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Regulation of Extracellular Matrix Remodeling and Epithelial-Mesenchymal Transition by Matrix Metalloproteinases: Decisive Candidates in Tumor Progression

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Proteases in Physiology and Pathology

Abstract

Tumor biology is intricate and multifaceted. The genetic and epigenetic alterations accelerate normal cells to transform into aggressive malignant phenotype. Molecular principles of invasion and metastasis are indeed indispensable for profound understanding of tumorigenesis. The seeding pioneer cells from growing tumor eventually discharge from the original clump of mutant cells, invading adjacent tissues and mobilizing to distant sites. This attribute of cancer cells reduces patient’s survival rate and prognosis. Inquisition of mechanistic approach for metastasis is bestowed by two processes—extracellular matrix (ECM) remodeling and epithelial-mesenchymal transition (EMT). Proteases pave the way for invaders by breaking down the ECM and releasing pro-invasive factors from cell surface and ECM. Indeed, highly conserved EMT program leads to dissemination of single tumor cells from primary tumors. The zinc-dependent matrix MMPs are the most important effectors in these processes and frequently overexpressed in most of the tumors. Besides proteolysis, by activating or deactivating several growth factors, MMPs affect tumor neoangiogenesis and proliferation. The tissue inhibitors of metalloproteinases (TIMPs) play a central role in complex regulation of MMPs. An apt equilibrium between TIMPs and MMPs is significant in cell invasion and metastasis. These concepts are encouraged for pursuing MMPs as a signature for predicting metastasis and also as therapeutic target. A comprehensive understanding regarding enzyme-substrate interactions and regulation and specific MMPs’ functionality in cancer addresses that MMP inhibitors (MMPIs) should be specific in terms of MMP or degrading definite substrates. The scientific and clinical drive for second-generation MMPIs through the development of pharmaceutical reagents and clinical trials determining the therapeutic benefit to cancer patients should be geared up.

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Acknowledgments

We gratefully acknowledge the Department of Science and Technology (DST)—INSPIRE—India.

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  1. School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, 721302, India

    Y. Rajesh & Mahitosh Mandal

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  1. Y. Rajesh
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  2. Mahitosh Mandal
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  1. Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

  2. St. Boniface Hospital Research Centre, University of Manitoba, Faculty of Health Sciences, College of Medicine, Institute of Cardiovascular Sciences, Manitoba, Winnipeg, Canada

    Naranjan S. Dhalla

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Rajesh, Y., Mandal, M. (2017). Regulation of Extracellular Matrix Remodeling and Epithelial-Mesenchymal Transition by Matrix Metalloproteinases: Decisive Candidates in Tumor Progression. In: Chakraborti, S., Dhalla, N. (eds) Proteases in Physiology and Pathology. Springer, Singapore. https://doi.org/10.1007/978-981-10-2513-6_9

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