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Beyond the Oncogene Paradigm: Understanding Complexity in Cancerogenesis

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Abstract

In the past decades, an enormous amount of precious information has been collected about molecular and genetic characteristics of cancer. This knowledge is mainly based on a reductionistic approach, meanwhile cancer is widely recognized to be a ‘system biology disease’. The behavior of complex physiological processes cannot be understood simply by knowing how the parts work in isolation. There is not solely a matter how to integrate all available knowledge in such a way that we can still deal with complexity, but we must be aware that a deeply transformation of the currently accepted oncologic paradigm is urgently needed. We have to think in terms of biological networks: understanding of complex functions may in fact be impossible without taking into consideration influences (rules and constraints) outside of the genome. Systems Biology involves connecting experimental unsupervised multivariate data to mathematical and computational approach than can simulate biologic systems for hypothesis testing or that can account for what it is not known from high-throughput data sets. Metabolomics could establish the requested link between genotype and phenotype, providing informations that ensure an integrated understanding of pathogenic mechanisms and metabolic phenotypes and provide a screening tool for new targeted drug.

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References

  • Akagi T, Sasai K, Hanafusa H (2003) Refractory nature of normal human diploid fibroblasts with respect to oncogene-mediated transformation. Proc Natl Acad Sci USA 100:13567–13572

    Google Scholar 

  • Albino AP, Le Strange R, Oliff AI, Furth ME, Old LJ (1984) Transforming ras genes from human melanoma: a manifestation of tumor heterogeneity? Nature 308:69–72

    Google Scholar 

  • Aranda-Anzaldo A (2001) Cancer development and progression: a non-adaptive process driven by genetic drift. Acta Biotheor 49:89–108

    Google Scholar 

  • Aranda-Anzaldo A (2002) Toward a morphogenetic perspective on cancer. Riv Biol 95:35–62

    Google Scholar 

  • Arnold JT, Lessey BA, Seppälä M., Kaufman DG (2002) Effect of normal and endometrial stroma on growth and differentiation in Ishikawa endometrial adenocarcinoma cells. Cancer Res 62:79–88

    Google Scholar 

  • Ashby J, Purchase IF (1988) Reflections on the declining ability of the Salmonella assay to detect rodent carcinogens as positive. Mutat Res 205:51–58

    Google Scholar 

  • Bailey JE (1999) Lessons from metabolic engineering for functional genomics and drug discovery. Nat Biotechnol 17:616–618

    Google Scholar 

  • Bailey JE (2001) Reflections on the scope and the future of metabolic engineering and its connections to functional genomics and drug discovery. Metab Eng 3:111–114

    Google Scholar 

  • Baisse B, Bouzourene H, Sarago EP, Bosman FT, Benhattar J (2001) Intratumor genetic heterogeneity in advanced human colorectal adenocarcinoma. Int J Cancer 93:346–352

    Google Scholar 

  • Baker SG, Kramer BS (2007) Paradoxes in carcinogenesis: new opportunities for research directions. BMC Cancer 7:151–157

    Google Scholar 

  • Barabasi AL, Oltvai ZN (2004) Network Biology: understanding the cell’s functional organization. Nat Rev Genet 5:101–113

    Google Scholar 

  • Barcellos-Hoff MH (2001) It takes a tissue to make a tumor: epigenetics, cancer and the microenvironment. J Mam Gland Biol Neoplasia 6(2):213–221

    Google Scholar 

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

    Google Scholar 

  • Becker FF (1975) Introduction. In: Becker FF (ed) Cancer. A comprehensive treatise, vol 3. Biology of tumors: cellular biology and growth. Plenum, New York

  • Beloussov LV, Opitz JM, Gilbert SF (1997) Contributions to field theory and life of Alexander G Gurwitsch. Int J Dev Biol 41:771–779

    Google Scholar 

  • Bhalla US, Yvengar R (1999) Emergent properties of networks of biological signaling pathways. Science 283:381–387

    Google Scholar 

  • Biskind MS, Biskind GS (1944) Development of tumors in the rat ovary after transplantation in the spleen. Proc Soc Exptl Med 55:176–181

    Google Scholar 

  • Bissell MJ, Radisky DC, Rizki A, Weaver VM, Petersen OW (2002) The organizing principle microenvironmental influences in the normal and malignant breast. Differentiation 70:537–546

    Google Scholar 

  • Bizzarri M, Cucina A, Valente MG, Mariani V, Stipa F, Tagliaferri F, Cavallaro A (2003) Enhanced TGF-β 1 secretion and inhibition of breast cancer cell growth by combined treatment with vitamin D3 and melatonin. J Surg Res 110:332–337

    Google Scholar 

  • Bloom FE (2001) What does it all mean to you? J Neurosci 21:8304–8305

    Google Scholar 

  • Boland CR, Ricciardiello L (1999) How many mutations does it take to make a tumor? Proc Natl Acad Sci USA 96(26):14675–14677

    Google Scholar 

  • Boveri T (1914) Zur frage der entstehung maligner tumoren. Fischer, Jena

    Google Scholar 

  • Bray D (1997) Reductionism for biochemists: how to survive the protein jungle. TIBS 22:325–326

    Google Scholar 

  • Breivik J (2005) The evolutionary origin of genetic instability in cancer development. Semin Cancer Biol 15:51–60

    Google Scholar 

  • Brinster RL (1974) The effect of cells transferred into the mouse blastocyst on subsequent development. J Exp Med 140:1049–1056

    Google Scholar 

  • Brown R, Strathdee G (2002) Epigenomics and epigenetic therapy of cancer. Trends Mol Med 8(4, Suppl.):s43–s48

    Google Scholar 

  • Calin GA, Vasilescu C, Negrini M, Barbanti-Brodano G (2003) Genetic chaos and anti-chaos in human cancers. Med Hypotheses 60(2):258–262

    Google Scholar 

  • Capp JP (2005a) Cancer cell undifferentiation: a matter of expression rather than mutations? Bioessays 28:102

    Google Scholar 

  • Capp JP (2005b) Stochastic gene expression, disruption of tissue averaging effects and cancer as a disease of development. Bioessays 27:1277–1285

    Google Scholar 

  • Cascante M, Boros LG, Comin-Anduix B, de Atauri P, Centelles JJ, Lee PW-N (2002) Metabolic control analysis in drug discovery and disease. Nat Biotechnol 20:243–249

    Google Scholar 

  • Challis GB, Stam HJ (1990) The spontaneous regression of cancer. A review of cases from 1900 to 1987. Acta Oncol 29(5):545–550

    Google Scholar 

  • Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy N, Shen Q, O’Hagan R., Pantginis J, Zhou, Horner JW 2nd, Cordon-Cardo C, Yancopoulos GD, DePinho RA (1999) Essential role for oncogenic Ras in tumor maintenance. Nature 400:468–472

    Google Scholar 

  • Coffey DS (1998) Self-organization, complexity and chaos: the new biology for medicine. Nat Med 4:882–883

    Google Scholar 

  • Colafranceschi M, Capuani G, Miccheli A, Campo S, Valerio M, Tomassini A, Giuliani A, Arserni B, Rossi S, de Santis R, Carminati P, Ruggiero V, Conti F (2007) Dissecting drug and vehicle metabolic effects in rats by a metabonomic approach. J Biochem Biophys Methods 70:355–361

    Google Scholar 

  • Corn PG, El-Deiry WS (2002) Derangement of growth and differentiation control in oncogenesis. BioEssays 24:83–90

    Google Scholar 

  • Cornsih-Bowden A, Cardenas ML (2000) From genome to cellular phenotype – a role for metabolic flux analysis? Nat Biotechnol 18:267–268

    Google Scholar 

  • Crick FHC (1970) The central dogma of molecular biology. Nature 227:561–563

    Google Scholar 

  • Cross SS (1997) Fractals in pathology. J Pathol 182:1–8

    Google Scholar 

  • Cucina A, Biava PM, D’Anselmi F, Coluccia P, Conti F, di Clemente R, Miccheli A, Frati L, Gulino A, Bizzarri M (2006) Zebrafish embryo proteins induce apoptosis in human colon cancer cells (Caco2). Apoptosis 11:1617–1628

    Google Scholar 

  • Cusik ME, Klitgord N, Vidal M, Hill DE (2005) Interactome: gateway into systems biology. Hum Mol Genet 14:R171–R181

    Google Scholar 

  • Delsanto PP, Romano A, Scalerandi M, Pescarmona GP (2000) Analysis of “phase transition” from tumor growth to latency. Phys Rev E 62(2):2547–2554

    Google Scholar 

  • Dimitrov BD (1993) The storage of energy as a cause of malignant transformation. Med Hypotheses 41:425–433

    Google Scholar 

  • Dipple KM, McCabe ERB (2000) Phenotypes of patients with “simple” mendelian disorders are complex traits: thresholds, modifiers and systems dynamics. Am J Hum Genet 66:1729–1735

    Google Scholar 

  • Dipple KM, Phelan JK, McCabe ERB (2001) Consequences of complexity within biological networks: robustness and health, or vulnerability and disease. Mol Genet Metab 74:45–50

    Google Scholar 

  • Dokoumetzidis A, Iliadis A, Macheras P (2001) Non-linear dynamics and chaos theory: concepts and applications relevant to pharmacodynamics. Pharmacol Res 18(4):415–426

    Google Scholar 

  • Dong-Le Bourhis X, Bertholis Y, Millot G, Degerges A, Sylvi M, Martin PM, Calvo F (1997) Effect of stromal and epithelial cells derived from normal and tumorous breast tissue on the proliferation of human breast cancer cell lines in coculture. Int J Cancer 71:42–48

    Google Scholar 

  • Duelli DM, Padilla-Nash HM, Berman D, Murphy KM, Ried T, Lazebnik Y (2007) A virus causes cancer by inducing massive chromosomal instability through cell fusion. Curr Biol 17:431–437

    Google Scholar 

  • Duesberg PH (1995) Oncogenes and cancer. Science 267:407–408

    Google Scholar 

  • Duesberg P (2003) Are cancers dependent on oncogenes or on aneuploidy? Cancer Genet Cytogenet 143:89–91

    Google Scholar 

  • Duesberg P, Rasnick D (2000) Aneuploidy, the somatic mutation that makes cancer a species of its own. Cell Motil Cytosk 47:81–107

    Google Scholar 

  • Duesberg P, Stindl R, Hehlmann R (2001) Origin of multidrug resistance in cells with and without mulidrug resistance genes: chromosome reassortements catalyzed by aneuploidy. Proc Natl Acad Sci USA 98:11283–11288

    Google Scholar 

  • Duesberg P, Li R, Rasnick D (2004) Aneuploidy approaching a perfect score in predicting and preventing cancer: highlights from a conference held in Oakland, CA in January. Cell Cycle 3(6):823–828

    Google Scholar 

  • Duesberg P, Li R, Fabarius A, Hehlmann R (2005) The chromosomal basis of cancer. Cell Oncol 27:293–318

    Google Scholar 

  • Esteller M (2000) Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes. Eur J Cancer 36:2294–2300

    Google Scholar 

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

    Google Scholar 

  • Felsher DW, Bishop JM (1999) Transient excess of MYC activity can elicit genomic instability and tumorigenesis. Proc Natl Acad Sci USA 96:3940–3944

    Google Scholar 

  • Fiehn O (2002) Metabolomics – the link between genotypes and phenotypes. Plant Mol Biol 48:155–171

    Google Scholar 

  • Fogarthy MP, Kessler JD, Wechsler-Reya RJ (2005) Morphing into cancer: the role of developmental signaling pathways in brain tumor formation. J Neurobiol 64:458–475

    Google Scholar 

  • Friboulet A, Thomas D (2005) Systems biology: an interdisciplinary approach. Biosens Bioelectron 20:2404–2407

    Google Scholar 

  • Friedberg EC (1985) DNA repair. W.H. Freeman, San Francisco

    Google Scholar 

  • Gallagher R, Appenzeller T (1999) Beyond reductionism. Science 284:79–80

    Google Scholar 

  • Gatenby RA, Frieden BR (2002) Application of information theory and extreme physical information to carcinogenesis. Cancer Res 62:3675–3684

    Google Scholar 

  • Ge H, Walhout JM, Vidal M (2003) Integrating ‘omic’ information: a bridge between genomics and systems biology. Trends Genet 19(10):551–560

    Google Scholar 

  • Gilbert S (1997) Developmental biology. Sinauer Associates, MA

    Google Scholar 

  • Gilbert SF, Opitz J, Raff RA (1996) Resynthesizing evolutionary and developmental biology. Dev Biol 173:357–372

    Google Scholar 

  • Glansdorff P, Prigogine I (1971) Thermodynamic theory of structure, stability and fluctuations. Wiley, New York

    Google Scholar 

  • Goh KI, Cusik ME, Valle D, Childs B, Vidal M, Barabasi AL (2007) The human disease network. Proc Natl Acad Sci USA 21:8685–8690

    Google Scholar 

  • Gorre ME, Mohammed M, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876

    Google Scholar 

  • Guerroui S, Deschatrette J, Wolfrom C (2005) Prolonged perturbation of the oscillation of hepatoma Fao cell proliferation by a single small dose of méthotrexate. Pathol Biol 53:290–294

    Google Scholar 

  • Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg R (1999) Creation of human tumor cells with defined genetic elements. Nature 400:464–648

    Google Scholar 

  • Hamburger V (1988) The heritage of experimental embryology. O.U.P., Oxford

    Google Scholar 

  • Hanash S (2004) Integrated global profiling of cancer. Nat Rev Cancer 4:638–643

    Google Scholar 

  • Hauptman S (2002) A thermodynamic interpretation of malignancy: do the genes come later? Med Hypotheses 58:144–147

    Google Scholar 

  • Heffner DK (2005) Chaotic tumors and 2 mistakes of molecular oncologists. Ann Diagn Pathol 9:61–67

    Google Scholar 

  • Heinrich R, Rapoport TA (1974) A linear steady-state treatment of enzymatic chains. General properties, control and effector strength. Eur J Biochem 42:89–95

    Google Scholar 

  • Hendrix MJC, Seftor EA, Seftor REB, Kasemeier-Kulesa J, Kulesa PM, Postovit L-M (2007) Reprogramming metastatic tumour cells with embryonic microenvironments. Nat Rev Cancer 7:246–255

    Google Scholar 

  • Hirshberg C, Barasch MI (1995) Remarkable recovery. Lippincott, Philadelphia

    Google Scholar 

  • Hochedlinger K, Blelloch R, Brennan C, Yamada Y, Kim M, Chin L, Jaenisch R (2004) Reprogramming of a melanoma genome by nuclear transplantation. Genes Dev 18:1875–1885

    Google Scholar 

  • Hofmann WK, de Vos S, Elashoff D, Gschaidmeier H, Hoelzer D, Koeffler HP, Ottmann OG (2002) Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study. Lancet 359:481–486

    Google Scholar 

  • Holliday R (1996) Neoplastic transformation: the contrasting stability of human and mouse cells. Cancer Surv 28:103–115

    Google Scholar 

  • Hood L, Galas D (2003) The digital code of DNA. Nature 421:444–448

    Google Scholar 

  • Hooth MJ, Vincent JL, Coleman WB, Presnell SC, Grisham JW, Smith GJ (1998) Genomic fluidity is necessary event preceding the acquisition of tumorigenicity during spontaneous transformation of WB-F344 rat liver epithelial cells. Hepatology 28(1):78–85

    Google Scholar 

  • Hornberg JJ, Bruggeman FJ, Westerhoff HW, Lankelma J (2006) Cancer: a systems biology disease. BioSystems 83:81–90

    Google Scholar 

  • Horrobin DJ (2000) Innovation in the pharmaceutical industry. J Royal Soc Med 93:341–345

    Google Scholar 

  • Hua VY, Wang WK, Duesberg P (1997) Dominant transformation by mutated human ras genes in vitro requires more than 100 times higher expression than is observed in cancers. Proc Natl Acad Sci USA 94:9614–9619

    Google Scholar 

  • Huettner CS, Zhang P, Van Etten RA, Tenen DG (2000) Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nat Genet 24:57–60

    Google Scholar 

  • Inouc T, Toda S, Narisawa Y, Sugihara H (2001) Subcutaneous adipocytes promote the differentiation of squamous cell carcinoma cell line (DJM-1) in collegen gel matrix culture. J Invest Dermatol 117:244–250

    Google Scholar 

  • Jain M, Arvanitis C, Chu K, Dewey W, Leonhardt E, Trinh M, Sundberg CD, Bishop JM, Felsher DW (2002) Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297:102–104

    Google Scholar 

  • Johnson HA (1987) Thermal noise and biological information. Q J Med 62:141–152

    Google Scholar 

  • Kacser H, Burns JA (1973) The control of flux. Symp Soc Exp Biol 27:65–104

    Google Scholar 

  • Kacser H, Burns JA (1981) The molecular basis of dominance. Genetics 97:639–665

    Google Scholar 

  • Kacser H, Small JR (1996) How may phenotypes from one genotype? The case of prion diseases. J Theor Biol 182:209–218

    Google Scholar 

  • Kenny PA, Bissell MJ (2003) Tumor reversion: correction of malignant behavior by microenvironmental cues. Int J Cancer 107:688–695

    Google Scholar 

  • Khalil IG, Hill C (2005) Systems biology for cancer. Curr Opin Oncol 17:44–48

    Google Scholar 

  • Kitano H (2004) Cancer as a robust system: implications for anticancer therapy. Nat Rev Cancer 4:227–232

    Google Scholar 

  • Kolch W, Calder M, Gilbert D (2005) When kinases meet mathematics: the systems biology of MAPK signaling. FEBS Lett 579:1891–1895

    Google Scholar 

  • Konishi N, Hiasa Y, Matsuda H, Tao M, Tsuzuki T, Hayashi I, Kitahori Y, Shiraishi T, Yatani R, Shimazaki J, Lin IC (1995) Intratumor cellular heterogeneity and alterations in ras oncogene and p53 tumor suppressor gene in human prostate carcinoma. Am J Pathol 147:112–122

    Google Scholar 

  • Krutovskikh V (2002) Implication of direct host-tumor intercellular interactions in non-immune host resistance to neoplastic growth. Semin Cancer Biol 12:267–276

    Google Scholar 

  • Kuile BH, Westerhoff HV (2001) Trascriptome meets metabolome: hierarchical and metabolic regulation of the glycolytic pathway. FEBS Lett 500:169–171

    Google Scholar 

  • Laird PW (2005) Cancer epigenetics. Hum Mol Genet 14:R65–R76

    Google Scholar 

  • Laird PW, Jaenisch R (1996) The role of DNA methylation in cancer genetic and epigenetics. Annu Rev Genet 30:441

    Google Scholar 

  • Land H, Parada LF, Weinberg RA (1983) Cellular oncogenes and multistep carcinogenesis. Science 222:771–778

    Google Scholar 

  • Lawrence PA (1992) The making of a fly. Blackwell, London

    Google Scholar 

  • Lazebnik Y (2002) Can a biologist fix a radio? Cancer Cell 2:179–182

    Google Scholar 

  • Lee JT, Herlyn M (2006) Embryogenesis meets tumorigenesis. Nat Med 12(8):882–884

    Google Scholar 

  • Lee LMJ, Seftor EA, Bonde G, Cronell AR, Hendrix MJC (2005) The fate of human malignant melanoma cells transplanted into Zebrafish embryos: assessment of migration and cell division in the absence of tumor formation. Dev Dyn 233:1560–1570

    Google Scholar 

  • Lehtimaki KK, Valonen PK, Griffin JL, Vaisanen TH, Grohn OHJ, Kettunen MI, Vepsalainen J, Yla-Herttuala S, Nicholson J, Kauppinen RA (2003) Metabolite changes in BT4C rat gliomas undergoing ganciclovir-thymidine kinase gene therapy-induced programmed cell death as studied by 1H-NMR spectroscopy in vivo, ex vivo and in vitro. J Biol Chem 278:45915–45923

    Google Scholar 

  • Lengauer C, Kinzler KW, Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396:643–649

    Google Scholar 

  • Li R, Sonik A, Stindl R, Rasnick D, Duesberg PH (2000) Gene mutation hypothesis of cancer: recent study claims mutation but is found to support aneuploidy. Proc Natl Acad Sci USA 97:3236–3241

    Google Scholar 

  • Li L, Connelly M, Wetmore C, Curran T, Morgan JL (2003) Mouse embryos cloned from brain tumors. Cancer Res 63:2733–2736

    Google Scholar 

  • Liang H, Sha N (2004) Modeling antitumor activity by using a non-linear mixed-effects model. Math Biosci 189:61–73

    Google Scholar 

  • Lijinsky W (1989) A view of the relation between carcinogenesis and mutagenesis. Env Mol Mutagen 14(Suppl):1678–1684

    Google Scholar 

  • Lin JH-L, Weiogel H, Cotrina ML, Liu S, Bueno S, Hansen AJ, Hansen TW, Goldman S, Nedergaard M (1998) Gap junction-mediated propagation and amplification of cell injury. Nat Neurosci 1:494–500

    Google Scholar 

  • Liu G, Parant GM, Chau P, Chavez-Reyes A, El-Naggar AK, Multani A, Chang S, Lozano G (2004) Chromosome stability in the absence of apoptosis is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet 36:63–68

    Google Scholar 

  • Livraghi T, Meloni F, Lazzaroni S, Frati L, Biava PM, Bizzarri M (2005) Embryonic stem cells differentiation stage factors in controlling tumor growth: the experimental data. Oncol Res 15:399–408

    Google Scholar 

  • Loeb LA (1997) Transient expression of a mutator phenotype in cancer cells. Science 277:1449–1450

    Google Scholar 

  • Lotem J, Sachs L (2002) Epigenetics wins over genetics: induction of differentiation in tumor cells. Semin Cancer Biol 12:339–346

    Google Scholar 

  • Malins DC, Polissar NL, Schaefer S, Su Y And Vinson M (1998) A unified theory of carcinogenesis based on order-disorder transitions in DNA structure as studied in the human ovary and breast cancer. Proc Natl Acad Sci USA 95:7637–7642

    Google Scholar 

  • Manetti C, Bianchetti C, Bizzarri M, Casciani L, D’Ascenzo G, Delfini M, Laganà A, Miccheli A, Motto M, Conti F (2004) NMR-based metabonomic study of transgenic maize. Phytochemistry 65:3187–3198

    Google Scholar 

  • Marcum JA (2005) Metaphysical presuppositions and scientific practices: reductionism and organicism in cancer research. Int Stud Phil Sci 19:31–45

    Google Scholar 

  • Marshall JC (2000) Complexity, chaos and incomprehensibility: parsing the biology of critical illness. Crit Care Med 8(7):2646–2648

    Google Scholar 

  • Marx J Medicine (2004) Why a new cancer drug works well, in some patients. Science 304:658–659

    Google Scholar 

  • Mauro VP, Wood IC, Krushel L, Crossin KL, Edelman GM (1994) Cell adhesion alters gene transcription in chicken embryo brain cells and mouse embryonal carcinoma cells. Proc Natl Acad Sci USA 91:2868–2872

    Google Scholar 

  • Mc Cullogh KD, Coleman WB, Smith GJ, Grisham JW (1997) Age-dependent induction of hepatic tumor regression by the tissue microenvironment after transplantation of neoplastically transformed rat liver epithelial cells into the liver. Cancer Res 57(9):1807–1813

    Google Scholar 

  • Meijer GA (2005) Chromosomes and cancer, Boveri rivisited. Cell Oncol 27:272–275

    Google Scholar 

  • Miccheli A, Puccetti C, Capuani G, di Cocco ME, Conti F (2003) [1–13C]glucose entry in neuronal and astrocytic intermediary metabolism of aged rats. A study of the effect of nicergoline treatment by 13C NMR spectroscopy. Brain Res 966:116–125

    Google Scholar 

  • Miccheli AT, Miccheli A, Di Clemente R, Valerio M, Coluccia P, Bizzarri M, Conti F (2006) NMR-based metabolic profilino of human hepatoma cells in relation to cell growth by culture media analysis. Biochim Biophys Acta 1760:1723–1731

    Google Scholar 

  • Miklos GLG (2005) The Human Cancer Genome Project – one more misstep in the war on cancer. Nat Biotechnol 23:535–537

    Google Scholar 

  • Mikulecky DC (2001) Network thermodynamics and complexity: a transition to relational system theory. Comput Chem 25:369–391

    Google Scholar 

  • Mintz B, Illmensee K (1975) Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA 72:3585–3589

    Google Scholar 

  • Missale C, Codignola A, Sigala S, Finardi A, Paez-Pereda M, Sher E, Spano P-F (1998) Nerve growth factor abrogates the tumorigenicity of human small cell lung cancer cell lines. Proc Natl Acad Sci USA 95:5366–5371

    Google Scholar 

  • Mizrachi Y, Naranjo JR, Levi BZ, Pollard HB, Lelkes PI (1990) PC12 cells differentiate into chromaffin cell-like phenotype in coculture with adrenal medullary endothelial cells. Proc Natl Acad Sci USA 87:6161–6165

    Google Scholar 

  • Morales CP, Holt SE, Ouellette M, Kaur KJ, Yan Y, Wilson KS, White MA, Wright WE, Shay JW (1999) Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nat Genet 21:115–118

    Google Scholar 

  • Naeim F, Moatamed F, Sahini M (1996) Morphogenesis of the bone marrow: fractal structures and diffusion-limited growth. Blood 87:5027–5031

    Google Scholar 

  • Nathanson L (1976) Spontaneous regression of malignant melanoma: a review of the literature on incidence, clinical features and possible mechanisms. Natl Cancer Inst Monogr 44:67–76

    Google Scholar 

  • National Cancer Institute (1976) Conference on spontaneous regression of cancer. US Department of Health, Education and Welfare, NIH publ. No. 76-1038, Bethesda

  • Needham J (1950) Biochemistry and morphogenesis. Cambridge University Press, Cambridge

    Google Scholar 

  • Nicholson JK, Wilson ID (2003) Understanding ‘global’ systems biology: metabonomics and the continuum of metabolism. Nat Rev 2:668–676

    Google Scholar 

  • Nielsen J, Oliver S (2005) The next wave in metabolome analysis. Trends Biotech 23:544–546

    Google Scholar 

  • Odunsi K, Wollman RM, Ambrosone CB, Huston A, McCann SE, Tammela J, Geisler JP, Miller G, Sellers T, Cliby W, Quian F, Keitz B, Intengan M, Lele S, Alderfer JL (2005) Detection of ovarian cancer using 1H-NMR-based metabonomics. Int J Cancer 113:782–788

    Google Scholar 

  • Ohlsson R, Kanduri C, Whithead J (2003) Epigenetic variability and evolution of human cancer. Adv Cancer Res 88:145–168

    Google Scholar 

  • Onsager L (1931) Reciprocal relation in irreversible processes. Phys Rev 37:405–426

    Google Scholar 

  • Opitz JM (1985) The developmental field concept. Am J Med Genet 21:1–11

    Google Scholar 

  • Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, Hubner N, Chien KR, Birchmeier C, Garratt AN (2002) Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci USA 99:8880–8885

    Google Scholar 

  • Paez JG, Jänne PA, Lee JC et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500

    Google Scholar 

  • Park SH, Maeda T, Mohapatra G, Waldman FM, Davis RL, Fuerstein BG (1995) Heterogeneity, poliploidy, aneusomy, and 9p deletion in human glioblastoma multiforme. Cancer Genet Cytogenet 83:127–135

    Google Scholar 

  • Pellman D (2007) Aneuploidy and cancer. Nature 446:38–39

    Google Scholar 

  • Pescarmona GP, Scalerandi M, Del Santo PP, Condat CA (1999) Non-linear model of cancer growth and metastasis: a limiting nutrient as a major determinant of tumor shape and diffusion. Med Hypotheses 53(6):497–503

    Google Scholar 

  • Phelps TJ, Palombo AV, Beliaev AS (2002) Metabolomics and microarrays for improved understanding of phenotypic characteristics controlled by both genomic and environmental constraints. Curr Opin Biotechnol 13:20–24

    Google Scholar 

  • Pierce GB, Shikes R, Fink LM (1978) Cancer: a problem of developmental biology. Prentice-Hall Inc., Englewood Cliffs, New Jersey

    Google Scholar 

  • Pitot HC (1975) Metabolic control and neoplasia. In: Becker FF (ed) Cancer. A comprehensive treatise, vol 3. Biology of tumors: cellular biology and growth. Plenum, New York

    Google Scholar 

  • Plattner R, Anderson MJ, Sato KJ, Fashing CL, Der CJ, Stanbridge EJ (1996) Loss of oncogenic ras expression does not correlate with loss of tumorigenicity in human cells. Proc Natl Acad Sci USA 93:6665–6670

    Google Scholar 

  • Polany M (1968) Life’s irreductible structure. Science 160:1308–1312

    Google Scholar 

  • Pollack A (2005) Quoted in New York Times, March 28, A1

  • Pollack JR, Sorlie T, Perou CM, Rees CA, Jeffrey SS, Lonning PE, Tibshirani R, Botstein D, Borresen-Dale AL, Brown PO (2002) Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors. Proc Natl Acad Sci USA 99:12963–12968

    Google Scholar 

  • Posadas EH, Criley SR, Coffey D (1996) Chaotic oscillation in cultured cells: rat prostate cancer. Cancer Res 56:3682–3688

    Google Scholar 

  • Potter JD (2001) Morphostats: a missing concept in cancer biology. Cancer Epidemiol Biomarkers Prev 10:161–170

    Google Scholar 

  • Prasad J, Lengauer C (2001) Chromosome segregation and cancer: cutting through the mystery. Nat Rev Cancer 1(2):109–117

    Google Scholar 

  • Prehn RT (1994) Cancers beget mutations versus mutations beget cancers. Cancer Res 54:5296–5300

    Google Scholar 

  • Prehn RT (2005) The role of mutation in the new cancer paradigm. Cancer Cell Int 5:9–15

    Google Scholar 

  • Prigogine I (1962) Introduction to thermodynamics of irreversible processes. John Wiley, New York

    Google Scholar 

  • Raamsdonk LM, Teusink B, Broadhurst D, Zhang N, Hayes A, Walsh MC, Berden JA, Brindle KM, Kell DB, Rowland JJ, Westerhoff HV, van Dam K, Oliver SG (2001) A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations. Nat Biotechnol 19:45–50

    Google Scholar 

  • Radisky D, Hagios C, Bissel MJ (2001) Tumors are unique organs defined by abnormal signaling and context. Semin Cancer Biol 11:87–95

    Google Scholar 

  • Rajagopolan H, Jallepalli PV, Rago C, Velculescu VE, Kinzler KW, Vogelstein B, Lengauer C (2004) Inactivation of hCDC4 can cause chromosomal instability. Nature 428:77–81

    Google Scholar 

  • Rasnick D, Duesberg PH (1999) How aneuploidy affects metabolic control and causes cancer. Biochem J 340:621–630

    Google Scholar 

  • Rew DA (1999) Tumor biology, chaos and non-linear dynamics. Eur J Surg Oncol 25:86–89

    Google Scholar 

  • Rew DA (2000) Modelling in surgical oncology. Part III: massive data sets and complex systems. Eur J Surg Oncol 26:805–809

    Google Scholar 

  • Rubin H (1985) Cancer as a dynamic developmental disorder. Cancer Res 45:2935:2942

    Google Scholar 

  • Rubin H (2006) What keeps cells in tissues behaving normally in the face of myriad mutations? Bioessays 28:515–524

    Google Scholar 

  • Rubin H (2007) Ordered heterogeneity and its decline in cancer and aging. Adv Cancer Res 98:117–47

    Google Scholar 

  • Rubin AL, Arnstein P, Rubin H (1990) Physiological induction and reversal of focus formation and tumorigenicity in NIH 3T3 cells. Proc Natl Acad Sci USA 87:10005–10009

    Google Scholar 

  • Rubin AL, Sneade-Koenig A, Rubin H (1992) High rate of diversification and reversal among subclones of neoplastically transformed NIH 3T3 clones. Proc Natl Acad Sci USA 89:4183–4186

    Google Scholar 

  • Sauter GH, Moch H, Moore D, Carroll P, Kerschmann R, Chew K, Mihatsch MJ, Gudat F, Waldman F (1993) Heterogeneity of erbB-2 gene amplification in bladder cancer. Cancer Res 53:2199–2203

    Google Scholar 

  • Schipper H, Turley EA, Baum M (1996) Viewpoint: a new biological framework for cancer research. Lancet 348:1149–1151

    Google Scholar 

  • Scriver CR, Waters PJ (1999) Monogenic traits are not simple. Trends Genet 15:267–272

    Google Scholar 

  • Sedivy R (1999) Chaodynamic loss of complexity and self-similarity cancer. Med Hypotheses 52(4):271–274

    Google Scholar 

  • Sedivy R, Mader RM (1997) Fractals, chaos and cancer: do they coincide? Cancer Invest 15:601–607

    Google Scholar 

  • Sell S (2004) Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 51:1–28

    Google Scholar 

  • Sell S, Pierce GB (1994) Maturation arrest of stem cell differentiation is a common pathway for the cellular origin of teratocarcinomas and epithelial cancers. Lab Invest 70:6–22

    Google Scholar 

  • Shima N, Alcaraz A, Liancko I, Buske TR, Andrews CA, Munroe RJ, Hartford SA, Tye BK, Schimenti JC (2007) A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice. Nat Genet 39:93–98

    Google Scholar 

  • Skinner JE (1994) Low-dimensional chaos in biological systems. Biotechnology 12:596–600

    Google Scholar 

  • Sonnenscheim C, Soto AM (2000) Somatic mutation theory of carcinogenesis: why it should be dropped and replaced. Mol Carcinog 29:205–211

    Google Scholar 

  • Sonnenschein C, Soto AM (2005) Are times a ‘changin’ in carcinogenesis? Endocrinology 146:11–12

    Google Scholar 

  • Soto AM, Sonnenschein C (2004) The somatic mutation theory of cancer: growing problems with the paradigm? Bioessays 26:1097–1107

    Google Scholar 

  • Stehelin D, Varmus HE, Bishop JM, Vogt PK (1976) DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260:170–173

    Google Scholar 

  • Sthephanopoulos G, Sinskey AJ (1993) Metabolic engineering – methodologies and future prospects. Trends Biotechnol 11:392–396

    Google Scholar 

  • Sthephanopoulos G, Valin JJ (1991) Network rigidity and metabolic engineering in metabolite overproduction. Science 252:1675–1681

    Google Scholar 

  • Storchova Z, Pellman D (2004) From polyploidy to aneuploidy, genome instability and cancer. Mol Cell Biol 5:45–54

    Google Scholar 

  • Strange K (2004) The end of “naïve reductionism”: rise of systems biology or renaissance of physiology? Am J Physiol Cell Physiol 288:C968–C974

    Google Scholar 

  • Streheler BL (1986) Genetic instability as the primary cause of human ageing. Exp Gerontol 21:283–319

    Google Scholar 

  • Strohman RC (1997) The coming Kuhnian revolution in biology. Nat Biotechnol 15:194–200

    Google Scholar 

  • Strohman R (2002) Maneuvering in the complex path from genotype to phenotype. Science 296:701–703

    Google Scholar 

  • Suzuki T, Miyata N (2006) Epigenetic control using natural products and synthetic molecules. Curr Med Chem 23:935–958

    Google Scholar 

  • Sweetlove LJ, Fernie AR (2005) Regulation of metabolic networks: understanding metabolic complexity in the systems biology era. New Phytol 168:9–24

    Google Scholar 

  • Szollosi J, Balazs M, Fuerstein BG, Benz CC, Waldman FM (1995) ERBB-2 (HER2/neu) gene copy number, p185HER-2 overexpression and intratumor heterogeneity in human breast cancer. Cancer Res 55:5400–5407

    Google Scholar 

  • Tohge T, Nishiyama Y, Hirai MY, Yano M, Nakajima J, Awazuhara M, Inoue E, Takahashi H, Goodenowe DB, Kirayama M, Noji M, Yamazaki M, Saito K (2005) Functional genomics by integrated analysis of metabolome and transcriptome of Arabidoposis plants overexpressing a MYB transcription factor. Plant J 42:218–235

    Google Scholar 

  • Van Elsas A, Zerp S, van der Flier S, Kruse-Wolters M, Vacca A, Ruiter DJ, Schrier P (1995) Analysis of N-ras mutations in human cutaneous melanoma: a manifestation of tumor heterogeneity detected by polymerase chain reaction/single-stranded conformation polymorphism analysis. Recent Results Cancer Res 139:57–67

    Google Scholar 

  • Van’t Veer LJ, Dai H, van der Vijver MJ, He JD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536

    Google Scholar 

  • Vaudry D, Stork PJ, Lazarovici P, Eiden LE (2002) Signaling pathways for PC12 cell differentiation: making the right connections. Science 296:1648–1649

    Google Scholar 

  • Vidal M (2005) Interactome modelling. FEBS Lett 579:1834–1838

    Google Scholar 

  • Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9:138–141

    Google Scholar 

  • Von Bertalanffy L (1969) General system theory. Revised edn. George Braziller, New York

    Google Scholar 

  • Von Hansemann D (1890) Űber asymmetrische zelltheilung in epithelkrebsen und deren biologische bedeutung. Vircows Arch Pathol Anat 119:299–326

    Google Scholar 

  • Waliszewski P, Molski M, Konarski J (1998) On the holistic approach in cellular and cancer biology: non-linearity, complexity, and quasi-determinism of the dynamic cellular network. J Surg Oncol 68:70–78

    Google Scholar 

  • Waliszewski P, Molski M, Konarski J (2001) On the relationship between fractal geometry of space and time on which a system of interacting cells exists and dynamics of gene expression. Acta Bioc Pol 48(1):209–220

    Google Scholar 

  • Walleczek J (2000) Self-organized biological dynamics and non-linear control. Cambridge University Press, Cambridge

  • Wang F, Hansen RK, Radisky D, Yoend T, Barcellos-Hoff MH, Petersen OW, Turley EA, Bissell MJ (2002) Phenotypic reversion or death of cancer cells by altering signalling pathways in three-dimensional contexts. J Natl Cancer Inst 94:1494–1503

    Google Scholar 

  • Watson JD (1976) Molecular biology of the gene, 3rd edn. W. A. Benjamin Inc., New York

  • Weatherall DJ (2001) Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias. Nat Rev Genet 2:245–255

    Google Scholar 

  • Weaver BAA, Cleveland DW (2006) Does aneuploidy cause cancer? Curr Opion Cell Biol 18:68:667

    Google Scholar 

  • Webster G, Goodwin B (1996) Form and transformation. C.U.P., Cambridge

  • Weinstein IB (2002) Addiction to oncogenes: the Achille’s heal of cancer. Science 297:63–64

    Google Scholar 

  • Weiss P (1969) Principles of development [reprint of the original 1939, Holt]. Hafner, New York

  • Weiss JN, Garfinkel A, Spano ML, Ditto WL (1994) Chaos and chaos-control in biology. J Clin Invest 93:1355–1360

    Article  Google Scholar 

  • Westerhoff H, Palsson BO (2004) The evolution of molecular biology into system biology. Nat Biotechnol 22:1249–1252

    Google Scholar 

  • Whashington C, Dalbegué F, Abreo F, Taubenberger JK, Lichy JH (2000) Loss of heterozygosity in fibrocystic change of the breast: genetic relationships between benign proliferative lesions and associated carcinomas. Am J Pathol 157:323–329

    Google Scholar 

  • Wolf M, Mousses S, Hautaniemi S (2004) High-resolution analysis of gene copy number alterations in human prostate cancer using CGH on cDNA microarrays: impact of copy number on gene expression 2. Neoplasia 6:240–247

    Google Scholar 

  • Wolffe AP, Matzke MA (1999) Epigenetics: regulation through repression. Science 286:481

    Google Scholar 

  • Yang Y, Xu G, Zheng Y, Kong H, Pang T, Lu S, Yang Q (2004) Diagnosis of liver cancer using HPLC-based metabonomics avoiding false-positive result from hepatitis and hepatocirrhosis diseases. J Chromatogr B Analyt Technol Biomed Lefe Sci 813:59–65

    Google Scholar 

  • Yu C-L., Tsai M-H (2001) Embryonic apoptosis-inducing proteins exhibited anticancer activity in vitro and in vivo. Anticancer Res 21:1839–1856

    Google Scholar 

  • Zaichin AN, Zhabotinsky AM (1970) Concentration wave propagation in two-dimensional liquid-phase self-oscillating system. Nature 225:535–537

    Google Scholar 

  • Zhang L, Zhou W, Velculescu VE, Kern SE, Hruban RH, Hamilton SR, Vogelstein B, Kinzler KW (1997) Gene expression profiles in normal and cancer cells. Science 276:1268–1272

    Google Scholar 

  • Zhou X, Wang X, Pal R, Ivanov I, Bittner M, Dougherty ER (2004) A Bayesian connectivity-based approach to constructing probabilistic gene regulatory networks. Bioinformatics 20:2918–2927

    Google Scholar 

  • Zutter MM, Santoro SA, Staatz WD, Tsung YL (1995) Re-expression of the α2ß-1 integrin abrogates malignant phenotype of breast carcinoma cells. Proc Natl Acad Sci USA 92:7411–7415

    Google Scholar 

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We thank Dr. Lewis Baker for reviewing the English in the manuscript.

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Bizzarri, M., Cucina, A., Conti, F. et al. Beyond the Oncogene Paradigm: Understanding Complexity in Cancerogenesis. Acta Biotheor 56, 173–196 (2008). https://doi.org/10.1007/s10441-008-9047-8

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