Authors
Vladimir F. Niculescu
Abstract
Paper accepted by GENE (Elsevier) 2019, Vol. 274
At least 1/3 of all acquired solid cancers produce unusual cyst-like structures (CLSs , PGCCs) with simultaneous loss of p53 function. However, p53 deficiency or accumulated mutations are not the causes of aCLS cancers. The cause is the reversal to unicellularity of a metabolic stressed cell by activating silenced transition switches and ancestral gene networks inherited from early Metazoans. After reprogramming and transformation the cell-of-origin of cancer bypasses mitosis and forms the polyploid pCLS, the homemade pathogen of aCLS cancers. pCLS's daughter cells (microcells) generate the pretumorigenic cancer stem cell pool (pCSCs) that start in turn the unicellular cancer cell lineage containing reproductive and somatic sublines. While the reproductive subline gives rise to new autonomous aCLSs by asymmetric division and cyclic differentiation, the somatic subline grows aCLS free. In the course of cancer evolution, some of the somatic mutants convert to stem cell precursors (SCPs). Somatic SCPs transfer part of somatic mutations and epimutations to the genome of newly formed reproductive clones. In this way, subsequent generations of tumorigenic and metastatic CSCs are being produced. aCLS cancer development is neither chaotic nor deregulated it follows unicellular development patterns. The unicellular program is controlled by mechanisms from early eukaryotic evolution.
Keywords: cancer, unicellular, reproductive and somatic cell lines, stem cells (CSCs), somatic stem cell precursors (SCPs); protist stem cells
Abbreviations: CLS, cyst-like structure; pCLS, primary pretumorigenic cyst-like structure; aCLS, autonomous cyst-like structure; giCLS, genotoxic induced cyst-like structure; PGCC, polyploid giant cancer cell; CSC, cancer stem cell; UG, unicellular genes; MG, multicellular; genes; MG:UG gene conflicts; ACD, autonomous cyst differentiation (protists); ICD, induced cyst differentiation (protists); MUT, multicellular-unicellular transition switch; SCP, somatic stem cell precursors; SRT, somatic - reproductive transition; OCB, oxygen consuming bacteria
Further details
HIGHLIGHTS
· Ancestral MU switches reverse the cell-of-origin into a unicellular life form (pCLS)
· The reversal to unicellularity occurs through genomic and epigenetic rearrangements
· The pCLS starts an archaic life cycle that differentiates numerous aCLSs
The pCLS/aCLS progeny generates CSC pools that form reproductive and somatic cells
· Cancer evolution means the transition from pretumorigenic to malignant life cycles.
References
1. Niculescu VF (2018) Carcinogenesis: recent insights in protist stem cell biology lead to a better understanding of atavistic mechanisms implied in cancer development. MOJ Tumor Res 1(1): 00004. doi: 10.15406/mojtr.2018.01.00004
2. Niculescu VF (2018) The cancer stem cell family: atavistic origin and tumorigenic development. MOJ Tumor Res.1(2):71‒74. doi : 10.15406/mojtr.2018.01.00015
3. Niculescu VF (2019) The reproductive life cycle of cancer: Hypotheses of cell of origin, TP53 drivers and stem cell conversions in the light of the atavistic cancer cell theory. Medical Hypotheses, 123: 19-23. https://doi.org/10.1016/j.mehy.2018.12.006
4. Chen J, Niu N, Zhang J, Qi L, Shen W et al. (2019) Polyploid Giant Cancer Cells (PGCCs): The Evil Roots of Cancer. Curr Cancer Drug Targets. 19(5):360-367. doi: 10.2174/1568009618666180703154233.
5. Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G et al. (2013) Pan-cancer patterns of somatic copy number alteration. Nat Genet 45(10):1134-1140 doi:10.1038/ng.2760
6. Liu J (2018) The dualistic origin of human tumors. Seminars in Cancer Biology 53: 1-16. https://doi.org/10.1016/j.semcancer.2018.07.004
7. Mirzayans R, Andrais B, Murray D (2018) Viability Assessment Following Anticancer Treatment Requires Single-Cell Visualization. Cancers (Basel) 10(8): 255. doi: 10.3390/cancers10080255
8. Vitale L, Galluzzi L, Senovilla A, Criollo M, Jemaa M etal. (2011) Illicit survival of cancer cells during polyploidization and depolyploidization
Cell Death Differ 18 (9): 1403-1413 doi :10.1038/cdd.2010.145
9. Erenpreisa JA, Cragg MS, Fringes B, Sharakhov I, Illidge TM (2000) Release of mitotic descendants by giant cells from irradiated Burkitt's lymphoma cell line Cell Bio. Int 24(9): 635-648 doi: 10.1006/cbir.2000.0558
10. Walen KH (2004) Spontaneous cell transformation: karyoplasts derived from multinucleated cells produce new cell growth in senescent human epithelial cell cultures. In Vitro Cell De. Biol- Anim 40 (5–6): 150-158
11. Erenpreisa J, Kalejs M, Cragg MS (2005) Mitotic catastrophe and endomitosis in tumour cells: an evolutionary key to a molecular solution. Cell Biol. Int., 29(12): 1012-1018
https://doi.org/10.1016/j.cellbi.2005.10.005
12. Weinberg A (2014) Coming full circle-from endless complexity to simplicity and back again. Cell 157 (1):267-271. doi: 10.1016/j.cell.2014.03.004.
13. Merlo MF, Pepper JW, Reid BJ, Maley CC (2006) Cancer as an evolutionary and ecological process. Nature Reviews. Cancer 6: 924–935 doi: 10.1038/nrc2013
14. Vincent M (2011) Cancer: A de-repression of a default survival program common to all cells? Bioessays 34: 72-82 doi: 10.1002/bies.201100049
15. Niculescu VF (2015) The stem cell biology of the protist pathogen Entamoeba invadens in the context of eukaryotic stem cell evolution. Stem Cell Biol Res. 2015; 2:2. http://dx.doi.org/10.7243/2054-717X-2-2 (Researchgate)
16. Niculescu VF (2018) Molecular and Cell Biological Considerations in the Initiation and Development of Sporadic Non-Hereditary Solid Cancers. Journal of Cancer Genetics and Biomarkers 1 (2): 24-40. doi : 10.14302/issn.2572-3030.jcgb-18-2183
17. Rebolleda-Gomez M, Travisano M (2018) Adaptation, chance, and history inexperimental evolution reversalsto unicellularity. Evolution 73(1):
73-83 doi:10.1111/evo.13654
18. Rebolleda-Gomez M, Travisano M (2018) The cost of being big: local competition, importance of dispersal and experimental evolution of reversal to unicellularity. Am. Nat. 192:731–744 doi:10.1086/700095
19. Aktipis CA, Boddy AM, Jansen G, Hibner U, Hochberg ME et al. (2015) Cancer across the tree of life:cooperation and cheating in multicellularity. Philos. Trans. R. Soc. B.370:201402219. doi:10.1098/rstb.2014.0219
20. Chen H, F. Lin F, K. Xing K, X. He X (2015) The reverse evolution from multi-cellularity to unicellularity during carcinogenesis. Nat. Comm. 6:6367
doi:10.1038/ncomms7367
21. Tabassum DP, K. Polyak K (2015) Tumorigenesis: it takes a village. Nat.Rev. Cancer. 15:473–483 doi: 10.1038/nrc3971
22. Libby E, Ratcliff WC (2014) Ratcheting the evolution of multicellularity.
Science 346 (6208): 426-427 doi: 10.1126/science.1262053
23. Michod RE (2007) Evolution of individuality during the transition from unicellular to multicellular life. Proc Natl Acad Sci U S A. 104 (Suppl 1):8613–8618. doi:10.1073/pnas.0701489104
24. Folse HJ, Roughgarden J (2010) What is an individual organism? A multilevel selection perspective. Q Rev Biol. 85(4):447-72. PMID:21243964
25. Trigos AS, Pearson RB, Papenfuss AT, Goode DL (2018) How the evolution of multicellularity set the stage for cancer. British Journal of Cancer 118, 145–152 |doi: 10.1038/bjc.2017.398
26. Armstrong L, Lako M, Dean W, Stojkovic M (2006) Epigenetic Modification Is Central to Genome Reprogramming in Somatic Cell Nuclear Transfer. Stem cells 24: 805– 814 https://doi.org/10.1634/stemcells.2005-0350
27. Moss TJ, Wallrath LL (2007) Connections between epigenetic gene silencing and human disease. Mutat Res. 618(1-2):163–174. doi:10.1016/j.mrfmmm.2006.05.038
28. Varriale A (2014) DNA methylation, epigenetics, and evolution in vertebrates: facts and challenges. Int J Evol Biol. 2014:475981. doi:10.1155/2014/475981
29. Danchin É, Charmantier A, Champagne FA, Mesoudi A, Pujol B, Blanchet S (2011) Beyond DNA: integrating inclusive inheritance into an extended theory of evolution. Nature Reviews Genetics 12(7):475–486. doi:10.1038/nrg3028
30. Stajic D, Perfeito L, Jansen LET (2019) Epigenetic gene silencing alters the mechanisms and rate of evolutionary adaptation. Nature Ecology & Evolution 3(3): 491–498. doi: 10.1038/s41559-018-0781-2
31. Lind MI, Spagopoulou F (2018) Evolutionary consequences of epigenetic inheritance. Heredity 121:205–209 https://doi.org/10.1038/s41437-018-0113-y
32. Duncan EJ, Gluckman PD, Dearden PK (2014) Epigenetics, plasticity and evolution: How do we link epigenetic change to phenotype? J. Exp. Zool. (Mol. Dev. Evol.) 322B:208–220. doi: 10.1002/jez.b.22571
33. Anway MD, Cupp AS, Uzumcu M, Skinner MK. (2005). Epigenetic transgenerational actions of endocrine disruptors and male fertility.Science 308:1466–1469 doi: 10.1126/science.1108190
34. Stouder C, Paoloni‐Giacobino A. (2010) Transgenerational effects of the endocrine disruptor vinclozolin on the methylation pattern of imprinted genes in the mouse sperm. Reproduction 139:373–379. doi: 10.1530/REP-09-0340
35. Stouder C, Paoloni‐Giacobino A (2011). Specific transgenerational imprinting effects of the endocrine disruptor methoxychlor on male gametes. Reproduction 141:207–216. doi :10.1530/REP-10-0400
36. Greer EL, Maures TJ, Ucar D et al. (2011) Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479:365–371. doi: 10.1038/nature10572
37. Ashe A, Sapetschnig A, Weick EM et al. (2012) piRNAs can trigger amultigenerational epigenetic memory in the germline ofC. elegans.Cell 150: 88–99. doi:10.1016/j.cell.2012.06.018
38. Manikkam M, Tracey R, Guerrero‐Bosagna C, Skinner MK (2012).Dioxin (TCDD) induces epigenetic transgenerational inheritance of adult onset disease and sperm epimutations. PLoS ONE 7:e46249. https://doi.org/10.1371/journal.pone.0046249
39. Morris KV (2015) The theory of RNA-mediated gene evolution. Epigenetics. 10(1):1–5. doi:10.1080/15592294.2014.995536
40. Polak P, Karlic, Koren A, Thuman R …..Stamatoyannopoulos JA et al (2015) Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature 518 (7539) 360-364. doi: 10.1038/nature14221
41. Surani MA (2001) Reprogramming of genome functionthrough epigenetic inheritance. Nature 414:122 https://doi.org/10.1038
42. Blanpain C (2015) Three innovative ways to advance cancer research, Cancerstem project, ERC workshop "Funding Opportunities in Europe", University Libre de Bruxelles, Belgium
43. Wang Y, Yang J, Zheng H, Tomasek GJ, Zhang P et al. ( 2009) Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell 15 (6): 514–26. doi:10.1016/j.ccr.2009.04.001.
44. López-Lázaro M (2015) The migration ability of stem cells can explain the existence of cancer of unknown primary site. Rethinking metastasis. Oncoscience. 2 (5): 467–75. doi:10.18632/oncoscience.159.
45. López-Lázaro M (2015) Stem cell division theory of cancer. Cell Cycle. 14 (16): 2547–8. doi:10.1080/15384101.2015.1062330
46. Hoadley KA, Yau C, Hinoue T, Wolf DM, Lazar AJ et al. (2018) Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer. Cell 173: 291–304 https://doi.org/10.1016/j.cell.2018.03.022
47. Niculescu VF (2017) Regulatory Mechanisms of Asymmetric/ Symmetric Cell Division and Quiescence in the Primitive-/ Stem Progenitor Cell Lineage of Entamoeba. Stem Cells Regen Med. 1(2): 1-7 (Researchgate)
48. Niculescu VF (2017) Development, cell line differentiation and virulence in the primitive stem-/progenitor cell lineage of Entamoeba. J Stem Cell Res Med, 2(1): 1-8 doi: 10.15761/JSCRM.1000115
49. Niculescu1 VF, Salmina K, Erenpreisa J (2017) Reproductive polyploid cycles ensure cell system survival in protists and cancer cells by totipotency and stemness recovery. 21st Evolutionary Biology Meeting at Marseilles September 26th – 29th, 2017. (Researchgate)
50. Sonda S, Morf L, Bottova I, Baetschmann H, Rehrauer H et al. (2010)
Epigenetic mechanisms regulate stage differentiation in the minimized protozoan Giardia lamblia. Mol Microbiol 76: 48–67 doi:10.1111/j.1365-2958.2010.07062.x
51. Moon EK, Hong Y, Lee HA, Quan FS, Kong HH (2017) DNA Methylation of Gene Expression in Acanthamoeba castellanii Encystation. The Korean journal of Parasitology, 55(2): 115–120. doi:10.3347/kjp.2017.55.2.115
52. Illidge TM, Cragg MS, Fringes B, Olive P, Erenpreisa JA (2000) Polyploid giant cells provide a survival mechanism for p53 mutant cells after DNA damage. Cell Biol Int. 24 (9):621-33. doi: 10.1006/cbir.2000.0557
53. Mirzayans R, Andrais B, Scott A, Wang YW, Kumar P et al. (2017) Multinucleated Giant Cancer Cells Produced in Response to Ionizing Radiation Retain Viability and Replicate Their Genome. Int J Mol Sci 18(2): E360. doi: 10.3390/ijms18020360
54. Trigos AS, Pearson RB, Papenfuss AT, Goode DL (2017) Atavistic gene expression patterns in solid tumors. PNAS 114 (24): 6406-6411. doi: 10.1073/pnas.1617743114
55. Sundaram M, Guernsey DL, Rajaraman MM, Rajaraman R (2004) Neosis: a novel type of cell division in cancer. Cancer Biol Ther 3:207–18 PMID:14726689
56. Rajaraman R, Rajaraman MM, Rajaraman SR, Guernsey DL (2005) Neosis – a paradigm of self-renewal in cancer. Cell Biol Int 29(12): 1084-1097.
doi: 10.1016/j.cellbi.2005.10.003
57. Zhang S, Mercado-Uribe I, Xing Z, Sun B, Kuang J, Liu J (2014) Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene 33(1):116-128. doi: 10.1038/onc.2013.96.
58. Qu Y, Zhang L, Rong Z, He T, Zhang S (2013) Number of glioma polyploid giant cancer cells (PGCCs) associated with vasculogenic mimicry formation and tumor grade in human glioma. Journal of Experimental & Clinical Cancer Research 32:75. https://doi.org/10.1186/1756-9966-32-75
59. Zhang S, Mercado-Uribe I, Liu J (2014) Tumor stroma and differentiated cancer cells can be originated directly from polyploid giant cancer cells induced by paclitaxel. Int. J. Cancer 134: 508–518. doi:10.1002/ijc.28319
60. Zhang D, Yang X, Yang Z, Fei F, Li S, et al. (2017) Daughter Cells and Erythroid Cells Budding from PGCCs and Their Clinicopathological Significances in Colorectal Cancer. J Cancer 8(3):469-478. doi:10.7150/jca.17012. http://www.jcancer.org/v08p0469.htm
61. Siddiqui R, Jarroll EL ,Khan NA (2010) Balamuthia mandrillaris: role of galactose in encystment and identification of potential inhibitory targets. Exp.Parasitol.126: 22–27
62. Castillo-Romero A, Leon-Avila G, Perez Rangel A, Cortes Zarate R, Garcia Tovar C et al. (2009) Participation of actin on Giardia lamblia growth and encystation. PLoS One 4, e7156. doi: 10.1371/journal.pone.0007156
63. Dudley R, Alsam S, Khan NA (2008) The role of proteases in the differentiation of Acanthamoeba castellanii. FEMS Microbiol.Lett 286: 9–15
doi:10.1111/j.1574-6968.2008.01249.x
64. Abedkhojasteh H, Niyyati M, Rezaei S , Mohebali M , Farnia S et al (2014) Identifying differentially expressed genes in trophozoites and cysts of Acanthamoeba T4 genotype: Implications for developing new treatments for Acanthamoeba keratitis. Europ J Protistol 51(1):34-41 doi: 10.1016/j.ejop.2014.10.001
65. Erenpreisa J, Giuliani A, Vinogradov AE, Anatskaya OV, Vazquez-Martin A et al. (2018) Stress-induced polyploidy shifts somatic cells towards a pro-tumourogenic unicellular gene transcription network. Cancer Hypotheses 1: 1-20
66. Niu N, Mercado-Uribe I, Liu J (2017) Dedifferentiation into blastomere-like cancer stem cells via formation of polyploid giant cancer cells. Oncogene 36(34):4887-4900. doi: 10.1038/onc.2017.72
67. Niculescu VF (2016) Developmental and Non Developmental Polyploidy in Xenic and Axenic Cultured Stem Cell Lines of Entamoeba invadens and E. histolytica. Insights Stem Cells. 2:1 (Researchgate)
68. Jiang Q, Zhang Q, Wang S, Xie, S, Fang W et al. (2015) A Fraction of CD133+ CNE2 Cells Is Made of Giant Cancer Cells with Morphological Evidence of Asymmetric Mitosis. Journal of Cancer 2015, 6 (12), 1236-44. doi:10.7150/jca.12626
69. Díaz-Carballo D, Saka S, Klein J, Rennkamp T, Acikelli A et al.(2018) A Distinct Oncogenerative Multinucleated Cancer Cell Serves as a Source of Stemness and Tumor Heterogeneity. Cancer Research 78 (9), 2318-2331. doi: 10.1158/0008-5472.CAN-17-1861.
70. Salmina K, Jankevics E, Huna A, Perminov D, Radovica I et al. (2010) Up-regulation of the embryonic self-renewal network through reversible polyploidy in irradiated p53-mutant tumour cells. Exp Cell Res 316(13): 2099-112. doi: 10.1016/j.yexcr.2010.04.030
71. Dai C, Gu W (2010) p53 post-translational modification deregulated in tumorigenesis. Trends Mol. Med. 16: 528-536. doi:10.1016/j.molmed.2010.09.002
72. Hanahan, D.; Weinberg, R. (2000) The hallmarks of cancer. Cell 100 (1): 57–70. doi:10.1016/S0092-8674(00)81683-9.
73. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW (2013). Cancer genome landscapes. Science 339 (6127): 1546–58. doi:10.1126/science.1235122.
74. Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16 (1): 6–21. doi:10.1101/gad.947102. PMID 11782440.
75. Ginestier C, Charafe-Jauffret E, Birnbaum D (2012) p53 and cancer stem cells: The mevalonate connexion. Cell Cycle. 11(14):2583-2584. doi:10.4161/cc.21092
76. Aloni-Grinstein R, Shetzer Y, Kaufman T, Rotter V (2014) p53: the barrier to cancer stem cell formation. FEBS Letters. 588 (16): 2580–9. doi:10.1016/j.febslet.2014.02.011
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 667
- Comments 0