Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-1α

Schelter, Florian; Halbgewachs, Birgit; Bäumler, Petra; Neu, Caroline; Görlach, Agnes; Schrötzlmair, Florian; Krüger, Achim

doi:10.1007/s10585-010-9360-x

Cited by 35 publications

(23 citation statements)

References 21 publications

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“…TIMPs might display a dual influence on tumor progression: either beneficial by inhibiting MMPs and impairing angiogenesis or harmful by facilitating cancer cell generation and growth [41,42,43]. Four TIMPs have been characterized in humans (TIMP-1, -2, -3 and -4).…”

Section: Introductionmentioning

confidence: 99%

The Impact of Matrix Metalloproteinases and Their Tissue Inhibitors in Inflammatory Bowel Diseases

Lakatos

Hritz

Varga

et al. 2012

Dig Dis

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Background: It has been suggested that matrix metalloproteinases (MMPs) may play a role in the pathogenesis of inflammatory bowel diseases (IBD). However, the impact of serum MMPs and their inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] have scarcely been investigated in the same experimental setting in ulcerative colitis (UC) and Crohn’s disease (CD) as well as their correlation with IBD activity. Methods: MMP-2, MMP-7, MMP-9, TIMP-1 and TIMP-2 serum antigen levels were determined in 23 patients with UC, 25 patients with CD and 10 healthy control patients by enzyme-linked immunoassay technique. Statistical analysis with one-way ANOVA and Student’s t tests was performed. A linear regression analysis or a Spearman’s r test was used to assess correlation. Differences were considered significant with p < 0.05. Results: Serum antigen concentrations of MMP-9, TIMP-1 and TIMP-2 were significantly higher in UC and CD patients compared to controls. MMP-7 was also significantly higher in CD compared with controls. Elevated MMP-9 and TIMP-1 antigen levels showed significant positive correlation with disease activity of IBD. MMP-2 and TIMP-2 levels inversely correlated with CD activity. Significant correlations were found between MMP-9/TIMP-1 and MMP-2/TIMP-2 antigen levels in both UC and CD. Conclusions: We demonstrated that serum antigen concentrations of MMP-9, TIMP-1 and TIMP-2 were significantly increased in patients with UC and CD compared to controls. Our results suggest that MMPs and TIMPs may contribute to the inflammatory and remodeling processes in IBD. Serum MMP-9 and TIMP-1 might be useful as additional biomarkers in the assessment of IBD activity.

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Section: Introductionmentioning

confidence: 99%

The Impact of Matrix Metalloproteinases and Their Tissue Inhibitors in Inflammatory Bowel Diseases

Lakatos

Hritz

Varga

et al. 2012

Dig Dis

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“…While it is widely accepted that elevated proteolytic activity should support invasive events of the metastatic cascade such as intra-and extravasation [6,9], the fact that some MMPs, such as MMP-8 [10] and MMP-9 [11] were identified to play also a tumor-inhibiting role, depending on the specific microenvironmental context, excited some drawback to this concept. Even more paradoxical seemed to be the finding that MMP inhibition by synthetic inhibitors [12] and the natural inhibitor Timp-1 [13,14] promotes metastasis. This was one explanation of the failure of clinical trials with broad spectrum MMP inhibition [8,15].…”

Section: Introductionmentioning

confidence: 99%

Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10

Schelter

Grandl

Seubert

et al. 2011

Clin Exp Metastasis

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In many different tumor entities, increased expression of tissue inhibitor of metalloproteinases-1 (Timp-1) is associated with poor prognosis. We previously reported in mouse models that elevated systemic levels of Timp-1 induce a gene expression signature in the liver microenvironment increasing the susceptibility of this organ to tumor cells. This host effect was dependent on increased activity of the hepatocyte growth factor (Hgf)/hepatocyte growth factor receptor (Met) signaling pathway. In a recent study we showed that Met signaling is regulated by Timp-1 as it inhibits the Met sheddase A disintegrin and metalloproteinase-10 (Adam-10). The aim of the present study was to elucidate whether the metastatic potential of tumor cells benefits from autocrine Timp-1 as well and involves Adam-10 and Met signaling. In a syngeneic murine model of experimental liver metastasis Timp-1 expression and Met signaling were localized within metastatic colonies and expressed by tumor cells. Knock down of tumor cell Timp-1 suppressed Met signaling in metastases and inhibited metastasis formation and tumor cell-scattering in the liver. In vitro, knock down of tumor cell Timp-1 prevented Hgf-induced Met phosphorylation. Consequently, knock down of Met sheddase Adam-10 triggered auto-phosphorylation and responsiveness to Hgf. Accordingly, Adam-10 knock down increased Met phosphorylation in metastatic foci and induced tumor cell scattering into the surrounding liver parenchyma. In conclusion, these findings show that tumor cell-derived Timp-1 acts as a positive regulator of the metastatic potential and support the concept that proteases and their natural inhibitors, as members of the protease web, are major players of signaling during normal homeostasis and disease.

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“…In lymphoma, HIF1a and HIF1 signaling were increased during liver metastasis of T-lymphoma cells in vivo, and HIF1a knockdown significantly impaired Met expression and phosphorylation and inhibited scattered liver metastasis (47).…”

Section: The Role Of Hypoxia In Metastasis and Spreadmentioning

confidence: 98%

The Role of Hypoxia and Exploitation of the Hypoxic Environment in Hematologic Malignancies

Muz

Puente

Azab

et al. 2014

Molecular Cancer Research

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Tumor hypoxia is a well-described phenomenon during the progression of solid tumors affecting cell signaling pathways and cell metabolism; however, its role in hematologic malignancies has not been given the same attention in the literature. Therefore, this review focuses on the comparative differences between solid and hematologic malignancies with emphasis on the role of hypoxia during tumorigenesis and progression. In addition, contribution of the bone marrow and angiogenic environment are also discussed. Insight is provided into the role of hypoxia in metastatic spread, stemness, and drug resistance in hematologic conditions. Finally, emerging therapeutic strategies such as small-molecule prodrugs and hypoxia-inducible factor (HIF) targeting approaches are outlined to combat hypoxic cells and/or adaptive mechanisms in the treatment of hematologic malignancies. Mol Cancer Res; 12(10); 1347-54. Ó2014 AACR. IntroductionHypoxia is a level of oxygen tension below the physiologic level; physiologic range varies due to diversified blood vessel network in different organs (1). Hypoxic conditions develop during cancer progression due to rapidly proliferating tumor cells that reduce O 2 diffusion as well as impaired perfusion of the abnormal blood vessels in the tumor. The oxygen level in hypoxic tumor tissues is found to be less than 1.3% O 2 , far below the physiologic oxygenation level (5%-10% O 2 ; ref. 2).Cellular adaptation to hypoxia is mediated through protein stabilization of hypoxia-inducible factor (HIF) subunits (HIF1a, HIF2a and HIF3a) that are regulated by prolyl hydroxylase domain (PHD) and factor-inhibiting HIF1 (FIH-1) enzymes. In oxygenated cells, HIFa subunits are hydroxylated by PHD and FIH-1, polyubiquitinated, and degraded by the proteasome; in hypoxia, the PHD enzymes lose their activity and the HIF degradation is halted. The stabilized, non-hydroxylated HIFa translocate to the nucleus, where they dimerize with constitutively expressed HIFb subunit, and bind to DNA to initiate gene transcription of the adaptive pathways (3, 4). Cellular adaptations to hypoxia can also occur by HIFindependent mechanisms including mammalian target of rapamycin (mTOR) kinase, unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress

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Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-1α

Cited by 35 publications

References 21 publications

The Impact of Matrix Metalloproteinases and Their Tissue Inhibitors in Inflammatory Bowel Diseases

The Impact of Matrix Metalloproteinases and Their Tissue Inhibitors in Inflammatory Bowel Diseases

Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10

The Role of Hypoxia and Exploitation of the Hypoxic Environment in Hematologic Malignancies

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