Abstract
Since the 1970s, the origin of cancer is being explored from the point of view of genetic mutations and clonal expansion of somatic cells. As cancer research expanded in several directions, while the dominant focus on cells remained steady, more and more classes of genes and kinds of extra-genetic factors that were shown to have causal relevance in the onset of cancer. The wild heterogeneity of cancer-related mutations and phenotypes, along with the increasing complication of models, led to the oscillation recently described by Robert Weinberg between, on one hand, the hectic search of “the” few key factors that cause cancer, and, on the other hand, the discouragement in face of a seeming “endless complexity”. In this chapter, employing the consolidated strategy of ‘key models’, I review the evolution of explanatory models of cancer, from the Clonal Genetic Model to the Stochastic Model and the Multigenic Multiphasic Model of Cancer (combining Oncogenes and Tumor Suppressor Genes); I illustrate the importance of epigenetics in the Epigenetic Progenitor Model of Cancer, and the idea of Cancer Stem Cells in the Hierarchical Model of Cancer. I also review the Evolutionary Argument for carcinogenesis, and I confront the endurance of a more and more complicated Cell-Centred Perspective with the multiplicity of causes and with complex causality (i.e., the coexistence of different modes of causation interacting in a temporal dynamics).
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Notes
- 1.
The scientific payoff of transfection methodologies employed in the 1980s has been largely criticized. Further details and specifications are beyond the aim of the present volume (for a review see Blanpain 2013). I think that a more nuanced analysis is needed to understand why and to what extent those procedures are useful to draw conclusions in the scientific field. In particular, my suggestion would be to consider the relevance of control in experiments and the epistemological status of experiments.
- 2.
These features were pointed out by opponents of the SMT (Sonnenschein and Soto 1999). As we will see also in Chapter 4, supporters of SMT do not deny this schematization. For them, although emphases may vary, cancer mainly remains a sub-cellular molecular and genetic problem.
- 3.
By “immortalization”, I mean the production of a cell line capable of an unlimited number of cell divisions. Immortalization can be the result of a chemical or viral transformation or of fusion of the original cells with cells of a tumour line.
- 4.
Cell transformation is the change that a normal cell undergoes as it becomes malignant.
- 5.
This attention to genetic mutations and molecular mechanisms always struggled with the evidence that tumour cells change continuously during the neoplastic process, making it difficult to predict their course by using only genotypic or cytological analyses of the tumour cell, to make prognoses regarding how the pathology will progress, or even to describe them. The progressive changes seen in tumour cells motivated an early eccentric line of questioning upon which level of biological complexity is most adequate to study the phenomenon. I will turn to these issues again in the next Chapters. Some questions have been presented already in Sects. 1.2 and 1.4.2.
- 6.
Notice, however, that the relationship between ONG and their function is not 1:1: these genes usually integrate multiple pathways and are involved in various cellular functions at the same time, so that altering the gene’s sequence does not necessarily alter functions (cf. Sonnenschein and Soto 1999 on this point). It is therefore most appropriate to say that ONGs are involved in crucial signal transduction cascades. For example, an external growth factor signal leads to cytoplasmic signalling to a receptor through the nuclear membrane transcription that activates a transcription factor. When a genetic change in the growth factor or its receptor occurs, it can easily lead to its constitutive activation, and this will alter the function and the expression of a number of other genes or of their protein products downstream. The neoplastic phenotype thus observed is the result of this process. A concrete example is c-Myc. The c-Myc ONG is implicated in the control of neoplastic proliferation and also in the control of cell differentiation, and can be activated through gene amplification, that is, small chromosome pieces containing many copies of the same gene. It can also be deregulated through translocations that involve the immunoglobin heavy chain gene (Silva et al 2005; Klein and Klein 1986). Mainly, there are different chromosomal rearrangements that can constitutively activate genes like c-Myc. In chronic myelogenous leukaemia, instead, the translocation (9; 22) leads to the formation of the Philadelphia chromosome. On chromosome 22, a hybrid gene bcr/abl is formed in which the abl gene, which contains an internal tyrosine kinase domain, is removed from its physiological control and is put under the same control of bcr. In this way, a constitutively active tyrosine kinase is produced. Another example is the ONG fins, which loses its ability to be inactivated by a single point mutation, with the result that the encoded receptor is constitutively active and is not responsive to negative feedback control.
- 7.
A typical example is the gene involved in retinoblastoma. Cavanei and colleagues located the gene for retinoblastoma (known as Rb) in a region of chromosome 13 (Cavenee et al. 1983). They suggested that both sporadic and hereditary type tumours were due to a second alteration that involves this gene, either through a new mutation on the second allele, or through Loss of Heterozygosis (LOH), i.e., the loss of the second normal gene through deletion or other major rearrangements on chromosome 13. LOH reduces Rb to a homozygous state so that the mutation on the first allele is finally responsible for retinoblastoma clinical manifestation. This characterization of Rb alterations to get the kind of cancer known as retinoblastoma confirmed the hypothesis dating back to Knudson (Knudson 1971). Studies of cDNA were important in this development. cDNA is a DNA molecule made as a copy of messenger RNA and therefore lacking the introns that are present in genomic DNA. cDNA clones represent DNA cloned from cDNA and a collection of such clones, usually representing the genes expressed in a particular cell type or tissue, is a cDNA library. In 1986, Friend and colleagues isolated the cDNA that mapped in the human Rb locus, and demonstrated that it is often deleted in a high percentage of tumours. Other groups, working with cDNA fragments from hybrid-transcripts of normal tissue compartments, discovered that this gene was abnormally expressed or deleted in all retinoblastomas. The experimental data confirmed the inactivation of Rb as a cause of this cancer as well (Lee et al. 1987; Friend et al. 1986; Fung et al. 1987; Huang et al. 1988). In familial forms of cancer, then, a mutant allele is transmitted either from the mother or father, while the second mutation affecting the Rb locus occurs in retinal tissue after birth, giving rise to retinoblastoma. Conversely, in the much rarer sporadic form, both mutations in the Rb locus are acquired by independent mutational events after birth. Therefore, while inheriting the abnormal allele determines a high incidence of tumour formation, in the case of sporadic tumours the TSGs have a low correlation with the onset of cancer, as demonstrated also in breast cancer linked to BRCA1. Even if new experimental evidence subsequently showed how even benign tumours could correlate with LOH (Harris 2005), this persisted as one of the diagnostic factors that are used especially for the identification of predisposition of hereditary tumours.
- 8.
Weinberg even recalls emotionally that “For a brief moment in 1982, there was the illusion that cancer was as simple as it possibly could be—a normal cell differed from its neoplastic counterpart by one base out of three billion!” (Weinberg 2014, p. 269). He refers to a DNA sequencing study that revealed that the bladder carcinoma oncogene differed from its normal proto-oncogene counter-part by a single point mutation.
- 9.
In the wake of the Multistep Model, in recent years, a number of genes have been identified showing hypo-methylated DNA, usually in the promoter in pre-invasive stages of colon cancer and other cancers, but which are rarely mutated. These genes have been named “Epigenetic Gatekeepers”, assuming that their normal operation was to prevent a cell from acquiring an immortal phenotype or the ability of self-renewal, typical of malignant phenotypes, through epigenetic regulation (Jones and Baylin 2007). This possibility would be consistent with the presence of dysplastic areas that appear in the gut epithelium before a benign tumour is clinically detectable, that are not attributable to alterations in the genome sequence but rather to those in the epigenetic program regulating differentiation of the stem cell compartment of that tissue.
- 10.
Genomic Imprinting is the situation where a gene is either expressed or not expressed in the embryo depending on which parent it is inherited from.
- 11.
Indeed, epigenetic alterations in gene expression that persist after exposure to carcinogenic chemicals have been increasingly identified as important factors in the initiation and progression of cancer (Feinberg and Tycko 2004; Fukushima et al. 2005). As recent studies have revealed, the silencing action of many TSGs was indeed physiologically mediated by mechanisms such as hypermethylation of CpG islands in the genes’ region that regulate its expression, the ‘promoter’, or as the recruitment of transcription factors or inhibitors of enzymes such as histone deacetylases, which produce functional modifications on histones, and the Methyl-Binding Protein (Jones and Baylin 2007). Although some chemicals that cause cancer in rodents are not themselves genotoxic carcinogens in humans, both genotoxic and non-genotoxic compounds were described as being able to alter, at some stage of the neoplastic process, gene expression, via the induction of DNA transcription through methylation of histones, or other nuclear mechanisms, that influence the activity of the transcriptome, without the occurrence of genetic mutation (Jones and Baylin 2007).
- 12.
Epigenetics seems to be at the heart of all developmental processes of cellular differentiation and proliferation. It thus provides crucial data in order to understand what mechanisms, for example, make stem cell maintenance and differentiation, or ageing and cancer processes, possible. Dealing with processes and signals, epigenetic control unravels a regulatory program, which has been questioning our understanding of systemic control (see Chaps. 3, 4 and 5). Interestingly, it is difficult to define epigenetics through a positive statement (i.e. saying what it is). We usually describe epigenetic mechanisms saying that they are not related with alterations on the genetic sequence. This gives way to the reflection on the epistemological and ontological status of regulatory processes in biological systems and on the explanatory relevance of the context in biological explanations (cf. Bertolaso 2013b, Chapter 5).
- 13.
See footnote 7 for an explanation of LOH.
- 14.
Epigenetic changes are a substitute for these mutations or genetic alterations, in the sense that they affect genes’ effects, as a mutation would do.
- 15.
As Silvia Caianiello pointed out (personal communication), this position would have the ‘metaphysical consequence’ to give ontological consistency to the ‘bad’, creating a new caricature, a parody of natural selection. I think that this is not necessarily the case. It would be should we consider the Evolutionary Argument as a model, and, furthermore, as a satisfactory explanation in its own right. As will be clearer in the next chapters, however, this is not the case in some research programmes. The point is that scientists are often not able to make the conditions of validity of their own models explicit. As I will argue in Chaps. 5 and 6, peculiarities of biological behaviours do challenge epistemological assumptions as well as the domain of validity of models.
- 16.
Such evidence can be either interpreted as a proof of the irreversibility of some steps of cell differentiation or even as evidence in favour of the clonal origin of cancers that was assumed all through the present chapter. The next chapters will elaborate a more articulated view of cancer and of the role of clones and genetic mutations.
- 17.
Vineis et al. (2010) suggest that the term ‘Darwinian’ needs to be used cautiously, “being a short cut for ‘somatic cellular selection’” (ibidem, 1703): it has entered into use in cancer literature, but “it should not be used to imply that Darwinian selection at the population (rather than cellular) level is involved in carcinogenesis” (ibidem, 1704).
- 18.
The emphasis on genetic mutation also remained very stable, albeit it was complexified, for example with the functional diversification of kinds of mutations that get combined in the Clonal Genetic Model (Sect. 2.3) and then complemented by epigenetics. In the Stochastic Model, cancer develops as a heterogeneous population of cells, not as the clonal expansion of one cell. Still, the events that differentiate the cells within a population of tumour cells are genetic in nature.
- 19.
References
Bertolaso, M. (2013a). How science works: Choosing levels of explanation in biological sciences. Roma: Aracne.
Bertolaso, M. (2013b). On the structure of biological explanations: Beyond functional ascriptions in cancer research. Epistemologia, 36, 112–130.
Bertolaso, M. (2013c). Mechanisms & biological mechanisms. In New Catholic encyclopedia supplement 2012–2013: Ethics and philosophy. Detroit: Robert L. Fastiggi.
Bertolaso M. (2013d). Indeterminación Biológica y las Perspectivas Sistémicas de la Biología Contemporáne – Biological Uncertainty and the Systemic Perspectives of Contemporary Biology. Anuario Filosofico, 46, 365–386.
Bertolaso M. (2013e). Sulla ‘irriducibilità’ della prospettiva sistemica in biologia. Un’analisi delle convergenze dei modelli interpretativi del cancro. In L. Urbani Ulivi (Ed.), Strutture di Mondo (Vol. II, pp. 143–169). Bologna: Il Mulino.
Blanpain, C. (2013). Tracing the cellular origin of cancer. Nature Cell Biology, 15, 126–134.
Boman, B. M., & Wicha, M. S. (2008). Cancer stem cells: A step toward the cure. Journal of Clinical Oncology, 26, 2795–2799.
Bruce, W. R., & Van Der Gaag, H. (1963). A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature, 199, 79–80.
Cairns, J. (1975). Mutation selection and the natural history of cancer. Nature, 255, 197–200.
Campisi, J. (2005). Aging tumor suppression and cancer: A high wire act. Mechanisms of Ageing and Development, 26, 51–58.
Cavenee, W. K., Dryja, T. P., Phillips, R. A., Benedict, W. F., Godbout, R., Gallie, B. L., Murphreeparallel, A. L., Strong, L. C., & White, R. L. (1983). Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature, 305, 779–784.
Clarke, M. F., Dick, J. E., Dirks, P. B., Eaves, C. J., Jamieson, C. H. M., Jones, D. L., Visvader, J., Weissman, I. L., & Wahl, G. M. (2006). Cancer stem cells—Perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Research, 66, 9339–9344.
Colditz, G. A., Sellers, T. A., & Trapido, E. (2006). Epidemiology–identifying the causes and preventability of cancer? Nature Reviews Cancer, 6, 75–83.
Cooper, G. M., Okenquist, S., & Siiverman, L. (1980). Transforming activity of DNA of chemically transformed and normal cells. Nature, 284, 415–421.
Dalerba, P., Cho, R. W., & Clarke, M. F. (2007). Cancer stem cells: Models and concepts. Annual Review of Medicine, 58, 267–284.
Eden, A., Gaudet, F., Waghmare, A., & Jaenisch, R. (2003). Chromosomal instability and tumors promoted by DNA hypomethylation. Science, 300, 455.
Fearon, E. R., & Vogelstein, B. (1990). Genetic model for coloreotal tumorigenesis. Cell, 61, 759–767.
Feinberg, A. P. (2007). Phenotypic plasticity and the epigenetics of human disease. Nature, 447, 433–440.
Feinberg, A. P., & Tycko, B. (2004). The history of cancer epigenetics. Nature Reviews Cancer, 4, 143–153.
Feinberg, A. P., & Vogelstein, B. (1983). Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature, 301, 89–92.
Feinberg, A. P., Ohlsson, R., & Henikoff, S. (2006). The epigenetic progenitor origin of human cancer. Nature Reviews Genetics, 7, 21–33.
Fidler, I. J. (2003). The pathogenesis of cancer metastasis: The “seed and soil” hypothesis revisited. Nature Reviews Cancer, 3, 453–458.
Frank, S. (2003). Somatic mutation: Early cancer steps depend on tissue architecture. Current Biology, 13, 261–263.
Friend, S. H., Bernards, R., Rogelj, S., Weinberg, R. A., Rapaport, J. M., Albert, D. M., & Dryja, T. P. (1986). A human DMA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature, 323, 643–646.
Fukushima, S., Kinoshita, A., Puatanachokchai, R., Kushida, M., Wanibuchi, H., & Morimura, K. (2005). Hormesis and dose-response-mediated mechanisms in carcinogenesis: Evidence for a threshold in carcinogenicity of non-genotoxic carcinogens. Carcinogenesis, 26, 1835–1845.
Fung, Y. K., Murphree, A. L., T’Ang, A., Qian, J., Hinrichs, S. H., & Benedict, W. F. (1987). Structural evidence for the authenticity of the human retinoblastoma gene. Science, 236, 1657–1661.
Gupta, P. B., Chaffer, C. L., & Weinberg, R. A. (2009). Cancer stem cells: Mirage or reality? Nature Medicine, 15, 1010–1012.
Hamburger, A., & Salmon, S. E. (1977). Primary bioassay of human myeloma stem cells. The Journal of Clinical Investigation, 60(4), 846–854.
Hanahan, D., & Weinberg, R. A. (2000). The Hallmarks of cancer. Cell, 100, 57–70.
Harris, M. (1971). Cell fusion and the analysis of malignancy. Proceedings of the Royal Society of London: Biology Science, 179, 1–20.
Harris, H., Rawlins, J., & Sharps, J. (1996). A different approach to tumour suppression. Journal of Cell Science, 109, 2189–2197.
Harris, H. (2005). A long view of fashions in cancer research. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology, 27(8), 833–838.
Heng, H. H., Bremer, S. W., Stevens, J. B., Ye, K. J., Liu, G., & Ye, C. J. (2009). Genetic and epigenetic heterogeneity in cancer: A genome-centric perspective. Journal of Cellular Physiology, 220, 538–547.
Huang, H. J., Yee, J. K., Shew, J. Y., Chen, P. L., Bookstein, R., Friedmann, T., Lee, E. Y., & Lee, W. H. (1988). Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science, 242, 1563–1566.
Jaffe, L. (2005). Response to paper by Henry Harris. Bioessays, 27, 1206.
Jones, P. A., & Baylin, S. B. (2007). The epigenomics of cancer. Cell, 128, 683–692.
Kinzler, K. W., & Vogelstein, B. (1997). Cancer-susceptibility genes. Gatekeepers and caretakers. Nature, 386, 761–763.
Klein, G. (2002). Perspectives in studies of human tumor viruses. Frontiers in Bioscience, 7, d268–d274.
Klein, G., & Klein, E. (1986). Conditioned tumorigenicity of activated oncogenes. Cancer Research, 46, 3211–3224.
Knudson, A. G. (1971). Mutation and cancer: Statistical study of retinoblastoma. Proceedings of the National Academy of Sciences, 68(4), 820–823.
Lee, W. H., et al. (1987). Human retinoblastoma susceptibility gene: Cloning, identification, and sequence. Science, 235(4794), 1394–1399.
Lewontin, R. (1970). The units of selection. Annual Review of Ecology and Systematics, 1, 1–18.
Lobo, N. A., Shimono, Y., Qian, D., & Clarke, M. F. (2007). The biology of cancer stem cells. Annual Review of Cell Developmental Biology 23, 675–699, Table 1.
Magee, J. a., Piskounova, E., & Morrison, S. J. (2012). Cancer stem cells: Impact, heterogeneity, and uncertainty. Cancer Cell, 21(3), 283–296.
Merlo, L. M., Pepper, J. W., Reid, B. J., & Maley, C. C. (2006). Cancer as an evolutionary and ecological process. Nature Reviews Cancer, 6, 924–935.
Nicholson, D. J. (2010). Biological atomism and cell theory. Studies in History and Philosophy of Biological and Biomedical Sciences, 41, 202–211.
Nowak, M. (2006). Evolutionary dynamics: Exploring the equations of life. Cambridge: Harvard University Press.
Nowell, P. C. (1976). The clonal evolution of tumor cell populations. Science, 194, 23–28.
Nowell, P. C., & Hungerford, D. A. (1960). A minute chromosome in human chronic granulocytic leukaemia. Science, 132, 1488–1501.
Pardal, R., Clarke, M. F., & Morrison, S. J. (2003). Applying the principles of Stem-cell biology to cancer. Nature Reviews Cancer, 3, 895–902.
Parkin, D. M. (2004). International variation. Oncogene, 23, 6329–6340.
Pepper, J. W., Sprouffske, K., & Maley, C. C. (2007). Animal cell differentiation patterns suppress somatic evolution. PLoS Computational Biology, 3(12), e250.
Pierce, G. B., Nakane, P. K., Martinez-Hernandez, A., & Ward, J. M. (1977). Ultrastructural comparison of differentiation of stem cells of murine adenocarcinomas of colon and breast with their normal counterparts. Journal of the National Cancer Institute, 58, 1329–1345.
Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414, 105–111.
Rous, P. (1910). A transmissible avian neoplasm (sarcoma of the common fowl). Journal of Experimental Medicine, 12, 696–705.
Scrable, H., et al. (1989). A model for embryonal rhabdomyosarcoma tumorigenesis that involves genome imprinting. Proceedings of the National Academy of Sciences of the United States of America, 86(19), 7480–7484.
Shackleton, M., et al. (2009). Heterogeneity in cancer: Cancer stem cells versus clonal evolution. Cell, 138(5), 822–829.
Shih, C., & Weinberg, R. A. (1982). Isolation of a transforming sequence from a human bladder carcinoma cell line. Cell, 29, 161–169.
Shih, C., Shilo, B. Z., Goidfarb, M. P., Dannenberg, A., & Weinberg, R. A. (1979). Passage of phenotypes of chemically transformed ceils via transfection of DNA and chromatin. Proceedings of the National Academy of Sciences of the United States of America, 76, 5714–5718.
Silva, S., Wiener, F., Klein, G., & Janz, S. (2005). Location of Myc, Igh, and Igk on Robertsonian fusion chromosomes is inconsequential for Myc translocations and plasmacytoma development in mice, but Rb(6.15)-carrying tumors prefer Igk-Myc inversions over translocations. Genes, Chromosomes & Cancer, 42(4), 416–426.
Slaughter, D. P., Southwick, H. W., & Smejkal, W. (1953). Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer, 6, 963–968.
Sonnenschein, C., & Soto, A. M. (1999). The society of cells: Cancer and control of cell proliferation. New York: Springer.
Spencer, S. L., Gerety, R. A., Pienta, K. J., & Forrest, S. (2006). Modeling somatic evolution in tumorigenesis. PLoS Computational Biology, 2, e108.
Steel, D. M., & Harris, H. (1989). The effect of antisense RNA to fibronectin on the malignancy of hybrids between melanoma cells and normal fibroblasts. Journal of Cell Science, 93, 515–524.
Tabin, C. J., Bradley, S. M., Bargmann, C. I., Weinberg, R. A., Papageorge, A. G., Scolnick, E. M., Dhar, R., Lowy, D. R., & Chang, E. H. (1982). Mechanism of activation of a human oncogene. Nature, 300, 143–149.
Thiery, J. P. (2002). Epithelial-mesenchymal transitions in tumour progression. Nature Reviews Cancer, 2, 442–454.
Ushijima, T. (2007). Epigenetic field for cancerization. Journal of Biochemistry and Molecular Biology, 40, 142–150.
van Gent, D. C., Hoeijmakers, J. H., & Kanaar, R. (2001). Chromosomal stability and the DNA double-stranded break connection. Nature Reviews Genetics, 2(3), 196–206.
Vermeulen, L., Sprick, M. R., Kemper, K., Stassi, G., & Medema, J. P. (2008). Cancer stem cells – old concepts, new insights. Cell Death and Differentiation, 15, 947–958.
Vescovi, A. L., Galli, R., & Reynolds, B. A. (2006). Brain tumour stem cells. Nature Reviews Cancer, 6, 425–436.
Vineis, P., Schatzkin, A., & Potter, J. D. (2010). Models of carcinogenesis: An overview. Carcinogenesis, 31, 1703–1709.
Vogelstein, B., & Kinzler, K. W. (2004). Cancer genes and the pathways they control. Nature Medicine, 10, 789–799.
Weinberg, R. A. (1988). The genetic origins of human cancer. Cancer, 61, 1963–1968.
Weinberg, R. A. (2006). The biology of cancer. London: Garland Science.
Weinberg, R. A. (2008). Mechanisms of malignant progression. Carcinogenesis, 29, 1092–1095.
Weinberg, R. A. (2014). Coming full circle – From endless complexity to simplicity and back again. Cell, 157(1), 267–271.
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Bertolaso, M. (2016). The Evolution of Explanatory Models of Cancer. In: Philosophy of Cancer. History, Philosophy and Theory of the Life Sciences, vol 18. Springer, Dordrecht. https://doi.org/10.1007/978-94-024-0865-2_2
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