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Biochemistry of cancer: integrins, the desirable targets

Integrins are desirable to target cancer

Every year, 8 million people worldwide pass away from cancer, and this number is expected to rise. Cancer can damage a wide range of organs in people of various ages. It is quite honest to say that Cancer is the most common and severe problem in clinical medicine. Cancer's fundamental problems shed light on the biochemical and genetic processes underlying the unchecked expansion of cancer cells. The extracellular matrix (ECM)'s biochemical and biomechanical properties affect how sensitive cells are. Cell health depends on different reactions, such as proliferation, apoptosis, migration, and differentiation. The tumour microenvironment also largely influences cancer metastasis, medication resistance, and recurrence. Transmembrane glycoproteins called integrins mediate connections between cells and the ECM and connect it to the cytoskeleton. They relay the information from the ECM through downstream signalling pathways and can hence control the properties of the cell.


Mammals have so far been found to contain 24 different integrin heterodimers, formed by combining 18 α- and 8 β-subunits. A cell's ability to bind to specific ECM elements depends on the pattern of integrin expression, which also affects how a cell recognises and reacts to its surroundings. These same integrin-mediated pathways are used by tumour cells in the context of cancer to boost invasiveness and oncogenic survival as well as to create a host milieu that supports tumour development and metastatic dissemination (Figure 1). Hence, Integrins are interesting targets for cancer therapy due to their role in tumour progression, and several integrin antagonists, including antibodies and synthetic peptides, have been successfully used in clinics for cancer therapy. Unligated integrins may have a detrimental effect on tumour survival. They are generally unligated in adherent cells, which leads to the cleavage of caspase 8, which in turn causes tumour cells to undergo apoptosis through a process known as integrin-mediated death (IMD) (Figure 2).


Integrins' precise chemical signals and the mechanical environment of the ECM control how cancer cells behave. A key role is also played by the ECM's physicochemical environment. Chemically altered substrate surfaces have been used to study this interaction, but topology and functionality control are still difficult to achieve. Modifying a cell's local chemical environment does offer a viable method for selectively controlling the behaviour of cancer cells. Together, targeted external cue presentation has the potential to enhance existing intracellular cancer therapy approaches. When combined with other targeted therapies (tyrosine kinase inhibitors, anti-growth factor antibodies) for anticancer treatment, integrin inhibition may be used as a potential target for drug development. However, it needs to be thoroughly evaluated in the pre-clinical phase, possibly taking into account all of the plausible escape mechanisms by which tumour cells can develop.



By Navnidhi Sharma



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REFERENCES

Hamidi, H., Pietilä, M., & Ivaska, J. (2016). The complexity of integrins in cancer and new scopes for therapeutic targeting. British Journal of Cancer, 115(9), 1017–1023. https://doi.org/10.1038/bjc.2016.312

Jacob, M., Varghese, J., Murray, R. K., & Weil, P. A. (2016). Cancer: An Overview (V. W. Rodwell, D. A. Bender, K. M. Botham, P. J. Kennelly, & P. A. Weil, Eds.). Access Medicine; McGraw-Hill Education. https://accessmedicine.mhmedical.com/content.aspx?bookid=1366§ionid=73247495

Li, M., Wang, Y., Li, M., Wu, X., Setrerrahmane, S., & Xu, H. (2021). Integrins as attractive targets for cancer therapeutics. Acta Pharmaceutica Sinica B. https://doi.org/10.1016/j.apsb.2021.01.004

Yoshii, T., Geng, Y., Peyton, S., Mercurio, A. M., & Rotello, V. M. (2016). Biochemical and biomechanical drivers of cancer cell metastasis, drug response and nanomedicine. Drug Discovery Today, 21(9), 1489–1494. https://doi.org/10.1016/j.drudis.2016.05.011

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