Aneuploidy, an imbalanced complement of chromosomes, was identified as a distinct feature of cancer cells more than a century ago. Indeed, ~90% of solid tumors are aneuploidy. The random gain and loss of complete chromosomes has many favorable properties as a mechanism for phenotypic switching, both in the context of a preemptive bet-hedging strategy as well as a rapid means for coping with unfamiliar environmental stresses. Aneuploidy might be a useful bet-hedging strategy for responding to environmental perturbations that are not frequently encountered. As aneuploidy perturbs hundreds of genes simultaneously, it has the potential to affect larger numbers of genes and processes per event relative to a spontaneous mutation. Importantly, unlike a spontaneous mutation, aneuploidy and any associated growth defects can also revert at a high frequency (cancer reversion).
So, aneuploidy may be the proof of “cancer is adaptation mechanism”
Dear Mezut,
The question if aneuploidy is proof of cancer adaptation to the unfamiliar environment? You are reasoning from the point of genes and mutations.
I think that first of all - aneuploidy concerns the genome. In the most general form, my answer is that it is polyploidy (genome multiplication) which is an adaptive tool of the cell, due to the capability to mask deleterious mutations and adapt the unfamiliar environment. But polyploidy itself is a source of the genome instability, which is necessary for adaptation, due to the capability of the genetic and epigenetic diversification and thus, plasticity (stemness). The instability of the polyploid genome inevitably leads to aneuploidy, mostly CIN, preventing/delaying normal cell divisions, favouring multipolar divisions. Further, clonal selection can act in selecting more fit de-polyploidized survivors. But this process cannot be endless - the mutations, neutral and harmful accumulate and this strain has to die. Therefore, an opposing process through meiotic-like recombination and gene conversion is acting for counterbalancing the aneuploidy. In general, it is acting in the genome reduction (de-polyploidisation) process.
Dear Jekaterina
First of all, thanks for your answer. main target of adaptation is to reduce free energy of the system. If The free energy of the system (Environment - cell) is closer to zero, it is good for system. Aneuploidy is a good tool for this search. You are right it is not endless process.
Article The Blebbishield Emergency Program Overrides Chromosomal Ins...
this will help to understand why chromosomal instability is important in cancer.
Dear Mesut,
In my opinion, polyploidy may be the proof of "cancer is adaptation mechanism to unfamilar environment".
Aneuploidy may be the proof that strange organisms can be still alive.
Dear Andrzej and dear Mezut,
Polyploidy usually results in aneuploidy but it (polyploidy) has the means to counteract aneuploidy (through some variant of somatic meiosis). In turn, aneuploidy may also have its contribution to adaptation by clonal selection, even if transient. Likely, it is a balanced process resolving at the population level. Our review of meiotic genes in cancer is just accepted, where we tried to update this conundrum. After I get the proofs, I shall attach it here.
Katrina
The mechanism of clonal selection is the main strength of cancer and a major problem in fighting it. This mechanism causes cancer cells to almost always find a solution to stay alive. In my opinion, aneuploidy enable the formation of strange living forms. In general, cancer is like the emergence of a new life, over and over again. The old (cancerous) life form dies and a new cancerous form arises...
A CENTURY AGO:
"Boveri proposed cancer is caused by aneuploidy, because it correlates with cancer and because it generates "pathological" phenotypes in sea urchins"
HALF A CENTURY LATER:
"when cancers were found to be non-clonal for aneuploidy, but clonal for somatic gene mutations, this hypothesis was abandoned"
TODAY:
"The aneuploidy above a threshold is clonal"
https://www.researchgate.net/publication/341387317_Aneuploidy_the_somatic_mutation_that_makes_cancer_a_species_of_its_own
Dear Andrzej and Mezut,
Peter Duesberg was very clever. We are slowly approaching the truth, which always has two sides. Now we have submitted the next review. But even while writing it and then editing and re-thinking again and again, and discussing with co-authors, we guessed more. The long latent period of carcinogenesis highlighted by Duesberg, even after acquiring a driver mutation (at least so in colorectal cancer and melanoma) is proportional to species life-span - Hayflick limit (as calculated by Janis Erenpreiss) and, thus, associated with senescence. What follows - cell fate change and renewal, through tetraploidy (starting of a new life cycle - thus cancer is born from cellular senescence). Polyploidy inevitably generates aneuploidy. What is a cause and what a consequence? The causation is reciprocal.
Dear Mezut,
You give difficult questions: reciprocal causation of polyploidy and aneuploidy - holistic or mechanistic? I would answer - both stochastic and deterministic, Wait a bit for the review - will be published next week. Then we can discuss - no final view, of course, only the approach.
Dear Mesut and Jakaterina,
Yes, I also think so. Cancer as per itself is not fatal. Death is only the sequential outcome. I see cancerous very efficient in drawing out oxygen, shunting aerobic respiration and putting off useless metabolism cycles. It is indeed body's most intelligent and dynamic response to stressful and noxious environment. It can be harnessed for age related problems.
Dear Rahul,
Do you want to say that cancer is a more successful metabolism manager than its host? A bold thought. Cancer is age-related but autonomous. How do you imagine to harness it for age-related problems? By embryonic extracts? This is a vision!!
Cancer activates primitive metabolism pathways just to stay alive - cloning and natural selection complete this picture. This egoistic and primitive life form does not cooperate with the complex multicellular host organism, gradually killing it (especially organisms of older people).
Dear Andrzej,
I see your picturesque description as a ready scenario of the movie. Very expressive! I just joke - in this difficult time, to keep humour is healthy!
Let us keep!
With best friendly wishes,
Katrina
Dear Katrina,
The type of this movie is horror. The film is about organisms that undergo transformation into aggressive organisms. After transformation they start to live a different life, which is like a zombie life. To live they constantly changing themself and kill other organisms that are around. They are permanently looking for better living conditions, so they can suddenly appear in other remote places.
For sure we will find a way to end this movie well. Let's continue working on the positive ending...
a lot of health and smile,
Andrzej
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