Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis

Bergers, Gabriele; Brekken, Rolf A.; McMahon, Gerald; Vu, Thiennu H.; Itoh, Takeshi; Tamaki, Koreaki; Tanzawa, Kazuhiko; Thorpe, Philip E.; Itohara, Shigeyoshi; Werb, Zena; Hanahan, Douglas

doi:10.1038/35036374

Cited by 2,483 publications

(2,097 citation statements)

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“…MMP9 mobilizes VEGF and initiates angiogenesis. Importantly, when the Mmp9 mutation is crossed into the RIP1-Tag background, fewer tumours become angiogenic, supporting the role of MMP9 in mobilizing VEGF 63 .…”

Section: Mmps and Vegf Signalingmentioning

confidence: 79%

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

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Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.The founding member of the matrix metalloproteinase (MMP) family, collagenase, was identified in 1962 by Gross and Lapiere, who found that tadpole tails during metamorphosis contained an enzyme that could degrade fibrillar collagen 1,2 . Subsequently, an interstitial collagenase, collagenase-1 or MMP1, was found in diseased skin and synovium 3 . In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775-Ile776 or Gly775-Lys776 in native type I, II or III collagen molecules 3,4 . Further research led to the discovery of a family of structurally related proteinases (23 in human, 24 in mice), now referred to as the MMP family.Interest in MMPs increased in the late 1960s and early 1970s following observations that MMPs are upregulated in diverse human diseases including rheumatoid arthritis and cancer. Importantly, high levels of MMPs often correlated with poor prognosis in human patients (reviewed in REF. 5 ). However, recent clinical data indicate that the relationship between § These authors contributed equally to this paper. Competing interests statementThe authors declare no competing financial interests. DATABASESThe following terms in this article are linked online to: Entrez Genome: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene DmMmp1 | DmMmp2 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMMPs and disease is not simple; for example, increased MMP activity can enhance tumour progression or can inhibit it (reviewed in REF. 6 ). This complex relationship between MMP expression and cancer has increased the basic and clinical interest in understanding MMP function in vivo, but it has also focused attention on MMPs and pathology, and relatively less attention has been focused on the normal roles of these enzymes. MMP proteolysisMMPs are members of the metzincin group of proteases, which are named after the zinc ion and the conserved Met residue at the active site 11,12 . Recent work has generated a unified peptidase nomenclature 13 Functions of MMP proteolysisHistorically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. However, MMP proteolysis can create space for cells to migrate, can produce specific substrate-cleavage fragments with independent biological activity, can MMPs in bone modelling and remodellingBone is an important site of ongoing tissue remodelling during development...

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Section: Mmps and Vegf Signalingmentioning

confidence: 79%

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

Self Cite

2,584

2,180

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“…MMPs have been implicated in angiogenesis, either directly or via the upregulation or activation of pro-angiogenic factors such as VEGF (Bergers et al, 2000;Sounni et al, 2002) and in the case of MT1-MMP there is recent evidence that this regulation may occur at a transcriptional level (Sounni et al, 2004). However, not all MMP activity is proangiogenic; for example the gelatinases and MMP-7 can cleave plasminogen to form the angiogenesis inhibitor angiostatin (Cornelius et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma

et al. 2006

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The matrix metalloproteinases (MMPs) are endopeptidases which break down the extracellular matrix and regulate cytokine and growth factor activity. Several MMPs have been implicated in the promotion of invasion and metastasis in a broad range of tumours including urothelial carcinoma. In this study, RNA from 132 normal bladder and urothelial carcinoma specimens was profiled for each of the 24 human MMPs, the four endogenous tissue inhibitors of MMPs (TIMPs) and several key growth factors and their receptors using quantitative real time RT -PCR. Laser capture microdissection (LCM) of RNA from 22 tumour and 11 normal frozen sections was performed allowing accurate RNA extraction from either stromal or epithelial compartments. This study confirms the over expression in bladder tumour tissue of well-documented MMPs and highlights a range of MMPs which have not previously been implicated in the development of urothelial cancer. In summary, MMP-2, MT1-MMP and the previously unreported MMP-28 were very highly expressed in tumour samples while MMPs 1, 7, 9, 11, 15, 19 and 23 were highly expressed. There was a significant positive correlation between transcript expression and tumour grade for MMPs 1, 2, 8, 10, 11, 12, 13, 14, 15 and 28 (Po0.001). At the same confidence interval, TIMP-1 and TIMP-3 also correlated with increasing tumour grade. LCM revealed that most highly expressed MMPs are located primarily within the stromal compartment except MMP-13 which localised to the epithelial compartment. This work forms the basis for further functional studies, which will help to confirm the MMPs as potential diagnostic and therapeutic targets in early bladder cancer.

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“…The role of these cells in adult angiogenesis, including that in the revascularisation of pancreatic islets, has recently been demonstrated [45,46]. Moreover, the macrophage-derived factor matrix metalloproteinase-9 has been reported to be pivotal for the angiogenic switch to occur in insulin-producing tumours [47].…”

Section: Discussionmentioning

confidence: 99%

Better vascular engraftment and function in pancreatic islets transplanted without prior culture

Olsson

Carlsson

2005

Diabetologia

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Aims/hypothesis: Recent studies suggest that donor endothelial cells may contribute to islet graft revascularisation. Since islet endothelial cells disappear during culture, we hypothesised that transplantation of islets without prior culture is beneficial for their engraftment. Methods: Cultured (4-7 days) or freshly isolated islets (<4 h after donor pancreas extirpation) were syngeneically transplanted into Wistar-Furth rats and C57Bl/6 mice beneath the renal capsule. Islet graft revascularisation was evaluated by measuring vascular density, blood flow and tissue oxygen tension. Islet graft function was investigated by a minimal islet mass model in inbred mice (C57Bl/6). Results: Four days after implantation, the partial pressure of oxygen (pO 2 ) in the transplanted cultured islets was less than 10 mmHg (1.33 kPa), but tended to be higher in grafts composed of freshly isolated islets. The pO 2 in the grafts of freshly isolated islets had more than doubled 4 weeks later, whereas the pO 2 in the grafts of cultured islets remained at values similar to those recorded 4 days after transplantation. Transplanted freshly isolated islets also had a higher vascular density than transplanted cultured islets (∼40 vs ∼25% of that in endogenous islets) when investigated 1 month post-implantation. When applying a minimal islet mass model in inbred mice, 200 freshly isolated islets cured alloxan-diabetic mice in all cases, whereas only 33% of the group receiving similar numbers of cultured islets were cured. Conclusions/interpretation: Transplantation of pancreatic islets without prior culture is beneficial for their vascular engraftment and function.

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Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis

Cited by 2,483 publications

References 41 publications

Matrix metalloproteinases and the regulation of tissue remodelling

Matrix metalloproteinases and the regulation of tissue remodelling

Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma

Better vascular engraftment and function in pancreatic islets transplanted without prior culture

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