Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

First identified nearly 40 years ago, macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine and is an essential component of immune and inflammatory responses. Recent studies suggest that MIF may also contribute to multiple aspects of tumor progression and neoplasia. This review will attempt to summarize these findings focusing on MIF's ability to modulate cell proliferation, tumor angiogenesis and tumor suppressor activity.
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PMID:Tumor growth-promoting properties of macrophage migration inhibitory factor (MIF). 1110 Aug 84

Macrophage migration inhibitory factor (MIF) may contribute to multiple aspects of tumor progression, including control of cell proliferation, differentiation, cell survival and angiogenesis. However, the potential roles of MIF in regulating hepatocellular carcinoma (HCC) tumor cell migration and the expression of angiogenic factors by HCC tumor cells have not been studied yet. In our study, we reported that intracellular MIF mRNA and protein were overexpressed in HCC tissues compared to nontumor tissues by using in situ hybridization and immunohistochemic staining. HCC tumor cell lines also secreted large amounts of MIF into the supernatants of tumor cell culture. To assess the role of MIF in HCC, we employed the transwell invasion chamber to study the effect of MIF on tumor cell migration. Our results showed that recombinant MIF and the supernatants of tumor cell line culture could enhance the invasion and migration of HCC cells. This effect can be inhibited by the addition of a neutralizing anti-MIF antibody. We observed that increased MIF serum levels correlated with higher levels of interleukin-8 (IL-8) in the sera of patients with HCC than in normal volunteers. We therefore hypothesized that MIF may regulate the production of angiogenic factors by HCC cells. To test this hypothesis, we examined the effect of MIF treatment on vascular endothelial growth factor (VEGF) and IL-8 expression by HCC cell lines. MIF induced a significant dose-dependent increase in IL-8 and VEGF production. Taken together, our results indicated that MIF may act as an autocrine-acting factor that stimulates angiogenesis and metastasis in HCC by promoting expression of angiogenic factors and migration of tumor cells. A more detailed understanding of the MIF regulatory mechanisms involved may provide insight into new direction in the treatment of HCC.
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PMID:Macrophage migration inhibitory factor: roles in regulating tumor cell migration and expression of angiogenic factors in hepatocellular carcinoma. 1292 52

The quantitative comparison of two or more microarrays can reveal, for example, the distinct patterns of gene expression that define different cellular phenotypes or the genes that are induced in the cellular response to certain stimulations. Normalization of the measured intensities is a prerequisite of such comparisons. However, a fundamental problem in cDNA microarray analysis is the lack of a common standard to compare the expression levels of different samples. Several normalization protocols have been proposed to overcome the variabilities inherent in this technology. We have developed a normalization procedure based on within-array replications via a semilinear in-slide model, which adjusts objectively experimental variations without making critical biological assumptions. The significant analysis of gene expressions is based on a weighted t statistic, which accounts for the heteroscedasticity of the observed log ratios of expressions, and a balanced sign permutation test. We illustrated the use of the techniques in a comparison of the expression profiles of neuroblastoma cells that were stimulated with a growth factor, macrophage migration inhibitory factor (MIF). The analysis of expression changes at mRNA levels showed that approximately 99 genes were up-regulated and 24 were reduced significantly (P <0.001) in MIF-stimulated neuroblastoma cells. The regulated genes included several oncogenes, growth-related genes, tumor metastatic genes, and immuno-related genes. The findings provide clues as to the molecular mechanisms of MIF-mediated tumor progression and supply therapeutic targets for neuroblastoma treatment.
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PMID:Normalization and analysis of cDNA microarrays using within-array replications applied to neuroblastoma cell response to a cytokine. 1473 36

Macrophage migration inhibitory factor (MIF) has been linked to fundamental processes such as control of cell proliferation, cell survival, angiogenesis, and tumor progression. The expression of MIF has been reported in several tumors. However, the precise role of MIF in tumor cells remains unclear. In the present study, we investigated the expression pattern and the function of MIF in neuroblastoma. Our results showed that intracellular MIF was upregulated in neuroblastoma tumor tissues and cell lines. MIF protein expression significantly correlated with the grade of tumor differentiation. In addition, we found that MIF induced a significant dose-dependent increase of vascular endothelial growth factor and interleukin-8 secretion. We also observed that an increased MIF expression level correlated with N-Myc protein (the N-myc oncogene product) expression in neuroblastoma tissues. MIF increased the expression of N-myc mRNA and N-Myc protein and induced N-Myc translocation from the cytoplasm to nucleus in neuroblastoma cell lines. MIF-induced N-Myc expression was found to be dependent on ERK signaling pathways. The inhibition of ERK activation reduced MIF-mediated N-Myc expression. These results suggest that MIF may contribute to the progression of neuroblastoma by (a) inducing N-Myc expression and (b) upregulating the expression of angiogenic factors.
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PMID:Upregulation of macrophage migration inhibitory factor contributes to induced N-Myc expression by the activation of ERK signaling pathway and increased expression of interleukin-8 and VEGF in neuroblastoma. 1506 33

Macrophage migration inhibitory factor (MIF) is a well-described pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. However, despite the compelling evidence that MIF is overexpressed in, and contributes to, the pathology of inflammatory and malignant diseases the mechanisms that contribute to exaggerated expression of MIF have been poorly described. Here we show that hypoxia, and specifically HIF-1alpha, is a potent and rapid inducer of MIF expression. In addition, we demonstrate that hypoxia-induced MIF expression is dependent upon a HRE in the 5'UTR of the MIF gene but is further modulated by CREB expression. We propose a model where hypoxia-induced MIF expression is driven by HIF-1 but amplified by hypoxia-induced degradation of CREB. Given the importance of MIF in inflammatory and malignant diseases these data reveal a HIF-1-mediated pathway as a potential therapeutic target for suppression of MIF expression in hypoxic tissues.
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PMID:Dual regulation of macrophage migration inhibitory factor (MIF) expression in hypoxia by CREB and HIF-1. 1685 77

Low oxygen tension-mediated transcription by hypoxia-inducible factors (HIF) has been reported to facilitate tumor progression, therapeutic resistance, and metastatic adaptation. One previously described target of hypoxia-mediated transcription is the cytokine/growth factor macrophage migration inhibitory factor (MIF). In studies designed to better understand hypoxia-stimulated MIF function, we have discovered that not only is MIF induced by hypoxia in pancreatic adenocarcinoma but MIF is also necessary for maximal hypoxia-induced HIF-1alpha expression. Cells lacking MIF are defective in hypoxia- and prolyl hydroxylase inhibitor-induced HIF-1alpha stabilization and subsequent transcription of glycolytic and angiogenic gene products. Moreover, COP9 signalosome subunit 5 (CSN5), a component of the COP9 signalosome previously reported to functionally interact with MIF, has recently been shown to interact with and stabilize HIF-1alpha. Our results indicate that MIF interacts with CSN5 in pancreatic cancer cells and that MIF-depleted cells display marked defects in hypoxia-induced CSN5/HIF-1alpha interactions. This functional interdependence between HIF-1alpha and MIF may represent an important and previously unrecognized pro-tumorigenic axis.
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PMID:Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization. 1721 Jun 98

Macrophage migration inhibitory factor (MIF) is a ubiquitously expressed pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. We used a genetic approach to show that deletion of the MIF gene in mice has several major consequences for the proliferative and transforming properties of cells. MIF-deficient cells exhibit increased resistance to oncogenic transformation. The transformation defects associated with MIF deficiency can be overcome through concomitant inactivation of the p53 and Rb/E2F tumor suppressor pathways. We have produced compelling evidence that the effects of MIF on cell survival and tumorigenesis are mediated through overlapping pathways, wherein MIF and p53 functionally antagonize each other in the cell. However, the involvement of MIF in p53 function is secondary to p53-independent mechanisms controlling protein stability, DNA damage checkpoints, and the integrity of the genome. Given the broad spectrum of cell types that normally express MIF and its elevated levels at sites of chronic inflammation, this pathway may be generic for many early stage tumors.
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PMID:MIF coordinates the cell cycle with DNA damage checkpoints. Lessons from knockout mouse models. 1764 Mar 78

Macrophage migration inhibitory factor (MIF) is known to be an important contributor to tumor progression. Overexpression of MIF has been reported in different types of tumors. However, the correlation between MIF expression and tumor pathologic features in patients with breast cancer has not been elucidated. In this study, we examined the expression of MIF, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) in human tissues with or without tumor. In addition, we investigated the expression of MIF in MDA-MB-231, MCF-7 (breast cancer cell lines) and MCF-10A (epithelial cell line) cells, and its effect on VEGF and IL-8. We found that MIF was overexpressed in breast cancer tissues compared with normal ones. The level of MIF showed the positive correlation between the expression of IL-8 and tumor microvessel density (MVD). The patients with positive MIF expression in tumor tissues showed a significantly worse disease-free survival compared with negative ones. Increased MIF serum levels were also found to correlate with higher levels of IL-8 in the sera of the patients with breast cancer. In vitro experiments successfully detected MIF in breast cell lines. However, the expression level of it by normal epithelial cells was much less than that of cancer cells. Exogenous MIF did not cause endothelial tube formation and migration but induced a dose dependent increase in VEGF and IL-8 secretion in breast cancer cell lines. In summary, our studies show that human breast cancer tissue expresses MIF. Its in vitro effect on VEGF and IL-8 indicates that MIF may contribute to tumor in angiogenesis and thus play an important role in the pathogenesis of breast cancer.
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PMID:Overexpression of macrophage migration inhibitory factor induces angiogenesis in human breast cancer. 1817 2

Neuroblastomas and many other solid tumors produce high amounts of macrophage migration inhibitory factor (MIF), which appears to play a role in tumor progression. We found that MIF expression in neuroblastoma inhibits T cell proliferation in vitro, raising the possibility that MIF promotes tumorigenesis, in part, by suppressing antitumor immunity. To examine whether tumor-derived MIF leads to suppression of T cell immunity in vivo, we generated MIF-deficient neuroblastoma cell lines using short hairpin small interfering RNAs (siRNA). The MIF knockdown (MIFKD) AGN2a neuroblastoma cells were more effectively rejected in immune-competent mice than control siRNA-transduced or wild-type AGN2a. However, the increased rejection of MIFKD AGN2a was not observed in T cell-depleted mice. MIFKD tumors had increased infiltration of CD8(+) and CD4(+) T cells, as well as increased numbers of macrophages, dendritic cells, and B cells. Immunization with MIFKD AGN2a cells significantly increased protection against tumor challenge as compared with immunization with wild-type AGN2a, and the increased protection correlated with elevated frequencies of tumor-reactive CD8(+) T cells in the lymphoid tissue of treated animals. Increased numbers of infiltrating tumor-reactive CD8(+) T cells were also observed at the site of tumor vaccination. In vitro, treatment of AGN2a-derived culture supernatants with neutralizing MIF-specific Ab failed to reverse T cell suppressive activity, suggesting that MIF is not directly responsible for the immune suppression in vivo. This supports a model whereby MIF expression in neuroblastoma initiates a pathway that leads to the suppression of T cell immunity in vivo.
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PMID:Expression of macrophage migration inhibitory factor by neuroblastoma leads to the inhibition of antitumor T cell reactivity in vivo. 1864 25

Mounting evidence suggests that macrophage migration inhibitory factor (MIF) may serve as an important link between chronic inflammation and cancer development. The proinflammatory and proangiogenic activities of MIF position it as a potentially important player in the development and progression of nonmelanoma skin cancer (NMSC). To assess the role of MIF in the development and progression of NMSC, we exposed MIF(-/-) BALB/c mice to acute and chronic ultraviolet B (UVB) irradiation. Our studies demonstrate that MIF(-/-) BALB/c mice have a significantly diminished acute inflammatory response to UVB exposure compared to wild-type mice, as measured by myeloperoxidase activity, dermal neutrophil infiltration, and edematous response. Relative to wild-type mice, MIF(-/-) mice also show significantly lower vascular endothelial growth factor (VEGF) concentrations in whole skin and significantly lower 8-oxo-dG adduct concentrations in epidermal DNA following UVB exposure. Furthermore, MIF(-/-) mice showed significant increases in p53 activity, epidermal thickness, and epidermal cell proliferation following acute UVB insult. In response to chronic UVB exposure, MIF(-/-) mice showed a 45% reduction in tumor incidence, significantly less angiogenesis, and delayed tumor progression when compared to their wild-type counterparts. These data indicate that MIF plays an important role in UVB-induced NMSC development and progression.
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PMID:Macrophage migration inhibitory factor (MIF) plays a critical role in pathogenesis of ultraviolet-B (UVB) -induced nonmelanoma skin cancer (NMSC). 1895 10


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