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Friday, 19 June 2020

Cancer Depends on Biophysics to Get Started


A team of researchers conclude that physics is behind the initiation of cancer.

The researchers document evidence that cancer is triggered by disruption of the normal physical characteristics of the cell environment, which removes suppression on oncogenic genes. The process for initiation of cancer is termed “Load (with a gene variant) and Trigger (by a dysregulated biophysical environment)”.



Exploring the link between biophysics and cancer

There are still numerous questions that are unresolved in cancer, including how it arises in the first place. The researchers accumulated evidence that a cell with an oncogenic variation of a gene will not, by itself, multiply into a tumor – there needs to be alterations around the cell, in the form of disruptions of the physical structures that shape the tissue.

There is substantial evidence that biophysics can modify cell behavior, but the roles of physical forces are frequently ignored in discussions of cancer. Professor John Evans and his colleagues have been undertaking studies to investigate whether simply altering the shape of the substrate that cancer cells grow upon will affect cell behavior. The researchers have shown that the rate of growth of cells and the way the cells respond to anticancer drugs is modified by the topography of the substrate, i.e. whether the substrate has lumps or dips or is flat. The effects on growth do not need changes in genes in the cells nor changes to the growth factors around the cell. Professors Evans, Alkaisi and Sykes, therefore, wondered if mechanical factors might underlie the reasons that, say, women with a BRCA mutation in every cell of their bodies do not all get breast cancer. Can biophysics explain why it is generally old people who get cancer? Can it shed light on why different sorts of cancer are seen usually in a restricted range of tissues?

Their findings suggest that appropriate mechanical forces on cells are vital for normal cell behavior, and that alterations that occur thence promote oncogene expression. Perplexing questions are thereby elegantly explained by executive control of tumors being within the biophysical and mechanical characteristics of the extracellular matrix (ECM) around the cell rather than at the level of gene activity within the cell. Clinical evidence for this alternative hypothesis is contained in, for example, studies of aging, of mutations in the ECM, of orthotopic transplants (compared to heterotopic tissues), and of physical trauma and scars (including skin, breast and liver).



Taking account of this approach, then if aberrant mechanically-derived signals from outside the cell are interrupted or inhibited (by, for example, using modified culture substrates, using anti-integrin antibodies or affecting COL mutation expression) cells exhibiting a cancer phenotype may be induced to revert to having a normal healthy phenotype. Such observations have already been reported. Further, this approach is consistent with recent observational clinical studies of high-grade serous ovarian carcinoma, asbestos-associated malignant mesothelioma and childhood acute lymphoblastic leukemia. Thus, Professor Evans and his colleagues suggest that the ECM may have both executive function in inducing initiation of a tumor and also may provide a route for controlling cancer.

Further, in this manner, some questions, that are not answered with certainty by current consensus mechanisms of tumorigenesis, are explained by the triggering of tumors being a property of the physical characteristics of the ECM, which is operative following loading of the tumor initiation process with a relevant gene variant. Hence the researchers have named the process “Load and Trigger”. Therefore, either restoring an ECM associated with homeostasis or targeting the related signal transduction mechanisms may possibly be utilized to modify or control the early progression of cancers. Targeted intervention may include repairing an ECM component gene function (such as for collagen), altering ECM composition, modifying polymer or protein chemistry or stereochemistry, or affecting polypeptide architecture and environment topography. The researchers suggest routes other than those that are focused on tumor genes should be vigorously investigated. The researchers provided a coherent and illustrated template for considering the notion.

Further investigations on deeper factors may be productive. For example, secondary control at the level of transcription factors may occur, because such factors have been observed to respond to mechanical signals. Their specific interactions might thereby confer tissue specificity on regulatory systems and explain why some cancers occur in only certain tissues.



Summary

Biophysics was noted to be a crucial central factor in cancer initiation and warrants urgent attention. As a corollary, the ECM appears to be a potential route for early targeted anticancer control or, perhaps, even prevention.

References

John J. Evans, Maan M. Alkaisi, Peter H. Sykes. (2019). Tumour Initiation: A Discussion on Evidence for a “Load-Trigger” Mechanism. Cell Biochemistry and Biophysics. 77:293–308. DOI: https://doi.org/10.1007/s12013-019-00888-z

Li Hui Tan, Peter H Sykes, Maan M Alkaisi, and John J Evans. (2017). Cell-like features imprinted in the physical nano- and microtopography of the environment modify the responses to anti-cancer drugs of endometrial cancer cells. Biofabrication. 9 015017. DOI: https://doi.org/10.1088/1758-5090/aa5c9a

Makhdoom Sarwar, Peter H. Sykes, Kenny Chitcholtan, John J Evans. (2020). Extracellular Biophysical Environment: Guilty of Being a Modulator of Drug Sensitivity in Ovarian Cancer Cells. Biochem Biophys Res Commun. Jun 18;527(1):180-186. DOI: https://doi.org/10.1016/j.bbrc.2020.04.107

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