Biopolym. Cell. 2023; 39(3):161-169.
http://dx.doi.org/10.7124/bc.000A99
Reviews
Key models and theories of carcinogenesis
1Gerashchenko G. V., 1Kashuba V. I., 1Tukalo M. A.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03143

Abstract

A brief overview of the most well-known seven types of carcinogenesis models is presented. They include mutation models, genomic instability models, non-genotoxic models, Darwinian models, tissue organization models, inflammation models, and an integrated model. Each model has specific oncogenic factors that cause certain types of cancer, have their own mechanisms, and are based on certain mathematical models.
Keywords: carcinogenesis, models and hypothesis, oncogenic factors, molecular mechanisms, genetic and epigenetic alterations, mutations, tumor microenvironment
Full text: (PDF, in English)

References

[1] Weiss RA. Multistage carcinogenesis. Br J Cancer. 2004; 91(12):1981-2.
[2] Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013; 339(6127):1546-58.
[3] Luzzatto L. Somatic mutations in cancer development. Environ Health. 2011; 10(Suppl 1):S12.
[4] Vineis P, Schatzkin A, Potter JD. Models of carcinogenesis: an overview. Carcinogenesis. 2010; 31(10):1703-9.
[5] Armitage P, Doll R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer. 1954; 8(1):1-12.
[6] Armitage P, Doll R. The age distribution of cancer and a multi-stage theory of carcinogenesis. 1954. Int J Epidemiol. 2004; 33(6):1174-9.
[7] Bevan RJ, Harrison PTC. Threshold and non-threshold chemical carcinogens: A survey of the present regulatory landscape. Regul Toxicol Pharmacol. 2017; 88:291-302.
[8] Hardonnière K, Huc L, Sergent O, Holme JA, Lagadic-Gossmann D. Environmental carcinogenesis and pH homeostasis: Not only a matter of dysregulated metabolism. Semin Cancer Biol. 2017; 43:49-65.
[9] Smith AJ, Smith LA. Viral Carcinogenesis. Prog Mol Biol Transl Sci. 2016; 144:121-68.
[10] Hatano Y, Ideta T, Hirata A, Hatano K, Tomita H, Okada H, Shimizu M, Tanaka T, Hara A. Virus-Driven Carcinogenesis. Cancers (Basel). 2021; 13(11):2625.
[11] Krump NA, You J. Molecular mechanisms of viral oncogenesis in humans. Nat Rev Microbiol. 2018; 16(11):684-98.
[12] Heldman MR, Wight DJ, Aiewsakun P, Aswad A, Fang M, Roychoudhury P, Stevens-Ayers T, Jerome KR, Zerr DM, Greninger AL, Kaufer BB, Boeckh M, Hill JA. Chromosome-Specific Human Herpesvirus 6 Integration and Hematologic Malignancies. J Virol. 2022; 96(17):e0093722.
[13] Herbein G. Tumors and Cytomegalovirus: An Intimate Interplay. Viruses. 2022; 14(4):812.
[14] Chen CJ, You SL, Hsu WL, Yang HI, Lee MH, Chen HC, Chen YY, Liu J, Hu HH, Lin YJ, Chu YJ, Huang YT, Chiang CJ, Chien YC. Epidemiology of Virus Infection and Human Cancer. Recent Results Cancer Res. 2021; 217:13-45.
[15] Knudson AG. Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol. 1996; 122(3):135-40.
[16] Knudson A. Retinoblastoma: teacher of cancer biology and medicine. PLoS Med. 2005; 2(10):e349.
[17] Lohmann DR. RB1 gene mutations in retinoblastoma. Hum Mutat. 1999; 14(4):283-8.
[18] Brassett C, Joyce JA, Froggatt NJ, Williams G, Furniss D, Walsh S, Miller R, Evans DG, Maher ER. Microsatellite instability in early onset and familial colorectal cancer. J Med Genet. 1996; 33(12):981-5.
[19] Norppa H, Bonassi S, Hansteen IL, Hagmar L, Strömberg U, Rössner P, Boffetta P, Lindholm C, Gundy S, Lazutka J, Cebulska-Wasilewska A, Fabiánová E, Srám RJ, Knudsen LE, Barale R, Fucic A. Chromosomal aberrations and SCEs as biomarkers of cancer risk. Mutat Res. 2006; 600(1-2):37-45.
[20] Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol. 1994; 145(1):148-56.
[21] Cho KR, Vogelstein B. Genetic alterations in the adenoma--carcinoma sequence. Cancer. 1992; 70(6 Suppl):1727-31.
[22] Denes J, Krewski D. An exact representation for the generating function for the Moolgavkar-Venzon-Knudson two-stage model of carcinogenesis with stochastic stem cell growth. Math Biosci. 1996; 131(2):185-204.
[23] Castrén O. Implications of a two-stage clonal expansion model to indoor radon risk assessment. Health Phys. 1999; 76(4):393-7.
[24] Zeka A, Gore R, Kriebel D. The two-stage clonal expansion model in occupational cancer epidemiology: results from three cohort studies. Occup Environ Med. 2011; 68(8):618-24.
[25] Moolgavkar SH, Day NE, Stevens RG. Two-stage model for carcinogenesis: Epidemiology of breast cancer in females. J Natl Cancer Inst. 1980; 65(3):559-69.
[26] Beerenwinkel N, Antal T, Dingli D, Traulsen A, Kinzler KW, Velculescu VE, Vogelstein B, Nowak MA. Genetic progression and the waiting time to cancer. PLoS Comput Biol. 2007; 3(11):e225.
[27] Jones S, Chen WD, Parmigiani G, Diehl F, Beerenwinkel N, Antal T, Traulsen A, Nowak MA, Siegel C, Velculescu VE, Kinzler KW, Vogelstein B, Willis J, Markowitz SD. Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci U S A. 2008; 105(11):4283-8.
[28] Moolgavkar SH, Dewanji A, Venzon DJ. A stochastic two-stage model for cancer risk assessment. I. The hazard function and the probability of tumor. Risk Anal. 1988; 8(3):383-92.
[29] Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971; 68(4):820-3.
[30] Little MP. Are two mutations sufficient to cause cancer? Some generalizations of the two-mutation model of carcinogenesis of Moolgavkar, Venzon, and Knudson, and of the multistage model of Armitage and Doll. Biometrics. 1995; 51(4):1278-91.
[31] Little MP, Wright EG. A stochastic carcinogenesis model incorporating genomic instability fitted to colon cancer data. Math Biosci. 2003; 183(2):111-34.
[32] Weinberg RA. Mechanisms of malignant progression. Carcinogenesis. 2008; 29(6):1092-5.
[33] Little MP, Vineis P, Li G. A stochastic carcinogenesis model incorporating multiple types of genomic instability fitted to colon cancer data. J Theor Biol. 2008; 254(2):229-38.
[34] Little MP. Cancer models, genomic instability and somatic cellular Darwinian evolution. Biol Direct. 2010; 5:19; discussion 19.
[35] Lichtenstein AV. Cancer: evolutionary, genetic and epigenetic aspects. Clin Epigenetics. 2010; 1(3-4):85-100.
[36] Lichtenstein AV. Cancer: shift of the paradigm. Med Hypotheses. 2008; 71(6):839-50.
[37] Grotenhuis BA, Wijnhoven BP, van Lanschot JJ. Cancer stem cells and their potential implications for the treatment of solid tumors. J Surg Oncol. 2012; 106(2):209-15.
[38] Italia M, Wertheim KY, Taschner-Mandl S, Walker D, Dercole F. Mathematical Model of Clonal Evolution Proposes a Personalised Multi-Modal Therapy for High-Risk Neuroblastoma. Cancers (Basel). 2023; 15(7):1986.
[39] Rahman M, Deleyrolle L, Vedam-Mai V, Azari H, Abd-El-Barr M, Reynolds BA. The cancer stem cell hypothesis: failures and pitfalls. Neurosurgery. 2011; 68(2):531-45; discussion 545.
[40] Bissell MJ, Weaver VM, Lelièvre SA, Wang F, Petersen OW, Schmeichel KL. Tissue structure, nuclear organization, and gene expression in normal and malignant breast. Cancer Res. 1999; 59(7 Suppl):1757-1763s; discussion 1763s-1764s.
[41] Laconi E, Doratiotto S, Vineis P. The microenvironments of multistage carcinogenesis. Semin Cancer Biol. 2008; 18(5):322-9.
[42] Potter JD. Morphostats: a missing concept in cancer biology. Cancer Epidemiol Biomarkers Prev. 2001; 10(3):161-70.
[43] Potter JD. Morphogens, morphostats, microarchitecture and malignancy. Nat Rev Cancer. 2007; 7(6):464-74.
[44] van den Brink GR, Offerhaus GJ. The morphogenetic code and colon cancer development. Cancer Cell. 2007; 11(2):109-17.
[45] Baker SG, Soto AM, Sonnenschein C, Cappuccio A, Potter JD, Kramer BS. Plausibility of stromal initiation of epithelial cancers without a mutation in the epithelium: a computer simulation of morphostats. BMC Cancer. 2009; 9:89.
[46] Bożyk A, Wojas-Krawczyk K, Krawczyk P, Milanowski J. Tumor Microenvironment-A Short Review of Cellular and Interaction Diversity. Biology (Basel). 2022; 11(6):929.
[47] Okada F. Inflammation-related carcinogenesis: current findings in epidemiological trends, causes and mechanisms. Yonago Acta Med. 2014; 57(2):65-72.
[48] Morgillo F, Dallio M, Della Corte CM, Gravina AG, Viscardi G, Loguercio C, Ciardiello F, Federico A. Carcinogenesis as a Result of Multiple Inflammatory and Oxidative Hits: a Comprehensive Review from Tumor Microenvironment to Gut Microbiota. Neoplasia. 2018; 20(7):721-33.
[49] Aggarwal BB, Sung B. The relationship between inflammation and cancer is analogous to that between fuel and fire. Oncology (Williston Park). 2011; 25(5):414-8.
[50] Korniluk A, Koper O, Kemona H, Dymicka-Piekarska V. From inflammation to cancer. Ir J Med Sci. 2017; 186(1):57-62.
[51] Wang S, Ma N, Zhao W, Midorikawa K, Kawanishi S, Hiraku Y, Oikawa S, Zhang Z, Huang G, Murata M. Inflammation-Related DNA Damage and Cancer Stem Cell Markers in Nasopharyngeal Carcinoma. Mediators Inflamm. 2016;2016:9343460.
[52] Jia D, Nagaoka Y, Katsumata M, Orsulic S. Inflammation is a key contributor to ovarian cancer cell seeding. Sci Rep. 2018; 8(1):12394.
[53] McDonald PC, Chafe SC, Dedhar S. Overcoming Hypoxia-Mediated Tumor Progression: Combinatorial Approaches Targeting pH Regulation, Angiogenesis and Immune Dysfunction. Front Cell Dev Biol. 2016; 4:27.
[54] Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010; 49(11):1603-16.
[55] Gonda TA, Tu S, Wang TC. Chronic inflammation, the tumor microenvironment and carcinogenesis. Cell Cycle. 2009; 8(13):2005-13.
[56] Fiaschi T, Chiarugi P. Oxidative stress, tumor microenvironment, and metabolic reprogramming: a diabolic liaison. Int J Cell Biol. 2012; 2012:762825.
[57] Gill JG, Piskounova E, Morrison SJ. Cancer, Oxidative Stress, and Metastasis. Cold Spring Harb Symp Quant Biol. 2016; 81:163-75.
[58] Pakravan N. Tumorigenesis: cell defense against hypoxia? Oncol Rev. 2013; 7(1):e1.
[59] Huang D, Li C, Zhang H. Hypoxia and cancer cell metabolism. Acta Biochim Biophys Sin (Shanghai). 2014; 46(3):214-9.
[60] Hatta MNA, Mohamad Hanif EA, Chin SF, Neoh HM. Pathogens and Carcinogenesis: A Review. Biology (Basel). 2021; 10(6):533.
[61] Kipanyula MJ, Seke Etet PF, Vecchio L, Farahna M, Nukenine EN, Nwabo Kamdje AH. Signaling pathways bridging microbial-triggered inflammation and cancer. Cell Signal. 2013; 25(2):403-16.
[62] Poutahidis T, Erdman SE. Commensal bacteria modulate the tumor microenvironment. Cancer Lett. 2016; 380(1):356-8.
[63] Read SA, Douglas MW. Virus induced inflammation and cancer development. Cancer Lett. 2014; 345(2):174-81.
[64] Akram N, Imran M, Noreen M, Ahmed F, Atif M, Fatima Z, Bilal Waqar A. Oncogenic Role of Tumor Viruses in Humans. Viral Immunol. 2017; 30(1):20-7.
[65] Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol. 2013; 190(8):3831-8.
[66] Shalapour S, Karin M. Immunity, inflammation, and cancer: an eternal fight between good and evil. J Clin Invest. 2015; 125(9):3347-55.
[67] Ivy KS, Brent Ferrell P Jr. Disordered Immune Regulation and its Therapeutic Targeting in Myelodysplastic Syndromes. Curr Hematol Malig Rep. 2018; 13(4):244-55.
[68] Sadighi Akha AA. Aging and the immune system: An overview. J Immunol Methods. 2018; 463:21-6.
[69] Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013; 75:685-705.
[70] Zhang X, Meng X, Chen Y, Leng SX, Zhang H. The Biology of Aging and Cancer: Frailty, Inflammation, and Immunity. Cancer J. 2017; 23(4):201-5.
[71] Riscuta G. Nutrigenomics at the Interface of Aging, Lifespan, and Cancer Prevention. J Nutr. 2016; 146(10):1931-9.
[72] Payne JK. State of the science: stress, inflammation, and cancer. Oncol Nurs Forum. 2014; 41(5):533-40.
[73] Powell ND, Tarr AJ, Sheridan JF. Psychosocial stress and inflammation in cancer. Brain Behav Immun. 2013; 30(Suppl):S41-7.
[74] Tir AMD, Labor M, Plavec D. The effects of physical activity on chronic subclinical systemic inflammation. Arh Hig Rada Toksikol. 2017; 68(4):276-86.
[75] Kerr J, Anderson C, Lippman SM. Physical activity, sedentary behaviour, diet, and cancer: an update and emerging new evidence. Lancet Oncol. 2017; 18(8):e457-e471.
[76] Bizzarri M, Cucina A. SMT and TOFT: Why and How They are Opposite and Incompatible Paradigms. Acta Biotheor. 2016; 64(3):221-39.
[77] Bedessem B, Ruphy S. SMT or TOFT? How the two main theories of carcinogenesis are made (artificially) incompatible. Acta Biotheor. 2015; 63(3):257-67.
[78] Soto AM, Sonnenschein C. The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory. Bioessays. 2011; 33(5):332-40.
[79] Sonnenschein C, Soto AM. An Integrative Approach Toward Biology, Organisms, and Cancer. Methods Mol Biol. 2018; 1702:15-26.
[80] Brücher BL, Jamall IS. Somatic Mutation Theory - Why it's Wrong for Most Cancers. Cell Physiol Biochem. 2016; 38(5):1663-80.
[81] Bedessem B, Ruphy S. SMT and TOFT Integrable After All: A Reply to Bizzarri and Cucina. Acta Biotheor. 2017; 65(1):81-5.
[82] Grocott MP. Integrative physiology and systems biology: reductionism, emergence and causality. Extrem Physiol Med. 2013; 2(1):9.
[83] Grizzi F, Di Ieva A, Russo C, Frezza EE, Cobos E, Muzzio PC, Chiriva-Internati M. Cancer initiation and progression: an unsimplifiable complexity. Theor Biol Med Model. 2006; 3:37.
[84] Janecka IP. Cancer control through principles of systems science, complexity, and chaos theory: a model. Int J Med Sci. 2007; 4(3):164-73.
[85] Giuliani A, Filippi S, Bertolaso M. Why network approach can promote a new way of thinking in biology. Front Genet. 2014; 5:83.
[86] Sigston EAW, Williams BRG. An Emergence Framework of Carcinogenesis. Front Oncol. 2017; 7:198.