In many (solid) tumors defect mitotic figures are frequent and the individual cells may vary strongly in shape and size. I attach a pic for illustration (H&E, liver tumor, cells of different size and shape, and several mitoses including a tripolar mitotic figure). The vast majority of tumor cells that divide their chromosomes unevenly will die – may be not immediately, may be only after another round of cell replication, but they will. The high mitotic activity in tumors is usually matched by an increased cell death rate as well. If the mitotic index of tumors were for real (i.e. not in great parts compensated by cell loss) the growth rate of many tumors would be exceedingly (unrealistically) high. The stem cells are the (few?) that self-replicate without excessive additional genetic damage. This is why in an individual tumor the morphology or gene expression pattern is rather constant (including different metastases that look quite alike). The genetic instability which is a landmark of most cancers (no doubt) is important, but in the stem cells it must be is several magnitudes less than what we’d expect when we see the abundant chromosomal aberrations and pathological mitotic figures. In other words, the crucial stem cells (which are needed for the survival of the cancer and its relatively stable phenotype) “hide” in a majority of dispensable cells (which are going to die anyway sooner or later). Personally I suspect this may be an important reason why pharmacologically induced tumor shrinkage is so often a very short-lived success, with deplorable little meaning for the patient. If the treatment is efficacious in many or most of the strongly altered cancer cells (with additional genetic damage, e.g. chromosomal aberrations) but does not target the stem cells, the success will be rather limited.

Possible exception– the innocent bystander effect, where the stem cells are not a direct target, but the damage to the non-stem cells in their surrounding will damage (kill) the stem cells as well (difficult to survive in a necrotic area…).

Here it is said that the reason for cancer with aneuploidy

lies in the elimination of tumor suppressor genes.

http://www.eurekalert.org/pub_releases/2009-12/mc-mcr120309.php

Related:

http://www.ncbi.nlm.nih.gov/pubmed/18974345

http://www.eurekalert.org/pub_releases/2007-06/uoc--sfc062707.php

http://www.eurekalert.org/pub_releases/2006-08/chb-oc081706.php

http://medicalxpress.com/news/2012-02-drugs-chromosomal-instability-breast-cancer.html

Regards,

Joachim (not a medic)

In most instances aneuploidy is lethal but the few cells that eliminate a growth inhibiting (i.e. tumor suppressor) gene have a growth advantage and grow out. Generation of aneuploid subclones can drastically disrupt the genomic architecture (chromotripsis) and create many sublones with different growth potential and drug resistance profiles.

In many (solid) tumors defect mitotic figures are frequent and the individual cells may vary strongly in shape and size. I attach a pic for illustration (H&E, liver tumor, cells of different size and shape, and several mitoses including a tripolar mitotic figure). The vast majority of tumor cells that divide their chromosomes unevenly will die – may be not immediately, may be only after another round of cell replication, but they will. The high mitotic activity in tumors is usually matched by an increased cell death rate as well. If the mitotic index of tumors were for real (i.e. not in great parts compensated by cell loss) the growth rate of many tumors would be exceedingly (unrealistically) high. The stem cells are the (few?) that self-replicate without excessive additional genetic damage. This is why in an individual tumor the morphology or gene expression pattern is rather constant (including different metastases that look quite alike). The genetic instability which is a landmark of most cancers (no doubt) is important, but in the stem cells it must be is several magnitudes less than what we’d expect when we see the abundant chromosomal aberrations and pathological mitotic figures. In other words, the crucial stem cells (which are needed for the survival of the cancer and its relatively stable phenotype) “hide” in a majority of dispensable cells (which are going to die anyway sooner or later). Personally I suspect this may be an important reason why pharmacologically induced tumor shrinkage is so often a very short-lived success, with deplorable little meaning for the patient. If the treatment is efficacious in many or most of the strongly altered cancer cells (with additional genetic damage, e.g. chromosomal aberrations) but does not target the stem cells, the success will be rather limited.

Possible exception– the innocent bystander effect, where the stem cells are not a direct target, but the damage to the non-stem cells in their surrounding will damage (kill) the stem cells as well (difficult to survive in a necrotic area…).

Interesting question..!! But rather than confined to aneuploidy, I would suggest all ploidy types. In fact, one of the longest standing hypothesis frequently proven was Thodre Boveri's hypothesis on tumorigenecity by multinucleated cells (ploidy). Its more than 100 years old hypothesis but frequently tested and supported by recent experiments. http://rsnr.royalsocietypublishing.org/content/65/4/359.long

and a review describing almost all your questions (and linking Boveri)

"Boveri revisited: Chromosomal instability, aneuploidy and tumorigenesis"

http://www.nature.com/nrm/journal/v10/n7/pdf/nrm2718.pdf

Also I recommend Dr. Harald Enzmann and Dr. Michal Mlacki, our recent paper on cancer stem cells to show why apoptosis cannot be the end for cancer stem cells (so the tripolar mitosis related apoptosis might not leads to death of cancer stem cells...it is my guess).

"Blebbishields, the Emergency Program for Cancer Stem Cells: Sphere Formation and Tumorigenesis after Apoptosis"

Goodwin Jinesh G, Woonyoung Choi, Jay B. Shah, Eugene K. Lee, Daniel Levi Willis, Ashish M. Kamat

https://www.researchgate.net/publication/233742776_Blebbishields_the_Emergency_Program_for_Cancer_Stem_Cells_Sphere_Formation_and_Tumorigenesis_after_Apoptosis

Article Blebbishields, the Emergency Program for Cancer Stem Cells: ...

Thank you for kind answers and I will look closer into these publications... (PS @ Goodwin Jinesh G.: not jet a dr. - still PhD student)

Dear Michal,

Have you read,"Is carcinogenesis a form of speciation?" (cell cycle 2011)? See attached. It may answer your question.

Regards,

Pdeter Duesberg

Dr. Enzmann makes good points about lower aneuploidy in stem cells. It also raises questions. 1. Does this happen because DNA repair works better in stem cells? I have seen some reports supporting this. 2. What about heterogeneity in stem cells? One would expect different stem cell clones to differ-correct?

Dr. Enzmann could you show a reference to "at same time that one metastatic lesion in liver will nicely shrink while another just continues to grow" please? Thanks.

Aneuploidy in solid tumour is not consistent as in haematologic and lymphoid tumours in my experience in karyotyping I found different patterns in patients with oral squamous cell carcinoma

To address the original question: The bottom line is cancer is a term used to describe thousands of different diseases! Haematological cancers are primarily driven by aneuploidy and translocations however other cancers are caused by mutation and disruptions in pathways that have no link to aneuploidy. Similarly, Cancer stem cells behave differently according to the type of cancer in question! Some driven by base mutations other driven by numerical or structural aberrations.

Given the rarity of stem cells in most cancer it is difficult to speculate on the level of aneuploidy however the proliferative advantage of these cells is often attributed to mutation /deletion of tumour suppressors or activation of oncogenes by various mechanisms rather than aneuploidy.

I would also like to comment on Ulrich Preffer's comments regarding aneuploidy and chromothripsis. Generation of aneuploid sub-clones has no link to chromothripsis. The term does not describe genomic architecture but rather a recent observation of chromosome shattering. To date there is no evidence for the cause of chromothripsis or indeed its incidence in cancer.

In summary, I think stem cells put their chromosomes on "overdrive" than "under control"

We have found that the generation of cancer "stem cells" are intricately connected to pathologies including infections, autoimmunity and defective apoptosis that explains the highly variable genomic contents of cancer cell populations. Please read the attached paper.

Normally aneuploidy can result in many different genetic diseases such as Downs syndrome, Edward syndrome, Patue syndrome etc. Gaining extrachromosome is not lethal, it means that cells with trisomies will live and survive but missing chromosome leads for cell death. Till now no report seen to document alive cell with 45 chromosome or less except in case of Turner syndrome where the cells contain only 45 chromosome due to missing X chromosome. Whereas missing autosomes in such case will lead to cell death.

In cancer cell the situation is different because so many numerical and structural chromosome changes may occur. Cancer cells apparently with less than 46 chromosome may have translocation of missing chromosomes that lead to no loss of genetic material. Even cancer cells with apparently no translocation may possess the ability to substitute the missing genes that required for cell surviving. Many solid tumour cells show aneuploidy but their fate still obscure. By using clonal evolution studies the fate of such cells can be revealed.

Effect of Aneuploidy at any given chromosomal locus of a cancer cell must be considered. If its predominantly heterozygous, then we have one "normal allele" to counteract the defective one which arose from aneuploidy condition. A study on LOH (Loss of heterozygosity) at such loci could give insights. Hope this helps!

Regarding whether cancer stem cells can be aneuploidic as seen in other cancer cells, we can get data from inherited cancer predispositions. Notably, defects in every DNA repair pathway have been linked to cancer predispositions. For DNA break repair, inherited defects in complexes such as MRE11 complex (MRE11/RAD50/NBS1) cause both chromosome aberrations and aneuploidy. So any cancer stem cells from patients with inherited MRE11 complex defects can be expected to show chromosome aberrations and aneuploidy. For DNA repair defects that generate cancers, the cancer stem cells will not be able to “keep their chromosomes more under control.” Rather they will show mutator phenotypes.

Having established several lines of cancer stem cells from breast and also pancreatic cancer, we see "normal" cell cycle profiles in the cells generating the tumor.

Current literature suggests that CSCs are aneuploidy the same as other tumor cells; this contributes to resistance during treatment. This is collectively due to chromosome instability.

The phenomena is not a ALL or NONE type of situation. The fact is that a few mutated cancer cells that manages to survive are good enough. to be fully blown in a full fledged tumor

We have to know that cancer cells tend to live autonomously, therefore these used to draw specific line for their growth. So many chromosomal and genetic changes can be occurred continuously in cancer cells to confer suitable growth ability for therm. Chromosome instability is important for cancer cell survive and invasion, without which the immune cells may overcome them and eradicate them soon.

You might look at this reference:

Merlo LMF, Wang L, Pepper JW, P. S. Rabinovitch & C. C. Maley, 2009. Chapter 1: Polyploidy, Aneuploidy and the Evolution of Cancer. Pp 1-13 in: Poon RYC, ed. Polyploidization and Cancer. Austin: Landes Bioscience, Inc.

Several decades ago cancer researcher tried to find cancer-specific chromosomal aberrations, they only found a few...whereas the majority of carcinomas (epithelial cancers) displayed chromosomal chaos.

So the focus shifted to mutations in cancer-causing genes. It was very promising at the beginning but after some time it turned out, that at the gene-mutational level cancer cells are characterized again by chaos.

You don't need genes to explain aneuploidy (structural and numerical) in cancer cells, replicative telomere erosion can do the job. Normal cells stop dividing, once telomeres are short, so they do not proceed to chromosomal instability. The precursors of cancer cells do and we have to find out why...

Article Defining the steps that lead to cancer: Replicative telomere...

Gnetic instability is an important charactertic for cancer ce ll to survive and progression. During mitosis different subclones of cancer cells appear , some of them cannot survive while other may go forward and gain more carcinogenicity. Aneuploidy although it means loss of chromosome but it may confer further beneficial factor for progression if the cell possesses the genetic components that let the cell sirvive.

I think the cancer stem cells are unlikely to have aneuploidy. Those cells derived from normal stem cells that acquired the uncontroled self-renew ability. Such cells further produce daughter cells, more differentiated, share the genetic features of themselves. The cancer stem cells may develop sublines with new genetic/epigenetic characters through genetic mutations or defect mitosis, which distribute the chromosomes unevenly cause aneuploidy. Aneuploidy may not be necessarily lethal. It is not uncommon that a tumor loss half of its chromosomes still well survived. I feel the the final is determined by the overall balance of life/ death factors.

Paediatric acute lymphoblastic leukaemia is a classic case where common initiating DNA aberrations are either translocations or hyperdiploidy (>50 chromosomes), each disease form have their own characteristics.

Only marginally, in preimplantation human embryos there originate relatively often complex aneuploidies (postmeiotic , as a consequence of mitotic errors mostly in 1st and 2nd mitosis). In the late blastocysts they are present already only exceptionally, while aneuploid cells dead during development and they are replaced by normal cells. But the meiotic (usually single monosomies and trisomies) aneuploidies survive, they are present in late blastocysts and foetuses with some aneuploidies (triploidy 13, 18, 21) can survive to the birth.

You can see this article "Ajay K. Yadav etal and Bredel et al., JAMA, July 15, 302 (2009). Explain a non- random genetic landscape model during gliomagenesis.