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MMP
The MMPs are a family of 24 endopeptidases that control the physiological turnover of the ECM. High levels of MMP correlate with unfavorable prognosis in multiple cancers. Human collagenase (now known as MMP-1) was identified in the skin 5 years later, and similar enzymes were further characterized across species. As MMPs cleave numerous substrates, their activity heavily impacts the extracellular environment and, left unchecked, their action can be disastrous. Their activity is therefore strictly regulated to prevent excessive ECM degradation. MMP synthesis is first controlled at the level of transcription and translation, and post-translational modifications also regulate MMP activity. Like all extracellular proteinases, MMPs are secreted as pro-enzymes, or zymogens, rendered inactive by the interaction between the zinc ion in the catalytic domain and a cysteine-sulphydryl group in the N-terminal (pro) domain. MMP proteolytic activity is further controlled by specific protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), comprising a family of four proteins (TIMP-1 to -4) that reversibly bind to the MMP catalytic site in a stoichiometric manner.
MMPs can also be inhibited by nonspecific inhibitors including α2-macroglobulin, thrombospondin-1 and -2. Multiple MMPs including MMP-2, -9, and -14 can degrade the basal lamina of capillary vessels and have been implicated in tumor cell extravasation. MMPs also have complex effects on growth factors and cytokines. Upregulation of the COX-2 pathway is associated with increased blood-brain barrier permeability and breast cancer cell entry into the CNS. Experimental studies of human melanoma have shown that MMP-2 upregulates tumor cell secretion of vascular endothelial growth factor-A (VEGF-A), which in turn activates the vascular endothelium favoring melanoma cell interaction with the blood vessel lining and their extravasation. A number of MMPs, including MMP-1, -2, -7, -9 and -14, contribute to angiogenesis via several mechanisms. In addition to mediating the ECM degradation necessary for endothelial cell migration into the tumor to be vascularized, MMPs contribute to the release of proangiogenic factors such as VEGF, fibroblast growth factor-2 (FGF-2), and transforming growth factor (TGF)-β from the ECM (2). These growth factors are sequestered in the stroma, and metastatic foci utilize MMPs to create a favorable metastatic niche by mobilizing these factors to support tumor growth. MMP overexpression has been well documented in multiple types of solid tumors. High levels of MMPs have been correlated with poor overall survival in virtually all solid malignancies. Distant metastases from breast cancer have been correlated with high levels of multiple MMPs including MMP -1, -7, -9, -11, and -13.
References
1.Winer A, et al. Mol Cancer Ther. 2018;17(6):1147–1155.
MMPs can also be inhibited by nonspecific inhibitors including α2-macroglobulin, thrombospondin-1 and -2. Multiple MMPs including MMP-2, -9, and -14 can degrade the basal lamina of capillary vessels and have been implicated in tumor cell extravasation. MMPs also have complex effects on growth factors and cytokines. Upregulation of the COX-2 pathway is associated with increased blood-brain barrier permeability and breast cancer cell entry into the CNS. Experimental studies of human melanoma have shown that MMP-2 upregulates tumor cell secretion of vascular endothelial growth factor-A (VEGF-A), which in turn activates the vascular endothelium favoring melanoma cell interaction with the blood vessel lining and their extravasation. A number of MMPs, including MMP-1, -2, -7, -9 and -14, contribute to angiogenesis via several mechanisms. In addition to mediating the ECM degradation necessary for endothelial cell migration into the tumor to be vascularized, MMPs contribute to the release of proangiogenic factors such as VEGF, fibroblast growth factor-2 (FGF-2), and transforming growth factor (TGF)-β from the ECM (2). These growth factors are sequestered in the stroma, and metastatic foci utilize MMPs to create a favorable metastatic niche by mobilizing these factors to support tumor growth. MMP overexpression has been well documented in multiple types of solid tumors. High levels of MMPs have been correlated with poor overall survival in virtually all solid malignancies. Distant metastases from breast cancer have been correlated with high levels of multiple MMPs including MMP -1, -7, -9, -11, and -13.
References
1.Winer A, et al. Mol Cancer Ther. 2018;17(6):1147–1155.
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