ArticleClinical & experimental metastasis2011
Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-1α.
Article in Clinical & experimental metastasis, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 36 citations in OpenAlex.
- Investigating hypoxia-inducible factor signaling in cancer: Mechanisms, clinical implications, targeted therapeutic strategies, and resistance.Cancer pathogenesis and therapy · 2026Review
- Canine adipose-derived mesenchymal stromal cells inhibit the growth of canine hematologic malignancy cell lines.Regenerative therapy · 2025Article
- TIMP-1 is an activator of MHC-I expression in myeloid dendritic cells with implications for tumor immunogenicity.Genes and immunity · 2024Article
- Article
- Alternative splicing of CEACAM1 by hypoxia-inducible factor-1α enhances tolerance to hepatic ischemia in mice and humans.Science translational medicine · 2023Article
- Differential Gene Expression of fresh tissue and patient-derived explants' matricellular proteins augment inflammatory breast cancer metastasis: the possible role of IL-6 and MCP-1.QJM : monthly journal of the Association of Physicians · 2023Article
- Colorectal liver metastasis: molecular mechanism and interventional therapy.Signal transduction and targeted therapy · 2022Review
- Food components with antifibrotic activity and implications in prevention of liver disease.The Journal of nutritional biochemistry · 2018Review
- Article
- Hepatic metastatic niche: from normal to pre-metastatic and metastatic niche.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Review
- Molecular targets and pathways involved in liver metastasis of colorectal cancer.Clinical & experimental metastasis · 2015Review
- Article
- Down-regulation of TIMP-1 inhibits cell migration, invasion, and metastatic colonization in lung adenocarcinoma.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2015Article
- Curcumin protects against CCl4-induced liver fibrosis in rats by inhibiting HIF-1α through an ERK-dependent pathway.Molecules (Basel, Switzerland) · 2014Article
- Impact of proteolytic enzymes in colorectal cancer development and progression.World journal of gastroenterology · 2014Review
- Cytokine functions of TIMP-1.Cellular and molecular life sciences : CMLS · 2014Review
- In papillary thyroid carcinoma, TIMP-1 expression correlates with BRAF (V600E) mutation status and together with hypoxia-related proteins predicts aggressive behavior.Virchows Archiv : an international journal of pathology · 2013Article
- MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines.Cell death & disease · 2013Article
- The behavior of matrix metalloproteinases and their inhibitors in colorectal cancer.International journal of molecular sciences · 2012Review
- New and paradoxical roles of matrix metalloproteinases in the tumor microenvironment.Frontiers in pharmacology · 2012Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The "protease web", representing the network of proteases, their inhibitors, and effector molecules, arises as a pivotal determinant of tissue homeostasis. Imbalances of this network, for instance caused by elevated host levels of tissue inhibitor of metalloproteinases-1 (TIMP-1), have been shown to increase the susceptibility of target organs to scattered metastasis by inducing the hepatocyte growth factor (HGF) pathway. Increased expression of the hypoxia-inducible factor-1α-subunit (HIF-1α) is also associated with tumour progression and is also known to induce HGF-signaling via up-regulation of the HGF-receptor Met, namely under canonical stress conditions like lack of oxygen. Here, we aimed to identify a possible metastasis-promoting connection between TIMP-1, HIF-1α, and HGF-signaling. We found that HIF-1α and HIF-1-signaling were increased during liver metastasis of L-CI.5s T-lymphoma cells in TIMP-1 overexpressing syngeneic DBA/2 mice. In vitro, exposure of L-CI.5s cells to recombinant TIMP-1 revealed that TIMP-1 itself was able to induce HIF-1α and HIF-1-signaling. Knock-down of HIF-1α identified tumour cell-derived HIF-1α as mediator of this TIMP-1-induced invasiveness in vitro. In vivo, HIF-1α knock-down significantly impaired Met expression as well as Met phosphorylation and inhibited scattered liver metastasis. Furthermore, HGF-dependent TIMP-1-promoted Met phosphorylation and HGF-dependent TIMP-1-induced invasiveness in vitro was mediated by HIF-1α. We conclude that elevated levels of TIMP-1 in the microenvironment of tumour cells can promote metastasis by inducing HIF-1α-dependent HGF-signaling. This connection between a protease inhibitor (TIMP-1) and a classically stress-related factor (HIF-1α) is a so far undiscovered impact of the "protease web" on tissue homeostasis with important implications for metastasis.
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