Abstract
During the last fifty years the dominant stance in experimental biology has been reductionism. For the most part, research programs were based on the notion that genes were in ’the driver’s seat’ controlling the developmental program and determining normalcy and disease (genetic reductionism and genetic determinism). Philosophers were the first to realize that the belief that the Mendelian genes were reduced to DNA molecules was questionable. Soon after these pronouncements, experimental data confirmed their misgivings. The optimism of molecular biologists, fueled by early success in tackling relatively simple problems, has now been tempered by the difficulties found when attempting to understand complex biological problems.
Here, we analyse experimental data that illustrate the shortcomings of this sort of reductionism. We also examine the prevailing paradigm in cancer research, the somatic mutation theory (SMT), the premises of which are: (i) cancer is derived from a single somatic cell that has accumulated multiple DNA mutations; (ii) the default state of cell proliferation in metazoa is quiescence; and (iii) cancer is a disease of cell proliferation caused by mutations in genes that control proliferation and the cell cycle. We challenge the notion that cancer is a cellular problem caused by mutated genes by assessing data gathered both from within the reductionist paradigm and from an alternative view that regards carcinogenesis as a developmental process gone awry. This alternative view, explored under the name of the tissue organization field theory (TOFT), is based on premises that place cancer in a different hierarchical level of complexity from that proposed by the SMT, namely: (i) carcinogenesis represents a problem of tissue organization comparable to organogenesis, and (ii) proliferation is the default state of all cells.
We propose that the organicist view, in which the TOFT is based, is a good starting point from which to explore emergent phenomena. However, new theoretical concepts are needed in order to grapple with the apparent circular causality of complex biological phenomena in development and carcinogenesis.
Similar content being viewed by others
Abbreviations
- APC:
-
Adenomatous polyposis coli
- EPO:
-
erythropoietin
- hDdl:
-
human homologue ofDrosophila discs large
- HNPCC:
-
hereditary non-polyposis colorectal cancer
- Rb:
-
retinoblastoma
- SMT:
-
somatic mutation theory of carcinogenesis
- TGF-β:
-
transforming growth factor-beta
- TOFT:
-
tissue organization field theory
References
Alberts B, Bray D, Lewis J, Raff M, Roberts K and Watson J D 1994Molecular biology of the cell (New York: Garland Publishing Inc.) p. 891
Alberts B, Johnson A, Lewis J, Raff M, Roberts K and Walter P 2001Molecular biology of the cell (New York: Garland Publishing Inc.) pp 1313–1362
Alberts B, Johnson A, Lewis J, Raff M, Roberts K and Walter P 2002Molecular biology of the cell (New York: Garland Publishing Inc.) p. 1015
Ayala F J 1968 Biology as an autonomous science;Am. Sci. 56 207–221
Baron U, Gossen M and Bujard H 1997 Tetracycline-controlled transcription in eukaryotes: novel transactivators with graded transactivation potential;Nucleic Acids Res. 25 2723–2729
Bassett D E Jr, Eisen M B and Boguski M S 1999 Gene expression informatics It’s all in your mine;Nature Genet. 21 51–55
Benson K 2001 T H Morgan’s resistance to the chromosome theory;Nat. Rev. Genet. 2 469–474
Bishop J M 1985 Viral oncogenes;Cell 42 23–38
Bissell M J and Radisky D 2001 Putting tumours in context;Nat. Rev. Cancer 1 46–54
Brisken C, Socolovsky M, Lodish H F and Weinberg R 2002 The signaling domain of the erythropoietin receptor rescues prolactin receptor-mutant mammary epithelium;Proc. Natl. Acad. Sci. USA 99 14241–14245
Brown P O and Botstein D 1999 Exploring the new world of the genome with DNA microarrays;Nature Genet. 21 33–37
Bunge M 2004Emergence and convergence (Toronto: University of Toronto Press) pp 40–52
Clark W H 1991 Tumour progression and the nature of cancer;Br. J. Cancer 64 631–644
Cooper G M 1983 Transforming genes of neoplasms;Prog. Nucleic Acid Res. Mol. Biol. 29 273–277
Curtis H J 1965 Formal discussion of: Somatic mutations and carcinogenesis;Cancer Res. 25 1305–1308
Dawkins R 1976The selfish gene (Oxford: Oxford University Press)
De Robertis E A, Morita E M and Cho K W Y 1991 Gradient fields and homeobox genes;Development 112 669–678
Dennett D C 1995aDarwin’s dangerous idea (New York: Simon and Schuster) p. 21
Dennett D C 1995bDarwin’s dangerous idea (New York: Simon and Schuster)
DiBerardino M A, Orr N H and McKinnell R G 1986 Feeding tadpoles cloned from Rana erythrocyte nuclei;Proc. Natl. Acad. Sci. USA 83 8231–8234
Downie S A and Newmann S A 1994 Morphogenetic differences between fore and hind limb precartilage mesenchyme: Relation to mechanisms of skeletal pattern formation;Dev. Biol. 162 195–208
Farge E 2003 Mechanical induction of twist in theDrosophila foregut/stomodeal primordium;Curr. Biol. 13 1365–1377
Fox-Keller E 2000The century of the gene (Cambridge: Harvard University Press) pp 73–132
Gilbert S F and Sarkar S 2000 Embracing complexity: Organicism for the 21st century;Dev. Dynamics 219 1–9
Greenspan R J 2001 The flexible genome;Nat. Rev. Genet. 2 383–387
Griffiths P E and Gray R D 2000 Darwinism and developmental systems; inCycles of contingency: Developmental systems and evolution (eds) S Oyama, P E Griffiths and R D Gray (Cambridge: MIT Press) pp 195–218
Guerra C, Mijimolle N, Dhawahir A, Dubus P, Barradas M, Serrano M, Campuzano V and Barbacid M 2003 Tumor induction by an endogenousK-ras oncogene is highly dependent on cellular context;Cancer Cell. 4 111–120
Hahn W C and Weinberg R A 2002a Mechanisms of disease: Rules for making human tumor cells;New Engl. J. Med. 347 1593–1603
Hahn W C and Weinberg R A 2002b Modelling the molecular circuitry of cancer;Nat. Rev. Cancer 2 331–342
Harris H 1995The cells of the body: A history of somatic cell genetics (New York: Cold Spring Harbor Laboratory Press) pp 211–247
Harris H 2004 Tumor suppression: putting on the breaks;Nature (London) 427 201
Hough C D, Woods D F, Park S and Bryant P J 1997 Organizing a functional junctional complex requires specific domains of theDrosophila MAGUK Discs large;Genes Dev. 11 3242–3253
Hull D 1974The philosophy of biological science (Englewood Clifts NJ: Prentice Hall) pp 8–44
Humpherys D, Eggan K, Akutsu H, Friedman A, Hochedlinger K, Yanagimachi R, Lander E S, Golub T R and Jaenisch R 2002 Abnormal gene expression in cloned mice derived from embryonic stem cell and cumulus cell nuclei;Proc. Natl. Acad. Sci. USA 99 12889–12894
Iau P T, Macmillian R D and Blamey R W 2001 Germ line mutations associated with breast cancer susceptibility;Eur. J. Cancer 37 300–321
Illmensee K and Mintz B 1976 Totipotency and normal differentiation of single teratocarcinoma cell cloned by injection into blastocysts;Proc. Natl. Acad. Sci. USA 73 549–553
Jacks T and Weinberg R A 2002 Taking the study of cancer cell survival to a new dimension;Cell 111 923–925
Jacob F 1982The possible and the actual (Seattle: University of Washington Press)
Jursnich V A, Fraser S E, Held L I Jr, Ryerse J and Bryant P J 1990 Defective gap-junctional communication associated with imaginal disc overgrowth and degneration caused by mutations of the dco gene inDrosophila;Dev. Biol. 140 413–429
Kemler R 1993 From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion;Trends Genet. 9 317–321
Kim J 1999 Making Sense of Emergence;Philos. Stud. 95 3–36
Kinzler K W and Vogelstein B 1996 Lessons from hereditary colorectal cancer;Cell 87 159–170
Knudson A G Jr 1989 Hereditary cancers disclose a class of cancer genes;Cancer 63 1888–1891
Knudson A G Jr 1993 Pediatric molecular oncology: Past as prologue to the future;Cancer 71 3320–3324
Knudson A G Jr 1995 Mutation and cancer: a personal odyssey;Adv. Cancer Res. 67 1–23
Land H, Parada L F and Weinberg R A 1983 Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes;Nature (London) 304 596–602
Levine A J 1997 p53, the cellular gatekeeper for growth and division;Cell 88 323–331
Loeb L A 2001 A mutator phenotype in cancer;Cancer Res. 61 3230–3239
Maffini M V, Soto A M, Calabro J M, Ucci A A and Sonnenschein C 2004 The stroma as a crucial target in rat mammary gland carcinogenesis;J. Cell Sci. 117 1495–1502
Martins-Green M, Boudreau N and Bissell M J 1994 Inflammation is responsible for the development of wound-induced tumors in chickens infected with Rous Sarcoma virus;Cancer Res. 54 4334–4341
Matsumine Aet al 1996 Binding of APC to the human homolog of theDrosophila discs large tumour suppressor protein;Science 272 1020–1023
Mayr E 1982The growth of biological thought: Diversity, evolution and inheritance (Cambridge: Belknap Press) pp 1–146
McCullough K, Coleman W B, Ricketts S L, Wilson A W, Smita G J and Grisham J W 1998 Plasticity of the neoplastic phenotypein vivo is regulated by epigenetic factors;Proc. Natl. Acad. Sci. USA 95 15333–15338
McKinnell R Get al 1993 Genomic plasticity of the Lucke renal carcinoma: a review;Int. J. Dev. Biol. 37 213–219
Mechler B Met al 1991Drosophila as a model system for molecular analysis of tumorogenesis;Environ. Health Perspect. 93 63–71
Morange M 2002 The gene: Between holism and generalism; inPromises and limits of reductionism in the biomedical sciences (eds) D L Hull and M H V Van Regenmortel (Weinheim: John Wiley) pp 179–190
Moss L 2003aWhat genes can’t do (Cambridge: MIT Press) p. 129
Moss L 2003bWhat genes can’t do (Cambridge: MIT Press) p. 186
Moss L 2003cWhat genes can’t do (Cambridge: MIT Press)
Needham J 1931Chemical embryology (Cambridge: Cambridge University Press)
Needham J 1936 New advances in chemistry and biology of organized growth;Proc. R. Soc. B. 29 1577–1626
Newbold R F and Overell R W 1983 Fibroblast immortality is a prerequisite for transformation by EJ c-HA-ras oncogene;Nature (London) 304 648–651
Nyhan W L 2000 Dopamine function in Lesch-Nyhan disease;Environ. Health Perspect. (Suppl. 3) 108 409–411
Orr J W 1958 The mechanism of chemical carcinogenesis;Br. Med. Bull. 14 99–101
Parsons Ret al 1995 Mismatch repair deficiency in phenotypically normal human cells;Science 268 738–740
Pierce G B, Shikes R and Fink L M 1978Cancer: A problem of developmental biology (Englewoods Cliffs: Prentice-Hall)
Poisson A, Zablewska B and Gaudray P 2003 Menin interacting proteins as clues toward the understanding of multiple endocrine neoplasia type 1;Cancer Lett. 189 1–10
Powell C Eet al 2003 Plasma membrane-resident albumin binding protein associated with the proliferation of MCF7 serum-sensitive cells;Steroids 68 487–496
Prehn R T 1994 Cancers beget mutationsversus mutations beget cancers;Cancer Res. 54 5296–5300
Rangarajan A and Weinberg R A 2003 Comparative biology of mouse versus human cells: modelling human cancer in mice;Nat. Rev. Cancer 3 952–959
Reitmair A H, Cai J C, Bjerknes M, Redston M, Cheng C, Pind M T, Hay K, Mitri S, Bapat B V, Mak T W and Gallinger S 1996 MSH2 deficiency contributes to accelerated APC-mediated intestinal tumorigenesis;Cancer Res. 56 2922–2926
Rideout W M, Eggan K and Jaenisch R 2001 Nuclear cloning and epigenetic reprogramming of the genome;Science 293 1093–1098
Robanus-Maandag E, Dekker M, van der Valk M, Carrozza M L, Jeanny J C, Dannenberg J H, Berns A and te Riele H 1998 p107 is a suppressor of retinoblastoma development in pRb-deficient mice;Genes Dev. 12 1599–1609
Rosenberg A 1994Instrumental biology, or, The disunity of science (Chicago: University of Chicago Press)
Rowlatt C 1994 Some consequences of defining the neoplasm as focal self-perpetuating tissue disorganization; inNew frontiers in cancer causation (ed.) O H Iversen (Washington DC: Taylor and Francis) pp 45–58
Rubin H 1985 Cancer as a dynamic developmental disorder;Cancer Res. 45 2935–2942
Rubinfeld Bet al 1993 Association of the APC gene product with beta-catenin;Science 262 1731–1734
Schaub J 1991Inborn errors of metabolism (Philadelphia: Lippincott, Williams and Wilkins)
Smith K J, Johnson K A, Bryan T M, Hill D E, Markowitz S, Willson J K V, Paraskeva C, Peterson G M, Hamilton S R, Vogelstein B and Kinzler K W 1993 The APC gene product in normal and tumor cells;Proc. Natl. Acad. Sci. USA 90 2846–2850
Socolovsky M, Fallon A E J and Lodish H F 1998 The prolactin receptor rescues EpoR-/- erythroid progenitors and replaces EpoR in a synergistic interaction with c-kit;Blood 92 1491–1496
Sonnenschein C and Soto A M 1991 Cell proliferation in metazoans: negative control mechanisms;Cancer Treat. Res. 53 171–194
Sonnenschein C and Soto A M 1999a Cell proliferation: the background and the premises; inThe society of cells: Cancer and control of cell proliferation (New York: Springer Verlag) pp 1–13
Sonnenschein C and Soto A M 1999b TEpilogue Moving toward the integration of cell proliferation, carcinogenesis and neoplasia into biology; inThe society of cells: Cancer and control of cell proliferation (New York: Springer Verlag) pp 134–143
Sonnenschein C and Soto A M 1999c The enormous complexity of cancer; inThe society of cells: Cancer and control of cell proliferation (New York: Springer Verlag) pp 99–111
Sonnenschein C and Soto A M 1999dThe society of cells: Cancer and control of cell proliferation (New York: Springer Verlag) pp 41–59
Sonnenschein C and Soto A M 1999eThe society of cells: Cancer and control of cell proliferation (New York: Springer Verlag) pp 91–143
Sonnenschein C and Soto A M 1999fThe society of cells: Cancer and control of cell proliferation (New York: Springer Verlag)
Sonnenschein C and Soto A M 2000 The somatic mutation theory of carcinogenesis: Why it should be dropped and replaced;Mol. Carcinog. 29 1–7
Sonnenschein C, Soto A M and Michaelson C L 1996 Human serum albumin shares the properties of estrocolyone-I, the inhibitor of the proliferation of estrogen-target cells;J. Steroid Biochem. Mol. Biol. 59 147–154
Soto A M and Sonnenschein C 1985 The role of estrogens on the proliferation of human breast tumor cells (MCF-7);J. Steroid Biochem. 23 87–94
Soto A M and Sonnenschein C 1987 Cell proliferation of estrogen-sensitive cells: the case for negative control;Endocrinol. Rev. 8 44–52
Soto A M and Sonnenschein C 1991 Regulation of cell proliferation: the negative control perspective;Ann. NY Acad. Sci. 628 412–418
Soto A M and Sonnenschein C 1993 Regulation of cell proliferation: is the ultimate control positive or negative?; inNew frontiers in cancer causation (ed.) O H Iversen (Washington DC: Taylor and Francis) pp 109–123
Steel D M and Harris H 1989 The effect of antisense RNA to fibronectin on the malignancy of hybrids between melanoma cells and normal fibroblasts;J. Cell Sci. 93 515–524
Sternlicht M D, Lochter A, Sympson C J, Huey B, Rougier J-P, Gray J W, Pinkel D, Bissell M J and Werb Z 1999 The stromal proteinase MMP3/Stromelysin-1 promotes mammary carcinogenesis;Cell 98 137–146
Stewart T A and Mintz B 1981 Successful generations of mice produced from an established culture line of euploid teratocarcinoma cells;Proc. Natl. Acad. Sci. USA 78 6314–6318
Su L K, Burrell M, Hill D E, Gyuris J, Brent R, Wiltshire R, Trent J, Vogelstein B and Kinzler K W 1995 APC binds to the novel protein EB1;Cancer Res. 55 2972–2977
van Obberghen-Schilling E, Roche N S, Flanders K C, Sporn M B and Roberts A B 1988 Transforming growth factor beta1 positively regulates its own expression in normal and transformed cells;J. Biol. Chem. 263 7741–7746
Waddington C H 1935 Cancer and the theory of organizers;Nature (London) 135 606–608
Waddington C H 1942 Canalization of development and its inheritance of acquired characters;Nature (London) 150 563–565
Wang T-L, Rogo C, Silliman N, Ptak J, Markowitz S, Willson J K V, Parmigiani G, Kinzler K W, Vogelstein B and Velculescu V E 2002 Prevalence of somatic alterations in the colorectal cancer cell genome;Proc. Natl. Acad. Sci. USA 99 3076–3080
Weaver V M, Lelievre S, Lakins J N, Chrenek M A, Jones J C, Gianeotti F, Werb Z and Bissell M J 2002 β4 integrindependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium;Cancer Cell. 2 205–216
Weaver V M, Petersen O W, Wang F, Larabell C A, Briand P, Damsky C and Bissell M J 1997 Reversion of the malignant phenotype of human breast cells in three-dimensional culture andin vivo integrin blocking antibody;J. Cell Biol. 137 231–245
Weinberg R A 1998One renegade cell: how cancer begins (New York: Basic Books)
Weinstein I B 2002 Cancer. Addiction to oncogenes the Achilles heal of cancer;Science 297 63–64
Willis R A 1967Pathology of tumors (London: Butterworths)
Wolpert L 2002 Unpersuasive thoughts and unhelpful ideals;Science 295 633
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Soto, A.M., Sonnenschein, C. Emergentism as a default: Cancer as a problem of tissue organization. J Biosci 30, 103–118 (2005). https://doi.org/10.1007/BF02705155
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF02705155