title: Immortality of cancers: a consequence of inherent karyotypic variations and selections for autonomy.
abstract: Immortality is a common characteristic of cancers, but its origin and purpose are still unclear. Here we advance a karyotypic theory of immortality based on the theory that carcinogenesis is a form of speciation. Accordingly, cancers are generated from normal cells by random karyotypic rearrangements and selection for cancer-specific reproductive autonomy. Since such rearrangements unbalance long-established mitosis genes, cancer karyotypes vary spontaneously but are stabilized perpetually by clonal selections for autonomy. To test this theory we have analyzed neoplastic clones, presumably immortalized by transfection with overexpressed telomerase or with SV40 tumor virus, for the predicted clonal yet flexible karyotypes. The following results were obtained: (1) All immortal tumorigenic lines from cells transfected with overexpressed telomerase had clonal and flexible karyotypes; (2) Searching for the origin of such karyotypes, we found spontaneously increasing, random aneuploidy in human fibroblasts early after transfection with overexpressed telomerase; (3) Late after transfection, new immortal tumorigenic clones with new clonal and flexible karyotypes were found; (4) Testing immortality of one clone during 848 unselected generations showed the chromosome number was stable, but the copy numbers of 36% of chromosomes drifted ± 1; (5) Independent immortal tumorigenic clones with individual, flexible karyotypes arose after individual latencies; (6) Immortal tumorigenic clones with new flexible karyotypes also arose late from cells of a telomerase-deficient mouse rendered aneuploid by SV40 virus. Because immortality and tumorigenicity: (1) correlated exactly with individual clonal but flexible karyotypes; (2) originated simultaneously with such karyotypes; and (3) arose in the absence of telomerase, we conclude that clonal and flexible karyotypes generate the immortality of cancers.
authors: Department of Molecular and Cell Biology, Donner Laboratory, University of California at Berkeley, Berkeley, CA, USA. Duesberg@berkeley.edu
authors: Peter
authors: P
authors: Duesberg
authors: Amanda
authors: A
authors: McCormack
mesh_terms: D000369:Aged, 80 and over; D000782:Aneuploidy; D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D002877:Chromosomes, Human / Q000378:metabolism; D002999:Clone Cells; D004171:Diploidy; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007621:Karyotyping; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D013539:Simian virus 40 / Q000378:metabolism; D019098:Telomerase / Q000172:deficiency / Q000378:metabolism; D057891:Tetraploidy; D014162:Transfection
chemical_list: D019098:Telomerase
keywords: Muller’s ratchet; aneuploidy proximate carcinogen; clonal and flexible cancer karyotypes; growth advantages of aneuploidy; karyotypes of immortal clones of telomerase-deficient mice; karyotypic linkage of immortality and tumorigenicity; long preneoplastic latency; low probability of speciation; selection for cancer-specific autonomy; sub-speciation via karyotypic drift
references: Cancer Res. 1984 Jun;44(6):2259-65
references: 6372991
references: Exp Cell Res. 1965 Mar;37:614-36
references: 14315085
references: Cancer Res. 2008 Mar 1;68(5):1417-26
references: 18316605
references: Exp Cell Res. 2002 Jan 15;272(2):146-52
references: 11777339
references: Cell. 2006 Aug 11;126(3):477-87
references: 16901782
references: Adv Cancer Res. 2011;112:43-75
references: 21925301
references: Med Hypotheses. 2006;67(1):172-6
references: 16516400
references: Cancer Genet Cytogenet. 2008 Jan 15;180(2):89-99
references: 18206533
references: Annu Rev Genomics Hum Genet. 2010;11:291-316
references: 20438362
references: J Cell Physiol. 2006 Aug;208(2):461-72
references: 16688757
references: Science. 1952 Sep 12;116(3011):265-9
references: 12984095
references: Exp Cell Res. 2001 Aug 1;268(1):14-25
references: 11461114
references: Science. 1996 Sep 6;273(5280):1384-6
references: 8703072
references: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14723-8
references: 9843956
references: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3236-41
references: 10725343
references: Cancer Res. 1961 Sep;21:957-74
references: 13712320
references: Cancer Genet Cytogenet. 1986 Jan 1;19(1-2):129-40
references: 3455660
references: Adv Cancer Res. 2011;112:283-350
references: 21925308
references: Eur J Cancer. 1997 Apr;33(5):767-73
references: 9282115
references: Stem Cell Rev. 2007 Fall;3(3):192-200
references: 17917132
references: Science. 1998 Jan 16;279(5349):349-52
references: 9454332
references: Nature. 1999 Jul 29;400(6743):464-8
references: 10440377
references: Genes Chromosomes Cancer. 2004 Aug;40(4):298-306
references: 15188452
references: Biochem Biophys Res Commun. 2003 Sep 5;308(4):914-21
references: 12927806
references: Cancer Genet Cytogenet. 2007 Oct 15;178(2):173-4
references: 17954278
references: OMICS. 2012 Jan-Feb;16(1-2):24-36
references: 22321013
references: Nature. 2010 Nov 11;468(7321):321-5
references: 20962780
references: Exp Cell Res. 1989 Sep;184(1):109-18
references: 2551703
references: Cancer Genet Cytogenet. 2009 Jan 1;188(1):1-25
references: 19061776
references: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11283-8
references: 11553793
references: Environ Mutagen. 1986;8(1):129-59
references: 3510860
references: Ann Rheum Dis. 2006 Nov;65(11):1444-8
references: 17038452
references: Genetics. 1974 Oct;78(2):737-56
references: 4448362
references: Proc Natl Acad Sci U S A. 1963 Feb 15;49:171-9
references: 13997682
references: Oncogene. 2002 Jul 4;21(29):4577-86
references: 12085236
references: Cancer Cell. 2004 Oct;6(4):373-85
references: 15488760
references: Cancer Res. 2002 Nov 1;62(21):6345-8; author reply 6348-9
references: 12414667
references: Carcinogenesis. 2005 Apr;26(4):725-31
references: 15677631
references: Drug Resist Updat. 2007 Feb-Apr;10(1-2):51-8
references: 17387035
references: Int J Biochem Cell Biol. 2002 Nov;34(11):1382-94
references: 12200033
references: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14295-300
references: 11121035
references: Cancer Lett. 2010 Jul 1;293(1):41-51
references: 20092939
references: Cancer Res. 2005 Nov 1;65(21):9824-8
references: 16267004
references: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):3076-80
references: 11867767
references: Cancer Prev Res (Phila). 2009 May;2(5):459-65
references: 19401529
references: Recent Results Cancer Res. 1972;38:1-122
references: 4578033
references: Ann Rheum Dis. 2008 Dec;67(12):1780-2
references: 18662931
references: Mol Cell Biol. 1999 Mar;19(3):2373-9
references: 10022923
references: Mutat Res. 1964 May;106:2-9
references: 14195748
references: Theor Biol Med Model. 2010 Nov 09;7:42
references: 21062473
references: Cell. 1997 Oct 3;91(1):25-34
references: 9335332
references: Cancer Genet Cytogenet. 2010 Jul 15;200(2):79-99
references: 20620590
references: Cancer Genet Cytogenet. 2005 Nov;163(1):44-56
references: 16271955
references: PLoS One. 2011 Jan 31;6(1):e14632
references: 21297939
references: Cell Cycle. 2003 Jul-Aug;2(4):296-9
references: 12851477
references: Cancer Res. 2003 Nov 1;63(21):7147-57
references: 14612508
references: Science. 1999 Oct 15;286(5439):458-62, 479-81
references: 10521336
references: Oncogene. 1998 Mar 5;16(9):1217-22
references: 9528864
references: Bioessays. 1996 Jan;18(1):3-5
references: 8593161
references: Cell. 2000 Jan 7;100(1):57-70
references: 10647931
references: Genes Chromosomes Cancer. 1994 Nov;11(3):171-7
references: 7530486
references: Oncogene. 2002 Jan 3;21(1):128-39
references: 11791183
references: Nature. 2010 Nov 11;468(7321):183-4
references: 21068824
references: Cytogenetics. 1962;1:314-24
references: 14002574
references: Oncogene. 2005 Nov 21;24(52):7729-45
references: 16299533
references: Cancer Genet Cytogenet. 2000 Jun;119(2):83-93
references: 10867141
references: Cancer Genet Cytogenet. 2009 Oct 15;194(2):96-110
references: 19781442
references: Adv Cancer Res. 2011;112:217-53
references: 21925306
references: J Biosci. 2012 Jun;37(2):211-20
references: 22581326
references: Ann N Y Acad Sci. 1958 Sep 30;71(6):1022-53
references: 13583868
references: DNA Repair (Amst). 2010 Aug 5;9(8):858; discussion 859-60
references: 20605538
references: Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10148-53
references: 20479226
references: Cancer Lett. 2007 Aug 18;253(2):155-69
references: 17250959
references: Bioessays. 2005 Aug;27(8):833-8
references: 16015588
references: Cancer Res. 2005 Dec 15;65(24):11411-8
references: 16357149
references: Evolution. 2010 Apr 1;64(4):1173-83
references: 20059538
references: Exp Cell Res. 1961 Dec;25:585-621
references: 13905658
references: Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16395-6
references: 15546980
references: Cell Cycle. 2011 Jul 1;10(13):2100-14
references: 21666415
references: J Cell Sci. 1983 Sep;63:77-99
references: 6313714
references: J Cell Biochem. 1988 Feb;36(2):147-56
references: 3281959
references: Nature. 1975 May 15;255(5505):197-200
references: 1143315
references: Cell Cycle. 2012 Mar 15;11(6):1151-66
references: 22377695