MMP2

72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an is_associated_with::enzyme that in humans is encoded by the MMP2 is_associated_with::gene. The MMP2 gene is located on chromosome 16 at position 12.2.

Function
Proteins of the is_associated_with::matrix metalloproteinase (MMP) family are involved in the breakdown of is_associated_with::extracellular matrix (ECM) in normal physiological processes, such as is_associated_with::embryonic development, is_associated_with::reproduction, and tissue remodeling, as well as in disease processes, such as is_associated_with::arthritis and is_associated_with::metastasis. Most MMP's are secreted as inactive is_associated_with::proproteins which are activated when cleaved by extracellular is_associated_with::proteinases. This gene encodes an enzyme which degrades type IV is_associated_with::collagen, the major structural component of is_associated_with::basement membranes. The enzyme plays a role in endometrial menstrual breakdown, regulation of vascularization and the inflammatory response.

Activation
Activation of MMP-2 requires is_associated_with::proteolytic processing. A complex of membrane type 1 MMP (MT1-MMP/MMP14) and tissue inhibitor of metalloproteinase 2 recruits pro-MMP 2 from the extracellular milieu to the cell surface. Activation then requires an active molecule of MT1-MMP and auto catalytic cleavage. Clustering of is_associated_with::integrin chains promotes activation of MMP-2. Another factor that will support the activation of MMP-2 is cell-cell clustering. A wild-type activated leukocyte cell adhesion molecule (is_associated_with::ALCAM) is also required to activate MMP-2.

Clinical significance
Mutations in the MMP2 gene are associated with Torg-Winchester syndrome, multicentric is_associated_with::osteolysis, is_associated_with::arthritis syndrome, and possibly keloids.

Role of MMP-2 in chronic disease
Activity of MMP-2 relative to the other is_associated_with::gelatinase (is_associated_with::MMP-9) has been associated with severity of chronic airway diseases including is_associated_with::Idiopathic interstitial pneumonia and is_associated_with::Bronchiectasis. In idiopathic interstitial pneumonia, MMP-2 activity was elevated in patients with the less severe disease phenotype which is more responsive and reversible with corticosteroid therapy. In non-cystic fibrosis bronchiectasis, MMP-2 concentration was elevated in patients with is_associated_with::Haemophilus influenzae airway infection compared to is_associated_with::Pseudomonas aeruginosa airway infection. Bronchiectasis patients with P. aeruginosa infection have a more rapid decline in lung function.

Role of MMP-2 in cancer progression
Altered expression and activity levels of MMPs have been strongly implicated in the progression and is_associated_with::metastasis of many forms of cancer. Increased MMP-2 activity has also been linked with a poor is_associated_with::prognosis in multiple forms of cancer including colorectal, is_associated_with::melanoma, breast, lung, ovarian, and prostate. Furthermore, changes in MMP-2 activity can come from alterations in levels of transcription, MMP secretion, MMP activation, or MMP inhibition. MMP production in many cancers may be upregulated in surrounding stromal tissue rather than simply in the tumor lesion. For instance, Mook, et al. showed that MMP-2 mRNA levels are strikingly similar between metastatic and non-metastatic lesions in colorectal cancer, but metastatic cases are correlated with higher levels of MMP-2 mRNA in surrounding healthy tissue. For this reason, it is difficult to fully understand the complex role of MMPs in cancer progression.

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 is_associated_with::MMP-9) is capable of degrading is_associated_with::type IV collagen, the most abundant component of the is_associated_with::basement membrane. The basement membrane is important for maintaining tissue organization, providing structural support for cells, and influencing cell signaling and polarity. Degradation of the basement membrane is an essential step for the metastatic progression of most cancers.

Cancer cell invasion, ECM degradation, and metastasis are highly linked with the presence of is_associated_with::invadopodia, protrusive and adhesive structures on cancer cells. Invadopodia have been shown to concentrate MMPs (including is_associated_with::MT1-MMP, MMP-2, and is_associated_with::MMP-9) for localized release and activation. Furthermore, degradation products of MMP activity may further promote invadopodia formation and MMP activity. Finally, MMP-2 and several other MMPs have been shown to proteolytically activate is_associated_with::TGF-β, which has been shown to promote is_associated_with::epithelial mesenchymal transition (EMT), a key process involved in cancer metastasis.

Role in cell signaling
MMP degradation of the ECM affects cellular behavior through changes in is_associated_with::integrin-cell binding, by releasing growth factors harbored by the ECM, by generating ECM degradation products, and by revealing cryptic binding sites in ECM molecules. For instance, MMP-2 degradation of is_associated_with::collagen type I can reveal a previously inaccessible cryptic binding site that binds with the αvβ3 integrin expressed by human melanoma cells. Signaling through this integrin is necessary for melanoma cell viability and growth in a collagen matrix and can potentially rescue the cells from is_associated_with::apoptosis. As another example, cleavage of laminin-5, a component of the basement membrane, by MMP-2 has been shown to reveal a cryptic site inducing migration of breast epithelial cells.

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. MMP-2 has also been shown to cleave other non-ECM substrates including growth factors such as is_associated_with::TGF-β, FGF receptor-1, proTNF, is_associated_with::IL-1β and various is_associated_with::chemokines. For instance, MMP-2 has been implicated, along with is_associated_with::MMP-9 in cleaving latent is_associated_with::TGF-β, which has complex interactions with cancer cells. TGF-β generally plays a role in maintaining tissue homeostasis and preventing tumor progression. However, genetically unstable cancer cells can often evade regulation by TGF-β by altering TGF-β receptors in downstream signaling processes. Furthermore, expression of TGF-β is also correlated with immune tolerance and may help shield cancer cells from immune regulation.

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 is_associated_with::angiogenesis. This process is essential for tumor progression, because as tumors grow they need increasing supplies of oxygen and nutrients. Localized MMP-2 activity plays an important role in endothelial cell migration, a key feature of is_associated_with::angiogenesis. Additionally, is_associated_with::MMP-9 and other MMPs have been suggested to also play a complex, indirect role in angiogenesis by promoting is_associated_with::VEGF mobilization and generating antiangiogenic factors.

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 is_associated_with::VEGF, a potent stimulator of angiogenesis. Additionally, the group determined that MMP-2 knockout mice showed decreased rates of tumor growth relative to tumor growth rates in wild type mice. Furthermore, increased expression and activity of MMP-2 has been tied to increased vascularization of lung carcinoma metastases in the central nervous system, which likely increases survival rate of these metastases.

Finally, MMP-2 has been also shown to drive is_associated_with::lymphangiogenesis, which is often excessive in tumor environments and can provide a route of is_associated_with::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. 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.

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 is_associated_with::marimastat did show a slight increase in survival of patients with gastric or pancreatic cancer.

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.

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.

Interactions
MMP2 has been shown to interact with:


 * is_associated_with::CCL7,
 * is_associated_with::THBS2,
 * is_associated_with::TIMP2,
 * is_associated_with::TIMP4, and
 * is_associated_with::Thrombospondin 1.