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Nature versus nurture: The role of tissue environment in cancer

by Kate Turton

Cancerous cells have DNA mutations that cause them to divide uncontrollably.

Cancer research has therefore focused on understanding how mutations arise, whether they can be prevented and how to stop cancer cells dividing.

But what if DNA mutation doesn’t hold the key to cancer?

An emerging evolutionary theory suggests that the tissue microenvironment is the determining factor in whether or not cancerous cells are able to reproduce and proliferate.

Cell division is a normal biological process that replaces damaged cells and allows organisms to grow.

Part of the cell division cycle is the replication of DNA, so that each offspring cell will have a full copy of the genetic information it needs to function.

But DNA replication is an imperfect process and, each time a cell divides, there is a chance it will make a mistake.

Some errors have no effect but some change the way the cell behaves.

If mutations affect a cell’s ability to control how it grows and divides, cancer can develop.

In a paper published in Science earlier this year, researchers at Johns Hopkins University looked at whether cancers are more likely to result from mutations caused by inheritance, environmental factors or DNA replication error.

They studied data from 69 countries to investigate the number of times stem cells divide in 17 different human tissues and the incidence of cancer in those tissues.

Using statistical analysis, Tomasetti & Vogelstein found that the number of cell divisions is strongly correlated with the incidence of cancer - i.e. the more times a cell divides, the greater the risk of it becoming cancerous.

Furthermore, the correlation was strong for all 69 countries, suggesting that DNA replication error is likely to be responsible for the majority of human cancers.

However, this statistical approach didn’t look at cancer risk factors and the authors point out that information on environmental factors, hereditary risks and gene sequencing are needed to clarify the relationship between mutations and cancer.

Indeed, the environmental aspect is attracting attention - not external factors, such as exposure to tobacco smoke or UV radiation, but the internal micro-environments of biological tissues.

This has led to the development of a so-called ‘evolutionary theory’ of cancer, which is gaining momentum.

Evolution is not a continuous process but a phenomenon that reflects adaptations in response to intermittent environmental changes.

Mutation doesn’t drive evolution but it can create survival bias in an altered environment.

We commonly think about this in terms of organisms, when adaptation generates new species.

But what if a similar process can explain how and when cancers develop?

Professor James DeGregori at the University of Colorado School of Medicine believes that whilst mutations can cause cells to become cancerous, it is the local environment of the tissue in which mutated cells exist that determines whether or not they develop into tumours.

“Cancer isn’t due to constant mutation, it is adaptation to a tissue environment” he says.

In healthy tissues, normal cells are primed to survive whilst mutated cells are less able to compete for resources.

The evolutionary theory posits that alterations to tissues, caused by external factors and ageing processes, enable mutated cells to survive and proliferate at the expense of normal cells.

Whilst mutation cannot be avoided, altering the trajectory of mutated cells could make them less advantageous.

This could lead to new approaches for developing anti-cancer strategies, for example by restoring healthy tissue environments.

DeGregori’s team is studying inflammation and senescence, which are known risk factors for the development of cancer.

Pointing to a recent study published in The Lancet (as part of the CANTOS trial), which suggests that anti-inflammatory therapy can reduce the incidence and mortality of lung cancer, DeGregori says “If we can restore the original environment, we can make it less conducive to cancer.”

The take-home message is one that we all know too well: eat a balanced diet, exercise regularly and don’t smoke.

Or, as DeGregori puts it, “Exercise, diet and not smoking should all support a more youthful environment, so think of this as a tissue-level strategy for keeping cancer at bay.”

References

Tomasetti, C., Lu, L. & Vogelstein, B. (2017) Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science. 355. 1330-1334

DeGregori, J. (2017) Connecting cancer to its causes requires incorporation of effects on tissue microenvironments. Cancer Research. DOI: 10.1158/0008-5472

Ridker, P.M. et al (2017) Effect of interleukin-1B inhibition with canakinumab on incident lung cancer in patients with athersclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. The Lancet. DOI: 10.1016/S0140-6736(17)32247-X

 

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