Matrix Metalloproteinases (MMPs)

Roles-of-MMPs-in-tumor-cell-metastasis-The-roles-of-MMPs-in-metastasis-are-multifold.

Matrix metalloproteinases (MMPs) are a family of Zinc-dependent endopeptidase that degrade various proteins of the extracellular matrix (ECM). As members of the metzincin group of proteases, they share the conserved zinc-binding motif in their catalytic active site. Initially, MMPs were thought to function mainly in degrading ECM, but recent studies has shown that they also function significantly as regulators of extracellular tissue signaling networks.

MMPs are defined by the presence of two conserved zinc-binding motifs. One motif is a cysteine-containing pro-domain, whose function is partly to restrain catalytic; whereas the other motif is a histidine-rich catalytic domain, responsible for the endopeptidase activity.

MMPs Are Involved in Various Physiological and Pathological Processes.

MMPs are involved in numerous physiological and pathological processes. In physiological process, MMPs are involved in embryonic development, wound repair, ovulation, bone remodeling, macrophage function and in neutrophil function. They are also involved in pathological processes such as inflammation, tumor metastasis, rheumatoid arthritis, gastric ulcer, among others.

 Matrix Metalloproteinases and EMT in Tumor Metastasis

Epithelia-mesenchymal transition (EMT) plays its central role in normal embryonic development. But recent studies have shown its roles in pathological processes, such as cancer progression, fibrosis, and chronic inflammation.

MMPs associate with EMT in cancer progression through three mechanisms:

  • Elevated levels of MMPs in the tumor microenvironment induce EMT in epithelia cells.
  • EMT in cancer then produces more MMPs, thereby facilitating cell invasion and metastasis.
  • EMT can generate activated stromal-like cells that drive cancer progression through further MMPs production.

Role of MMPs in Tumor Metastasis

The role of MMPs in tumor metastasis was initially believed to be limited to the degradation of ECM and basement membrane collagen. But now, we know that MMPs paly critical roles at every step of tumor progression. MMPs influence several biological functions, such as modification of signaling pathways, regulation of cytokines involved in immune responses, and tumor growth by stimulating angiogenesis, which leads to the spread of cancer.

MMP-11 Plays Dual Roles in Tumors

Unlike many members of MMPs, MMP-8 and MMP-12 were reported to exert antitumor effects, thereby suppressing tumor growth. MMP-11 on the other hand plays a dual role in cancer progression. In one hand, MMP-11 promotes cancer development by inhibiting apoptosis and enhancing the invasion of cancer cells; on the other hand, however, MMP-11 plays a negative role against cancer development through the suppression of metastasis.

MMPs play Major Roles In Rheumatoid Arthritis

Rheumatoid arthritis (RA) is characterized by progressive joint destruction with loss of bone and cartilage as well as the aggressive activation of synovian fibroblasts (SFs) bearing a tumor-like appearance.

During joint destruction, RASFs secrete various proteases, including MMPs that degrade ECM
components, mainly proteoglycans and collagens, of articular cartilage in the affected joints.

However, among the various MMPs involved in articular degradation, MMP-1 and MMP-13 cleave collagens, whereas MMP-3 and MMP-9 target proteoglycans which are comprised of aggrecan.

This way, the degradation of proteoglycans at the surface and the subsequent degradation of collagen fibrils in the deep zone together result in the destruction of articular cartilage.

MMPs Play Major Roles In Infectious Diseases

In a normal immune responses, when the host immune system is challenged by an invading
organism, it must first recruit leucocytes to the site of infection, eradicate the pathogen and then dampen the response to allow the resolution of inflammation.

Matrix metalloproteinases play an important role in this process both by degrading components of the extracellular matrix and by modulating cytokine and chemokine activity.

 

REFERENCES

Hook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev. 2003;120(11):1351–83.

Cheng S, Lovett DH. Gelatinase A (MMP-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation. Am J Pathol. 2003;162(6):1937–49.

Lopez-Otin C., Matrisian L.M. Emerging roles of proteases in tumour suppression. Nat. Rev. Cancer. 2007;7:800–808.

Zhang X., Huang S., Guo J., Zhou L., You L., Zhang T., Zhao Y. Insights into the distinct roles of MMP-11 in tumor biology and future therapeutics (Review) Int. J. Oncol. 2016;48:1783–1793.

Araki, Y., & Mimura, T. (2017). Matrix Metalloproteinase Gene Activation Resulting from Disordred Epigenetic Mechanisms in Rheumatoid Arthritis. International journal of molecular sciences, 18(5), 905. https://doi.org/10.3390/ijms18050905

Elkington, P. T., O’Kane, C. M., & Friedland, J. S. (2005). The paradox of matrix metalloproteinases in infectious disease. Clinical and experimental immunology142(1), 12–20. https://doi.org/10.1111/j.1365-2249.2005.02840.x