What is it about?
All human cancers are the result of three distinct processes that ultimately convert a normal cell to an invasive metastasizing cancer cell. The normal cell that is the "target" cell to start this "initiation", "promotion" and "progression' process is the organ-specific adult stem cell. While a few of the ~ 25,000 genes in any cell seem to be mutated during the "initiation" of a normal stem cell by either an "error of DNA repair" or by an "error of DNA replication", that initiated single cell is not yet a cancer cell. It can remain in the human body during the life time without it ever becoming a cancer. All humans have initiated cells in their bodies. Two thirds of us die before we are diagnosed with a cancer, while one third get a cancer before they die. The different between these two outcomes is that those that get a cancer were exposed to "epigenetic" or non-mutagenic agents ( hormones, growth factors, inflammatory agents, pollutants, drugs, dietary factors, life style factors- alcohol, cigarettes, etc.) Those who did not get a cancer before they died also were exposed to these "epigenetic " agents , but also anti-oxidants and other anti-promoting agents. In brief, it is the epigenetic agents that are the rate-limiting steps of human carcinogenesis.
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Why is it important?
We can never reduce the risk to having our step cells from being mutated or "initiated". However, since the promotion step to increase the number of these "initiated" cells takes a long time to accumulate all the other genetic and epigenetic changes to bring about a cancer phenotype of being able to invade other tissues and to migrate to other organs, this promotion step is the place of intervention to prevent that single "initiated" cell to accrue all these changes. Epigenetic "promotors" need threshold levels to be functional; need regular exposures for long periods of time and; must occur in the absence of "anti-promoters". Therefore blockage of the promotion process is the most efficacious step to prevent cancers.
Perspectives
I have had over 50 years studying the evolutionary, genetic, epigenetic, environmental, dietary and cultural factors that influence human carcinogenesis. I was a pioneer in detecting DNA damagfe and repir that affect mutations in human cells. I was also a pioneer in studying the mechanism of epigenetic changes , as well as various in vitro assays to detect these "epigenetic" agents. My lab was the first in the world to have isolated human organ-specific adult stem cells and then demonstrating that they were the "target" cells for the "initiation" event in human carcinogenesis. Lastly, I have recently provided a explanation for the "Barker" hypothesis, that by increasing or decreasing the number of organ-specific adult stem cells during in utero development of the fetus, one can increase or decrease the ris to cancer ( and other chronic diseases) later in life.
james Trosko
Michigan State University
Read the Original
This page is a summary of: “Bad Luck Mutations”: DNA Mutations Are not the Whole Answer to Understanding Cancer Risk, Dose-Response, June 2017, SAGE Publications,
DOI: 10.1177/1559325817716585.
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