Cancer is the deadly transformation of a rogue cell and its struggle for survival, escaping and evading the normal regulation of tissue growth. It tends to occur not in a single stage but due to progressive errors leading to the formation of a malignant tumor cell which upon continued existence cause tumors.
Aneuploidy is caused when there is a disruption in the cell division process, which leads to abnormal division or segregation of chromosomes in the resultant daughter cells .This characteristic of aneuploid cells is considered to cause chromosomal instability leading to missagregation often observed in tumor cells. Theodor Boveri, German zoologist, was the first to illustrate Aneuploidy having a role in the detrimental effect, leading to undifferentiation and malignant transformation of the cells. [Boveri, Gustav Fisher, Jena, 1914][Boveri.Verh.Phys, Med. 67-90, 1902]
Aneuploidy occurs due to a numerous reasons, but the key regulatory element is the spindle check point, which delays the onset of anaphase until the centrosomes have attached to microtubules accordingly.[Cleveland etal,2003][Kops et al ,2005][Musacchio etal,2007].A number of multifunctional proteins (BUBR1,BUB1,CENP-E,MAD2,etc) when over-expressed or depleted cause mitotic dysfunction and subsequent aneuploidy. This phenomena has been studied using mouse models, however it was noted that the degree of aneuploidy was different for each of the gene product.
Aneuploidy theory of cancer
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The serious contender for the aneuploidy theory is the Gene-mutation theory of cancer, according to which certain genes, when mutated, turn a normal cell into a cancer cell. This theory though more recent has been in picture since the 1970's , and more than one Nobel Prize laureates were awarded in supporting this theory. According to some researchers, the mutation of three or more genes, is sufficient to transform a normal cell into a cancer cell.
Where has this theory been demonstrated? It would be a front-liner in the newspapers. The truth being scientists have not yet produced any convincing example of diploid cancer.
In fact chromosomal imbalance disengages the normal balance and interactions of many thousands of genes, because just one chromosome may contain several thousand genes. This reason alone, aneuploidy can be considered to be a far more devastating condition to the life of a cell than a small handful of gene mutations.
Why was the theory still not proven???
The difficulty in generating aneuploidy without affecting other cellular functions or structural alterations in the chromosomes has been a challenge till date. The result of studies on different mitotic multifunctional mitotic proteins has been unexpected and inconclusive. Thus the truth about tumor susceptibility with respect to cancer is still not apparent.
CENP-E+/- heterozygous model : Success or Failure ??
After a lot of research CENP-E(Centromere-associated Protein-E,kinase-like motor protein) haplosufficient models created were shown to develop stable aneuploidy in diploid cells, without incurring DNA damage or structural rearrangements to the chromosomes.[Weaver etal,2007].The protein acts as the main regulatory switch by controlling the important spindle checkpoint proteins mainly BUBR1/MAD2 signaling during the "wait anaphase" stage in Mitosis. This model was supposedly different from the present models as it is not known to play a role in other cellular events.
The exploration using CENP-E+/- heterozygous models to test the hypothesis of aneuploidy's role in tumor initiation, concluded that aneuploidy drives tumorigenesis both invitro and invivo; also using a carcinogen the study identified the effects of aneuploidy in tumor suppression.
However the published results in the paper did provide the solution for the existing question. The paper did not explain the frequency of the aneuploidy generated in the models; also stating that stable aneuploidy did not lead to malignant tumor formation in most of the animals tested.
The model created was indeed an extraordinary one, taking into account the previous models, but the Authors could have extended the controls of the experiment and the thorough research of each animal in use its genetic make-up, because they were testing a hypothesis using a precarious model.
Hypothesis of possible mechanism of events happening in the models
The most important factor that was not accounted for in the paper was Mutational Meltdown[Lynch etal,1993]: chromosome loss or gain in the models was not presented and validated. These conclusions lead to a lot of speculation about the genes which were attenuated or escalated, one hypothesis suggests that gain in the number of chromosomes would lead to greater instability , thus triggering apoptotic response and thereby elimination of the cell from the pool. This could be a possible reason for the tumor inhibition or decrease in the tumor size in some of the models when exposed to carcinogen.
Oncogene or Tumor suppressor gene:
Always on Time
Marked to Standard
One other aspect unaccounted for was the type and number of chromosome or the description of the gene that was lost or gained in the event of aneuploidy, in this case the aneuploidy in most of the CENP-E+/- models was chromosome loss, if the lost chromosome had the tumor suppression gene, the tumor would form inevitably .If it was the oncogene which was lost then the effect would be quite opposite. As suggestedÂ by the Salmon and the Yen laboratories (ShannonÂ et al., 2002). A certain threshold levelÂ of the wait-anaphase signal may be needed for a cell to induceÂ chromosomal instability in the cell.
BUBR1 effect in CENP-E models:
According to Marcel Tanudji etal,2003 BubR1 gets partiallyÂ phosphorylated in CENP-E siRNA-transfected cells, suggestingÂ that its activity may be impaired .One of the studies showed that not only CENP-E directlyÂ stimulated BubR1 kinase activity in vitro but also that theÂ BubR1 kinase activity was lost in cells depletedÂ of CENP-E.[Weaver et al ,2003]
Thus the effect of BUBR1 cannot be ruled out in the proposed model, making this model questionable in terms of accurate predictor of aneuploidy.
Switch theory :
This theory can be compared with the hen and the egg problem; we cannot answer as to which appeared first the hen or the egg. In the same way, is aneuploidy causing cancer or is it a consequence.
The Switch theory is about the stage of occurrence of aneuploidy and its subsequent effect on tumor initiation or progression.
For example, consider Aneuploidy, chromosomal instability, mutations, structural rearrangements and other factors causing the transformation of a normal diploid cell to a malignant one to be like switches connected in a row. So if all the switches are turned on, the cell attains the tumor status. Here the question would be "Where is the aneuploidy switch in the above stated factors". In different kinds of tumors, it occurs in different order of sequence, if it was the first switch then is the primary cause for tumor initiation. Otherwise if it occurs later in the cycle of events it causes tumor progression. Thus aneuploidy though it plays a role in cancer, it cannot considered as a singular factor instigating tumorigenesis.
The several assumptions which should be satisfied in order to end this quest on a positive note:
Aneuploidy should be present in pre-cancerous cells, which was validated in premalignant colon and breast cancer lesions in experimental mice.[ Medina Det al ,2002;51. Dooleyet al 1993]
2. Aneuploidy should play a major role in global transcription , downregulation of tumor suppressor genes and upregulation of oncogene (has to be proved ).
3. Aneuploidy causing tumorigenesis , should require many generations to establish the complicated karyotypes contained in tumor cells that permit patterns of uninhibited cell growth.
The destination of this quest would unlock a lot of doors and provide revelation regarding anti-cancer therapy, early detection of tumor cells and selective or specific destruction of malignant cells in the body.
Last but not the least, the genetic environment or the context serves as a template for the transformation of a normal diploid cell into the rebellion - uncontrollable tumor cell. This has to be put in the forefront while creating and testing models as many publications and resources have shown the alterations in protein expression leading to different outcomes in varied cell types. Thus the interactions of the karyotype and the microenvironment at different levels of the tissue also should be kept in mind.