- Email: [email protected]
Cancer follows chromosome missegregation when all endogenous repair mechanisms fail
Medical Hypotheses 120 (2018) 121–123
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Cancer follows chromosome missegregation when all endogenous repair mechanisms fail
T
Kjeld C. Engvild Eco Center, Technical University of Denmark, Roskilde, Denmark
A R T I C LE I N FO
A B S T R A C T
Keywords: Cause of cancer Mutation generator Hayflick limit Chromosome malsegregation Multiple hit hypothesis Mutagenesis Carcinogenesis
Almost all solid tumors consist of aneuploid cells with highly abnormal chromosome numbers. Such cancer cells could very well originate from chromosome missegregation which is a disturbingly common phenomenon, happening in 0.01 to 4 percent of cell divisions. Missegregated cells are aneuploid, typically lacking a chromosome or having one in surplus. Missegregated cells have mutation in the gene dose of the perhaps a thousand genes on a chromosome in one step. After missegregation cell division cannot be done right, as at least one daughter cell has a faulty chromosome number. At division in cells with surplus chromosomes the number will tend to increase due to mismatch in the division machinery. The organism has a number of repair mechanisms in place to prevent potential damage of accumulating aneuploidy. The first is the roll-back of the cell division itself, leading to tetraploidy or sometimes two nuclei in one cell; another is the prevention of further divisions. A very important one is induction of apoptosis, the cellular suicide. A special case is the elimination of the nucleus itself in the formation of red blood cells. Many aneuploid cells are probably eliminated by the immune system. A hypothetical mechanism would be the prevention of metastasis. Missegregation increases with age when the chromosomes lose their protective telomere ends at the Hayflick limit after about 50 divisions, and the unraveled chromosomes fuse and break. For cancer to develop all of these repair mechanisms must fail. The hypothesis offers a straightforward rationale for the multiple hit hypothesis of cancer development.
Introduction
Chromosome missegregation
Why do people get cancer? This has been a central question for very many years. But, perhaps the question should rather be: why do people (and other organisms) not get cancer? It has been known for more than a hundred years that cells in solid tumors are usually aneuploid and have deviating chromosome numbers, most often many more than the standard diploid number of 46. Hansemann and Boveri [1–3] proposed that the aneuploidy was the cause of cancer and this was a standard explanation for cancer up to about 1940. However, the aneuploidy hypothesis was not of much immediate use in treatment and prevention of cancer. The focus shifted to another common characteristic of cancers: their tendency to obtain energy by anaerobic metabolism of glucose, even in the presence of plenty of oxygen. This is the Warburg hypothesis of cancer [4–6]. Later it was found that cancer could be due to mutation in specific genes: oncogenes, proto-oncogenes, and tumor suppressor genes [7–9]. However, it turned out that cancers only develop after mutation in several different genes. Cancer may well be a genetic disease, but it is a multigene genetic disease [8–9]. So attention is returning to the Hansemann-Boveri aneuploidy hypothesis as an explanation for the multiple mutations in cancer cells [10,11].
When a cell begins to divide, the DNA in the cell nucleus condenses into visible chromosomes. The chromosomes double, and the two identical sets of chromosomes split and travel to opposite poles in the cell, after which cell membranes form between the two new cells. This is a very complicated process with many steps, and it can quite easily go wrong [12]. The DNA is replicated faithfully, and possible errors are usually rectified by enzymes for that purpose; otherwise mutations are introduced in the DNA, and this happens only very rarely. Sometimes, however, there are faults in the sophisticated machinery that separates the chromosomes into the two new cells. One doubled chromosome may fail to split properly, or a chromosome is lagging in moving to the pole. The end result is that one daughter cell has a chromosome too many, and another a chromosome too few. This is called missegregation, and the two daughter cells are aneuploid. In somatic tissue with mature specialized cells this may be of little consequence, but it is a very dangerous situation in dividing cells. It is a mutation in the number of gene copies of the about 1000 genes on a chromosome. It is well known that missegregation in the fertilized egg leads to deleterious consequences such as Down’s syndrome or spontaneous abortion. After
E-mail address: [email protected]. https://doi.org/10.1016/j.mehy.2018.08.028 Received 8 August 2018; Accepted 31 August 2018 0306-9877/ © 2018 Elsevier Ltd. All rights reserved.
Medical Hypotheses 120 (2018) 121–123
K.C. Engvild
aneuploid “potential” cancer cells at a very early stage.
missegregation cell division cannot be done right. The cell missing a chromosome will always have at least one daughter cell missing a chromosome, and the cell with a superfluous chromosome will always have a daughter with a chromosome too many. However, in some cases a daughter cell will have two chromosomes too many, due to the mismatch between chromosomes and the separation machinery. If aneuploid cells with a surplus of chromosomes are allowed to divide, the chromosome number will tend to increase, especially at higher chromosome numbers. Missegregation happens in 0.01 to 4 percent of cell divisions [13–15]. With tens of trillions of cells in the human body and tens of billions of cell divisions every day, one would expect millions of missegregations every day. The numbers are uncertain, because methods for counting aberrant mitoses in a living organism are quite difficult. A direct estimate of missegregation in the body is counting of micronuclei in buccal cells in scrapes from the inside of the chin [13,14]. Some of the missegregations show up as cells with a nucleus plus a micronucleus that is the encapsulated extra chromosome [13,14]. Here it is possible to assess the effects of smoking and carcinogenic compounds in the food. The most reliable, but also somewhat artificial method is counting of micronuclei in lymphocytes induced to divide in culture by phytohemagglutinin [16]. The divisions are stopped prematurely by cytochalasin-B, so that the results are cells with two nuclei plus a micronucleus. This cytokinesis-block micronucleus cytome assay is a standard procedure for estimating the exposure of people to mutagens and carcinogens [16,17]. Missegregation is increased dramatically by x-rays and other ionizing radiation, as well as by mutagens and carcinogens. In old people the missegregation frequency is 3–4 times higher than in young people, corresponding to the higher number of cancers in elderly people [15].
Mutations and the Hayflick limit Missegregation represents an instantaneous mutation in copy number of all the genes on a chromosome. Down’s syndrome show how deleterious that can be. If an aneuploid cell with extra chromosomes is “allowed” to divide, some of the daughter cells may have even more extra chromosomes representing further mutation in gene copy numbers. Normal diploid cells are able to go through about 50 cell divisions after fertilization of the egg. Then they reach the Hayflick [19,20] limit and are no more able to divide. At every division the protective telomere end caps of the chromosomes get shorter, and at the Hayflick limit some of the chromosomes have no telomere end cap protection. The chromosomes unravel, some of them break and stick to other fragments in “breakage-fusion-bridge” events, causing all sorts of mutations of genes at every division. Cells “allowed” to divide after the Hayflick limit become mutation factories and present the chaotic chromosome pictures and genetic instability of tumor cells. Cells from children can divide close to 50 times, but cells from old people can only divide 10–20 times. Cells in older people reach the Hayflick limit much earlier than cells in young people and therefore old people have a greater risk of developing cancer. The DNA in micronuclei seems to get easily damaged. If a cell with micronuclei is “allowed” to divide, the damaged DNA sometimes mingles with the normal DNA and seems to generate a number of mutations, a phenomenon called chromothripsis [24]. The immune system and metastases
Repair mechanisms
Millions of aneuploid cells, that is, potential cancers are formed every day, but most are probably eliminated by apoptosis. If the remaining aneuploids do not divide they are not dangerous; if they do divide, they form benign tumors, which are also not very dangerous, except in confined space like the brain. Only dividing cells that wander and form daughter tumors or metastases elsewhere are dangerous. Metastasizing cells have probably more than five or six mutations in cancer related genes, compared to normal cells [8,9]. Unfortunately there seems to be another way for a potential cancer cell to become metastasizing. This happens when the immune system goes wrong. Sometimes white blood cells like a monocytes seem to fuse with cancer cells. The results are cells that combine cell division from the cancer cells with the motility of the monocytes. This has been demonstrated in animals. It has also been seen in people with bone-marrow transplants from persons of the opposite sex, where renal cancers had cells with chromosomes from both host and donor [25,26].
Humans and other organisms have several mechanisms in place to hinder the deleterious effects of missegregation. The first is abolishing the cell division itself [18]. If the ingrowing cell membranes encounter a lagging chromosome the division is stopped, and the result may be a cell with a tetraploid nucleus that hold two sets of chromosome. In some cases the result may be a cell with two diploid nuclei and a micronucleus with an encapsulated lagging chromosome. Another repair mechanism is cell division arrest [19]. Cell division is a tightly regulated in numerous different ways in differentiated organisms, responding to both external and cell-internal signals. An example is the contact inhibition of cells in tissue culture, where division stops when the cells have formed a confluent single cell layer. Another example is the cell division arrest at the Hayflick limit [20]. After about 50 divisions after fertilization the cells then become senescent and will no longer divide, although they may live on for years [19,20]. A very important repair mechanism is apoptosis or cellular suicide [21]. Apoptosis is a standard mechanism for eliminating cells with some kind of defect. The signals may be external such as lack of specific growth hormones, but the signal is often internal to the cell and regulated through the mitochondria [5,20]. If the mitochondria membranes leak and release cytochrome c, a self-destruct process is set in motion; caspase enzymes break down proteins, the cell is split up into “blebs”, and everything is cleaned up tidily by phagocytosis, so that a short while later it is impossible to see that there ever was a cell. An ultimate type of repair is the elimination of all chromosomes which happens during the formation of red blood cells as they don’t have any nucleus at all. An aneuploid cell with a profound gene imbalance would probably present “non-allowed” proteins on the outer cell membrane [22]. Specific antibodies against cancer do exist [23], and some of them are already used in the treatment of cancer. It is also known that leukocytes fuse with cancer cells. What is perhaps not known is whether the various components of the immune system can detect and eliminate
Possible implications The present hypothesis that cancer follows failure of all repair mechanisms offers a straightforward rationale for the multiple-hit hypothesis [8,9] of cancer development, but it will probably only have little direct use in cancer treatment. This is also the case with most of the other hypotheses of the causes of cancer. A possible implication would be the importance of the immune system in the daily elimination of missegregated cells [22]; how common is it, how many mechanisms are involved, how often do fusion of immune cell and aneuploid cell go wrong and result in long-lived cells forming metastases? Another implication might be that two- or three-pronged treatment methods directed at for example DNA synthesis, apoptosis, and the immune system simultaneously might be successful, as the threepronged treatment of HIV infection has been. The aneuploid cells that are not eliminated by repair mechanisms will remain as potential foci for the development of cancer. 122
Medical Hypotheses 120 (2018) 121–123
K.C. Engvild
Consequently, an adult will probably have billions of potential cancer foci. It is known that zebrafish develop many cancer foci spontaneously when only one oncogene has been added and a tumor suppressor gene has been disabled [27].
[14]
[15]
Conflict of interest statement
[16]
There is no conflict of interest.
[17]
References
[18] [1] Bignold LP, Coghlan BLD, Jersmann HPA. Hansemann, Boveri, chromosomes and the gametogenesis-related theories of tumours. Cell Biol Int 2006;30:640–4. [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: chromosomal instability, aneuploidy and tumorigenesis. Nature Rev Mol Cell Biol 2009;10:478–87. [4] Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell 2008;134:703–7. [5] Fulda S, Galluzzi L, Kroemer G. Targeting mitochondria for cancer therapy. Nature Rev Drug Disc 2010;9:447–64. [6] Gogvadze V, Zhivotovsky B, Orrenius S. The Warburg effect and mitochondrial stability in cancer cells. Mol Asp Med 2010;31:60–74. [7] Harris H. A long view of fashions in cancer research. BioEssays 2005;27:833–8. [8] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70. [9] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. [10] Duesberg P. Chromosomal chaos and cancer. Sci Am 2007;296(5):35–41. [11] Duesberg P, Mandrioli D, McCormack A, Nicholson JM. Is carcinogenesis a form of speciation? Cell Cycle 2011;10:2100–14. [12] Weaver BAA, Cleveland DW. Does aneuploidy cause cancer? Curr Opin Cell Biol 2006;18:658–67. [13] Sarto F, Finotto S, Giacomelli L, Mazzotti D, Tomanin R, Levis AG. The
[19] [20] [21] [22]
[23] [24]
[25] [26]
[27]
123
micronucleus assay in exfoliated cells of the human buccal mucosa. Mutagenesis 1987;2:11–7. Holland N, Bolognesi C, Kirch-Volders M, Bonassi S, Zeiger E, Knasmueller S, 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 2008;659:93–108. 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;26:43–9. Fenech M. Cytokinesis-block micronucleus cytome assay. Nat Protoc 2007;2:1084–104. Luzhna L, Kathiria P, Kovalchuk O. Micronuclei in genotoxicity assessment: from genetics to epigenetics and beyond. Front Genet 2013;4:1–17. art 131. Shi QH, King RW. Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature 2005;437:1038–42. Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nature Rev Mol Cell Biol 2007;8:729–40. Shay JW, Wright WE. Hayflick, his limit, and cellular aging. Nature Rev Mol Cell Biol 2000;1:72–6. Zhivotovsky B, Kroemer G. Apoptosis and genomic instability. Nature Rev Mol Cell Biol 2004;5:752–62. Santaguida S, Richardson A, Iyer DR, M’Saad O, Zazadil L, Knouse KA, et al. Chromosome mis-segregation generates cell-cycle-arrested cells with complex caryotypes that are eliminated by the immune system. Develop Cell 2017;41:638–51. Finn OJ. Cancer Immunol. N Eng J Med 2008;358:2704–15. Zhang C-Z, Leibowitz ML, Pellman D. Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Gen Devel 2013;27:2513–30. Lu X, Kang Y. Cell fusion as a hidden force in tumor progression. Canc Res 2009;69:8536–9. Dittmar T, Zänker KS. Tissue regeneration in the chronically inflamed tumor environment: implications for cell fusion driven tumor progression and therapy resistant tumor hybrid cells. Int J Mol Sci 2015;16:30362–81. Kaufman CK, Mosimann C, Fan ZP, Yang S, Thomas AJ, Ablain J, et al. A zebrafish melanoma model reveals the emergence of neural crest idendity during melanoma initiation. Science 2016;351:A46.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Cancer follows chromosome missegregation when all endogenous repair mechanisms fail
T
Kjeld C. Engvild Eco Center, Technical University of Denmark, Roskilde, Denmark
A R T I C LE I N FO
A B S T R A C T
Keywords: Cause of cancer Mutation generator Hayflick limit Chromosome malsegregation Multiple hit hypothesis Mutagenesis Carcinogenesis
Almost all solid tumors consist of aneuploid cells with highly abnormal chromosome numbers. Such cancer cells could very well originate from chromosome missegregation which is a disturbingly common phenomenon, happening in 0.01 to 4 percent of cell divisions. Missegregated cells are aneuploid, typically lacking a chromosome or having one in surplus. Missegregated cells have mutation in the gene dose of the perhaps a thousand genes on a chromosome in one step. After missegregation cell division cannot be done right, as at least one daughter cell has a faulty chromosome number. At division in cells with surplus chromosomes the number will tend to increase due to mismatch in the division machinery. The organism has a number of repair mechanisms in place to prevent potential damage of accumulating aneuploidy. The first is the roll-back of the cell division itself, leading to tetraploidy or sometimes two nuclei in one cell; another is the prevention of further divisions. A very important one is induction of apoptosis, the cellular suicide. A special case is the elimination of the nucleus itself in the formation of red blood cells. Many aneuploid cells are probably eliminated by the immune system. A hypothetical mechanism would be the prevention of metastasis. Missegregation increases with age when the chromosomes lose their protective telomere ends at the Hayflick limit after about 50 divisions, and the unraveled chromosomes fuse and break. For cancer to develop all of these repair mechanisms must fail. The hypothesis offers a straightforward rationale for the multiple hit hypothesis of cancer development.
Introduction
Chromosome missegregation
Why do people get cancer? This has been a central question for very many years. But, perhaps the question should rather be: why do people (and other organisms) not get cancer? It has been known for more than a hundred years that cells in solid tumors are usually aneuploid and have deviating chromosome numbers, most often many more than the standard diploid number of 46. Hansemann and Boveri [1–3] proposed that the aneuploidy was the cause of cancer and this was a standard explanation for cancer up to about 1940. However, the aneuploidy hypothesis was not of much immediate use in treatment and prevention of cancer. The focus shifted to another common characteristic of cancers: their tendency to obtain energy by anaerobic metabolism of glucose, even in the presence of plenty of oxygen. This is the Warburg hypothesis of cancer [4–6]. Later it was found that cancer could be due to mutation in specific genes: oncogenes, proto-oncogenes, and tumor suppressor genes [7–9]. However, it turned out that cancers only develop after mutation in several different genes. Cancer may well be a genetic disease, but it is a multigene genetic disease [8–9]. So attention is returning to the Hansemann-Boveri aneuploidy hypothesis as an explanation for the multiple mutations in cancer cells [10,11].
When a cell begins to divide, the DNA in the cell nucleus condenses into visible chromosomes. The chromosomes double, and the two identical sets of chromosomes split and travel to opposite poles in the cell, after which cell membranes form between the two new cells. This is a very complicated process with many steps, and it can quite easily go wrong [12]. The DNA is replicated faithfully, and possible errors are usually rectified by enzymes for that purpose; otherwise mutations are introduced in the DNA, and this happens only very rarely. Sometimes, however, there are faults in the sophisticated machinery that separates the chromosomes into the two new cells. One doubled chromosome may fail to split properly, or a chromosome is lagging in moving to the pole. The end result is that one daughter cell has a chromosome too many, and another a chromosome too few. This is called missegregation, and the two daughter cells are aneuploid. In somatic tissue with mature specialized cells this may be of little consequence, but it is a very dangerous situation in dividing cells. It is a mutation in the number of gene copies of the about 1000 genes on a chromosome. It is well known that missegregation in the fertilized egg leads to deleterious consequences such as Down’s syndrome or spontaneous abortion. After
E-mail address: [email protected]. https://doi.org/10.1016/j.mehy.2018.08.028 Received 8 August 2018; Accepted 31 August 2018 0306-9877/ © 2018 Elsevier Ltd. All rights reserved.
Medical Hypotheses 120 (2018) 121–123
K.C. Engvild
aneuploid “potential” cancer cells at a very early stage.
missegregation cell division cannot be done right. The cell missing a chromosome will always have at least one daughter cell missing a chromosome, and the cell with a superfluous chromosome will always have a daughter with a chromosome too many. However, in some cases a daughter cell will have two chromosomes too many, due to the mismatch between chromosomes and the separation machinery. If aneuploid cells with a surplus of chromosomes are allowed to divide, the chromosome number will tend to increase, especially at higher chromosome numbers. Missegregation happens in 0.01 to 4 percent of cell divisions [13–15]. With tens of trillions of cells in the human body and tens of billions of cell divisions every day, one would expect millions of missegregations every day. The numbers are uncertain, because methods for counting aberrant mitoses in a living organism are quite difficult. A direct estimate of missegregation in the body is counting of micronuclei in buccal cells in scrapes from the inside of the chin [13,14]. Some of the missegregations show up as cells with a nucleus plus a micronucleus that is the encapsulated extra chromosome [13,14]. Here it is possible to assess the effects of smoking and carcinogenic compounds in the food. The most reliable, but also somewhat artificial method is counting of micronuclei in lymphocytes induced to divide in culture by phytohemagglutinin [16]. The divisions are stopped prematurely by cytochalasin-B, so that the results are cells with two nuclei plus a micronucleus. This cytokinesis-block micronucleus cytome assay is a standard procedure for estimating the exposure of people to mutagens and carcinogens [16,17]. Missegregation is increased dramatically by x-rays and other ionizing radiation, as well as by mutagens and carcinogens. In old people the missegregation frequency is 3–4 times higher than in young people, corresponding to the higher number of cancers in elderly people [15].
Mutations and the Hayflick limit Missegregation represents an instantaneous mutation in copy number of all the genes on a chromosome. Down’s syndrome show how deleterious that can be. If an aneuploid cell with extra chromosomes is “allowed” to divide, some of the daughter cells may have even more extra chromosomes representing further mutation in gene copy numbers. Normal diploid cells are able to go through about 50 cell divisions after fertilization of the egg. Then they reach the Hayflick [19,20] limit and are no more able to divide. At every division the protective telomere end caps of the chromosomes get shorter, and at the Hayflick limit some of the chromosomes have no telomere end cap protection. The chromosomes unravel, some of them break and stick to other fragments in “breakage-fusion-bridge” events, causing all sorts of mutations of genes at every division. Cells “allowed” to divide after the Hayflick limit become mutation factories and present the chaotic chromosome pictures and genetic instability of tumor cells. Cells from children can divide close to 50 times, but cells from old people can only divide 10–20 times. Cells in older people reach the Hayflick limit much earlier than cells in young people and therefore old people have a greater risk of developing cancer. The DNA in micronuclei seems to get easily damaged. If a cell with micronuclei is “allowed” to divide, the damaged DNA sometimes mingles with the normal DNA and seems to generate a number of mutations, a phenomenon called chromothripsis [24]. The immune system and metastases
Repair mechanisms
Millions of aneuploid cells, that is, potential cancers are formed every day, but most are probably eliminated by apoptosis. If the remaining aneuploids do not divide they are not dangerous; if they do divide, they form benign tumors, which are also not very dangerous, except in confined space like the brain. Only dividing cells that wander and form daughter tumors or metastases elsewhere are dangerous. Metastasizing cells have probably more than five or six mutations in cancer related genes, compared to normal cells [8,9]. Unfortunately there seems to be another way for a potential cancer cell to become metastasizing. This happens when the immune system goes wrong. Sometimes white blood cells like a monocytes seem to fuse with cancer cells. The results are cells that combine cell division from the cancer cells with the motility of the monocytes. This has been demonstrated in animals. It has also been seen in people with bone-marrow transplants from persons of the opposite sex, where renal cancers had cells with chromosomes from both host and donor [25,26].
Humans and other organisms have several mechanisms in place to hinder the deleterious effects of missegregation. The first is abolishing the cell division itself [18]. If the ingrowing cell membranes encounter a lagging chromosome the division is stopped, and the result may be a cell with a tetraploid nucleus that hold two sets of chromosome. In some cases the result may be a cell with two diploid nuclei and a micronucleus with an encapsulated lagging chromosome. Another repair mechanism is cell division arrest [19]. Cell division is a tightly regulated in numerous different ways in differentiated organisms, responding to both external and cell-internal signals. An example is the contact inhibition of cells in tissue culture, where division stops when the cells have formed a confluent single cell layer. Another example is the cell division arrest at the Hayflick limit [20]. After about 50 divisions after fertilization the cells then become senescent and will no longer divide, although they may live on for years [19,20]. A very important repair mechanism is apoptosis or cellular suicide [21]. Apoptosis is a standard mechanism for eliminating cells with some kind of defect. The signals may be external such as lack of specific growth hormones, but the signal is often internal to the cell and regulated through the mitochondria [5,20]. If the mitochondria membranes leak and release cytochrome c, a self-destruct process is set in motion; caspase enzymes break down proteins, the cell is split up into “blebs”, and everything is cleaned up tidily by phagocytosis, so that a short while later it is impossible to see that there ever was a cell. An ultimate type of repair is the elimination of all chromosomes which happens during the formation of red blood cells as they don’t have any nucleus at all. An aneuploid cell with a profound gene imbalance would probably present “non-allowed” proteins on the outer cell membrane [22]. Specific antibodies against cancer do exist [23], and some of them are already used in the treatment of cancer. It is also known that leukocytes fuse with cancer cells. What is perhaps not known is whether the various components of the immune system can detect and eliminate
Possible implications The present hypothesis that cancer follows failure of all repair mechanisms offers a straightforward rationale for the multiple-hit hypothesis [8,9] of cancer development, but it will probably only have little direct use in cancer treatment. This is also the case with most of the other hypotheses of the causes of cancer. A possible implication would be the importance of the immune system in the daily elimination of missegregated cells [22]; how common is it, how many mechanisms are involved, how often do fusion of immune cell and aneuploid cell go wrong and result in long-lived cells forming metastases? Another implication might be that two- or three-pronged treatment methods directed at for example DNA synthesis, apoptosis, and the immune system simultaneously might be successful, as the threepronged treatment of HIV infection has been. The aneuploid cells that are not eliminated by repair mechanisms will remain as potential foci for the development of cancer. 122
Medical Hypotheses 120 (2018) 121–123
K.C. Engvild
Consequently, an adult will probably have billions of potential cancer foci. It is known that zebrafish develop many cancer foci spontaneously when only one oncogene has been added and a tumor suppressor gene has been disabled [27].
[14]
[15]
Conflict of interest statement
[16]
There is no conflict of interest.
[17]
References
[18] [1] Bignold LP, Coghlan BLD, Jersmann HPA. Hansemann, Boveri, chromosomes and the gametogenesis-related theories of tumours. Cell Biol Int 2006;30:640–4. [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: chromosomal instability, aneuploidy and tumorigenesis. Nature Rev Mol Cell Biol 2009;10:478–87. [4] Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell 2008;134:703–7. [5] Fulda S, Galluzzi L, Kroemer G. Targeting mitochondria for cancer therapy. Nature Rev Drug Disc 2010;9:447–64. [6] Gogvadze V, Zhivotovsky B, Orrenius S. The Warburg effect and mitochondrial stability in cancer cells. Mol Asp Med 2010;31:60–74. [7] Harris H. A long view of fashions in cancer research. BioEssays 2005;27:833–8. [8] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70. [9] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. [10] Duesberg P. Chromosomal chaos and cancer. Sci Am 2007;296(5):35–41. [11] Duesberg P, Mandrioli D, McCormack A, Nicholson JM. Is carcinogenesis a form of speciation? Cell Cycle 2011;10:2100–14. [12] Weaver BAA, Cleveland DW. Does aneuploidy cause cancer? Curr Opin Cell Biol 2006;18:658–67. [13] Sarto F, Finotto S, Giacomelli L, Mazzotti D, Tomanin R, Levis AG. The
[19] [20] [21] [22]
[23] [24]
[25] [26]
[27]
123
micronucleus assay in exfoliated cells of the human buccal mucosa. Mutagenesis 1987;2:11–7. Holland N, Bolognesi C, Kirch-Volders M, Bonassi S, Zeiger E, Knasmueller S, 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 2008;659:93–108. 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;26:43–9. Fenech M. Cytokinesis-block micronucleus cytome assay. Nat Protoc 2007;2:1084–104. Luzhna L, Kathiria P, Kovalchuk O. Micronuclei in genotoxicity assessment: from genetics to epigenetics and beyond. Front Genet 2013;4:1–17. art 131. Shi QH, King RW. Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature 2005;437:1038–42. Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nature Rev Mol Cell Biol 2007;8:729–40. Shay JW, Wright WE. Hayflick, his limit, and cellular aging. Nature Rev Mol Cell Biol 2000;1:72–6. Zhivotovsky B, Kroemer G. Apoptosis and genomic instability. Nature Rev Mol Cell Biol 2004;5:752–62. Santaguida S, Richardson A, Iyer DR, M’Saad O, Zazadil L, Knouse KA, et al. Chromosome mis-segregation generates cell-cycle-arrested cells with complex caryotypes that are eliminated by the immune system. Develop Cell 2017;41:638–51. Finn OJ. Cancer Immunol. N Eng J Med 2008;358:2704–15. Zhang C-Z, Leibowitz ML, Pellman D. Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Gen Devel 2013;27:2513–30. Lu X, Kang Y. Cell fusion as a hidden force in tumor progression. Canc Res 2009;69:8536–9. Dittmar T, Zänker KS. Tissue regeneration in the chronically inflamed tumor environment: implications for cell fusion driven tumor progression and therapy resistant tumor hybrid cells. Int J Mol Sci 2015;16:30362–81. Kaufman CK, Mosimann C, Fan ZP, Yang S, Thomas AJ, Ablain J, et al. A zebrafish melanoma model reveals the emergence of neural crest idendity during melanoma initiation. Science 2016;351:A46.