Cancers: Looking beyond molecules

A person on ground has access to many details of what exists on earth, but a drone picture or a satellite image reveals something that you can’t perceive from ground. The drone’s or satellite’s view actually misses so many details but still gives some realizations that one can’t get on the ground. This is applicable to the field of research as well. Some researchers are obsessed by details, their research reveals more and more details and keep on adding to the data. In biology the details are often so intricate that getting lost in details is a commonplace. Having lost thus, the researchers themselves do not know where the research is going. In order to make sense often one has to leave the ground and take a perspective. This comes at a cost of resolution. The details are no more visible but the path which was obscured by the details might be revealed.

Take the example of cancer. We now know so many molecular details about it that understanding the fundamentals of cancer has become almost impossible. In the history of cancer research, some important insights about cancer were obtained before molecular biology came into existence. Cancer was identified as a multi-stage process by mathematical and statistical analysis of population patterns itself.  Then it was realized that a series of mutations are required to transform a normal cell into cancer cell. Later came the tools of molecular biology which revealed that what mathematical models had suspected was actually true. Then on molecular biology kept on adding a huge volume of details, accompanied by much smaller increments in the fundamental understanding.

Cancers arise by a series of mutational and functional changes in some or the other stem cells of the body. These changes are quite like evolution, which happens by a process of random mutations accompanied by natural selection on the mutants. Cancer is nothing else but evolution of normal cells into cancer cells by a similar process of mutations and selection. Cancer researchers, so far have focused their attention on the details of mutational and other molecular changes in cells. Unlike rest of the evolutionary biology, cancer evolutionary biology has paid inadequate attention to selection on the mutants.

Recent research is now converging to show that the rate limiting process in most cancers is not mutation, but selection. Cancer causing mutations can arise in any individual at any time, but most people do not get cancer because their internal environment does not support the mutants. Cancer causing mutations do not have an all-time growth advantage over normal cells. Cancer cells need to compete with normal cells to survive. They can survive and outcompete normal cells only under a certain set of conditions. These conditions are provided by the body’s internal environment. The importance of the tissue microenvironment in the development of cancer is being increasingly recognized only over the last decade, but it was not incorporated adequately in the cancer evolution models.

And now a mathematical model of the cancer evolution process built by us shows that the known population patterns in cancers can be explained only by incorporating different selective forces in different individuals. If the internal environments of all individuals were similar, by all probability almost everyone would get cancer by a threshold age.  The mutation probability alone does not explain why only some individuals get cancer. The population patterns of cancer are matched only when the model considers that every individual has a different tissue environment and thereby different selection on the mutants.  Many other known patterns in cancer biology cannot be explained without taking individual differences in the selective environment of the mutant cells. So our concept that cancer is limited by the process of selection rather than mutation is supported by multiple lines of evidence.

Can cancers be prevented?

In 2017, a paper appeared in the journal Science claiming that cancer is shear bad luck. This implied that perhaps nothing can be done to prevent cancers. The paper immediately attracted substantial criticism because the methods used for analysis were not sound. This paper delighted me since I used to teach a preliminary course in bio-statistics and I got a real life example of how not to use statistics. I could warn my students, beware!! If you use wrong statistics you are likely to get a paper published in Science!!

Now using the same data but analyzing it more carefully, and using novel mathematical approaches we infer exactly the other way. That cancer is only marginally bad luck and potentially largely preventable by maintaining a healthy internal environment. If the internal environment is healthy, mutants may still arise but are unlikely to outcompete normal cells. This paper is published in Nature publication’s Scientific Reports on 6th March 2020. (https://www.nature.com/articles/s41598-020-61046-7)

Future research in cancer should focus on which factors of the internal environment govern the competition between cells and what regulates these factors. Experiments so far have indicated that the levels of different hormones, expression of a class of molecules called growth factors and the properties of the matrix in which cells of a tissue are embedded are critical components of the selective environment. If maintained at their natural healthy level the tissue environment can prevent cancer causing mutants form growing into a fully evolved cancer cell. Many lifestyle and behavioural factors modulate the tissue microenvironment but our understanding of the links between lifestyle, behaviour and microenvironment is still quite primitive. This understanding will be the key to prevent cancers and future research should mainly focus on this question.

This goes very well with my thinking about the behavioural origins of many of the modern disorders. We evolved for stone age life and a number of behaviours evolved with us to fine tune with that life. Every behaviour is linked to a set of neuro-endocrine pathways and all pathways form a complex network structure. So when we give up certain behaviours for which our body evolved, the entire network changes; the body’s internal environment changes and at least some of these changes set the stage favourable for the cancer driver mutants.

About 10 years ago an interesting paper that appeared in Cell has interesting implications for this theory. In this experiment one group of mice was kept in the conventional caged environment and another group was given a behaviourally rich environment. Both groups were implanted with xenografts and observed for several weeks. In the ones with a behaviourally rich environment the tumours regressed but in those with a monotonous caged environment they grew bigger. Todays human lifestyle is like the monotonous caged mice. We need to gain back the behaviourally rich natural life to get rid of cancers.

Now again, a number of molecular details should follow the new line of thinking. How life-style and behaviours modulate the tissue microenvironment, which microenvironmental factors alter the selective environment for cancer driver mutants, how mutations accumulate and how cancer grows given the selective conditions will make multiple fascinating molecular stories. But the details make sense only when you have the low resolution picture. Unfortunately in today’s science molecular details have become prestigious and perspective taking is not. Both are equally important but not equally prestigious. What you value depends upon whether you want good science or prestigious science.

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