Skip to main content

Is cancer a disease set up by cellular stress responses?

Cell Stress and Chaperones volume 26, pages 597–609 (2021)Cite this article

Abstract

For several decades, the somatic mutation theory (SMT) has been the dominant paradigm on cancer research, leading to the textbook notion that cancer is fundamentally a genetic disease. However, recent discoveries indicate that mutations, including “oncogenic” ones, are widespread in normal somatic cells, suggesting that mutations may be necessary but not sufficient for cancer to develop. Indeed, a fundamental but as yet unanswered question is whether or not the first step in oncogenesis corresponds to a mutational event. On the other hand, for some time, it has been acknowledged the important role in cancer progression of molecular processes that participate in buffering cellular stress. However, their role is considered secondary or complementary to that of putative oncogenic mutations. Here we present and discuss evidence that cancer may have its origin in epigenetic processes associated with cellular adaptation to stressful conditions, and so it could be a direct consequence of stress-buffering mechanisms that allow cells with aberrant phenotypes (not necessarily associated with genetic mutations) to survive and propagate within the organism. We put forward the hypothesis that there would be an inverse correlation between the activation threshold of the cellular stress responses (CSRs) and the risk of cancer, so that species or individuals with low-threshold CSRs will display a higher incidence or risk of cancer.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Notes

  1. This theory suggests that induced or spontaneous mutations in critical genes accumulate within the genome of a given somatic cell that becomes transformed as a consequence of this, and as such, it becomes the founder of a clone of transformed cells. Then further mutations in further genes occur in such transformed cells, and those cells with mutations resulting in a selective “growth advantage” are further selected, thus giving origin to new clones that compete for space and resources in a sort of Darwinian evolutionary process, leading to the appearance of clones able to invade other tissues and furthermore, to spread elsewhere (metastasize) within the organism (Cairns 1975; Nowell 1976; Fearon and Vogelstein 1990; Stratton et al. 2009).

  2. In dynamical systems, an attractor state is a set of points or values toward which the system evolves from a wide variety of initial conditions. The attractor state constitutes a preferential stable regime for the system. In cells, the concept of attractor has been applied to cellular phenotypes and to the internal gene regulatory network (Huang et al. 2009; Aranda-Anzaldo and Dent 2018).

  3. Hormesis refers to any process that exhibits a biphasic response to a substance or environmental condition characterized by a low-dose stimulation or beneficial effect and a high-dose inhibitory or toxic effect (Mattson 2008). Hormesis is an important concept within evolutionary theory as organisms should develop complex mechanisms for coping with environmental hazards. It is a fact that several chaperones associated with the heat shock response participate in the cellular hormetic response (Mattson 2008). Many carcinogens behave as hormetic compounds that induce the stress response at low dose and given their cytotoxic effects, kill cells at high dose. Interestingly, experiments of cell transformation in vitro by exposure to X-rays indicate that the yield of transformed foci increases as a function of the dose up to 400 rads. Yet, further increases in the dose up to 1400 rads result in augmented cell mortality but negligible or null increase in the yield of transformed foci from the surviving cells (Terzaghi and Little 1976).

References

  • Abascal F, Harvey LMR, Mitchel E et al (2021) Somatic mutation landscapes at single-molecule resolution. Nature 593:405–410

  • Abegglen LM, Caulin AF, Chan BS et al (2015) Potential mechanism for cancer resistance in elephants and comparative cellular response to DNA damage in humans. JAMA 314:1850–1860

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Aranda-Anzaldo A, Dent MAR (2003) Developmental noise, ageing and cancer. Mech Ageing Dev 124:711–720

    CAS  PubMed  Article  Google Scholar 

  • Aranda-Anzaldo A, Dent MAR (2007) Reassessing the role of p53 in cancer and ageing from an evolutionary perspective. Mech Ageing Dev 128:293–302

    CAS  PubMed  Article  Google Scholar 

  • Aranda-Anzaldo A, Dent MAR (2018) Landscaping the epigenetic landscape of cancer. Prog Biophys Mol Biol 140:155–174

    CAS  PubMed  Article  Google Scholar 

  • Armstrong N, Ryder S, Forbes C, Ross J, Quek RGW (2019) A systematic review of the international prevalence of BRCA mutations in breast cancer. Clinical Epidemiol 11:543–561

    Article  Google Scholar 

  • Azpurua J, Ke Z, Chen IX, Zhang Q, Ermolenko DN, Zhang ZD, Gorbunova V, Seluanov A (2013) Naked mole rat has increased translational fidelity compared with the mouse, as well as unique 28S ribosomal cleavage. Proc Natl Acad Sci U S A 110:17350–17355

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Barcellos-Hoff MH, Ravani SA (2000) Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 60:1254–1260

    CAS  PubMed  Google Scholar 

  • Barna J, Csermely P, Vellai T (2018) Roles of heat shock factor 1 beyond the heat shock response. Cell Mol Life Sci 75:2897–2916

    CAS  PubMed  Article  Google Scholar 

  • Berry RJ, Bronson FH (1992) Life history and bioeconomy of the house mouse. Biol Rev Camb Philos Soc 67:519–550

    CAS  PubMed  Article  Google Scholar 

  • Blockzijl F, de Ligt J, Jager M et al (2016) Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538:260–264

    Article  CAS  Google Scholar 

  • Bouthwell RK (1964) Some biological aspects of skin carcinogenesis. Prog Exp Tumor Res 4:207–250

    Article  Google Scholar 

  • Brash D, Cairns J (2009a) The mysterious steps in carcinogenesis. Brit J Cancer 101:379–380

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Brash D, Cairns J (2009b) The mysterious steps in carcinogenesis: addendum. Brit J Cancer 101:1490

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Bredberg A (2009) Cancer resistance and Peto’s paradox. Proc Natl Acad Sci U S A 106:E51

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Cairns J (1975) Mutation selection and the natural history of cancer. Nature 255:197–200

    CAS  PubMed  Article  Google Scholar 

  • Casola C (2016) TP53 gene and cancer resistance in elephants. JAMA 315:1788–1789

    PubMed  Article  Google Scholar 

  • Cavalli G, Heard E (2019) Advances in epigenetics link genetics to the environment and disease. Nature 571:489–499

    CAS  PubMed  Article  Google Scholar 

  • Challis GB, Stam HJ (1990) The spontaneous regression of cancer. Acta Oncol 29:545–550

    CAS  PubMed  Article  Google Scholar 

  • Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive and treatment implications. Cell Stress Chaperones 10:86–103

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Clark WH (1995) The nature of cancer, morphogenesis and progressive (self)-disorganization in neoplastic development and progression. Acta Oncol 34:3–21

    PubMed  Article  Google Scholar 

  • Conant JC, Wagner A (2004) Duplicate genes and robustness to transient knock-downs in Caenorhabditis elegans. Proc R Soc London B Biol Sci 271:89–96

  • D’Alessandro A, Nemkov T, Sun K, Liu H, Song A, Monte AA, Subudhi AW, Lovering AT, Dvorkin D, Julian CG, Kevil CG, Kolluru GK, Shiva S, Gladwin MT, Xia Y, Hansen KC, Roach RC (2016) AltitudeOmics: red blood cell metabolic adaptation to high altitude hypoxia. J Proteome Res 15:3883–3895

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Dai C (2018) The heat shock, or HSF1-mediated proteotoxic stress response in cancer: from proteomic stability to oncogenesis. Philos Trans R Soc B 373:20160525

    Article  CAS  Google Scholar 

  • Dai C, Whitesell L, Rogers AB, Lindquist S (2007) Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130:1005–1018

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • De Pinho RA (2000) The age of cancer. Nature 408:248–254

    Article  CAS  Google Scholar 

  • Delaney MA, Ward JM, Walsh TF, Chinnadurai SK, Kerns K, Kinsel MJ, Treuting PM (2016) Initial case reports of cancer in naked mole-rats (Heterocephalus glaber). Vet Pathol 53:691–696

    CAS  PubMed  Article  Google Scholar 

  • Dent MAR, Aranda-Anzaldo A (2019) Lessons we can learn from neurons to make cancer cells quiescent. J Neurosci Res 97:1141–1152

    CAS  PubMed  Article  Google Scholar 

  • Dentro SC, Leshchiner I, Hasse K et al (2021) Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell 184:2239–2254

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Du Z, Chakrabarti S, Kulaberoglu Y, St John Smith E, Dobson CM, Itzhaki LS, Kumita JR (2020) Probing the unfolded protein response in long-lived naked mole-rats. Biochem Biophys Res Commun 529:1151–1157

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Enomoto T, Weghorst CM, Ward JM, Anderson LM, Perantoni AO, Rice JM (1993) Low frequency of H-ras activation in naturally occurring hepatocellular tumors of C3H/HeNCr mice. Carcinogenesis 4:1939–1944

    Article  Google Scholar 

  • Fang F, Chang R, Yang L (2012) Heat shock factor 1 promotes invasion and metastasis of hepatocellular carcinoma in vitro and in vivo. Cancer 118:1782–1794

    CAS  PubMed  Article  Google Scholar 

  • Farber E (1984) Pre-cancerous steps in carcinogenesis. Their physiological adaptive nature. Biochem Biophys Acta 738:171–180

  • Fearon ER, Vogelstein B (1990) A genetic model for colorectal carcinogenesis. Cell 61:759–767

    CAS  PubMed  Article  Google Scholar 

  • Fernandez A, Mondal S, Heidelberg C (1980) Probabilistic view of the transformation of cultured C3H/10T1/2 mouse embryo fibroblasts by 3-methylcholanthrene. Proc Natl Acad Sci U S A 77:7272–7276

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Feyerabend PK (1975) Against method: outline of an anarchist theory of knowledge. New left Books, London

    Google Scholar 

  • Gabai VL, Meng L, Kim G, Mills TA, Benjamin IJ, Sherman MY (2012) Heat shock transcription factor Hsf1 is involved in tumor progression via regulation of hypoxia-inducible factor 1 and RNA-binding protein HuR. Mol Cell Biol 32:929–940

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Gallagher EJ, LeRoith D (2015) Obesity and diabetes: the increased risk of cancer and of cancer-related mortality. Physiol Rev 95:727–748

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • García-Cao I, García-Cao M, Martín-Caballero J, Criado LM, Klatt P, Flores JM, Weill JC, Blasco MA, Serrano M (2002) ‘Super p53’ mice exhibit enhanced DNA damage response are tumor resistant and age normally. EMBO J 21:6225–6235

    PubMed  PubMed Central  Article  Google Scholar 

  • Gavrilov LA, Gavrilova NS (2002) Evolutionary theories of aging and longevity. Sci World J 2:339–356

    Article  Google Scholar 

  • Gómez-Pastor R, Burchfiel ET, Thiele DJ (2018) Regulation of heat shock transcription factors and their roles in physiology and disease. Nat Rev Mol Cell Biol 19:4–19

    PubMed  Article  CAS  Google Scholar 

  • Gu Z, Steinmetz LM, Gu X, Scharfe C, Davis RW, Li WH (2003) Role of duplicate genes in genetic robustness against null mutations. Nature 421:63–66

    CAS  PubMed  Article  Google Scholar 

  • Hacking I (1983) Representing and intervening. Cambridge University Press, Cambridge

    Book  Google Scholar 

  • Hadi F, Kulaberoglou Y, Lazarus KA et al (2020) Transformation of naked mole rat cells. Nature 583:E1–E7

    CAS  PubMed  Article  Google Scholar 

  • Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Books MW, Weinberg RA (1999) Creation of human tumor cells with defined genetic elements. Nature 399:464–468

    Article  CAS  Google Scholar 

  • Hanson NR (1958) Patterns of discovery. Cambridge University Press, Cambridge

    Google Scholar 

  • Harding C, Pompei F, Wilson R (2012) Peak and decline in cancer incidence, mortality and prevalence at old ages. Cancer 118:1371–1386

    PubMed  Article  Google Scholar 

  • Harrison, ER (2000) Cosmology: the science of the universe. 2nd ed., Cambridge University Press, Cambridge, chapter 24.

    Book  Google Scholar 

  • Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) P53 mutations in human cancers. Science 253:49–53

    CAS  PubMed  Article  Google Scholar 

  • Huang S (2012) Tumor progression: chance and necessity in Darwinian and Lamarckian somatic (mutationless) evolution. Prog Biophys Mol Biol 110:69–86

    CAS  PubMed  Article  Google Scholar 

  • Huang S, Ernberg I, Kauffman S (2009) Cancer attractors: a systems view of tumors from a gene network dynamics and developmental perspective. Semin Cell Dev Biol 20:869–876

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Jarvis JUM, Sherman PW (2002) Heterocephalus glaber. Mamm Species 706:1–9

    Article  Google Scholar 

  • Jin X, Moskophidis D, Mivechi NF (2011) Heat shock transcription factor 1 is a key determinant of HCC development by regulating hepatic steatosis and metabolic syndrome. Cell Metab 14:91–103

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Jolly C, Morimoto RI (2000) Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Inst 92:1564–1572

    CAS  PubMed  Article  Google Scholar 

  • Kaplan RM, Porzolt F (2008) The natural history of breast cancer. Arch Intern Med 168:2302–2303

    PubMed  Article  Google Scholar 

  • Kato S, Lippman SM, Flaherty KT, Kurzrock R (2016) The conundrum of genetic “drivers” in benign conditions. J Natl Cancer Inst 108:djw036

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Keane M, Semeiks J, Webb AE, Li YI, Quesada V, Craig T, Madsen LB, van Dam S, Brawand D, Marques PI, Michalak P, Kang L, Bhak J, Yim HS, Grishin NV, Nielsen NH, Heide-Jørgensen MP, Oziolor EM, Matson CW, Church GM, Stuart GW, Patton JC, George JC, Suydam R, Larsen K, López-Otín C, O’Connell MJ, Bickham JW, Thomsen B, de Magalhães JP (2015) Insights into the evolution of longevity from the bowhead whale genome. Cell Rep 10:112–122

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Kennedy AR, Fox M, Murphy G, Little JB (1980) Relationship between x-ray exposure and malignant transformation in C3H/10T1/2 cells. Proc Natl Acad Sci U S A 77:7262–7266

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Kennedy AR, Cairns J, Little JB (1984) Timing of the steps of transformation of C3H/10T1/2 cells by X-irradiation. Nature 307:85–86

    CAS  PubMed  Article  Google Scholar 

  • Krimmel JD, Schmitt MW, Harrell MI, Agnew KJ, Kennedy SR, Emond MJ, Loeb LA, Swisher EM, Risques RA (2016) Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues. Proc Natl Acad Sci U S A 113:6005–6010

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Kuhn TS (1970) The structure of scientific revolutions, 2nd edn. University of Chicago Press, Chicago

    Google Scholar 

  • Lakatos PL, Lakatos L (2008) Risk of colorectal cancer in ulcerative colitis: changes, causes and management strategies. World J Gastroenterol 14:3937–3947

    PubMed  PubMed Central  Article  Google Scholar 

  • Lapin BA, Yakovleva LA (2014) Spontaneous and experimental malignancies in non-human primates. J Med Primatol 43:100–110

    PubMed  Article  Google Scholar 

  • Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortés ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Lee RS, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CWM, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G (2013) Mutational heterogeneity in cancer and the search for new cancer associated genes. Nature 499:214–218

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Ling S, Hu Z, Yang Z, Yang F, Li Y, Lin P, Chen K, Dong L, Cao L, Tao Y, Hao L, Chen Q, Gong Q, Wu D, Li W, Zhao W, Tian X, Hao C, Hungate EA, Catenacci DVT, Hudson RR, Li WH, Lu X, Wu CI (2015) Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution. Proc Natl Acad Sci U S A 112:E6496–E6505

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • López-Otín C, Blasco MA, Patridge L, Serrano M, Kremer G (2013) The hallmarks of aging. Cell 153:1194–1217

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Lynch M (2010) Evolution of mutation rate. Trends Genet 26:346–352

    Article  CAS  Google Scholar 

  • Macieira-Coelho A, Azzarone B (1988) The transition from primary culture to spontaneous immortalization in mouse fibroblast populations. Anticancer Res 8:669–676

    CAS  PubMed  Google Scholar 

  • Maffini MV, Soto AM, Calabro JM, Ucci AA, Sonnenschein C (2004) The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci 117:1495–14502

    CAS  PubMed  Article  Google Scholar 

  • Manam S, Storer RD, Prahalada S, Leander KR, Kraynak AR, Ledwith BJ, van Zwieten M, Bradley MO, Nichols WW (1992) Activation of the Ha-ras, Ki-ras, and N-ras genes in chemically induced liver tumors from CD-1 mice. Cancer Res 52:3347–3352

    CAS  PubMed  Google Scholar 

  • Martincorena I, Campbell PJ (2015) Somatic mutation in cancer and normal cells. Science 349:1483–1489

    CAS  PubMed  Article  Google Scholar 

  • Martincorena I, Roshan A, Gerstung M, Ellis P, van Loo P, McLaren S, Wedge DC, Fullam A, Alexandrov LB, Tubio JM, Stebbings L, Menzies A, Widaa S, Stratton MR, Jones PH, Campbell PJ (2015) High burden and pervasive selection of somatic mutations in normal human skin. Science 348:880–886

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Martincorena I, Fowler A, Wabik ARJ et al (2018) Somatic mutant clones colonize the human esophagus with age. Science 362:911–917

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Martínez-Ramos I, Maya-Mendoza A, Gariglio P, Aranda-Anzaldo A (2005) A global but stable change in HeLa cell morphology induces reorganization of DNA structural loop domains in the cell nucleus. J Cell Biochem 96:79–88

    PubMed  Article  CAS  Google Scholar 

  • Mattson MP (2008) Hormesis defined. Ageing Res Rev 7:1–7

    CAS  PubMed  Article  Google Scholar 

  • Milholland B, Dong X, Zhang L, Hao X, Suh Y, Vijg J (2017) Differences between germline and somatic mutation rates in humans and mice. Nat Commun 8:15183

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Mouse genome sequencing consortium (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420:520–562

    Article  CAS  Google Scholar 

  • Munn L (2017) Cancer and inflammation. Wiley Interdiscip. Rev Syst Biol Med 9. https://doi.org/10.1002/wsbm.1370

  • Nakamura Y, Fujimoto M, Fukushima S, Nakamura A, Hayashida N, Takii R, Takaki E, Nakai A, Muto M (2014) Heat shock factor 1 is required for migration and invasion of human melanoma in vitro and in vivo. Cancer Lett 354:329–335

    CAS  PubMed  Article  Google Scholar 

  • Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194:123–128

    Article  Google Scholar 

  • O’Neill C (2015) The epigenetics of embryo development. Animal Frontiers 5:42–49

    Article  Google Scholar 

  • Otha S (2020) Somatic mutations-evolution within the individual. Methods 176:91–98

    Article  CAS  Google Scholar 

  • Park CC, Henshall-Powell R, Erickson AC et al (2003) Ionizing radiation induces heritable disruption of epithelial cells interactions. Proc Natl Acad Sci U S A 100:10728–10733

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Peng M, Mo Y, Wang Y, Wu P, Zhang Y, Xiong F, Guo C, Wu X, Li Y, Li X, Li G, Xiong W, Zeng Z (2019) Neoantigen vaccine: an emerging tumor immunotherapy. Mol Cancer 18:128

    PubMed  PubMed Central  Article  Google Scholar 

  • Perez RP, Komiya T (2016) TP53 and cancer resistance in elephants. JAMA 315:1789–1780

    PubMed  Article  Google Scholar 

  • Pérez VI, Buffenstein R, Masamsetti V et al (2009) Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked-mole rat. Proc Natl Acad Sci U S A 106:3059–3064

    PubMed  PubMed Central  Article  Google Scholar 

  • Peto R (2015) Quantitative implications of the approximate irrelevance of mammalian body size and lifespan to lifelong cancer risk. Philos Trans R Soc Lond Ser B Biol Sci 370:20150198

    Article  Google Scholar 

  • Peto R, Doll R (1997) There is no such a thing as aging. BMJ 315:1030–1032

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Peto R, Roe FJC, Lee PN, Levy L, Clack J (1975) Cancer and ageing in mice and men. Brit J Cancer 32:411–426

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Peto R, Gray R, Brantom P, Grasso P (1997) Dose and time relationship for tumor induction in the liver and esophagus of 4080 inbred rats by chronic ingestion of N-nitrosodiethylamine or N-nitrosodimethylamine. Cancer Res 51:6452–6469

    Google Scholar 

  • Prahlad V, Cornelius T, Morimoto RI (2008) Regulation of the cellular heat shock response in Caenorhabditis elegans by thermosensory neurons. Science 320:811–814

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Prehn RT (1975) Non-genetic variability in susceptibility to oncogenesis. Science 190:1095–1096

    CAS  PubMed  Article  Google Scholar 

  • Puustinen MC, Sistonen L (2020) Molecular mechanisms of heat shock factors in cancer. Cells 9:1202

    CAS  PubMed Central  Article  Google Scholar 

  • Reich MR, Ikegami N, Shibuya K, Takemi K (2011) 50 years of pursuing a healthy society in Japan. Lancet 378:1051–1053

    PubMed  Article  Google Scholar 

  • Rodríguez KA, Valentine JM, Kramer DA, Gelfond JA, Kristan DM, Nevo E, Buffenstein R (2016) Determinants of rodent longevity in the chaperone-protein degradation network. Cell Stress Chaperones 21:453–466

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Rubin H, Rubin AL (2018) Phenotypic selection as the biological mode of epigenetic conversion and reversion in cell transformation. Proc Natl Acad Sci U S A 115:E725–E732

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Santagata S, Hu R, Lin NU, Mendillo ML, Collins LC, Hankinson SE, Schnitt SJ, Whitesell L, Tamimi RM, Lindquist S, Ince TA (2011) High levels of nuclear heat shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. Proc Natl Acad Sci U S A 108:18378–18383

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Scherz-Schouval R, Santagata S, Mendillo ML et al (2014) The reprograming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell 158:564–578

    Article  CAS  Google Scholar 

  • Siegal M (2017) Chaperone protein gets personal. Nature 545:36–37

    CAS  PubMed  Article  Google Scholar 

  • Speakman JR (2005) Body size, energy metabolism and lifespan. J Exp Biol 208:1717–1730

    PubMed  Article  Google Scholar 

  • Stratton MR, Campbell PJ, Futreal PA et al (2009) The cancer genome. Nature 458:719–724

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Taha EA, Ono K, Eguchi T (2019) Role of extracellular HSPs as biomarkers in immune surveillance and immune evasion. Int J Mol Sci 20:4588

    CAS  PubMed Central  Article  Google Scholar 

  • Tamaru T, Kobayashi H, Kishimoto S, Kajiyama G, Shimamoto F, Brown WR (1993) Histochemical study of colonic cancer in experimental colitis of rats. Dig Dis Sci 38:529–537

    CAS  PubMed  Article  Google Scholar 

  • Taylor RC, Dillin A (2013) XBP-1 is a cell non-autonomous regulator of stress resistance and longevity. Cell 153:1435–1447

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Taylor RC, Berendzen KM, Dillin A (2014) Systemic stress signalling: understanding the cell non-autonomous control of proteostasis. Nat Rev Mol Cell Biol 15:211–217

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Taylor KR, Milone NA, Rodriguez CE (2016) Four cases of spontaneous neoplasia in the naked mole-rat (Heterocephalus glaber), a putative cancer-resistant species. J Gerontol A Biol Sci Med Sci 72:38–43

    PubMed  Article  Google Scholar 

  • Terzaghi M, Little JB (1976) X-radiation induced transformation in a C3H mouse embryo-derived cell line. Cancer Res 36:1367–1374

    CAS  PubMed  Google Scholar 

  • Tomasetti C, Vogelstein B (2015) Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347:78–81

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Tomasetti C, Vogelstein B, Parmigiani G (2013) Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation. Proc Natl Acad Sci U S A 110:1999–2004

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Tomasetti C, Marchionni L, Nowak MA, Parmigiani G, Vogelstein B (2015) Only three driver gene mutations are required for the development of lung and colorectal cancers. Proc Natl Acad Sci U S A 112:118–123

    CAS  PubMed  Article  Google Scholar 

  • Tunçer S, Gurbanov R, Sheraj I, Solel E, Esenturk O, Banerjee S (2018) Low dose dimethyl sulfoxide driven gross molecular changes have the potential to interfere with various cellular processes. Sci Rep 8:14828

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Varki A, Altheide TK (2005) Comparing the human and chimpanzee genomes: searching for needles in a haystack. Genome Res 15:1746–1758

    CAS  PubMed  Article  Google Scholar 

  • Varki NM, Varki A (2015) On the apparent rarity of epithelial cancers in captive chimpanzees. Philos Trans R Soc B 370:20140225

    Article  Google Scholar 

  • Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ (2011) Natural innate and adaptive immunity to cancer. Annu Rev Immunol 29:235–271

    CAS  PubMed  Article  Google Scholar 

  • Weinberg RA (2014) Coming full circle-from endless complexity to simplicity and back again. Cell 157:267–271

    CAS  Article  PubMed  Google Scholar 

  • Weisburger EK (1988) Chemical carcinogens in experimental animals and humans. In: Sirica AE (ed) The patholobiology of neoplasia. Plenum Press, New York and London, pp 39–56

    Google Scholar 

  • Whitesell L, Lindquist S (2005) Hsp90 and the chaperoning of cancer. Nat Rev Cancer 5:761–772

    CAS  PubMed  Article  Google Scholar 

  • Wood BM, Watts DP, Mitani JC, Langerbraber KE (2017) Favorable ecological circumstances promote life expectancy in chimpanzees, similar to that of human hunter-gatherers. J Hum Evol 105:41–56

    PubMed  PubMed Central  Article  Google Scholar 

  • Wu S, Powers S, Zhu W, Hannun YA (2016) Substantial contribution of extrinsic risk factors to cancer development. Nature 529:43–47

    CAS  PubMed  Article  Google Scholar 

  • Xi C, Hu Y, Buckhaults P, Moskophidis D, Mivechi NF (2012) Heat shock factor Hsf1 cooperates with ErbB2 (Her2/Neu) protein to promote mammary tumorigenesis and metastasis. J Biol Chem 287:35646–35657

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Xiao X, Zuo X, Davis AA, McMillan DR, Curry BB, Richardson JA, Benjamin IJ (1999) HSF1 is required for extra-embryonic development, postnatal growth and protection during inflammatory response in mice. EMBO J 18:5943–5952

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Yap KN, Yamada K, Sikeli S, Kiaris H, Hood WR (2021) Evaluating endoplasmic reticulum stress and unfolded protein response through the lens of ecology and evolution. Biol Rev Camb Philos Soc 96:541–556

    PubMed  Article  Google Scholar 

  • Yu Z-W, Quinn PJ (1994) Dimethyl sulphoxide: a review of its applications in cell biology. Biosci Rep 14:259–281

    CAS  PubMed  Article  Google Scholar 

  • Yun CW, Kim HJ, Lim JH, Lee SH (2020) Heat shock proteins: agents of cancer development and therapeutic targets in anti-cancer therapy. Cells 9:60. https://doi.org/10.3390/cells9010060

    CAS  Article  Google Scholar 

  • Zahl P-H, Maehlen J, Welch HG (2008) The natural history of invasive breast cancers detected by screening mammography. Arch Intern Med 168:2311–2316

    PubMed  Article  Google Scholar 

  • Zaridze D, Peto R (1986) Influence of dose and duration of smoking on lung cancer rates. In: Tobacco, major international health hazard. Vol. 74. IARC Sci. Publs, Lyon, pp 23–33

    Google Scholar 

Download references

Acknowledgements

We thank the anonymous referees for their comments and suggestions for improving the manuscript.

Availability of data and materials

Not applicable

Code availability

Not applicable

Funding

This work was supported by Universidad Autónoma del Estado de México grant no. 4971/2020CIB. The funding source had no role in the preparation of the manuscript or in the decision to publish it.

Author information

Authors and Affiliations

  1. Laboratorio de Biología Molecular y Neurociencias, Facultad de Medicina, Universidad Autónoma del Estado de México, Paseo Tollocan y Jesús Carranza s/n, Toluca, 50180, Edo. Méx, México

    Armando Aranda-Anzaldo & Myrna A. R. Dent

Authors
  1. Armando Aranda-Anzaldo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Myrna A. R. Dent
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A Aranda-Anzaldo: conceptualization, investigation, writing—original draft, funding acquisition. MAR Dent: investigation, writing—reviewing and editing, funding acquisition.

Corresponding author

Correspondence to Armando Aranda-Anzaldo.

Ethics declarations

Consent to participate

Not applicable

Consent for publication

Not applicable

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Aranda-Anzaldo, A., Dent, M.A.R. Is cancer a disease set up by cellular stress responses?. Cell Stress and Chaperones 26, 597–609 (2021). https://doi.org/10.1007/s12192-021-01214-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12192-021-01214-4

Keywords

  • Heat shock response
  • Hormesis
  • Phenotypic selection
  • Physiological adaptation
  • Peto’s paradox
  • Protein folding
  • Unfolded protein response