Elevated expression of macrophage migration inhibitory factor correlates with tumor recurrence and poor prognosis of patients with gliomas

Wang, Xiao-Bing; Tian, Xiao Ying; Li, Yang; Li, Bin; Li, Zhi

doi:10.1007/s11060-011-0640-3

Cited by 34 publications

(37 citation statements)

References 38 publications

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“…Elevated MIF levels occur in multiple human malignancies. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 57 Recently, we identified MIF as a highly stabilized novel HSP90 client in cancer cells. 7 Degradation of MIF protein by HSP90 inhibition via 17AAG strongly inhibits growth of spontaneous breast cancers in MMTV-ErbB2 mice, identifying MIF as a potential drug target for breast cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

“…8, 9, 10 Human cancers of the breast, colon, ovary, prostate, liver, lung, pituitary and brain frequently express elevated MIF levels. 7, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 Importantly, elevated MIF levels correlate with clinical aggressiveness of the breast, lung, liver, brain, ovary and prostate, implicating MIF in poor prognosis and resistance to chemotherapeutic drugs. 16, 18, 22, 23, 25, 26, 28 In clear genetic support of MIF as an important pathophysiologic tumor driver, MIF deletion delays tumor progression and lowers tumors stages, and decreases angiogenesis in several mouse cancer models, including Myc-induced lymphomagenesis, 29 UVB-exposed skin cancer progression, 30 adenomatous polyposis coli protein (Apc) MIN/+ -mediated intestinal adenomas 31 and nitrosamine-induced bladder tumorigenesis.…”

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confidence: 99%

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HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer

Schulz

Streller

Ah³

et al. 2014

Cell Death Dis

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Overexpression of the human epidermal growth factor receptor-2 (HER2) in breast cancer strongly correlates with aggressive tumors and poor prognosis. Recently, a positive correlation between HER2 and MIF (macrophage migration inhibitory factor, a tumor-promoting protein and heat-shock protein 90 (HSP90) client) protein levels was shown in cancer cells. However, the underlying mechanistic link remained unknown. Here we show that overexpressed HER2 constitutively activates heat-shock factor 1 (HSF1), the master transcriptional regulator of the inducible proteotoxic stress response of heat-shock chaperones, including HSP90, and a crucial factor in initiation and maintenance of the malignant state. Inhibiting HER2 pharmacologically by Lapatinib (a dual HER2/epidermal growth factor receptor inhibitor) or CP724.714 (a specific HER2 inhibitor), or by knockdown via siRNA leads to inhibition of phosphoactivated Ser326 HSF1, and subsequently blocks the activity of the HSP90 chaperone machinery in HER2-overexpressing breast cancer lines. Consequently, HSP90 clients, including MIF, AKT, mutant p53 and HSF1 itself, become destabilized, which in turn inhibits tumor proliferation. Mechanistically, HER2 signals via the phosphoinositide-3-kinase (PI3K)–AKT– mammalian target of rapamycin (mTOR) axis to induce activated pSer326 HSF1. Heat-shock stress experiments confirm this functional link between HER2 and HSF1, as HER2 (and PI3K) inhibition attenuate the HSF1-mediated heat-shock response. Importantly, we confirmed this axis in vivo. In the mouse model of HER2-driven breast cancer, ErbB2 inhibition by Lapatinib strongly suppresses tumor progression, and this is associated with inactivation of the HSF1 pathway. Moreover, ErbB2-overexpressing cancer cells derived from a primary mouse ErbB2 tumor also show HSF1 inactivation and HSP90 client destabilization in response to ErbB2 inhibition. Furthermore, in HER2-positive human breast cancers HER2 levels strongly correlate with pSer326 HSF1 activity. Our results show for the first time that HER2/ErbB2 overexpression controls HSF1 activity, with subsequent stabilization of numerous tumor-promoting HSP90 clients such as MIF, AKT and HSF1 itself, thereby causing a robust promotion in tumor growth in HER2-positive breast cancer.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer

Schulz

Streller

Ah³

et al. 2014

Cell Death Dis

View full text Add to dashboard Cite

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“…Tumor-derived factors attract circulating monocytes into the tumor tissues where they differentiate into macrophages, which undergoes two distinct phenotypes, M1 macrophages (classically activated) and M2 macrophages (alternatively activated) (Biswas and Mantovani, 2010;Gordon and Martinez, 2010;Cui et al, 2013). It is mostly accepted that tumor associated macrophages (TAMs) have M2 phenotype and TAMs infiltration has been shown to correlate with poor prognosis in lung, breast, bladder cancer, papillary renal cell carcinoma and gliomas Wang et al, 2012;Ajili et al, 2013;Hutterer et al, 2013;Tang, 2013). Increasing evidence shows that TAMs have tumor-promotion function.…”

Section: Discussionmentioning

confidence: 99%

Macrophages Promote Coal Tar Pitch Extract-induced Tumorigenesis of BEAS-2B Cells and Tumor Metastasis in Nude Mice Mediated by AP-1

Zhang

Jin²,

Zhang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…For example, its expression correlates well with glioma recurrence and poorer prognosis and, thereby, MIF is currently being considered as a valuable and independent prognostic indicator for patients with glioma [106]. MIF is also expressed by a variety of immune cells, including macrophages, lymphocytes, and eosinophils, as well as by endothelial cells and epithelial cells.…”

Section: Mifmentioning

confidence: 99%

Emerging Role of Tumor-associated Macrophages as Therapeutic Targets in Glioblastoma Multiforme

Lin¹,

Hu²,

Fu³

et al. 2014

Nano BioMed ENG

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The most common types of primary brain tumors in adults are gliomas. Glioblastoma multiforme (GBM) is the most highly aggressive type of glioma. GBM contains various numbers of cells with characteristics of activated or dysmorphic macrophages/microglia. Among them, some cell types provide significant support for tumor growth, while others are able to inhibit tumor progression. These cells are generally considered part of the tumor stroma and are often described as TAMs (tumourassociated macrophages). The presence of TAMs has been linked to increased tumor grade and poor clinical outcome in GBM, suggesting that depletion or inhibition of these cells may suppress tumor growth. A better understanding of tumor microenvironment in the brain would therefore be expected to contribute to the development of improved therapies for brain tumors that are urgently required due to a poor availability of treatments for these malignancies. This review summarizes some of the known interactions between brain tumors and different stromal cells, and also discusses potential therapeutic approaches within this context.

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Elevated expression of macrophage migration inhibitory factor correlates with tumor recurrence and poor prognosis of patients with gliomas

Cited by 34 publications

References 38 publications

HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer

HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer

Macrophages Promote Coal Tar Pitch Extract-induced Tumorigenesis of BEAS-2B Cells and Tumor Metastasis in Nude Mice Mediated by AP-1

Emerging Role of Tumor-associated Macrophages as Therapeutic Targets in Glioblastoma Multiforme

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