Indicates a Critical Role for Angiogenesis in Glioblastoma Multiforme

Bacher, Michael; Schrader, Jörg; Thompson, Nancy; Kuschela, Karen; Gemsa, Diethard; Waeber, Gérard; Schlegel, Jürgen

doi:10.1016/s0002-9440(10)63793-5

Cited by 97 publications

(106 citation statements)

References 25 publications

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“…From a subtractive hybridization screen emerged the cytokine MIF, which was found to be associated with the ability of colon cancer cells to enter apoptosis in response to hypoxia. MIF expression was induced by hypoxia in some but not all colon cancer cell lines, whereas induction has also been reported in glioma and squamous cell cancers (16,17). In our experiments, the expression of MIF protein was closely correlated with that of the RNA, suggesting regulation at the level of transcription.…”

Section: Discussionsupporting

confidence: 77%

Macrophage Migration Inhibitory Factor Is a Determinant of Hypoxia-Induced Apoptosis in Colon Cancer Cell Lines

Yao

Shida

Selvakumaran

et al. 2005

Clinical Cancer Research

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Hypoxia contributes to cytotoxic chemotherapy and radiation resistance and may play a role in the efficacy of antiangiogenesis cancer therapy. We have generated a series of cell lines derived from the colon adenocarcinoma models HT29 and HCT116 by exposing cells in vitro to repeated sublethal periods of profound hypoxia. These cell lines have altered sensitivity to hypoxia-induced apoptosis: those derived from HT29 are resistant, whereas those from HCT116 are more susceptible. We used cDNA selected subtractive hybridization to identify novel genes mediating sensitivity to hypoxia-induced apoptosis and isolated macrophage migration inhibitory factor (MIF) from the hypoxia-conditioned cell lines. MIF expression correlates with susceptibility of the cell lines to apoptosis. In hypoxia-resistant cells, the induction of apoptosis by hypoxia can be restored by the addition of exogenous recombinant MIF protein, suggesting that resistance may result in part from down-regulation of MIF production possibly through an autocrine loop. Inhibition of MIF using small interfering RNA in the susceptible lines conferred resistance to hypoxia-induced cell death. The relative expression of MIF in the hypoxia-conditioned cells implanted s.c. in severe combined immunodeficient mice in vivo was similar to that observed in vitro. In an analysis of 12 unrelated colon tumor cell lines, MIF expression and response to hypoxia varied widely. Cell lines in which MIF was inducible by hypoxia were more sensitive to oxaliplatin. In human colon tumor specimens analyzed by immunohistochemistry, MIF expression was similarly variable. There was no detectable expression of MIF in normal colon mucosa or adenoma but positive staining in all carcinomas tested. Taken together, these data indicate that MIF may be a determinant of hypoxia-induced apoptosis in vitro and that its variable expression in human colon cancers may indicate a functional role in vivo. We suggest that MIF expression in colorectal cancer may be a marker of susceptibility to therapies that may depend on induction of hypoxia, possibly including antiangiogenic therapy.Colon cancer is characterized by regions of variable hypoxia, known to be a consequence of disordered vasculature (1). Cells in these hypoxic regions are resistant to radiation and to cytotoxic drugs (2). We have shown previously that hypoxia induces increased expression of genes involved in the detoxification of cytotoxic drugs (3), an effect exerted in part by activation of transcription factors, including activator protein-1 and nuclear factor-nB (4, 5). Hurwitz et al. have shown recently that antiangiogenic therapy adds to the efficacy of chemotherapy in colorectal cancer (6), whereas Willett et al. showed that bevacizumab alone in rectal cancer markedly decreased blood flow to the tumor (7). These findings raise the possibility that apoptosis as a result of oxygen or nutrient withdrawal contributes to the therapeutic effect and prompted an investigation of the resistance of hypoxic cancer cells to apoptos...

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Section: Discussionsupporting

confidence: 77%

Macrophage Migration Inhibitory Factor Is a Determinant of Hypoxia-Induced Apoptosis in Colon Cancer Cell Lines

Yao

Shida

Selvakumaran

et al. 2005

Clinical Cancer Research

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“…Furthermore, our data confirmed worst prognosis for high-grade glioblastoma with high levels of CD74 expression. However, our data suggest that CD74 expression alone is not an independent marker for poor prognosis and it requires the expression of MIF for tumor pathogenesis, as previously reported in other studies (4,7,16,17,18) . Although we did not perform co-localization staining for MIF-CD74 in this retrospective study, evidence of MIF and CD74 co-localization reported in several other studies (7,8,9,10,11,12,13,14) .…”

Section: Discussionsupporting

confidence: 78%

“…In line with this observation, we demonstrated overexpression of MIF in grade II-IV astrocytoma, and that overexpression of CD74 is associated with tumor progression in astrocytoma at the gene and transcription levels. MIF exerts multimodal functions in glioblastoma including pro-proliferative, promigratory, pro-angiogenic as well as immune-evasive properties through CD74 (16,17,18) . The binding of MIF to the extracellular domain of CD74 is necessary as an initial step in the MIF signaling cascade (4) resulting in tumor vascularization and the promotion of neoplastic Fig.…”

Section: Discussionmentioning

confidence: 99%

CD74 as a Potential Prognostic Marker in Glioblastoma

Narsia

Ramagiri

Lomtadze³

et al. 2017

IAM

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CD74 is a cell membrane receptor for macrophage migration inhibitory factor (MIF) that is believed to play a role in tumor progression and metastasis. Astrocytoma is the most common type of brain cancers, which are classified by the World Health Organization (WHO) into four grades according to the degree of malignancy. In this study, we investigated MIF and CD74 gene expression levels in a large cohort of publicly available RNA sequencing data and evaluated the correlation between their protein expression with clinicopathological features as well as prognosis in an independent cohort of astrocytoma samples. Seventy-three patients with different grades of astrocytoma (WHO grade II diffuse astrocytoma, grade III anaplastic astrocytoma, and grade IV glioblastoma) were used for protein expression in this study. The expression of CD74 was assayed by immunohistochemistry and was significantly higher in highgrade glioblastoma than grade II and grade III astrocytoma (P < 0.004). Upregulated CD74 expression was frequently found in older patients (≥ 62 years). The expression of CD74 is correlated with overall survival (P = 0.05). Multivariate analysis shows that the CD74 expression is associated with poor prognosis in the presence of MIF expression (P = 0.039) and that CD74 is not an independent prognostic marker in glioblastoma. However, similar studies on larger sample size are required to make a definite conclusion on the role of CD74 in prognosis in glioblastoma.

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“…MIF is also one of the genes found to be over-expressed under hypoxia (Bifulco et al, 2008). MIF is a target in hypoxia-induced transcription in many cancers such as the glioblastoma, neck cancer, cervical cancer (Bacher et al, 2003). This transcription is due to the presence of HIF-1 response element found on the 5' untranslated region of MIF (Baugh et al, 2006).…”

Section: Mif and Hypoxiamentioning

confidence: 99%

“…Marred function of MIF is observed in non-small cell lung cancer, lung adenocarcinoma and squamous cell lung cancer Liu et al, 2010). Glioblastoma, neuroblastoma, colonic cancer and colorectal cancer have elevated levels of MIF (Shkolnik et al, 1987;Bacher et al, 2003;Ren et al, 2006;Lee et al, 2008). Through ELISA, it was found that the intratumoral level of MIF is indirectly proportional to the tumor involved loco-regional nodes (Bando et al, 2002).…”

Section: Mif and Tumorsmentioning

confidence: 99%

Macrophage Migration Inhibitory Factor: a Potential Marker for Cancer Diagnosis and Therapy

Babu¹,

Chetal²,

Kumar³

2012

Asian Pacific Journal of Cancer Prevention

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Macrophage migration inhibitory factor (MIF) is a pluripotent cytokine which plays roles in inflammation, immune responses and cancer development. It assists macrophages in carrying out functions like phagocytosis, adherence and motility. Of late, MIF is implicated in almost all stages of neoplasia and expression is a feature of most types of cancer. The presence of MIF in almost all tumors and all stages of cancer makes it an interesting candidate for cancer therapy. This review explores the roles of MIF in neoplasia.

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Up-Regulation of Macrophage Migration Inhibitory Factor Gene and Protein Expression in Glial Tumor Cells during Hypoxic and Hypoglycemic Stress Indicates a Critical Role for Angiogenesis in Glioblastoma Multiforme

Cited by 97 publications

References 25 publications

Macrophage Migration Inhibitory Factor Is a Determinant of Hypoxia-Induced Apoptosis in Colon Cancer Cell Lines

Macrophage Migration Inhibitory Factor Is a Determinant of Hypoxia-Induced Apoptosis in Colon Cancer Cell Lines

CD74 as a Potential Prognostic Marker in Glioblastoma

Macrophage Migration Inhibitory Factor: a Potential Marker for Cancer Diagnosis and Therapy

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