Despite over a century of intensive efforts, the great gains promised by the War on Cancer nearly 50 years ago have not materialized. Since 1999, we have analyzed the lack of progress in explaining and “curing” cancer by examining the merits of the premises that determine how cancer is understood and treated. Our ongoing critical analyses have aimed at clarifying the sources of misunderstandings at the root of the cancer puzzle while providing a plausible and comprehensive biomedical perspective as well as a new theory of carcinogenesis that is compatible with evolutionary theory. In this essay, we explain how this new theory, the tissue organization field theory (TOFT), can help chart a path to progress for cancer researchers by explaining features of cancer that remain unexplainable from the perspective of the still hegemonic somatic mutation theory (SMT) and its variants. Of equal significance, the premises underlying the TOFT offer new perspectives on basic biological phenomena.
Citation: Sonnenschein C, Soto AM (2020) Over a century of cancer research: Inconvenient truths and promising leads. PLoS Biol 18(4): e3000670. https://doi.org/10.1371/journal.pbio.3000670
Published: April 1, 2020
Copyright: © 2020 Sonnenschein, Soto. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the National Institute of Environmental Health Sciences grants ES08314 (AMS), ES030045 (AMS), and ES026283 (AMS). The funders had no role in the content of this essay, and it does not necessarily represent the official views of the funding agencies.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: SMT, somatic mutation theory; TOFT, tissue organization field theory
“About 30 years ago there was much talk that Geologists ought only to observe & not theorise; & I well remember some one saying, that at this rate a man might as well go into a gravel-pit & count the pebbles & describe their colours. How odd it is that every one should not see that all observation must be for or against some view, if it is to be of any service.”—Charles Darwin letter to Henry Fawcett. 18 September 1861.: The correspondence of Charles Darwin. Edited by Frederick Burkhardt et al. Cambridge: Cambridge University Press. 1985.
The lack of significant improvements in the understanding of carcinogenesis, and the failure to reach the cherished goal of “curing” cancer as envisioned by the 1971 War on Cancer declaration, encouraged several researchers to question the strategy of the war effort during the last quarter century [1–7]. The consensus reached by critics centered on the recognition that advances in understanding what happens within cells (in nuclei, mitochondria, endoplasmic reticulum, cell metabolism, plasma membrane, etc.) remained mostly irrelevant both to understanding carcinogenesis and to significantly benefiting the object of the whole effort, the cancer patient [8,9]. As a result, researchers, clinicians, and patients have called for a critical evaluation of theories of carcinogenesis [8,10–24].
In this Essay, we address these issues from a historical perspective, outline the merits of the 2 main theories of carcinogenesis, and draw—when possible—constructive conclusions. Given the vastness of the topic, we are necessarily leaving out a few historical milestones [6,25–28].
During the second half of the 19th century, cancer was considered a tissue-based disease, and proliferation was a constitutive property of cells. In 1914, the famed embryologist/zoologist Theodor Boveri, who admitted to not having hands-on experience in carcinogenesis, stated that the initial steps of the carcinogenic process (initiation and early progression), unlike those of the embryos he studied, were not accessible to observers because tumors had already accumulated billions of cells by the time they were detected . Therefore, it was not possible to accurately describe how a palpable tumor initially arose. This conclusion remains unaltered today. Also, Boveri agreed—as did his predecessors—that the default state of cells was proliferation, but in opposition to the then prevailing view, he posited that cancer was a cell-based disease due to chromatin changes (mutations) that modified the proliferative behavior of what he considered to be “the cancer cell” . Over the years, alternative conjectures and hypotheses about cancer initiation have been proposed by scientists who, in some cases, like Boveri, had no first-hand experience on the subject yet freely speculated about it [31–34], while others expounded their empirical-based views on carcinogenesis [6,35–40].
In addition to Boveri’s remarks on cancer initiation’s observability, other factors have contributed to obfuscation in this field. Namely, since the beginning of the 20th century, leading cell and developmental biologists who once considered theories necessary to understand the objects of inquiry adopted, instead, the belief that reality is directly accessible by the accumulation of data, which made theories superfluous [41–43]. Concomitantly, they embraced a reductionist stance . Evolutionary biologists, on the other hand, continued to appreciate theory’s practical benefits in framing observations and experiments while incorporating new discoveries that did not fit the current version of Darwin’s theory [45–47] along with new and updated theoretical perspectives . This updating is possible because evolution’s principles have been clearly stated, i.e., it is not a vague theory (see below). In contrast, experimental biologists dealing with aspects of the life cycle of organisms distanced themselves even more from theoretical concerns during the second half of the 20th century as the molecular biology revolution took off. Indeed, molecular biologists radically modified the way organisms were thought about by introducing mathematical information theories into biology concepts without a proper analysis while using metaphors that were eventually taken literally . By the 1950s, the standard view of carcinogenesis became dominated by the somatic mutation theory (SMT), which is rooted in a reductionist and genetic deterministic stance, including the erroneous assumption of a linear causal link between genotype and phenotype . This stance predicates that cells are like tiny computers run by a program [51–58]. The lack of a robust theoretical background to frame experiments and explanations has hindered the adoption of productive alternatives in the fields of experimental biology and cancer research for decades [22,59–61].
Evaluating theories of carcinogenesis
We will first compare the merits of what we consider the 2 main theories of carcinogenesis, namely, the still hegemonic SMT and the more recently proposed tissue organization field theory (TOFT)  (see Table 1). The rationale for reducing the number of theories on carcinogenesis to 2 is due to the fact that they can be distinctively separated by their alleged place of origin within the host organism and by the different roles that mutations play in both theories. In the latter regard, mutations are central for the SMT, whereas they are considered as an epiphenomenon by the TOFT.
The SMT is anchored at the cellular level of biological organization, which has theoretical and experimental implications. If “a cell” is the crucial target of carcinogens, the research strategy to be followed highlights events to be found inside cells. Adequate models for this strategy can then be adopted as exemplified by experiments using a single cell type in a 2D cell culture. In contrast, the TOFT, which is anchored at the tissue level of biological organization, explores carcinogenesis as a relational problem whereby the reciprocal interactions among the diverse cell types of the morphogenetic field take place. The TOFT focuses not on a single cell type but, as in organogenesis, on the interactions among different cell types and compartments. The difference between these theories can be summarized as “the renegade cell” of the SMT  versus “development gone awry” of the TOFT .
Equally important, if not more so, these 2 theories adopt distinctive premises regarding inherent cell behavior. That is, the cell-centered theories implicitly adopt the premise that quiescence is the constitutive (default) state of cells in multicellular organisms, and therefore cells require intrinsic or extrinsic stimulation by either “oncogenes” or “growth factors,” respectively, in order to proliferate [36,54]. In contrast, the TOFT posits that proliferation is the default state of all cells, and therefore only inhibitory constraints prevent them from entering the cell cycle [6,39]. Thus, according to the TOFT, cells constitutively proliferate and generate movement, and the tissues in which they reside constrain their ability to proliferate and move. When a carcinogen loosens the tissue constraints, cells regain their default state and proliferate again, eventually forming a tumor mass, also allowing cells to move, invade tissues, and metastasize. Therefore, the relevant question is not what drives proliferation and motility but what tissue constraints inhibit both processes and how they operate in the altered morphogenetic field.
In light of the SMT’s failure to explain carcinogenesis and deliver promised therapeutic successes, a third group of cancer theories has been introduced that combines a cell-based theory with elements of the tissue-based theory to explain the initial steps of carcinogenesis [36,37]. In essence, this latter group of theories retain the core of the SMT while adding the microenvironment in the form of the multiple cell types that surround the single initiating “cancer cell” [64–68]. They claim that either the cancer cell and its descendants “recruit” the cells in their microenvironment to “prosper” or that perturbations in the stroma induce DNA mutations and translocations in the parenchymal cells [69–71]. In short, this latter group of theories is proposed as a sort of compromise between the SMT and the TOFT [15,68,72–75]. In reality, they are variants of the SMT, given that somatic mutations still play a causal role in them (Table 1). These SMT theories may have generated confusion about a role of mutations in the TOFT; the central idea of the SMT, that DNA mutations are causal, is so ingrained that some authors have taken it for granted that the TOFT also claims a causal role for mutations , even though the TOFT has always considered DNA mutations an epiphenomenon.
A sequence of misperceptions in biology
The resolution of the controversy about theories of carcinogenesis is not an inconsequential “academic” pursuit but directly impacts glaring inconsistencies that arise when interpreting data generated under the premises of the SMT. More significantly, resolving this controversy will help correct misunderstandings about basic biological phenomena such as the default state of cells and causality among levels of biological organization. In addition, the resolution of this controversy will provide guidance in medically related issues such as cancer diagnosis and treatment .
Adoption of the cell-centered theory of carcinogenesis, i.e., the SMT and its variants, has led to several misconceptions. According to the SMT, somatic DNA mutations in cancer cells induce them to proliferate incessantly; this is not supported by evidence given that those cells can either proliferate or be dormant [77,78]. Moreover, they do not proliferate autonomously, as exemplified by their fate in hormone-dependent cancers . The implicit premise that the constitutive (default) state of cells in multicellular organisms is quiescence generated the search, identification, and characterization of putative growth factors  and oncogenes [81–85]. Paradoxically, however, conclusions that those putative growth factors and oncogenes are indeed direct stimulators of cell proliferation have been duly contradicted by evidence and acknowledged even by those who originated this significant misperception [6,80–87]. Given that proliferation is considered the noncontroversial default state of unicellular organisms [54, 88], a switch from proliferation as the default state in unicellular organisms to quiescence in multicellular ones is an evolutionary novelty that should have been noted, highlighted, and explained. Curiously, notwithstanding, the current dominant perception in the field of biology at large that the proliferation of cells in multicellular organisms depends on being directly stimulated by “growth factors” and/or “oncogenes” remains practically unaltered. A clarification of this basic biological principle is highly overdue through a rigorous analysis of the published record. Next, the subsequent adoption of evolutionarily relevant premises that replace the unreliable ones should be implemented (proliferation as the default state of all cells and a search and characterization of inhibitors of cell proliferation), as we have argued previously [6,28,89–91]. Altogether, the unchallenged adoption of the misleading premises of the SMT gave way to the primacy of a strict reductionist approach to the subject of carcinogenesis.
For decades, the management of clinical cancers has been based on the premises of the SMT that, in short, meant to kill the allegedly immortalized, mutated “cancer cells.” This approach ignores evidence that the carcinogenic process is reversible, as repeatedly proven both experimentally [92–95] and clinically [14,16,38,96]. Regardless of these damning conclusions, the SMT and its variants have maintained their hegemony in academic circles, in the hospital ward, in BigPharma, in the specialized and lay media at large, and, equally important, in study sections of funding agencies, in which short- and long-term future trends in cancer research are decided.
Examining explicit and implicit premises
Theories and their principles not only provide likely explanations of phenomena but also play a central role in determining what can be observed and in framing experiments. Thus, experiments can be designed to simultaneously test alternative theories, such as the TOFT and the SMT, to explain mammary gland carcinogenesis after exposure to a chemical carcinogen. Whereas the TOFT posits that the target of carcinogens is the reciprocal interactions between tissues (stroma and epithelium) and their cells, the SMT, in contrast, claims that carcinogens directly cause cancer by inducing mutations in the cells that will become “cancer cells” (in this case, the epithelial cells). In order to simultaneously test both theories, we separately exposed the mammary gland epithelium and stroma to carcinogens and then recombined these tissues to identify the target of the carcinogen (either the epithelium or the stroma or both components of the morphogenetic field). These experiments revealed that, as expected from the TOFT, the stroma is the target of the carcinogen and showed that unexposed epithelial cells acquired neoplastic properties. This experimental design could not have been conceived when adopting the premises of the SMT, for which the direct target is an epithelial cell .
SMT explanations of carcinogenesis remain narrowly framed at a molecular level, centered on mutated genes and their altered coded proteins [1,36,57,98,99]. That narrow focus, along with the acceptance of metaphors for information, program, and signal as real entities, has led to the erroneous assumption that there is no need to define the theoretical framework for the experimental design and the interpretation of data on carcinogenesis. In contrast, the TOFT is rooted in 3 fundamental, interdependent biological principles explicitly proposed for the construction of a Theory of Organisms : (a) a principle of biological inertia, i.e., the default state (proliferation with variation and motility) [6,91]; (b) the principle of variation, which applies both at the cellular and supracellular levels, generating novelty ; and, finally, (c) the principle of organization, which deals with the generation and maintenance of stability by the closure of constraints [17,102].
Central to our Theory of Organisms lies a fundamental biological concept: the cell theory. According to Darwin’s theory of evolution, all living organisms originated from a common ancestor that must have been endowed with the capacity to proliferate constitutively, as long as conditions for survival were met. As multicellularity emerged , sexually reproducing multicellular organisms developed from a unicellular entity, i.e., the zygote [91,100,104]; moreover, development proceeds under theoretical principles that govern cell behavior. The default state entails that cells are normative agents that initiate actions, including proliferation and motility, which figure prominently in the process of carcinogenesis and metastasis. In addition, because a cell generates 2 slightly different daughter cells, proliferation produces variation . Again, the principle of variation applies to the incessant changes that occur throughout the life span of organisms and generate individuation and novelty . Also, the principle of organization addresses the stability of organisms by the interdependence of vital processes, technically referred to as “closure of constraints” . These principles provide a testable framework whereby normal development and its alterations, including carcinogenesis, can be conceptually understood, experimentally explored, and mathematically modeled [100,101,107].
Differing theoretical frames of the SMT and TOFT
One reason the field of cancer theories has remained controversial, in our view, relates to the terms used under the 2 main frameworks. For instance, the meaning of the terms “cell-centered” and “tissue-centered” ought to be spelled out in a clinical context. As claimed by the SMT, carcinogenesis is initiated in a single cell, namely, an epithelial cell in carcinomas, which represent 90% of clinical cancers. From the original simple claim that a single mutated gene (an oncogene) originated a cancer, the SMT was amended repeatedly when evidence failed to fit theory. For example, from a single dominant oncogene, there are now more than 300 “driver” genes. Later, the notion of antioncogenes (or suppressor genes) was introduced . Finally, as mentioned above, the SMT was further extended by invoking elements of the TOFT while retaining the original mutated cell as crucial to the carcinogenic process.
As more new elements are added to the SMT to accommodate the lack of fit between the original theory and evidence, the vaguer the theory becomes. As Richard Feynman stated, a vague theory cannot be proven wrong . Indeed, the original version of the SMT could have been proven wrong early on when it was shown that one so-called oncogene did not cause cancer. However, instead of a critical analysis and eventual rejection, criticisms were ignored, and the theory was temporarily rescued by adding more and more elements.
Under the cell-centered SMT narrative, “the cancer cell” in humans eventually “progresses” (through iterative proliferation) after either weeks, months, years, or decades to become a palpable, primary tumor and to metastasize. Under the tissue-centered TOFT, the initial carcinogenic event that generates the palpable primary tumor mass takes place at the tissue level of biological organization in which the interaction among multiple epithelial cells and adjacent stromal components (i.e., the morphogenetic field) has been broken and is being repaired [6,17,39,110]. It is not the timetable required for a tumor mass to be noted that differs in these theories but the protagonists of the process—the cell for the SMT and the morphogenetic field for the TOFT. In essence, the genomic mutations alleged to be causal for the SMT are irreversible and so should be the cancers formed from them, whereas the perturbations of the morphogenetic field are reversible (“development gone awry”) and so would be their cancers (see Table 1).
The classification of neoplasms according to when tumors appear during the host’s lifetime remains mostly intact in the TOFT. That is, “sporadic” cancers are those diagnosed in adults (about 95% of clinical cancers), while what we have called “inborn errors of development” occur in just about less than 5% of cancer patients . In turn, the “inherited” variety of these inborn errors of development are cancers that mostly appear early in life (in fetuses, infants, and young adults). In carriers of germline mutations (less than 2% of all detected cancers), all the cells of these young patients carry these mutations, and therefore all the cells in the affected morphogenetic field (epithelium/parenchyma and stroma) are actively involved in the carcinogenic process.
Corollaries and predictions
Theories determine what can be observed and thus the type of experiments that could be performed within the frame proposed by the theory. If the SMT is adopted, one will look inside cells and search for DNA mutations and stimulatory factors that would enhance cell proliferation, motility, and thus invasion and the ability to metastasize. From the SMT perspective, mutational events are hardwired, and cancer is considered irreversible. However, this theoretical framework is challenged by an increasing number of publications showing the presence of mutated oncogenes  and of aneuploidy in normal tissues . Coupled with the existence of tumors containing neither gene mutations nor epigenetic aberrations , these findings show that somatic mutations are neither necessary nor sufficient for cancer to develop . A corollary of this view is that “the cancer cell” does not exist, per se .
These conceptual differences result in different predictions and outcomes. Cancer normalization is explained by the TOFT but not by the SMT. Spontaneous cancer regression is due not only to the death of cells in a tumor but also to the remodeling of the cancerous tissue and the consequent “normalization” of the cells inside it. This normalization phenomenon has been documented in neuroblastomas in which the Schwann cells of the stroma are thought to induce the maturation of proliferating neuroblasts into mature, nonproliferating ganglion cells . Moreover, conclusions drawn from the original experiments by Mintz and Illmensee in the 1970s and others since then buttress the notion that normalization is experimentally reproducible [94,116,117] and that it also occurs in clinical settings.
For the sake of the current and future credibility in the fields of biology at large and cancer in particular, a rigorous, critical assessment of the odd situation biologists and cancer researchers are facing is in order. Our long-term analysis of the theoretical bases under which cancer research has been and is conducted, and the empirical evidence collected after more than a century of intensive research, indicates that the reductionist SMT should be abandoned and replaced by an organicist theory that adopts reliable principles relevant to the theories of evolution and organisms . Switching theories will have profound effects on biology at large and, critically, on how researchers frame experiments and interpret observations in normalcy and cancer.
We appreciate valuable conceptual input by Mariano Bizzarri, Sui Huang, Michael Levin, and the members of the ORGANISM group, Paris, France. We would also like to thank Cheryl Schaeberle for her critical reading of this manuscript.
- 1. Sonnenschein C, Soto AM. Why is it that despite signed capitulations the War on Cancer is still on? Organisms. 2017;1:45–52.
- 2. Sporn MB. The War on Cancer. Lancet. 1996;347(9012):1377–81. Epub 1996/05/18. pmid:8637346.
- 3. Huang S. The War on Cancer: lessons from the war on terror. Front Oncol. 2014;4:293. Epub 2014/11/05. pmid:25368844; PubMed Central PMCID: PMC4202687.
- 4. Davies P. What scientific idea is ready for retirement? Edge [Internet]. 2014. Available from: https://www.edge.org/response-detail/25380. [cited 2020 Jan 13].
- 5. Bailar JC 3rd, Smith EM. Progress against cancer? N Engl J Med. 1986;314(19):1226–32. Epub 1986/05/08. pmid:3702918.
Sonnenschein C, Soto AM. The Society of Cells: Cancer and Control of Cell Proliferation. New York: Springer Verlag; 1999.
- 7. Prasad V. Our best weapons against cancer are not magic bullets. Nature. 2020;577(7791):451. Epub 2020/01/23. pmid:31965108.
- 8. Lin A, Giuliano CJ, Palladino A, John KM, Abramowicz C, Yuan ML, et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci Transl Med. 2019;11(509). Epub 2019/09/13. pmid:31511426.
- 9. Hanahan D. Rethinking the war on cancer. Lancet. 2014;383:558–63. pmid:24351321
- 10. Ledford H. Cancer studies clash over mechanisms of malignancy. Nature. 2015;528(7582):317. Epub 2015/12/18. pmid:26672533.
- 11. Allegra CJ, Goodwin PJ, Ganz PA. Can we find the positive in negative clinical trials? J Natl Cancer Inst. 2019. Epub 2019/05/12. pmid:31077298.
- 12. Wilkins AS. Cancer: time for a new theory and new clinical approaches? BioEssays. 2016;39:2.
- 13. Baker SG. A cancer theory kerfuffle can lead to new lines of research. J Natl Cancer Inst. 2014;107(2). Epub 2014/12/22. pmid:25528755; PubMed Central PMCID: PMC4326310.
- 14. Teixeira VH, Pipinikas CP, Pennycuick A, Lee-Six H, Chandrasekharan D, Beane J, et al. Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions. Nat Med. 2019;25(3):517–25. Epub 2019/01/22. pmid:30664780.
Davies P. A new theory of cancer 2018. Available from: https://www.themonthly.com.au/issue/2018/november/1540990800/paul-davies/new-theory-cancer. [cited 2019 Dec 23].
- 16. Sonnenschein C, Soto AM. Cancer-causing somatic mutations: they are neither necessary nor sufficient. Organisms. 2018;2(1):55–62.
- 17. Montévil M, Pocheville A. The hitchhiker's guide to the cancer galaxy. How two critics missed their destination. Organisms. 2017;1:37–48.
- 18. Horgan J. Cancer medicine is failing us. Scientific American [Internet]. 2019. Available from: https://blogs.scientificamerican.com/cross-check/cancer-medicine-is-failing-us/. [cited 2020 Feb 13].
- 19. Feldman R. Why the cancer "moonshot" has been so disappointing. Washington Post. 2019.
- 20. Welch HG. Blame rising cancer overdiagnosis on "irrational exuberance" for early detection. STAT [Internet]. 2019. Available from: https://www.statnews.com/2019/10/02/overdiagnosis-cancer-irrational-exuberance-early-detection/. [cited 2020 Mar 1].
- 21. Raza A. Cancer is still beating us—we need a new start. Wall Street Journal—Online. 2019.
- 22. Huang S. The Tension Between Big Data and Theory in the "Omics" Era of Biomedical Research. Perspect Biol Med. 2018;61(4):472–88. Epub 2019/01/08. pmid:30613031.
- 23. Bizzarri M, Cucina A. Tumor and the microenvironment: a chance to reframe the paradigm of carcinogenesis. Biomed Research International. 2014;2014.
- 24. Bizzarri M, Cucina A. SMT and TOFT: Why and How They are Opposite and Incompatible Paradigms. Acta Biotheor. 2016;64(3):221–39. Epub 2016/06/11. pmid:27283400.
- 25. Soto AM, Longo G. From the century of the genome to the century of the organism: New theoretical approaches—Special Issue. Progress in Biophysics and Molecular Biology. 2016;122(1):1–82. pmid:27814788
Sonnenschein C, Soto AM. Cancer genes: the vestigial remains of a fallen theory. In: Krimsky S, Gruber J, editors. Genetic Explanations, Sense and Nonsense. Cambridge, MA: Harvard University Press; 2013. p. 81–93.
Sonnenschein C, Lee D, Nguyen J, Soto AM. Unanticipated trends stemming from the history of cell culture: Vitalism in 2012? In: Normandin S, Wolfe C, editors. Vitalism and the Scientific Image in Post-Enlightenment Life Science, 1800–2010: Springer; 2013. p. 293–310.
- 28. Sonnenschein C, Soto AM. Misperceptions in cell and cancer biology. What pioneers and followers of cell culture bestowed on these fields. Organisms. 2017;1:83–92.
Boveri T. The Origin of Malignant Tumors. Baltimore, MD: Williams & Wilkins; 1929.
- 30. Soto AM, Sonnenschein C. One hundred years of somatic mutation theory of carcinogenesis: is it time to switch? BioEssays. 2014;36:118–20. pmid:24323923
- 31. Plankar M, Del Giudice E, Tedeschi A, Jerman I. The role of coherence in a systems view of cancer development. Theor Biol Forum. 2012;105(2):15–46. Epub 2012/01/01. pmid:23757952.
- 32. Laplane L, Duluc D, Larmonier N, Pradeu T, Bikfalvi A. The Multiple Layers of the Tumor Environment. Trends Cancer. 2018;4(12):802–9. Epub 2018/11/25. pmid:30470302.
- 33. Waddington CH. Cancer and the theory of organizers. Nature. 1935;135:606–8.
Bertolaso M, Dupré J. A processual perspective on cancer. In: Dupré J, Nicholson DJ, editors. Everything Flows: Towards a Processual Philosophy of Biology. Oxford: Oxford University Press; 2018.
- 35. Rous P. THE INFLUENCE OF DIET ON TRANSPLANTED AND SPONTANEOUS MOUSE TUMORS. J Exp Med. 1914;20(5):433–51. Epub 1914/11/01. pmid:19867833; PubMed Central PMCID: PMC2125200.
- 36. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. pmid:10647931
- 37. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74. pmid:21376230
Clark WH. The role of tumor progression in prevention of cancer and reduction of cancer mortality. In: Greenwald P, Kramer BS, Weed DL, editors. Cancer Prevention & Control. New York: Marcel Decker; 1995. p. 135–59.
- 39. Sonnenschein C, Soto AM. Carcinogenesis explained within the context of a theory of organisms. Prog Biophys Mol Biol. 2016;122(1):70–6. Epub 2016/08/09. pmid:27498170; PubMed Central PMCID: PMC5501415.
- 40. Warburg O. On the origin of cancer cells. Science. 1956;123:309–14. pmid:13298683
- 41. Perret N, Sonnenschein C, Soto AM. Metaphysics: the proverbial elephant in the room. Organisms. 2017;1:17–22.
- 42. Perret N, Longo G. Reductionist perspectives and the notion of information. Prog Biophys Mol Biol. 2016;122(1):11–5. Epub 2016/07/28. pmid:27458079.
- 43. Longo G, Soto AM. Why do we need theories? Prog Biophys Mol Biol. 2016;122(1):4–10. Epub 2016/07/09. pmid:27390105; PubMed Central PMCID: PMC5501401.
Moss L. What Genes Can't Do. Cambridge, MA: MIT Press; 2003.
- 45. Ayala FJ. Biology as an autonomous science. American Scientist. 1968;56:207–21. pmid:5684549
Gould SJ. The Structure of Evolutionary Theory. Cambridge, MA: Harvard University Press; 2004.
- 47. Noble D, Jablonka E, Joyner MJ, Muller GB, Omholt SW. Evolution evolves: physiology returns to centre stage. J Physiol. 2014;592(11):2237–44. Epub 2014/06/03. pmid:24882808; PubMed Central PMCID: PMC4048083.
- 48. Huang S. The molecular and mathematical basis of Waddington's epigenetic landscape: a framework for post-Darwinian biology? Bioessays. 2012;34(2):149–57. Epub 2011/11/22. pmid:22102361.
- 49. Longo G, Miquel PA, Sonnenschein C, Soto AM. Is information a proper observable for biological organization? ProgBiophysMolBiol. 2012;109:108–14.
- 50. Brock A, Huang S. Precision Oncology: Between Vaguely Right and Precisely Wrong. Cancer Res. 2017;77(23):6473–9. Epub 2017/11/23. pmid:29162615.
- 51. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194:123–8.
Weinberg RA. The Biology of Cancer. New York: Garland Science; 2014.
- 53. Otto T, Sicinski P. Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer. 2017;17(2):93–115. Epub 2017/01/28. pmid:28127048; PubMed Central PMCID: PMC5345933.
Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. London: Garland Science; 2008.
Frank SA. Dynamics of Cancer. Princeton NJ: Princeton University Press; 2007. https://doi.org/10.1038/nrc2029
- 56. Brucher BL, Jamall IS. Somatic Mutation Theory—Why it's Wrong for Most Cancers. Cell Physiol Biochem. 2016;38(5):1663–80. Epub 2016/05/11. pmid:27160408.
- 57. Auslander N, Wolf YI, Koonin EV. In silico learning of tumor evolution through mutational time series. Proc Natl Acad Sci U S A. 2019;116(19):9501–10. Epub 2019/04/25. pmid:31015295; PubMed Central PMCID: PMC6510994.
- 58. Lawson DA, Kessenbrock K, Davis RT, Pervolarakis N, Werb Z. Tumour heterogeneity and metastasis at single-cell resolution. Nat Cell Biol. 2018;20(12):1349–60. Epub 2018/11/30. pmid:30482943; PubMed Central PMCID: PMC6477686.
- 59. Longo G, Montevil M. The inert vs. the living state of matter: Extended criticality, time geometry,anti-entropy—an overview. Frontiers in Physiology. 2012;3:39. pmid:22375127
- 60. Soto AM, Sonnenschein C. Reductionism, Organicism, and Causality in the Biomedical Sciences: A Critique. Perspect Biol Med. 2018;61(4):489–502. Epub 2019/01/08. pmid:30613032.
- 61. Levin M. The Biophysics of Regenerative Repair Suggests New Perspectives on Biological Causation. Bioessays. 2020;42(2):e1900146. Epub 2020/01/30. pmid:31994772.
Weinberg RA. One renegade cell: how cancer begins. New York: Basic Books; 1998.
- 63. Soto AM, Maffini MV, Sonnenschein C. Neoplasia as development gone awry: the role of endocrine disruptors. International Journal of Andrology. 2008;31:288–93. pmid:17971158
- 64. Ganesh K, Basnet H, Kaygusuz Y, Laughney AM, He L, Sharma R, et al. L1CAM defines the regenerative origin of metastasis-initiating cells in colorectal cancer. Nature Cancer. 2020;1(1):28–45.
- 65. Gatenby RA, Brown J. Mutations, evolution and the central role of a self-defined fitness function in the initiation and progression of cancer. Biochim Biophys Acta Rev Cancer. 2017;1867(2):162–6. Epub 2017/03/28. pmid:28341421; PubMed Central PMCID: PMC5441954.
- 66. Nelson AC, Machado HL, Schwertfeger KL. Breaking through to the Other Side: Microenvironment Contributions to DCIS Initiation and Progression. J Mammary Gland Biol Neoplasia. 2018;23(4):207–21. Epub 2018/09/01. pmid:30168075; PubMed Central PMCID: PMC6237657.
- 67. Tabassum DP, Polyak K. Tumorigenesis: it takes a village. Nat Rev Cancer. 2015;15(8):473–83. Epub 2015/07/15. pmid:26156638.
- 68. Tlsty TD, Gascard P. Stromal directives can control cancer. Science. 2019;365(6449):122–3. Epub 2019/07/13. pmid:31296756; PubMed Central PMCID: PMC6855670.
- 69. Sternlicht MD, Bissell MJ, Werb Z. The matrix metalloproteinase stromalysin-1 acts as a natural mammary tumor promoter. Oncogene. 2000;19:1102–13. pmid:10713697
- 70. Radisky DC, Bissell MJ. Matrix metalloproteinase-induced genomic instability. Current Opinion in Genetics and Development. 2006;16:45–50. pmid:16377172
- 71. Capp JP. Stochastic gene expression, disruption of tissue averaging effects and cancer as a disease of development. Bioessays. 2005;27(12):1277–85. Epub 2005/11/22. pmid:16299757.
- 72. Rosenfeld S. Are the somatic mutation and tissue organization field theories of carcinogenesis incompatible? Cancer Inform. 2013;12:221–9. Epub 2013/12/11. pmid:24324325; PubMed Central PMCID: PMC3855256.
Bertolaso M. Philosophy of Cancer: Springer; 2016.
- 74. Bedessem B, Ruphy S. SMT or TOFT? How the two main theories of carcinogenesis are made (artificially) incompatible. Acta Biotheor. 2015;63(3):257–67. Epub 2015/04/09. pmid:25851566.
- 75. Maley CC, Aktipis A, Graham TA, Sottoriva A, Boddy AM, Janiszewska M, et al. Classifying the evolutionary and ecological features of neoplasms. Nat Rev Cancer. 2017;17(10):605–19. Epub 2017/09/16. pmid:28912577; PubMed Central PMCID: PMC5811185.
- 76. Rondeau E, Larmonier N, Pradeu T, Bikfalvi A. Characterizing causality in cancer. Elife. 2019;8. Epub 2019/11/30. pmid:31782731; PubMed Central PMCID: PMC6884405.
- 77. Sonnenschein C, Soto AM. The death of the cancer cell. Cancer Research. 2011;71:4334–7. pmid:21507929
- 78. Linde N, Fluegen G, Aguirre-Ghiso JA. The Relationship Between Dormant Cancer Cells and Their Microenvironment. Adv Cancer Res. 2016;132:45–71. Epub 2016/09/11. pmid:27613129; PubMed Central PMCID: PMC5342905.
- 79. Shafi AA, Yen AE, Weigel NL. Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacol Ther. 2013;140(3):223–38. Epub 2013/07/19. pmid:23859952.
Cohen S. Growth factors and morphogenic induction. Developmental and Metabolic Control Mechanisms and Neoplasia. Baltimore, MD: Williams and Wilkins; 1965. p. 251–72.
- 81. Weinberg RA. Coming full circle-from endless complexity to simplicity and back again. Cell. 2014;157:267–71. pmid:24679541
- 82. Bishop JM. Molecular themes in oncogenesis. Cell. 1991;64:235–48. pmid:1988146
Varmus HE, Weinberg RA. Genes and the Biology of Cancer. New York, NY: Scientific American Library; 1992. 123 p.
- 84. Tabin CJ, Bradley SM, Bargmann CI, Weinberg RA, Papageorge AG, Scolnick EM, et al. Mechanism of activation of a human oncogene. Nature. 1982;300:143–9. pmid:6290897
- 85. Huebner RJ, Todaro GJ. Oncogenes of RNA tumor viruses as determinants of cancer. Proc Natl Acad Sci U S A. 1969;64(3):1087–94. Epub 1969/11/01. pmid:5264139; PubMed Central PMCID: PMC223347.
Durum SK, Muegge K. Cytokine Knockouts. Durum SK, Muegge K, editors. Totowa: Humana Press; 1998. VII–XVI p.
- 87. Soto AM, Sonnenschein C. Cell proliferation of estrogen-sensitive cells: the case for negative control. Endocrine Reviews. 1987;8:44–52. pmid:3549277
Luria SE. 36 Lectures in Biology. Cambridge: MIT Press; 1975.
- 89. Soto AM, Sonnenschein C. Regulation of cell proliferation: the negative control perspective. Annals of the New York Academy of Sciences. 1991;628:412–8. pmid:2069318
- 90. Sonnenschein C, Soto AM. Theories of carcinogenesis: an emerging perspective. Seminars in Cancer Biology. 2008;18:372–7. pmid:18472276
- 91. Soto AM, Longo G, Montevil M, Sonnenschein C. The biological default state of cell proliferation with variation and motility, a fundamental principle for a theory of organisms. Prog Biophys Mol Biol. 2016;122(1):16–23. Epub 2016/07/07. pmid:27381480; PubMed Central PMCID: PMC5659334.
- 92. Illmensee K, Mintz B. Totipotency and normal differentiation of single teratocarcinoma cell cloned by injection into blastocysts. Proceedings of the National Academy of Science of the United States of America. 1976;73:549–53.
- 93. Bissell MJ, Hines WC. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. NatMed. 2011;17:320–9.
- 94. Maffini MV, Calabro JM, Soto AM, Sonnenschein C. Stromal regulation of neoplastic development: Age-dependent normalization of neoplastic mammary cells by mammary stroma. American Journal of Pathology. 2005;167:1405–10. pmid:16251424
- 95. Cheng Z, He Z, Cai Y, Zhang C, Fu G, Li H, et al. Conversion of hepatoma cells to hepatocyte-like cells by defined hepatocyte nuclear factors. Cell Res. 2019;29(2):124–35. Epub 2018/12/19. pmid:30560924; PubMed Central PMCID: PMC6355772.
- 96. Proietti S, Cucina A, Pensotti A, Biava PM, Minini M, Monti N, et al. Active Fraction from Embryo Fish Extracts Induces Reversion of the Malignant Invasive Phenotype in Breast Cancer through Down-regulation of TCTP and Modulation of E-cadherin/beta-catenin Pathway. Int J Mol Sci. 2019;20(9). Epub 2019/05/06. pmid:31052313; PubMed Central PMCID: PMC6539734.
- 97. Maffini MV, Soto AM, Calabro JM, Ucci AA, Sonnenschein C. The stroma as a crucial target in rat mammary gland carcinogenesis. Journal of Cell Science. 2004;117:1495–502. pmid:14996910
- 98. Horne SD, Pollick SA, Heng HH. Evolutionary mechanism unifies the hallmarks of cancer. Int J Cancer. 2015;136(9):2012–21. Epub 2014/06/25. pmid:24957955.
- 99. Yaffe MB. Why geneticists stole cancer research even though cancer is primarily a signaling disease. Sci Signal. 2019;12(565). Epub 2019/01/24. pmid:30670634.
- 100. Soto AM, Longo G, Miquel PA, Montevil M, Mossio M, Perret N, et al. Toward a theory of organisms: Three founding principles in search of a useful integration. Prog Biophys Mol Biol. 2016;122(1):77–82. Epub 2016/08/09. pmid:27498204; PubMed Central PMCID: PMC5097676.
- 101. Montevil M, Mossio M, Pocheville A, Longo G. Theoretical principles for biology: Variation. Prog Biophys Mol Biol. 2016;122(1):36–50. Epub 2016/08/18. pmid:27530930.
- 102. Mossio M, Montevil M, Longo G. Theoretical principles for biology: Organization. Prog Biophys Mol Biol. 2016;122(1):24–35. Epub 2016/08/16. pmid:27521451.
- 103. Bengtson S, Sallstedt T, Belivanova V, Whitehouse M. Three-dimensional preservation of cellular and subcellular structures suggests 1.6 billion-year-old crown-group red algae. PLoS Biol. 2017;15(3):e2000735. Epub 2017/03/16. pmid:28291791; PubMed Central PMCID: PMC5349422.
- 104. Soto AM, Sonnenschein C, Miquel PA. On physicalism and Downward Causation in Developmental and Cancer Biology. Acta Biotheoretica. 2008;56:257–74. pmid:18542843
- 105. Longo G, Montevil M, Sonnenschein C, Soto AM. In search of principles for a Theory of Organisms. J Biosci. 2015;40(5):955–68. Epub 2015/12/10. pmid:26648040; PubMed Central PMCID: PMC5505559.
- 106. Montevil M, Mossio M. Biological organisation as closure of constraints. J Theor Biol. 2015;372:179–91. Epub 2015/03/11. pmid:25752259.
- 107. Montevil M, Speroni L, Sonnenschein C, Soto AM. Modeling mammary organogenesis from biological first principles: Cells and their physical constraints. Prog Biophys Mol Biol. 2016;122(1):58–69. Epub 2016/08/22. pmid:27544910; PubMed Central PMCID: PMC5563449.
- 108. Levine AJ. Introduction: The changing directions of p53 research. Genes Cancer. 2011;2:382–4. pmid:21785490
Feynman R. The Character of Physical Law. Cambridge MA: MIT Press; 2017.
- 110. Soto AM, Sonnenschein C. The tissue organization field theory of cancer: A testable replacement for the somatic mutation theory. BioEssays. 2011;33:332–40. pmid:21503935
- 111. Sonnenschein C, Davis B, Soto AM. A novel pathogenic classification of cancers. Cancer Cell Int. 2014;14(1):113. Epub 2014/12/11. pmid:25493071; PubMed Central PMCID: PMC4260242.
- 112. Martincorena I, Campbell PJ. Somatic mutation in cancer and normal cells. Science. 2015;349(6255):1483–9. Epub 2015/09/26. pmid:26404825.
- 113. Mishra S, Whetstine JR. Different Facets of Copy Number Changes: Permanent, Transient, and Adaptive. Mol Cell Biol. 2016;36(7):1050–63. Epub 2016/01/13. pmid:26755558; PubMed Central PMCID: PMC4800790.
- 114. Versteeg R. Cancer: Tumours outside the mutation box. Nature. 2014;506(7489):438–9. Epub 2014/02/21. pmid:24553138.
- 115. Ambros IM, Zellner A, Roald B, Amann G, Ladenstein R, Printz D, et al. Role of ploidy, chromosome 1p, and Schwann cells in the maturation of neuroblastoma. N Engl J Med. 1996;334(23):1505–11. Epub 1996/06/06. pmid:8618605.
- 116. Kasemeier-Kulesa JC, Teddy JM, Postovit LM, Seftor EA, Seftor RE, Hendrix MJ, et al. Reprogramming multipotent tumor cells with the embryonic neural crest microenvironment. DevDyn. 2008;237:2657–66.
- 117. Frank-Kamenetskii A, Booth BW. Redirecting Normal and Cancer Stem Cells to a Mammary Epithelial Cell Fate. J Mammary Gland Biol Neoplasia. 2019;24(4):285–92. Epub 2019/11/17. pmid:31732837.
- 118. Sonnenschein C, Soto AM. The somatic mutation theory of carcinogenesis: Why it should be dropped and replaced. Molecular Carcinogenesis. 2000;29:1–7. pmid:11020241