Missegregation Causes Potential Cancers Millions of Times every Day
Main Article Content
Abstract
People ask: Why do we get cancer? But perhaps it would be more pertinent to ask: Why do we not get cancer? Cells mis-segregate in about 1 percent of divisions, which means that you have a beginning of aneuploidy or potential cancer millions of times every day. If a trisomic cell (a typical result of missegregation) is allowed to divide the progeny becomes susceptible to the highly mutagenic effects of breakage-fusion-bridge cycles or to chromothripsis, where the surplus chromosome is shattered and the pieces inserted at random in the corresponding chromosome, but also elsewhere in the genome. The organism has a number of mitigating mechanisms to prevent that run-away mis-segregation/chromosome instability turns into cancer. The first line of prevention is a roll-back of the mis-segregation itself, and the cell becomes tetraploid. A second line of prevention is cell division arrest. A third line of prevention is the cellular suicide: apoptosis. A further prevention mechanism is elimination by the immune system. If all prevention mechanisms are circumvented in a cell line the result could be cancer. Large, long lived animals rarely get cancer (Peto’s paradox); they seem to have many more genes for prevention mechanisms.
Keywords:
chromothripsis; malsegregation; aneuploidy; nondisjunction; endogenous cancer prevention; Warburg effect; cause of cancer; Peto’s paradox; Hansemann-Boveri
Article Details
How to Cite
ENGVILD, Kjeld C..
Missegregation Causes Potential Cancers Millions of Times every Day.
Medical Research Archives, [S.l.], v. 13, n. 9, sep. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6919>. Date accessed: 05 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i9.6919.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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32. Gumbiner BM, Kim NG. The Hippo-YAP signaling pathway and contact inhibition of growth. J Cell Sci 2014;127:709-717. doi:10.1242/jcs.140103
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34. Mendonsa A, Na TY. Gumbiner BM. E-cadherin in contact inhibition and cancer. Oncogene 2018; 37:4769-4780. doi:10.1038/s41388-018-0304-2
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Genes Development 1994;8:9-22.
36. Shay JW. Wright WE. Hayflick, his limit, and cellular ageing. Nature Rev Mol Cell Biol 2000;1: 72-76.
37. Campisi J, d’Adda di Fagagna F. Cellular senescence: When bad things happen to good cells. Nature Rev Mol Cell Biol 2007;8:729-740. doi:10.1038/nrm2233
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39. Zhivotovsky B, Kroemer G. Apoptosis and genomic instability. Nature Rev Mol Cell Biol 2004; 5:752-762. doi:10.1038/nrm1443
40. Lopez J, Tait SWG. Mitochondrial apoptosis: killing cancer using the enemy within. Brit J Cancer 2015;112:957-962. doi:10.1038/bjc.2015.85
41. Portt L, Norman G, Clapp C, Greenwood M, Greenwood MT. Anti-apoptosis and cell survival: a review. Biochim Biophys Acta 2011;1813:238-259. doi:10.1016/j.bbamcr.2010.10.010
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49. Vazquez JM, Sulak M, Chigurupati S, Lynch VJ. A zombie LIF gene in elephants is upregulated by TP53 to induce apoptosis in response to DNA damage. Cell Rep. 2018;24:1765-1776. doi:10.101 6/j.celrep.2018.07.042
50. Tejeda-Martinez D, Magalhaes JP, Opazo JC. Positive selection and gene duplications in tumour suppressor genes reveal clues about how cetacians resist cancer. Proc R Soc B 2021;288:20202592. doi:10.1098/rspb.2020.2592
51. Herrera-Alvarez S, Karlsson E, Ryder OA, Lindblad-Toh K, Crawford AJ. How to make a rodent giant: genomic basis and tradeoffs of gigantism in the capybara, the worlds largest rodent. Mol Biol Evol 2020;38:1715-1730. doi:10.1093/molbev/ms aa285
52. Seluanov A, Hine C, Azpurua J et al. Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat. Proc Natl Acad Sci 2009;106:19352-19357. doi:10.1073/p nas.0905252106
53. Hafner A, Bulyk ML Jambhekar A, Lahav G. The multiple mechanisms that regulate p53 activity and cell fate. Nature Rev Mol Cell Biol 2019;20:199-210. doi:10.1038/s41580-019-0110-x
54. Rizzotto D, Englmaier L, Villunger A. At the crossroads to cancer: How p53-induced cell fate decisions secure genome integrity. Int J Mol Sci 2021;22:10883. doi:10.3390/ijms221910883
55. Villaroya-Beltri C, Osorio A, Torres-Ruiz R et al. Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility. Sci Adv 2022;8: eabq5914. doi:10.1126/sciadv.ab q5914
56. Engvild KC. Cancer follows chromosome missegregation when all endogeneous repair mechanisms fail. Med Hypot 2018;120:121-123. doi:10.1016/j.mehy.2018.08.028
57. Engvild KC. Combination of the Hansemann-Boveri, Warburg, and Knudson theories of cancer, based on failure of mis-segregation damage mitigation. OBM Genetics 2019;3:art1904100.
doi:10.21926/obm.genet.1904100
58. Hsu P, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell 2008;134:703-707. doi:10.1016/j.cell.2008.08.021
59. Gogvadze V, Zhivotovsky B, Orrenius S. The Warburg effect and mitochondrial stability in cancer cells. Mol Asp Med 2010;31:60-74. doi:10.1016/j.m am.2009.12.004
60. Blackadar CB. Historical review of the causes of cancer. World J Clin Oncol 2016;7:54-86. doi;10.53 06/wjco.v7.i1.54
61. Porporato PE, Filigheddu N, Pedro JMBS, Kroemer G, Galluzzi L. Mitochondrial metabolism and cancer. Cell Res 2018;28:265-280. doi:10.1038/cr.2017.155
62. Fulda S, Galluzzi L, Kroemer G. Targeting mitochondria for cancer therapy. Nature Rev Drug Disc 2010;9:447-464. doi:10.1038/nrd3137
63. Michelakis ED, Webster L, Mackey JR. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Brit J Canc 2008; 99:989-994. doi:10.1038/sj.bjc.6604554
64. Tataranni T, Piccoli C. Dichloroacetate (DCA) and cancer: an overview towards clinical applications. Oxidative Med Cell Long 2019;art ID 8201079, 1-14. doi:10.1155/2019/8201079
65. Khan A, Andrews D, Blackburn AC. Long-term stabilization of stage 4 colon cancer using sodium dichloracetate therapy. World J Clin Cases 2016; 4:336-343. doi:10.12998/wjcc.v4.i10.336
66. Khan, Andrews D, Shainhouse J, Blackburn AC. Long-term stabilization of metastatic melanoma with sodium dichloroacetate. World J Clin Oncol 2017;8:371-377. doi:10.5306/wjco.v8.i4.371
67. Kankotia S, Stacpoole PW. Dichloroacetate and cancer: New home for an orphan drug? Biochim Biophys Acta Rev Canc 2014;1846:617-629. doi:10.1016/j.bbcan.2014.08.005
68. Koltai T, Fliegel L. Dichloroacetate for cancer treatment; Some facts and many doubts. Pharmaceuticals 2024;17:744:1-60. doi:10.3390/p h17060744
2. Balmain A. Cancer genetics: from Boveri and Mendel to microarrays. Nature Rev Cancer 2001; 1:77-82.
3. Holland AJ, Cleveland DW. Boveri revisited: Chromosome instability, aneuploidy and tumorigenesis. Nature Rev Mol Cell Biol 2009;10: 478-487. doi:10.1038/nrm2718
4. Duesberg P, Li RH, Fabarius A, Hehlmann R. The chromosomal basis of cancer. Cell Oncol 2005;27: 293-318.
5. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70.
6. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011;144:646-674. doi:10.1016/j.cell.2011.02.013
7. Nordling CD. A new theory on the cancer-inducing mechanism. Brit J Canc 1953;7:68-72.
8. Knudson AG. Mutation and cancer: Statistical study of retinoblastoma. Proc Nat Acad Sci 1971; 68:820-823.
9. Knudson, A.G. Two genetic hits (more or less) to cancer. Nature Rev Canc 2001;1:157-162.
10. Tomasetti C, Marchionni L, Nowak MA, Parmigiani G, Vogelstein B. Only three driver mutations are required for the development of lung and colorectal cancers. Proc Natl Acad Sci 2015;112:118-123. doi:10.1073/pnas.1421839112
11. Levine MS, Holland AJ. The impact of mitotic errors on cell proliferation and tumorigenesis. Genes Dev 2018;32:620-638. doi:10.1101/gad.314351
12. Siegel JJ, Amon A. New insights into the troubles of aneuploidy. Annu Rev Cell Dev Biol 2012;28:189-214. doi:10.1146/annurev-cellbio-101011-155807
13. Iemura K, Yoshizaki Y, Kuniyasu K,Tanaka K. Attenuated chromosome oscillation as a cause of chromosomal instability in cancer cells. Cancers 2021;13:4531. doi:10.3390/cancers13184531
14. Bakhoum SF, Cantleyl LC. The multifaceted role of chromosomal instability in cancer and its microenvironment. Cell 2018;174:1347-1360. doi:10.1016/j.cell.2018.08.027
15. Simonetti G, Bruno S, Padella A, Tenti E, Martinelli G. Aneuploidy: Cancer strength or vulnerability? Int J Cancer 2019;144:8-25. doi:10.1 002/ijc.31718
16. Fenech M. Cytokinesis-block micronucleus cytome assay. Nature Protoc 2007;2:1084-1104. doi:10.1038/nprot.2007.77
17. Fenech M, Bonassi S. The effect of age, gender, diet and lifestyle on DNA damage measured using micronucleus frequency in human peripheral blood lymphocytes. Mutagenesis 2011;26:43-49. doi:10.1093/mutage/geq050
18. Holland N, Bolognesi C, Kirsch-Volders M et al. The micronucleus assay in human buccal cells as a tool for biomonitoring DNA damage: The HUMN project perspective on current status and knowledge gaps. Mut Res Rev Mut Res 2008;659:93-108. doi:10.1016/j.mrrev.2008.03.007
19. Luzhna L, Kathiria P, Kovalchuk O. Micronuclei in genotoxicity assessment: From genetics to epigenetics and beyond. Front Genet 2013;4:131. doi:10.3389/fgene.2013.00131
20. Rehen S, Yung YC, McCreight MP et al. Constitutional aneuploidy in the normal human brain. J Neurosci 2005;25:2176-2180. doi: 10.1523/jneuro sci.4560-04.2005
21. Duncan AW, Newell AEH, Smith L et al. Frequent aneuploidy among normal human hepatocytes. Gastroenterology 2012;142:25-28. doi:10.1053/j.g astro.2011.10.029
22. Yang M, Rito T, Metzger J et al. Depletion of aneuploid cells in human embryos and gastruloids. Nature Cell Biol 2021;23:314-321. doi:10.1038/s41 556-021-00660-7
23. Passerini V, Ozeri-Galai E, Pagter MS et al. The presence of extra chromosomes leads to genomic instability. Nature Commun 2016;7: art10754, 1-14. doi:10.1038/ncomms10754
24. Zhang CZ, Spektor A, Cornils H et al. Chromothripsis from DNA damage in mi-cronuclei.
Nature 2015;522:179-184. doi:10.1038/nature14493
25. Zhang CZ, Leibowitz ML, Pellman, D. Chromothripsis and beyond: Rapid genome evolution from complex chromosome rearrangements. Gen Devel 2013;27: 2513-2530. doi:10.1101/gad.229559.113
26. Voronina N, Wong JKL, Hübschmann D et al. The landscape of chromothripsis across adult cancer types. Nature Commun 2020;11: 2320. doi:10.1038/s41467-020-16134-7
27. Sender R, Fuchs S, Milo, R. Revised estimates for the number of human and bacteria cells in the body. PLOS Biol 2016;14:e1002533. doi:10.1371/jo urnal.pbio.1002533
28. Sender R, Milo R. The distribution of cellular turnover in the human body. Nature Med 2021;27: 45-48. doi:10.1038/s41591-020-01182-9
29. Tomasetti C, Vogelstein B. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2015;347:78-81. doi:10.1126/science.1260825
30. Shi QH, King RW. Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature 2005;437:1038-1042. doi:10.1038/nature03958
31. Orr B, Sousa F, Gomes AM et al. An anaphase surveillance mechanism prevents micronuclei formation from frequent chromosome segregation errors. Cell Reports 2021;37:109783. doi:10.101 6/j.celrep.2021.109783
32. Gumbiner BM, Kim NG. The Hippo-YAP signaling pathway and contact inhibition of growth. J Cell Sci 2014;127:709-717. doi:10.1242/jcs.140103
33. Zhao B, Wei XM, Li WQ et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Development 2007;21:2747-2761. doi:10.1 101/gad.1602907
34. Mendonsa A, Na TY. Gumbiner BM. E-cadherin in contact inhibition and cancer. Oncogene 2018; 37:4769-4780. doi:10.1038/s41388-018-0304-2
35. Polyak K, Kato JY, Solomon MJ et al. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-β and contact inhibition to cell cycle arrest.
Genes Development 1994;8:9-22.
36. Shay JW. Wright WE. Hayflick, his limit, and cellular ageing. Nature Rev Mol Cell Biol 2000;1: 72-76.
37. Campisi J, d’Adda di Fagagna F. Cellular senescence: When bad things happen to good cells. Nature Rev Mol Cell Biol 2007;8:729-740. doi:10.1038/nrm2233
38. Engeland, K. Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death Diff 2018;25:114-132. doi:10.1038/cd d.2017.172
39. Zhivotovsky B, Kroemer G. Apoptosis and genomic instability. Nature Rev Mol Cell Biol 2004; 5:752-762. doi:10.1038/nrm1443
40. Lopez J, Tait SWG. Mitochondrial apoptosis: killing cancer using the enemy within. Brit J Cancer 2015;112:957-962. doi:10.1038/bjc.2015.85
41. Portt L, Norman G, Clapp C, Greenwood M, Greenwood MT. Anti-apoptosis and cell survival: a review. Biochim Biophys Acta 2011;1813:238-259. doi:10.1016/j.bbamcr.2010.10.010
42. Santaguida S, Richardson A, Iyer DR et al. Chromosome mis-segregation generates cell-cycle-arrested cells with complex karyotypes that are eliminated by the immune system. Dev Cell 2017; 41:638-651. doi:10.1016/j.devcel.2017.05.022
43. Wang RW, Vigano S, Ben-David U, Amon A, Santaguida S. Aneuploid senescent cells activate NF-kB to promote their immune clearance by NK cells. EMBO Reports 2021;22: e52032, 1-16. doi:10.15252/embr.202052032
44. Zhang HM, Chen JB. Current status and future directions of cancer immunotherapy. J Canc 2018; 9:1773-1781. doi:10.7150/jca.24577
45. Lu X, Kang YB. Cell fusion as a hidden force in tumor progression. Canc Res 2009;69:8536-8539. doi:10.1158/0008-5472.can-09-2159
46. Shabo I, Svanvik J, Lindstöm A et al. Roles of cell fusion, hybridization and polyploid cell formation in cancer metastasis. World J Clin Oncol 2020;11: 121-135. doi:10.5306/wjco.v11.i3.121
47. Peto R. Quantitative implications of the approximate irrelevance of mammalian body size and lifespan to lifelong cancer risk. Philos Trans R Soc Lond B Biol Sci 2015;370:20150198. doi:10.10 98/rstb.2015.0198
48. Schiffman J, Maley CC, Nunney L, Hochberg M, Breen M (Eds.). Theme issue: Cancer across life: Peto’s paradox and the promise of comparative oncology. Philos Trans R Soc Lond B Biol Sci 2015; 370.
49. Vazquez JM, Sulak M, Chigurupati S, Lynch VJ. A zombie LIF gene in elephants is upregulated by TP53 to induce apoptosis in response to DNA damage. Cell Rep. 2018;24:1765-1776. doi:10.101 6/j.celrep.2018.07.042
50. Tejeda-Martinez D, Magalhaes JP, Opazo JC. Positive selection and gene duplications in tumour suppressor genes reveal clues about how cetacians resist cancer. Proc R Soc B 2021;288:20202592. doi:10.1098/rspb.2020.2592
51. Herrera-Alvarez S, Karlsson E, Ryder OA, Lindblad-Toh K, Crawford AJ. How to make a rodent giant: genomic basis and tradeoffs of gigantism in the capybara, the worlds largest rodent. Mol Biol Evol 2020;38:1715-1730. doi:10.1093/molbev/ms aa285
52. Seluanov A, Hine C, Azpurua J et al. Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat. Proc Natl Acad Sci 2009;106:19352-19357. doi:10.1073/p nas.0905252106
53. Hafner A, Bulyk ML Jambhekar A, Lahav G. The multiple mechanisms that regulate p53 activity and cell fate. Nature Rev Mol Cell Biol 2019;20:199-210. doi:10.1038/s41580-019-0110-x
54. Rizzotto D, Englmaier L, Villunger A. At the crossroads to cancer: How p53-induced cell fate decisions secure genome integrity. Int J Mol Sci 2021;22:10883. doi:10.3390/ijms221910883
55. Villaroya-Beltri C, Osorio A, Torres-Ruiz R et al. Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility. Sci Adv 2022;8: eabq5914. doi:10.1126/sciadv.ab q5914
56. Engvild KC. Cancer follows chromosome missegregation when all endogeneous repair mechanisms fail. Med Hypot 2018;120:121-123. doi:10.1016/j.mehy.2018.08.028
57. Engvild KC. Combination of the Hansemann-Boveri, Warburg, and Knudson theories of cancer, based on failure of mis-segregation damage mitigation. OBM Genetics 2019;3:art1904100.
doi:10.21926/obm.genet.1904100
58. Hsu P, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell 2008;134:703-707. doi:10.1016/j.cell.2008.08.021
59. Gogvadze V, Zhivotovsky B, Orrenius S. The Warburg effect and mitochondrial stability in cancer cells. Mol Asp Med 2010;31:60-74. doi:10.1016/j.m am.2009.12.004
60. Blackadar CB. Historical review of the causes of cancer. World J Clin Oncol 2016;7:54-86. doi;10.53 06/wjco.v7.i1.54
61. Porporato PE, Filigheddu N, Pedro JMBS, Kroemer G, Galluzzi L. Mitochondrial metabolism and cancer. Cell Res 2018;28:265-280. doi:10.1038/cr.2017.155
62. Fulda S, Galluzzi L, Kroemer G. Targeting mitochondria for cancer therapy. Nature Rev Drug Disc 2010;9:447-464. doi:10.1038/nrd3137
63. Michelakis ED, Webster L, Mackey JR. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Brit J Canc 2008; 99:989-994. doi:10.1038/sj.bjc.6604554
64. Tataranni T, Piccoli C. Dichloroacetate (DCA) and cancer: an overview towards clinical applications. Oxidative Med Cell Long 2019;art ID 8201079, 1-14. doi:10.1155/2019/8201079
65. Khan A, Andrews D, Blackburn AC. Long-term stabilization of stage 4 colon cancer using sodium dichloracetate therapy. World J Clin Cases 2016; 4:336-343. doi:10.12998/wjcc.v4.i10.336
66. Khan, Andrews D, Shainhouse J, Blackburn AC. Long-term stabilization of metastatic melanoma with sodium dichloroacetate. World J Clin Oncol 2017;8:371-377. doi:10.5306/wjco.v8.i4.371
67. Kankotia S, Stacpoole PW. Dichloroacetate and cancer: New home for an orphan drug? Biochim Biophys Acta Rev Canc 2014;1846:617-629. doi:10.1016/j.bbcan.2014.08.005
68. Koltai T, Fliegel L. Dichloroacetate for cancer treatment; Some facts and many doubts. Pharmaceuticals 2024;17:744:1-60. doi:10.3390/p h17060744