This is Part 3 of a four-part article. Part 1 provides a general introduction for the whole article. Part 2 is a critical review of the randomized trials of cancer treatments and screening. The whole article is available as a single PDF file on ResearchGate. The article was presented at the University of Ottawa on November 21, 2015, and is available in video as parts One and Two.
PART 3: What is cancer?
Dominant paradigm “metastasis”
Part III should make it clear that one reason that treatments are so “off” is that the medical profession has an incorrect model of what cancer actually is. I review the scientific literature about what cancer actually is and is not. There is no observational basis for the medical establishment’s dominant paradigm of cancer known as “metastasis”, as we shall see.
Ninety percent of patients who die from solid-tumour cancers die from a multitude of tumours on many organs in the body.1 The first diagnosis typically involves detection of a single tumour that is most evident because it is palpable near the outside of the body, such as in a breast. But those patients that die are found to be burdened with many tumours, which are detected by autopsy after death. As a result, since the surgeon sounded the alarm on the basis of the first-discovered single tumour, and since the surgeon has been focused on removing that first-discovered tumour, the surgeon saves face by proposing and believing that the other tumours are “secondary growths”, that the cancer is a “disseminated cancer”, and that the first-discovered tumour must have “spread” to internal organs. This temporal illusion of disease development has plagued oncology for well over one hundred years,2 and appears to be irresistible to virtually the entire medical profession.
Since the cancer must have “spread”, then the question becomes “How did it spread?” The overwhelmingly dominant model of cancer initiation and spread is mutation-centric (see below) and is called “metastasis”. It is also called the “seed and soil” model of cancer. In this model, a first tumour (the “primary tumour”) is postulated to be initiated by one or more cells that become genetically mutated into cells that have the ability to command tumour growth in their host organ or tissue. Then, supposedly, the primary tumour eventually releases genetically mutated cells (seeds) that spread to distant organs and tissues (soil) and that manage to initiate tumour growth in the new locations. The next question, since the “seeds” are spread throughout the entire body, is “Why do some organs develop “secondary” tumours more frequently than other organs?” The relative inferred capacity to grow tumours is taken to be a property of the host organ (soil).3
There is no proof that these steps actually occur. The idea was proposed by analogy with the population spread of infectious diseases4:
The eruptions of the specific fevers and of syphilis, the inflammations after typhoid, the lesions of tuberculosis, all show the dependence of the seed upon the soil.
And the idea itself was infectious. Now, a century later, we are at the same place:
In spite of the importance of this phenomenon, little is known about the pathogenesis of metastatic foci or their relationship to the primary tumor. (1977)5
Surprisingly though, in spite of the clinical importance of metastasis, much remains to be learned about the biology of the metastatic process. In part, knowledge is limited because metastasis is a ‘hidden’ process, which occurs inside the body and so is inherently difficult to observe. (2002)6
How tumors spread and kill their host organism remains an enigma, but not for lack of attention. For more than a century, cancer biologists have postulated that metastasis results from the interplay of wandering tumor cells with permissive target tissues. (2006)7
However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. (2015)8
There is no conclusive evidence to corroborate the dominant paradigm
(i) that cancer arises from genetic mutation,
(ii) that tumour growth is directed by mutated cells, and
(iii) that tumours spread by “seed and soil” metastasis;
despite technology to isolate and characterize “circulating tumor cells”,9 and despite all the genetic analysis work on tumours, circulating tumour cells, and tissues.
Bloated paradigm “metastasis”
The problem with a dominant paradigm that is incorrect is that as more and more observations emerge that are contradictory or somewhat inconsistent, the model must complexify to accommodate the observations, without the new complexity being of any predictive value. This is seen repeatedly with cancer.10 Is there a single seed per tumour or several seeds per tumour? Both. Do genetically identical virulent seeds always give rise to tumours in the same tissues of genetically identical mice? It depends. Can seeds survive and be dormant for decades? Sure. Why would cells genetically evolve abilities to induce tumour growth while further evolution would confer the opposite ability to proliferate? “Striking conceptual inconsistency”, indeed.11 Why are the most virulent cells in a primary tumour not the selected originators of the distant tumours?12 Because it’s random.13 How do relatively few genetic deviant cells recruit the majority of non-deviant cells in a tumour to grow a complex tumour and its supporting structural and vascular network, in what is otherwise healthy tissue of a healthy organ? Whatever.14
OK, let’s start again. What do we know for certain about cancer? And what have recognized medical researchers said outside of the dominant paradigm?
There are two fundamental and undeniable facts about cancer. First, cancer death rates, for all but rare cancers, increase exponentially with age, as a high power of age.15 Second, there is a large variation (some five orders of magnitude) in the rates of cancerous tumour occurrences in different organs or tissues.
The second fact relates to Paget’s hypothesis about propensity of cancer to form in specific “soils”, and to Ewing’s idea that such propensity is due to differences in the extents of the circulatory patterns in different organs.16 In contrast, seminal work in this regard was done this year. Tomasetti and Vogelstein showed that the 5-order of magnitude variation in lifetime cancer risk in different tissues varies systematically (log-log) with the 7-order of magnitude variation in lifetime stem cell divisions in those tissues, for 31 tissue types.17 Stem cells are “generic” or “undifferentiated” cells that get assigned to a specific role or identity in a tissue, which are used to construct or renew the tissue.
The latter recent observation somewhat contradicts classic metastasis because the “soil” is seen as playing a determinative role, whereas the “seed” is nowhere to be seen.
One might be tempted to draw the conclusion that the age-dependence of cancer incidence and its stem-cell-division tissue-dependence both arise from cancer being caused, in most circumstances, by accumulated random genetic mutations occurring through normal cell division over an individual’s lifetime. This would accord with a dominant but substantively challenged theory of aging wherein aging itself arises from the accumulation of random genetic mutations that degrade tissue quality.18,19
On the other hand, some rather sobering studies suggest that genetics itself is not directly implicated in cancer via mutations acting on an existing code. For example, in one study of 44,788 pairs of twins the authors concluded:
Inherited genetic factors make a minor contribution to susceptibility to most types of neoplasms. … The relatively large effect of heritability in cancer at a few sites (such as prostate and colorectal cancer) suggests major gaps in our knowledge of the genetics of cancer.20
Of course, genetics is important. But the question here is whether we should believe the hypothetical theory that cancer is caused by accumulating genetic mutations in individual cells, which confer abilities onto those cells themselves to: resist growth-inhibiting signals, avoid programmed cell death, direct tumour-structure development, and (later) disseminate into the body fluids in order to “seed” entirely different distant organs.
This dominant paradigm has such a life of its own that it is difficult for medical researchers to see the house of cards that it has become. But let us try.
Not all medical professionals have agreed to sing the same tune. One important departure from orthodoxy is represented in the seminal 1986 paper by Harold Dvorak.21 Dvorak reminds his colleagues that a tumour is a complex organ that could not grow and survive without a suitable intrinsic mechanistic-response of the host tissue, and concludes that tumour growth proceeds as does the process of wound healing, except that in a “successful” tumour the wound never heals and the healing sequence is continuously activated or re-activated. He also points to early classic studies (Trousseau’s sign of malignancy: 1860s) that found that aggressive cancer is associated with abnormal hemostasis (blood clotting).
This sustained-wound-healing idea, in my view, is supported by many studies that find that Aspirin (and non-steroidal anti-inflammatory drugs, NSAIDs, in general) acts as an effective tumour-growth inhibitor in colorectal cancers — because Aspirin is a powerful anti-coagulant, which prevents the clotting feature of wound healing.22 In contrast, medical researchers consider solely the potential molecular mechanisms for the antineoplastic (anti-cancer) activity of NSAIDs, rather than considering a tissue-scale tumour-formation sustained-wound-healing mechanism.23
The significance of Dvorak’s proposal is that tumour growth would primarily be dependent on the intrinsic tissue response or process of wound healing, rather than being primarily directed by mutated cells within the tissue. I extrapolate that this would imply that tumours cannot easily grow in a tissue or organ that has a strong and healthy ability to control its healing process, and to maintain itself (homeostasis), whereas tumours could easily develop in tissues or organs that are made susceptible to going out of whack, or that are physiologically stressed (see below).
Fortunately, a few major players have been injecting realism into cancer research ideas, possibly inspired by Dvorak’s foray. In her work, Mina Bissell has stressed the fact that a tumour is a growing organ, and that the “micro- and macroenvironment [of cancer cells] create a context that promotes tumour growth”, while downplaying the overemphasized genetic controls. In her words24:
Occasionally, the intercellular signals that define the normal context become disrupted. Alterations in epithelial tissues can lead to movement of epithelial sheets and proliferation — for example, after activation of mesenchymal fibroblasts due to wounding. Normally, these conditions are temporary and reversible, but when inflammation is sustained, an escalating feedback loop ensues. Under persistent inflammatory conditions, continual upregulation of enzymes such as matrix metalloproteinases (MMPs) by stromal fibroblasts can disrupt the [extracellular matrix], and invading immune cells can overproduce factors that promote abnormal proliferation.
Others are following suit, while not abandoning the mutation-centric paradigm component of cancer initiation25:
It is widely accepted that the development of carcinoma — the most common form of human cancer — is due to the accumulation of somatic mutations in epithelial cells. The behaviour of carcinomas is also influenced by the tumour microenvironment, which includes extracellular matrix, blood vasculature, inflammatory cells and fibroblasts. Recent studies reveal that fibroblasts have a more profound influence on the development and progression of carcinomas than was previously appreciated.
Bissell is also including stem-cell-preeminence results into her picture of the importance of the tissue “context”,26 and is pursuing her educational mission with her colleagues:
Lest we forget, within every higher organism, there are literally billions of cells with identical genetic information that serve as constituents of the different tissues and organs. Given that genetic information is the same in all cells, including the stem cells, by definition, cells in higher organisms do not possess a sense of place or purpose by themselves. Therefore, in order for each organ to operate successfully within the context of the organism, all cells must be integrated into an architectural and signaling framework such that each cell knows exactly which commands to execute at any given time. Success at this daunting task leads to homeostasis, while failure results in a spectrum of dysfunctions, including cancer. How do organisms achieve this remarkable feat, and how does each cell in return know what to do within the tissues? … If cancer were exclusively due to genetic mutations, then we should expect every organ to eventually become cancerous. Moreover, heritable cancer syndromes almost exclusively affect just a single tissue type, even though every cell contains the mutation. Therefore, in addition to known defense mechanisms such as DNA repair, factors from the tissue microenvironment must play key roles in cellular decision making and maintenance of homeostasis.
All of this has finally led a few researchers to boldly suggest that cancer research is on the verge of a paradigm overhaul: “Research on early-stage carcinogenesis: Are we approaching paradigm instability?”27 Baker et al. point out that the somatic mutation theory of cancer has had its day, has been extensively studied, has not provided a testable mechanistic understanding, has not resolved outstanding contradictions, and has not led to any treatment breakthroughs. They claim that cancer research is in a rut and that this might encourage a paradigm shift:
The more resources expended to try to uncover the exact nature of somatic mutation theory, the more you think that you are nearing a breakthrough in understanding somatic mutation theory and the more you think that a competing theory such as tissue organization field theory is correct, especially in light of observations that are paradoxical under somatic mutation theory. … The current paradigm also tends to be reinforced, because the experimental tools used to investigate it may be increasingly excellent for investigating somatic mutations but suboptimal for investigating a new paradigm, which adds another hurdle to exploring new paradigms. Just as there is no such thing as theory-free investigation, there are no such things as theory-free tools of investigation.
Baker et al. go on to suggest the alternative paradigm of “tissue organization field theory” (TOFT) as a promising progenitor theory. TOFT is a field theory — akin to the field theories of physics — in which the “field” (or fields) represent the spatiotemporal evolution of properties (mass, density, concentrations of bio-active substances, concentration of tissue-structure components, physical stress fields, chemical potentials, and so on) of the tissue or organ, on the scale of the tissue or organ rather than on the scale of an individual cell. In this way, general rules governing the field(s) can be postulated and tested, even if one does not know all of the tissue properties that are represented by the “field(s)” and does not know all the molecular-level mechanisms. As such, TOFT is a systems view of the tissue on which a tumour can develop, and the tumour is a manifestation of the field and appears as a local field distortion. In TOFT one largely admits ignorance at the cellular and molecular levels and looks for system-level organizational and time-evolutionary rules. It’s like looking for a theory of gravitation even if one does not yet understand the thermonuclear details of star creation and death or all the processes that can occur on the surfaces of planets (including life itself). The approach has had some success in physics.
Rozhok et al. have taken on the challenge of considering a paradigm shift and recently (2014) showed by stochastic modelling of “real data on age-dependent dynamics of [hematopoietic stem cell] division rates, pool size, and accumulation of genetic changes” that the somatic mutation-centric theories of both aging and cancer are not tenable. In their words (their abstract)28:
Age‐dependent tissue decline and increased cancer incidence are widely accepted to be rate‐limited by the accumulation of somatic mutations over time. Current models of carcinogenesis are dominated by the assumption that oncogenic mutations have defined advantageous fitness effects on recipient stem and progenitor cells, promoting and rate‐limiting somatic evolution. However, this assumption is markedly discrepant with evolutionary theory, whereby fitness is a dynamic property of a phenotype imposed upon and widely modulated by environment. We computationally modeled dynamic microenvironment‐dependent fitness alterations in hematopoietic stem cells (HSC) within the Sprengel‐Liebig system known to govern evolution at the population level. Our model for the first time integrates real data on age-dependent dynamics of HSC division rates, pool size, and accumulation of genetic changes and demonstrates that somatic evolution is not rate‐limited by the occurrence of mutations, but instead results from aged microenvironment‐driven alterations in the selective/fitness value of previously accumulated genetic changes. Our results are also consistent with evolutionary models of aging and thus oppose both somatic mutation‐centric paradigms of carcinogenesis and tissue functional decline. In total, we demonstrate that aging directly promotes HSC fitness decline and somatic evolution via non‐cell‐autonomous mechanisms.
This means that the somatic (differentiated cell) mutations are driven or constrained by limitations in the environment or tissue-context, as is believed to occur in evolution, rather than tumours being caused by the accumulation of random mutations in cells that somehow direct aberrations in tissue form and function, and that the tissue-context “quality” is itself determined by whole-system (body) circumstances (aging). Rozhok et al. suggest that the dominant paradigm has the cart before the horse. They cite current theories of aging,29,30 in which mutation-centric models have been discredited with reason, and in which system-views are prominent.
In conclusion to Part-III, it does appear that the medical establishment may be on the cusp of a discontinuous paradigm shift in the theory of cancer. If such a shift occurs honestly and without cover up, then it will be a painful transformation because many careers and an economic enterprise are committed to both genetic-centric thinking and the war against metastasis.
In my view, as an outsider, the mutation-centric metastasis paradigm of cancer is a Gold-Effect edifice on steroids (see Part-I), which is used to justify the unjustifiable. The medical professional’s ability to invent ever more elaborate imaginary and untestable molecular-and-cell mechanisms with erudite-sounding names in order to construct a self-serving “scientific” narrative is astounding, especially considering the deadly interventions that are performed as a matter of clinical protocol.
In Part 4, I will propose a conceptual model of cancer (“age-dependent and tissue-specific stress-induced breakdown of tissue-shape homeostasis”), which incorporates the leading criticisms of the dominant paradigm.
- G.P. Gupta and J. Massagué. “Cancer metastasis: Building a framework” (Review). Cell, 17 November 2006, pages 679-695. doi: 10.1016/j.cell.2006.11.001 [↩]
- S. Paget. “Distribution of secondary growths in cancer of the breast.” Lancet, 23 March 1889, pages 571-573, and references therein [↩]
- Ibid -1 [↩]
- Ibid – 2 [↩]
- I.J. Fidler and M.L. Kripke. “Metastasis results from pre-existing variant cells within a malignant tumor.” Science, 26 August 1977, vol.197, pages 893-895 [↩]
- A.F. Chambers et al. “Dissemination and growth of cancer cells in metastatic sites.” Nature Reviews Cancer, August 2002, vol.2, pages 563-572. doi: 10.1038/nrc865 [↩]
- G.P. Gupta and J. Massagué. “Cancer metastasis: Building a framework (Review).” Cell, November 17, 2006, pages 679-695. doi: 10.1016/j.cell.2006.11.001 [↩]
- G. Gundem et al. “The evolutionary history of lethal metastatic prostate cancer.” Nature, 16 April 2015, vol.520, pages 353-357. doi: 10.1038/nature14347 [↩]
- S.L. Stott et al. “Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer.” Science Translational Medicine, 31 March 2010, vol. 2, no. 25 25ra23, pages 1-10. doi: 10.1126/scitranslmed.3000403 [↩]
- See this review (that is biased towards genetic interpretations): B. Weigelt et al. Breast cancer metastasis: markers and models. Nature Reviews Cancer, August 2005, vol. 5, pages 591-602. doi: 10.1038/nrc1670 [↩]
- R. Bernards and R.A. Weinberg. “A progression puzzle: Metastasis genes – The prevailing model of tumour progression carries with it a striking conceptual inconsistency.” Nature, 22 August 2002, vol. 418, page 823 [↩]
- O. Schmidt-Kittler et al. “From latent disseminated cells to overt metastasis: Genetic analysis of systemic breast cancer progression.” Proceedings of the National Academy of Sciences (PNAS), 24 June 2003, vol. 100, no.13, pages 7737-7742. doi: 10.1073/pnas.1331931100 [↩]
- L. Milas et al. “Spontaneous metastasis: random or selective?” Clin. Expl. Metastasis, 1983, vol. 1, no. 4, pages 309-315 [↩]
- J.A. Joyce and J.W. Pollard. “Microenvironmental regulation of metastasis.” Nature Reviews Cancer, April 2009, vol. 9, pages 239-252. doi: 10.1038/nrc2618 [↩]
- See, for example, these modelling attempts of the measured death rates: P. Armitage and R. Doll. “The age distribution of cancer and a multi-stage theory of carcinogenesis.” British Journal of Cancer, March 1954, vol. VIII, no. 1, pages 1-12; and June 1957, vol. XI, no. 2, pages 161-169 [↩]
- See the Chambers et al. review of 2002; and Milas et al., 1983 [↩]
- C. Tomasetti and B. Vogelstein. “Variation in cancer risk among tissues can be explained by the number of stem cell divisions.” Science, January 2015, vol. 347, no. 6217, pages 78-81. doi: 10.1126/science.1260825 [↩]
- K. Jin. “Modern biological theories of aging. Aging and Disease,” October 2010, vol. 1, no. 2, pages 72-74 [↩]
- M.V. Blagosklonny. “Answering the ultimate question: “What is the proximal cause of aging?” Aging, December 2012, vol. 4, no. 12, pages 861-877 [↩]
- P. Lichtenstein et al. “Environmental and heritable factors in the causation of cancer: Analysis of cohorts of twins from Sweden, Denmark, and Finland.” New England Journal of Medicine (NEJM), 13 July 2000, vol. 343, no. 2, pages 78-85 [↩]
- H.F. Dvorak. “Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing.” New England Journal of Medicine (NEJM), 25 December 1986, vol. 315, no. 26, pages 1650-1659 [↩]
- A.I. Schafer. “Effects of nonsteroidal anti-inflammatory drugs on platelet function and systemic hemostasis.” Journal of Clinical Pharmacology, 1995, vol. 35, pages 209-219 [↩]
- For example: S.J. Shiff and B. Rigas. “Nonsteroidal anti-inflammatory drugs and colorectal cancer: Evolving concepts of their chemopreventative actions.” Gastroenterology, 1997, vol. 113, pages 1992-1998; and “Editorial — Aspirin, NSAIDs, and colon cancer prevention: Mechanisms?” Gastroenterology, 1998, vol. 114, pages 1095-1100 [↩]
- M.J. Bissell and D. Radisky. “Putting tumours in context. Nature Reviews Cancer, October 2001, vol. 1, pages 46-54 [↩]
- N.A. Bhowmick et al. Stromal fibroblasts in cancer initiation and progression (Review).” Nature, 18 November 2004, vol. 432, pages 332-337 [↩]
- M.J. Bissell and M.A. LaBarge. “Context, tissue plasticity, and cancer: Are tumor stem cells also regulated by the microenvironment?” Cancer Cell, January 2005, vol. 7, pages 17-23. doi: 10.1016/j.ccr.2004.12.013 [↩]
- S.G. Baker et al. “Research on early-stage carcinogenesis: Are we approaching paradigm instability?” Journal of Clinical Oncology, 10 July 2010, vol. 28, no. 20, pages 3215-3218. doi: 10.1200/jco.2010.28.5460 [↩]
- A.I. Rozhok et al. “Stochastic modelling indicates that aging and somatic evolution in the hematopoietic system are driven by non-cell-autonomous processes.” Aging, December 2014, vol. 6, no. 12, pages 1033-1048 [↩]
- K. Jin. “Modern biological theories of aging.” Aging and Disease, October 2010, vol. 1, no. 2, pages 72-74 [↩]
- M.V. Blagosklonny. “Answering the ultimate question “What is the proximal cause of aging?” Aging, December 2012, vol. 4, no. 12, pages 861-877 [↩]