Skip to main content
Log in

Cancer research in need of a scientific revolution: Using ‘paradigm shift’ as a method of investigation

  • Review
  • Published:
Journal of Biosciences Aims and scope Submit manuscript

Abstract

Despite important human and financial resources and considerable accumulation of scientific publications, patents, and clinical trials, cancer research has been slow in achieving a therapeutic revolution similar to the one that occurred in the last century for infectious diseases. It has been proposed that science proceeds not only by accumulating data but also through paradigm shifts. Here, we propose to use the concept of ‘paradigm shift’ as a method of investigation when dominant paradigms fail to achieve their promises. The first step in using the ‘paradigm shift’ method in cancer research requires identifying its founding paradigms. In this review, two of these founding paradigms will be discussed: (i) the reification of cancer as a tumour mass and (ii) the translation of the concepts issued from infectious disease in cancer research. We show how these founding paradigms can generate biases that lead to over-diagnosis and over-treatment and also hamper the development of curative cancer therapies. We apply the ‘paradigm shift’ method to produce perspective reversals consistent with current experimental evidence. The ‘paradigm shift’ method enlightens the existence of a tumour physiologic–prophylactic–pathologic continuum. It integrates the target/anti-target concept and that cancer is also an extracellular disease. The ‘paradigm shift’ method has immediate implications for cancer prevention and therapy. It could be a general method of investigation for other diseases awaiting therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Albini A and Sporn MB 2007 The tumour microenvironment as a target for chemoprevention. Nat. Rev. Cancer 7 139–147

    Article  CAS  PubMed  Google Scholar 

  • Allen M and Louise Jones J 2011 Jekyll and Hyde: the role of the microenvironment on the progression of cancer. J. Pathol. 223 162–176

    CAS  PubMed  Google Scholar 

  • Andrews GS 1949 Latent carcinoma of the prostate. J. Clin. Pathol. 2 197–208

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Arendt LM, Rudnick JA, Keller PJ and Kuperwasser C 2010 Stroma in breast development and disease. Semin. Cell Dev. Biol. 21 11–18

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bachelard 1938 La Formation de l'esprit scientifique, Gaston Bachelard, ed. Vrin; translated as The Formation of the Scientific Mind Clinamen, Bolton, (2002)

  • Barber B 1961 Resistance by scientists to scientific discovery. Science. 134 596–602

    Article  CAS  PubMed  Google Scholar 

  • Berrino F, De Angelis R, Sant M, Rosso S, Bielska-Lasota M, Lasota MB, Coebergh JW, Santaquilani M, et al. 2007 Survival for eight major cancers and all cancers combined for European adults diagnosed in 1995-99: results of the EUROCARE-4 study. Lancet Oncol. 8 773–783

    Article  PubMed  Google Scholar 

  • Bishop JM 1983 Cellular oncogenes and retroviruses. Annu. Rev. Biochem. 52 301–354

    Article  CAS  PubMed  Google Scholar 

  • Bissell MJ and Hines WC 2011 Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17 320–329

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bissell MJ and Radisky D 2001 Putting tumours in context. Nat. Rev. Cancer 1 46–54

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bissell MJ, Hall HG and Parry G 1982 How does the extracellular matrix direct gene expression? J. Theor. Biol. 99 31–68

    Article  CAS  PubMed  Google Scholar 

  • Booth BW, Boulanger CA, Anderson LH and Smith GH 2011 The normal mammary microenvironment suppresses the tumorigenic phenotype of mouse mammary tumor virus-neu-transformed mammary tumor cells. Oncogene 30 679–689

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Carrel A and Burrows M 1910 Cultivation of adult tissues and organs outside of the body. JAMA 55 1379–1381

    Article  Google Scholar 

  • Coleman WB, Wennerberg AE, Smith GJ and Grisham JW 1993 Regulation of the differentiation of diploid and some aneuploid rat liver epithelial (stemlike) cells by the hepatic microenvironment. Am. J. Pathol. 142 1373–1382

    PubMed Central  CAS  PubMed  Google Scholar 

  • Collado M and Serrano M 2010 Senescence in tumours: evidence from mice and humans. Nat. Rev. Cancer 10 51–57

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, Clouthier SG and Wicha MS 2012 Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc. Natl. Acad. Sci. USA 109 2784–2789

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D, Trama A, Visser O, et al. 2014 Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE--5-a population-based study. Lancet Oncol. 15 23–34

    Article  PubMed  Google Scholar 

  • Demicheli R, Retsky MW, Hrushesky WJM, Baum M and Gukas ID 2008 The effects of surgery on tumor growth: a century of investigations. Ann. Oncol. 19 1821–1828

    Article  CAS  PubMed  Google Scholar 

  • Druker BJ 2009 Perspectives on the development of imatinib and the future of cancer research. Nat. Med. 15 1149–1152

    Article  CAS  PubMed  Google Scholar 

  • DuFort CC, Paszek MJ and Weaver VM 2011 Balancing forces: architectural control of mechanotransduction. Nat. Rev. Mol. Cell Biol. 12 308–319

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dufour A and Overall CM 2013 Missing the target: matrix metalloproteinase antitargets in inflammation and cancer. Trends Pharmacol. Sci. 34 233–242

    Article  CAS  PubMed  Google Scholar 

  • Dvorak HF 1986 Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315 1650–1659

    Article  CAS  PubMed  Google Scholar 

  • Eagle H 1958 Animal cells and microbiology. Bacteriol. Rev. 22 217–222

    PubMed Central  CAS  PubMed  Google Scholar 

  • Esserman LJ, Thompson IM, Reid B, Nelson P, Ransohoff DF, Welch HG, Hwang S, Berry DA, et al. 2014 Addressing overdiagnosis and overtreatment in cancer: a prescription for change. Lancet Oncol. 15 e234–242

    Article  PubMed Central  PubMed  Google Scholar 

  • Folkman J and Kalluri R 2004 Cancer without disease. Nature 427 787

    Article  CAS  PubMed  Google Scholar 

  • Franco OE and Hayward SW 2012 Targeting the tumor stroma as a novel therapeutic approach for prostate cancer. Adv. Pharmacol. 65 267–313

    Article  CAS  PubMed  Google Scholar 

  • Franks LM 1954 Latent carcinoma. Ann. R. Coll. Surg. Engl. 15 236–249

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fukuda H, Mochizuki S, Abe H, Okano HJ, Hara-Miyauchi C, Okano H, Yamaguchi N, Nakayama M, et al. 2011 Host-derived MMP-13 exhibits a protective role in lung metastasis of melanoma cells by local endostatin production. Br. J. Cancer 105 1615–1624

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Garcion E, Naveilhan P, Berger F and Wion D 2009 Cancer stem cells: beyond Koch’s postulates. Cancer Lett. 278 3–8

    Article  CAS  PubMed  Google Scholar 

  • Gately S, Twardowski P, Stack MS, Patrick M, Boggio L, Cundiff DL, Schnaper HW, Madison L, et al. 1996 Human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor, angiostatin. Cancer Res. 56 4887–4890

    CAS  PubMed  Google Scholar 

  • Gattazzo F, Urciuolo A and Bonaldo P 2014 Extracellular matrix: a dynamic microenvironment for stem cell niche. Biochim. Biophys. Acta. 1840 2506–2519

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Good DJ, Polverini PJ, Rastinejad F, Le Beau MM, Lemons RS, Frazier WA and Bouck NP 1990 A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc. Natl. Acad. Sci. USA 87 6624–6628

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Greco FA 2014 Cancer of unknown primary site: still an entity, a biological mystery and a metastatic model. Nat. Rev. Cancer 14 3–4

    Article  CAS  PubMed  Google Scholar 

  • Guba M, Cernaianu G, Koehl G, Geissler EK, Jauch KW, Anthuber M, Falk W and Steinbauer M 2001 A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. Cancer Res. 61 5575–5579

    CAS  PubMed  Google Scholar 

  • Hadfield G 1954 The dormant cancer cell. Br. Med. J. 2 607–610

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hamano Y, Zeisberg M, Sugimoto H, Lively JC, Maeshima Y, Yang C, Hynes RO, Werb Z, et al. 2003 Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin. Cancer Cell 3 589–601

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hanahan D 2014 Rethinking the war on cancer. Lancet 383 558–563

    Article  PubMed  Google Scholar 

  • Heljasvaara R, Nyberg P, Luostarinen J, Parikka M, Heikkilä P, Rehn M, Sorsa T, Salo T, et al. 2005 Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteases. Exp. Cell Res. 307 292–304

    Article  CAS  PubMed  Google Scholar 

  • Hiscox S, Barrett-Lee P and Nicholson RI 2011 Therapeutic targeting of tumor-stroma interactions. Expert Opin. Ther. Targets 15 609–621

    CAS  PubMed  Google Scholar 

  • Hoffman BD, Grashoff C and Schwartz MA 2011 Dynamic molecular processes mediate cellular mechanotransduction. Nature 475 316–323

    Article  CAS  PubMed  Google Scholar 

  • Holmgren L, O’Reilly MS and Folkman J 1995 Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat. Med. 1 149–153

    Article  CAS  PubMed  Google Scholar 

  • Holton G 1975 On the role of themata in scientific thought. Science 188 328–334

    Article  CAS  PubMed  Google Scholar 

  • Ikushima H and Miyazono K 2010 TGFbeta signalling: a complex web in cancer progression. Nat. Rev. Cancer. 10 415–424

    Article  CAS  PubMed  Google Scholar 

  • Ingber DE 2008 Can cancer be reversed by engineering the tumor microenvironment? Semin. Cancer Biol. 18 356–364

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jain A, Betancur M, Patel GD, Valmikinathan CM, Mukhatyar VJ, Vakharia A, Pai SB, Brahma B, et al. 2014 Guiding intracortical brain tumour cells to an extracortical cytotoxic hydrogel using aligned polymeric nanofibres. Nat. Mater. 13 308–316

    Article  CAS  PubMed  Google Scholar 

  • Joyce JA 2005 Therapeutic targeting of the tumor microenvironment. Cancer Cell 7 513–520

    Article  CAS  PubMed  Google Scholar 

  • Kenny PA, Lee GY and Bissell MJ 2007 Targeting the tumor microenvironment. Front Biosci J Virtual Libr. 12 3468–3474

    Article  CAS  Google Scholar 

  • Kotsakis P and Griffin M 2007 Tissue transglutaminase in tumour progression: friend or foe? Amino Acids 33 373–384

    Article  CAS  PubMed  Google Scholar 

  • Kuhn TS 1962a Historical structure of scientific discovery. Science 136 760–764

    Article  CAS  PubMed  Google Scholar 

  • Kuhn T 1962b The structure of scientific revolutions (Chicago: University of Chicago Press)

  • Loges S, Mazzone M, Hohensinner P and Carmeliet P 2009 Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 15 167–170

    Article  CAS  PubMed  Google Scholar 

  • Lowe SW, Cepero E and Evan G 2004 Intrinsic tumour suppression. Nature 432 307–315

    Article  CAS  PubMed  Google Scholar 

  • Martin MD and Matrisian LM 2007 The other side of MMPs: protective roles in tumor progression. Cancer Metastasis Rev. 26 717–724

    Article  CAS  PubMed  Google Scholar 

  • Mayorca-Guiliani A and Erler JT 2013 The potential for targeting extracellular LOX proteins in human malignancy. Onco Targets Ther. 6 1729–1735

    PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Morris GJ, Greco FA, Hainsworth JD, Engstrom PF, Scialla S, Jordan WE 3rd and Thomas LC 2010 Cancer of unknown primary site. Semin. Oncol. 37 71–79

    Article  PubMed  Google Scholar 

  • Mueller MM and Fusenig NE 2004 Friends or foes - bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4 839–849

    Article  CAS  PubMed  Google Scholar 

  • Naumov GN, Bender E, Zurakowski D, Kang S-Y, Sampson D, Flynn E, Watnick RS, Straume O, et al. 2006 A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J. Natl. Cancer Inst. 98 316–325

    Article  PubMed  Google Scholar 

  • Nugue G and Wion D 2012 Angiogenesis and the tumor space–time continuum. Proc. Natl. Acad. Sci. USA 109 E914–E914

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nyberg P, Xie L and Kalluri R 2005 Endogenous inhibitors of angiogenesis. Cancer Res. 65 3967–3979

    Article  CAS  PubMed  Google Scholar 

  • O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, et al. 1994 Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 79 315–328

    Article  PubMed  Google Scholar 

  • Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu C-C, Simpson TR, Laklai H, Sugimoto H, et al. 2014 Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25 719–734

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pavlidis N and Pentheroudakis G 2012 Cancer of unknown primary site. Lancet. 379 1428–1435

    Article  PubMed  Google Scholar 

  • Pickup M, Novitskiy S and Moses HL 2013 The roles of TGFβ in the tumour microenvironment. Nat. Rev. Cancer 13 788–799

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pietras K and Ostman A 2010 Hallmarks of cancer: interactions with the tumor stroma. Exp. Cell Res. 316 1324–1331

    Article  CAS  PubMed  Google Scholar 

  • Principe DR, Doll JA, Bauer J, Jung B, Munshi HG, Bartholin L, Pasche B, Lee C, et al. 2014 TGF-β: duality of function between tumor prevention and carcinogenesis. J. Natl. Cancer Inst 106 djt369

    Article  PubMed Central  PubMed  Google Scholar 

  • Quail DF and Joyce JA 2013 Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19 1423–1437

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, et al. 2014 Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25 735–747

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rous P and Jones FS 1916 A method for obtaining suspensions of living cells from the fixed tissues, and for the plating out of individual cells. J. Exp. Med. 23 549–555

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schiller HB and Fässler R 2013 Mechanosensitivity and compositional dynamics of cell-matrix adhesions. EMBO Rep. 14 509–519

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Serrano M, Lin AW, McCurrach ME, Beach D and Lowe SW 1997 Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88 593–602

    Article  CAS  PubMed  Google Scholar 

  • Smithers DW 1962 An attack on cytologism. Lancet. 1 493–499

    Article  CAS  PubMed  Google Scholar 

  • Smithers DW 1969 Maturation in human tumours. Lancet. 2 949–952

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Sonnenschein C and Soto AM 2011 The death of the cancer cell. Cancer Res. 71 4334–4337

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Soto AM and Sonnenschein C 2014 One hundred years of somatic mutation theory of carcinogenesis: is it time to switch? BioEssays News Rev. Mol. Cell. Dev. Biol. 36 118–120

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Strauss DC and Thomas JM 2010 Transmission of donor melanoma by organ transplantation. Lancet Oncol. 11 790–796

    Article  PubMed  Google Scholar 

  • Tchou J and Conejo-Garcia J 2012 Targeting the tumor stroma as a novel treatment strategy for breast cancer: shifting from the neoplastic cell-centric to a stroma-centric paradigm. Adv. Pharmacol. 65 45–61

    Article  CAS  PubMed  Google Scholar 

  • Tlsty TD and Coussens LM 2006 Tumor stroma and regulation of cancer development. Annu. Rev. Pathol. 1 119–150

    Article  CAS  PubMed  Google Scholar 

  • Van der Sanden B, Appaix F, Berger F, Selek L, Issartel J-P and Wion D 2013 Translation of the ecological trap concept to glioma therapy: the cancer cell trap concept. Future Oncol. 9 817–824

    Article  PubMed  Google Scholar 

  • Watt FM and Huck WTS 2013 Role of the extracellular matrix in regulating stem cell fate. Nat. Rev. Mol. Cell Biol. 14 467–473

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Welch HG and Passow HJ 2014 Quantifying the benefits and harms of screening mammography. JAMA Intern. Med. 174 448–454

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Marie France, Laurent, Alessandro and Duane for their helpful discussions and support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Didier Wion.

Additional information

Corresponding editor: Indraneel Mittra

[Wion D, Appaix F, Burruss M, Berger F and van der Sanden B 2015 Cancer research in need of a scientific revolution: Using ‘paradigm shift’ as a method of investigation. J. Biosci.] DOI 10.1007/s12038-015-9543-3

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wion, D., Appaix, F., Burruss, M. et al. Cancer research in need of a scientific revolution: Using ‘paradigm shift’ as a method of investigation. J Biosci 40, 657–666 (2015). https://doi.org/10.1007/s12038-015-9543-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12038-015-9543-3

Keywords

Navigation