MMP2
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Location (UCSC) | Chr 16: 55.39 – 55.51 Mb | Chr 8: 93.55 – 93.58 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene.[5] The MMP2 gene is located on chromosome 16 at position 12.2.[6]
Function
Proteins of the
Activation
Activation of MMP-2 requires
Clinical significance
Mutations in the MMP2 gene are associated with Torg-Winchester syndrome, multicentric osteolysis, arthritis syndrome,[8][9] and possibly keloids.
Role of MMP-2 in chronic disease
Activity of MMP-2 relative to the other
Altered expression and activity levels of MMPs have been strongly implicated in the progression and
Role in cancer cell invasion
One of the major implications of MMPs in cancer progression is their role in ECM degradation, which allows cancer cells to migrate out of the primary tumor to form metastases. More specifically, MMP-2 (along with
Cancer cell invasion, ECM degradation, and metastasis are highly linked with the presence of
Role in cell signaling
MMP degradation of the ECM affects cellular behavior through changes in
More generally, by degrading the ECM, MMPs release growth factors that were previously bound to the ECM, allowing them to bind with cell receptors and influence cell signaling. Furthermore, many MMPs also activate other proMMPs along with growth factors.
Role in neovascularization and lymphangiogenesis
MMP-2 also plays an important role in the formation of new blood vessels within tumors, a process known as
For instance, when studying carcinogenesis of pancreatic islets in transgenic mice, Bergers et al. showed that MMP-2 and MMP-9 were upregulated in angiogenic lesions and that the upregulation of these MMPs triggered the release of bioactive
Finally, MMP-2 has been also shown to drive lymphangiogenesis, which is often excessive in tumor environments and can provide a route of metastasis for cancer cells. Detry, et al. showed that knocking down mmp2 in zebrafish prevented the formation of lymphatic vessels without altering angiogenesis, while MMP-2 inhibition slowed the migration of lymphatic endothelial cells and altered the morphology of new vessels.[15] These results suggest that MMP-2 may alter tumor viability and invasion by regulating lymphangiogenesis in addition to angiogenesis.
Inhibition of MMP-2 as cancer therapy
Clinical trials for cancer therapies using MMP inhibitors have yielded generally unsuccessful results. These poor results are likely due to the fact that MMPs play complex roles in tissue formation and cancer progression, and indeed many MMPs have both pro and anti-tumorogenic properties. Furthermore, most clinical studies involve advanced stages of cancer, where MMP inhibitors are not particularly effective. Finally, there are no reliable biomarkers available for assessing the efficacy of MMP inhibitors and MMPs are not directly cytotoxic (so they do not cause tumor shrinkage), so it is difficult for researchers to determine whether the inhibitors have successfully reached their targets.[14]
However, initial clinical trials using broad spectrum MMP inhibitors did show some positive results. Phase I clinical trials showed that MMP inhibitors are generally safe with minimal adverse side effects. Additionally, trials with marimastat did show a slight increase in survival of patients with gastric or pancreatic cancer.[14]
Various research groups have already suggested many strategies for improving the effectiveness of MMP inhibitors in cancer treatment. First, highly specific MMP inhibitors could be used to target the functions of specific MMPs, which should allow doctors to increase the treatment dosage while minimizing adverse side effects. MMP inhibitors could also be administered along with cytotoxic agents or other proteinase inhibitors. Finally, MMP inhibitors could be used during earlier stages of cancer to prevent invasion and metastasis.[14]
Additionally, tumor overexpression of MMPs can be used to potentially target the release of chemotherapeutic agents specifically to tumor sites. For instance, cytotoxic agents or siRNA could be encapsulated in liposomes or viral vectors that only become activated upon proteolytic cleavage by a target MMP. Finally, the tumor-targeting properties of MMP inhibitors offer a potential strategy for identifying small tumors. Researchers could couple MMP inhibitors to imaging agents to help detect tumors before they spread. Though initial trials yielded disappointing results, MMP inhibitors offer significant potential for improving cancer treatment by slowing the process of cancer cell invasion and metastasis.[14]
Interactions
MMP2 has been shown to
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000087245 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031740 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 1460022.
- ^ "MMP2 gene". Genetics Home Reference. Retrieved 19 May 2015.
- ^ "Entrez Gene: MMP2 matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase)".
- S2CID 24810941.
- ^ PMID 34307793.
- PMID 11069839.
- PMID 25679336.
- PMID 24592925.
- PMID 26601801.
- ^ PMID 15907591.
- ^ PMID 15588763.
- PMID 25699257.
- PMID 17483334.
- S2CID 2260074.
- ^ PMID 10740253.
- PMID 7522323.
- PMID 9211848.
- PMID 22490679.
- PMID 18662538.
- PMID 11025665.
- PMID 21151391.
- PMID 10947989.
- ^ PMID 10900205.
- PMID 12032297.
- PMID 10991943.
- ^ PMID 9182583.
- ^ PMID 12374789.
Further reading
- Massova I, Kotra LP, Fridman R, Mobashery S (1998). "Matrix metalloproteinases: structures, evolution, and diversification". FASEB J. 12 (25n26): 1075–95. PMID 9737711.
- Nagase H, Woessner JF (1999). "Matrix metalloproteinases". J. Biol. Chem. 274 (31): 21491–4. PMID 10419448.
- Goffin F, Frankenne F, Béliard A, Perrier D'Hauterive S, Pignon MR, Geenen V, Foidart JM (2002). "Human endometrial epithelial cells modulate the activation of gelatinase a by stromal cells". Gynecol. Obstet. Invest. 53 (2): 105–11. S2CID 45390394.
- Hrabec E, Naduk J, Strek M, Hrabec Z (2007). "[Type IV collagenases (MMP-2 and MMP-9) and their substrates--intracellular proteins, hormones, cytokines, chemokines and their receptors]". Postepy Biochem. 53 (1): 37–45. PMID 17718386.
External links