Genetic changes accumulate in tumor cells causing the formation of coexistence of different clones of cells, which manage to survive. When culturing cells in vitro, the numbers of chromosomes are always around multiple chromosome set numbers (for example, A. over 90% of cells have around 46 or around 92 chromosomes in one "cell line"; B. allmost all cells have around 92 chromosomes in another "cell line"). Can I consider these cells having similar number of chromosomes as one clone generated from one mother cell?
Given the inherent genetic instability of cancer cells, the number of chromosomes could very well change upon engraftment in vivo. However, it depends on what type of "clones" you are looking for. If you are talking about the number of founding clones (e.g. how many clones engrafted into this animal?) then chromosome number would be a bad indication of this. If you are just talking about putative genetic clones, those with different chromosome numbers are then different clones by definition, but cells with the same number of chromosomes or cytology may still be different "clones" as other mutations may be present.
The number of chromosomes will change in cancer cells, but if different structurally rearranged marker chromosomes are present (in different cell populations), each marker chromosome is specific for that clone. e.g. a chromosome containing material of two or three other chromosomes. For chromosome analysis you would need a mFISH system and mFISH probes from MetaSystems.
Dear Reinhard,
Thank you. But since cancer cells, especially ovarian cancer cells, most of which harbour the p53 mutation, are extremly instable, can I expect that such marker chromosomes will be kept unchanged if the cells survive? Our cytogenetist analyzed some of our cell lines. We observed changes of polyploidy through passages of the cells. But we are informed that the karyotypes of these cells is such a complexity that it is very difficult to catch some similarities, at least extensive work and expertise will be needed. Do you know any company in Vienna, which provides service of mFISH? We are still interested in studing the clonal evolution both in established cell lines and in vivo. However we are very limited with the techniques.
Kind regards, Dan
Dear Dan,
Until 2006 I did mFISH at the Institute of Medical Genetics in Vienna. They had several mFISH systems there. Dr. Hengstschläger should know.
You are right, carcinoma cells harbor lots of chromosomal aberrations and are usually chromosomaly unstable. It is generally thought that the caps of chromosomes (=telomeres) erode in somatic cells and once they are critically short, normal cells stop dividing. (Pre)cancerous cells don't.
So telomeres become critically short and the chromosome ends fuse with other chromosome ends. During cell division, when different chromosomes are pulled to opposite poles, fused chromosomes form so-called "anaphase bridges". (=histologic marker of cancer tissue) This can lead to fusion-bridge-breakage-cycles and causes the chromosomal chaos observed in carcinoma tissue.
Yet, once a structurally abnormal chromosome has formed and it harbors only one active centromere, it usually remains stable in successive generations...and might serve as a "clone marker".
(Pre)cancerous cells activate the enzyme telomerase after the initial phase of chromosomal instability and usually become more stable afterwards. Look e.g. at Hela cells, they have a rather "stable karyotype"...
Somehow most carcinoma cells stabilize their chromosome number in the triploid range. Nobody knows why...
The funny thing is that modern cancer geneticists mostly ignore the chromosomal mess and prefer to sequence mutations. Since every chromosome contains about 1000 genes, chromosomal analysis (mFISH) should be the first step in every sequencing experiment ;-)
Thanks, Qiang and Christopher. I am interested in studing the clonal evolution of ovarian cancer cells. Since all most all high grade serous ovarian tumors have TP53 mutation, the genom is very instable and the tumors are very heterogenous from individual to individual and among the cells in each tumor as well. Mutation is certainly an option to define the clonality of cells, but I am afaid that sequencing of each cell is technically not feasible. We observed the changes of ploidy of cells through passages. Therefore I raised the question. In some lines we established, we also observed death of big amount of cells, while the line continues proliferating. Change of growth rate or morpholog also happened (we have to confirm the authentisity first). Together with the clinical and patients' information, I got the impression that the clonal evolution in high grade serous ovarian cancer seems to happen accidentally (the TP53 mutations in tumors are also different ones, mostly at the DNA binding domain, some are in the oligomerization domain), probably the quick growing cells will be overwehlming. But this is not the end of the history, even in cell culture, the genetic make-up and the phenotype are changing continously. I would suppose that this also happens in vivo. I'll highly appreciate If you have better ideas how to get deeper into this. Best, Dan
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