Cancer as an evolutionary process at the cell level: an epidemiological perspective

Paolo Vineis

Department of Biomedical Sciences and Human Oncology, University of Torino, via Santena 7, 10126 Torino, Italy and ISI Foundation, Torino, Italy Email: paolo.vineis{at}unito.it


    Abstract
 Top
 Abstract
 Introduction
 A different view of...
 The Darwinian paradigm of...
 Is cancer due to...
 A new approach to...
 Some relevant hints from...
 Epidemiologic evidence
 Darwinian dynamics of neoplastic...
 Adaptation or speciation?
 References
 
Germ-line mutations (present in all cells) in genes that are crucial for the cell cycle cause cancer only in specific cell lines (e.g. mismatch repair genes in the colon; BRCA1-2 in breast and ovary; other cancers in Bloom syndrome, neurofibromatosis and xeroderma pigmentosum). The mutation rate of genes other than mismatch repair or p53 is the same in colon cancer and in normal cells, indicating that a `mutator phenotype', increasing the rate of mutations in many genes, is not an essential feature of sporadic cancers; conversely, fusion genes, TEL-AML1/AML1-ETO, typical of leukemia, are 100 times more frequent at birth than in overt leukemia in children, indicating that further selective events are needed to cause malignancy. The devastating impairment of immunity, as in AIDS patients, does not cause cancer other than Kaposi's sarcoma and non-Hodgkin's lymphoma, although immunological control is considered to be an essential mechanism in preventing the spread of cancer cells. These observations suggest that cell-specific additional events are needed to explain carcinogenesis. Carcinogenesis has been traditionally interpreted as the sequence of initiation (mutation) and promotion (clone expansion), with an interesting similarity with the neo-Darwinian theory of evolution, based on a first stage of genetic change (including recombination) and a second stage of selection. I propose that carcinogenesis consists in two general phases (not necessarily stages), i.e. genetic change followed by clone expansion (selective advantage). As in neo-Darwinian theory selection is chiefly represented by the elimination of the less fit, the selection of mutated cells would mainly consist in resistance to apoptosis or other types of `bottlenecks' that hamper a cell's survival; an example of such a bottleneck is the autoimmunity that induces paroxysmal nocturnal hemoglobinuria in individuals with PIG-A mutations. Cancer rates show great variation in different countries around the world, a variation only marginally explained by genetic differences. More interestingly, migrants change their risk of cancer by adapting to that of the population into which they move: as these changes are not likely to be entirely due to mutagens in the environment, we have to invoke selective pressure over mutated cells to explain them. My theory is that mutated cells adapt to environmental `niches' better than normal cells, in a `gene–environment interaction' that involves the history of the genetic changes the cell has undergone and the kind of environment in which it happens to live.

Abbreviations: GEI, gene–environment interactions


    Introduction
 Top
 Abstract
 Introduction
 A different view of...
 The Darwinian paradigm of...
 Is cancer due to...
 A new approach to...
 Some relevant hints from...
 Epidemiologic evidence
 Darwinian dynamics of neoplastic...
 Adaptation or speciation?
 References
 
`We are accustomed to thinking of the combination of natural variation and natural selection as a force for the good (...). But when we turn from the competition between individuals of a species to the competition between the individual cells within a single animal, we see that natural selection has now become a liability' (J. Cairns, 1975).


    A different view of gene–environment interactions
 Top
 Abstract
 Introduction
 A different view of...
 The Darwinian paradigm of...
 Is cancer due to...
 A new approach to...
 Some relevant hints from...
 Epidemiologic evidence
 Darwinian dynamics of neoplastic...
 Adaptation or speciation?
 References
 
Gene–environment interactions (GEI) in carcinogenesis are usually alluded to by referring to hereditary—germ-line—forms of susceptibility. However, one can also use the term GEI to refer to the interaction between somatic mutations and their relationships with the cell's environment. In a sense, the theory of evolution is just a theory of GEI, being focused on the selective advantage associated with certain genetic variants in a given environment.

Darwin's studies originated from the observation of diversity. One of the best current descriptions of the advantages of diversity has been made by Manfred Eigen. For any gene, the `normal' copy (or `wild-type') is supposed to be the one best adapted to the environment where the specific species lives. According to the interpretation put forward by Eigen (1), different individuals belonging to the species carry variants of the normal copy, which make it possible to find potentially better adaptation if the environment changes. `Functionally competent mutants, whose selection values come close to that of the wild-type (although remainining below it), reach far higher population numbers than those that are functionally ineffective. An asymmetric spectrum of mutants builds up, in which mutants far removed from the wild-type arise successively from intermediates. The population in such a chain of mutants is influenced decisively by the structure of the value landscape. The value landscape consists of connected plains, hills and mountain ranges. In the mountain ranges, the mutant spectrum is widely scattered, and along ridges even distant relatives of the wild-type appear with finite frequency. It is precisely in the mountainous region that further selectively superior mutants can be expected. As soon as one of these turns up on the periphery of the mutation spectrum the established ensemble collapses. A new ensemble builds up around the superior mutant, which thus takes over the role of the wildtype .... This causal chain results in a kind of `mass action', by which the superior mutants are tested with much higher probability than inferior mutants, even if the latter are an equal distance away from the wild-type' (1).

The existence of a wide distribution of genetic variants within the same population explains at least two important features of biology. One is why so many biological phenomena have a normal (gausssian) or log-normal distribution. As Figure 1Go shows, the side-effects of radiation in the population vary according to a `normal' curve (if we exclude a few subjects at the extreme left with a highly penetrant mutation of the AT gene), most probably because the different genes involved in the response to radiation, for example in DNA repair, are highly polymorphic.



View larger version (15K):
[in this window]
[in a new window]
 
Fig. 1. From reference 29.

 
The second implication has been clearly explained by Eigen: at the periphery of the distribution of variants, a subpopulation can acquire autonomy and thus create a new species, thanks to better adaptation to the environment.


    The Darwinian paradigm of carcinogenesis
 Top
 Abstract
 Introduction
 A different view of...
 The Darwinian paradigm of...
 Is cancer due to...
 A new approach to...
 Some relevant hints from...
 Epidemiologic evidence
 Darwinian dynamics of neoplastic...
 Adaptation or speciation?
 References
 
Cancer might represent an attempt by the cells of an individual to adapt to a changing environment, i.e. an environment, which is at odds with the normal genetic make-up of the species.

Table IGo suggests that the mechanism of selection can act at three different levels: (i) the appearance of a new species, as the consequence of isolation and/or environmental `bottlenecks' which lead to the selection of individuals who carry special genetic variants; (ii) the adaptation of single individuals to a changing environment (as in the classical example of the high prevalence of heterozygotes for the `sickle-cell' trait in areas of endemic malaria); (iii) the selection of single cells within an individual. The latter phenomenon is implicated for example in the selection of antibodies.


View this table:
[in this window]
[in a new window]
 
Table I. The effects of selection at different levels of biological organization
 
The origin of cancer can be likened to the process that leads either to speciation or to the adaptation of individuals to a certain environment (see below for a distinction), except that the selection process involves cells, not individuals. Individuals can be seen just as `carriers' of cells; cells are submitted to changing environments either because the carriers migrate or because the environment itself changes. Such a model can be used for an appraisal of the geography of cancer that is slightly different and perhaps more illuminating than the usual ones (see below). In addition to environmental `mutagens' we can refer to environmental `selectogens', as Albertini has suggested (2).

The best example of a selection of clones at the cellular level is represented by immunity. It was MacFarlane Burnet who first coined, in his `The Darwinian approach to immunity', the idea that the encounter between an antigen and the antibody on the cell surface induces the proliferation of that specific clone. These cells are selected in order to produce large amounts of the specific antibody. This idea led to the attribution to lymphocytes of the same evolutionary potential that Darwin attributed to a population of organisms that have to adapt to changing environmental conditions. Obviously, such evolutionary potential occurs, in the case of lymphocytes, in a much smaller time and space framework. Later, in 1959, Lederberg suggested that the genetic origin of antibodies was due to somatic mutations affecting the polypeptides that form an antibody. More recently, the process has been explained as the consequence of both mutations and recombination. In any case, the encounter with the antigen induces the (monoclonal) proliferation of the lymphocyte clone that carries the right antibody.

There has been a long debate about whether cancer is mono- or polyclonal. The latest conclusion is that the pre-neoplastic events are polyclonal, i.e. cell proliferation that precedes cancer tends to involve several cell clones. However, the crucial event leading to cancer seems to be the selection and further expansion of a single clone, characterized by a `carcinogenic advantage' (3).

However, which clone is going to proliferate? In the case of antibodies, it is the encounter with the antigen that is crucial, triggering the expansion of cells carrying the right antibody. Clearly, this mechanism does not help to explain cancer. On the contrary, the origin of cancer seems to lie in an opposite mechanism: even if all cells carry the same mutation, only one cell type will undergo malignant transformation. One striking observation is the fact that in genetic syndromes characterized by highly penetrant mutations predisposing to cancer, such as Bloom syndrome, neurofibromatosis, xeroderma pigmentosum and BRCA1-2 mutations, only a specific type of tumor is produced. Although all cells carry the mutation, cancer arises in a specific tissue, which is often represented by the lymphatic system, but also by the breast (BRCA1-2, Li-Fraumeni syndrome) or soft-tissues (Li-Fraumeni). This is strong evidence suggesting that even highly penetrant mutations need selective pressure to become effective, i.e. they do not confer a generic selective advantage on all cells, but only on some of them, in a specific milieu.


    Is cancer due to a mutator phenotype?
 Top
 Abstract
 Introduction
 A different view of...
 The Darwinian paradigm of...
 Is cancer due to...
 A new approach to...
 Some relevant hints from...
 Epidemiologic evidence
 Darwinian dynamics of neoplastic...
 Adaptation or speciation?
 References
 
The idea that cancer arises as a consequence of a `mutator phenotype' is attractive and originated from the observation of frequent mutations of `mismatch repair' genes in familial colon cancers (HNPCC). The underlying idea was that a mutation in genes that regulate DNA repair would be followed by a considerable increase in the rate of mutations in other genes, thus facilitating the onset of cancer clones. Although this theory is likely to be true for rare familial tumours, sporadic cancers do not seem to have a generalized increase of mutations, revealing a mutator phenotype. In an experiment, Wang et al. (4) have shown that in colon cancers that do not arise in families, random (or `passenger') mutations have the same frequency as in the normal epithelium, i.e. they are uncommon unless they are selected during tumorigenesis. However, a mutator phenotype is a feature of the progression phase of cancer, when the accumulation of mutations is a typical phenotypic characteristic of cancer.

With a totally different approach, Luebeck and Moolgavkar (5) have also ruled out the possibility that the mutator phenotype is an explanation for the origin of common cancers. Through a mathematical model based on the age-dependence of colon cancer, they have hypothesized that four events are necessary for carcinogenesis, including two rare mutations (pre-initiation) followed by clonal expansion, then a frequent event (which they suggest is the symmetric replication of a stem cell into two stem cells, instead of one stem and one differentiated cell), and finally a rare mutation. Although the authors are conscious of the difficulties inherent in the biological interpretation of their mathematical model, at least it eliminates the need for a mutator phenotype.

Further evidence comes from studies on mutations in `reporter' genes in children with lymphocytic leukemia. Finette et al. (6) have investigated the in vivo clonality and mutational spectra of hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations in T cells from children with acute lymphocytic leukemia, and observed multiple, independent HPRT mutations accumulating in vivo in T-cell receptor (TCR) gene clones that had undergone pre- and/or post-thymic expansion following chemotherapy. The pattern of clonally restricted hypermutability was considered to be compatible with extensive cell proliferation and selection alone without postulating genomic instability.


    A new approach to the descriptive epidemiology of cancer: cells adapting to environments
 Top
 Abstract
 Introduction
 A different view of...
 The Darwinian paradigm of...
 Is cancer due to...
 A new approach to...
 Some relevant hints from...
 Epidemiologic evidence
 Darwinian dynamics of neoplastic...
 Adaptation or speciation?
 References
 
The selective advantage of subjects heterozygous for the sickle-cell trait or thalassemia in areas of endemic malaria is one of the best examples of adaptation, but we have something very similar for cancer: the high incidence of Burkitt's lymphoma in malaric areas, which can be similarly explained through the selective advantage of EBV-infected cells (not individuals) in a situation of repeated contact with Plasmodium. Malaria seems to be a powerful `selectogen' for both cells and individuals.

Geographic patterns of cancer are complex and difficult to interpret. Let us consider digestive cancers (oesophagus, stomach, colon and rectum). Cancers at these sites have totally different geographic distributions (Table IIGo) and also diverging time trends.


View this table:
[in this window]
[in a new window]
 
Table II. Incidence rates of digestive cancers in different areas of the world, per 100 000 men per year [(from IARC website, www.iarc.fr, and ref. (28)]
 
In addition to geographic distribution, patterns in migrants are illuminating. For example (Table IIGo), stomach cancer decreased dramatically in the Japanese who migrated to Hawaii, while colon cancer increased by about three times.

Even more difficult to explain are the geographic distribution and the trends for different histologic forms of cancer on the same site. Carcinoma and non-Hodgkin's lymphoma of the stomach have been both attributed to infection with Helicobacter pylori. However, the latter is increasing in Western countries, while the former is decreasing. Why is that? One can hypothesize that H.pylori is mainly involved in the early stages of gastric carcinoma, which would be the consequence of early infection, while H.pylori would be involved as a `selectogen' in the late stages of non-Hodgkin's lymphoma (7). This can explain why stomach carcinoma is more frequent in poor countries, where the prevalence of infection is high, while gastric NHL is strongly increasing in developed countries, where infection is becoming rarer and occurs later in life.

If we consider the historical trends, GEI appear in a new light, i.e. the maladaptation of organisms with a given genetic make-up to a changing environment. There are two evident examples of such a phenomenon. One is a rather complex theory which has been developed to explain the high frequency in Western populations of the so-called `X syndrome', an association of obesity, hypertension, diabetes and cardiovascular disease (8). The theory claims that our metabolic `make-up' dates back to the Paleolithic human, who developed (like other animals) a `thrifty genotype': i.e. in conditions of scarcity, his/her body tended to accumulate as much energy as possible. In addition, the Paleolithic human consumed many more antioxidants and other protective agents than today's Western humans (9). In the current circumstances of abundance, the thrifty genotype has become a cause of chronic diseases, particularly if energy-rich food is consumed with a relatively low intake of protective agents (8). One of the most dramatic epidemiologic changes in recent decades has been the same increase in deaths from cardiovascular disease in some Eastern European countries, possibly due to rapid modifications in dietary habits with increased consumption of animal fats and the lower availability of fresh fruit and vegetables.

Not only the conditions listed above, but also colon cancer and breast cancer are currently attributed to the lack of correspondence between the metabolic genes and dietary habits. In fact there are several similarities (not only on epidemiological grounds) between cancer and cardiovascular disease. For example, both p53 mutations and an increased level of DNA adducts have been found in atherosclerosis and myocardial infarction (10), indicating that similar mechanisms are likely to be involved in several chronic degenerative conditions.


    Some relevant hints from the theory of evolution
 Top
 Abstract
 Introduction
 A different view of...
 The Darwinian paradigm of...
 Is cancer due to...
 A new approach to...
 Some relevant hints from...
 Epidemiologic evidence
 Darwinian dynamics of neoplastic...
 Adaptation or speciation?
 References
 
The presence of variants in the genetic pool of a population makes possible the processes of adaptation and speciation. According to one definition, adaptation is `the morphological, physiological and behavioural equipment of a species or of a member of a species that permits it to compete successfully with other members of its own species or with individuals of other species and that permits it to tolerate the extant physical environment. Adaptation is greater ecological-physiological efficiency than is achieved by other members of the population' (11). Natural selection refers mainly to an intrapopulation process, which favors the fittest.

Speciation is a much more complex phenomenon, which implies environmental isolation and the cumulation of many different changes. One of the main characteristics (not sufficient, however, to define a species) is the lack of cross-fertilization.

If we consider the current interpretation of the theory of evolution, i.e. the model of `punctuated equilibria', we find several interesting ideas for a theory of carcinogenesis.

  1. Stasis, rather than change, is the norm: species seem to be characterized by long periods of stasis with episodic, abrupt changes: `The history of evolution is not one of stately unfolding, but a story of homeostatic equilibria, disturbed only `rarely' by rapid and episodic events of speciation' (11).
  2. The reasons why species are essentially static is obscure, but seems to have to do with the `cohesion of the genome', i.e. the genome works like a single unit, protecting itself from threats to its integrity.
  3. Increased mutation rates are more easily seen in small than in large populations; therefore, new species arise in small, isolated populations or in large populations that undergo abrupt environmental changes (`bottlenecks').
  4. Paleontology gives a distorted view of the evolution of species, since it does not show traces of those species that failed because of unfitness.
  5. Evolution continues to push species toward a more extreme divergence, and intermediate types are more vulnerable to extinction.

Each of these statements has relevance to the theory and observation of carcinogenesis.

Stasis
Cancer is a relatively rare event in spite of the large number of mutations arising in the genome as a consequence, for example, of UV light. As there are about 30 000 genes, and cells of the bone marrow or the small intestine replicate themselves (and their genes) at a rate of 1011 per day, we should have a large number of tumors arising every day. Further evidence that mutations are not enough comes from the observation that in our skin epithelium there are 50 clones/cm2, which carry p53 mutations, each clone consisting of 60–30 000 cells (12). So, why do we not develop cancer more easily?

Cohesion of genome
The explanation seems to lie in the mechanisms that enable us to get rid of damaged DNA, either by repairing it or by directly eliminating the mutated cells by apoptosis (programmed cell death).

An example of `bottleneck': paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired stem cell disorder characterized by intravascular hemolysis, hypercoagulability and bone marrow failure. The characteristic defect in paroxysmal nocturnal hemoglobinuria is the somatic mutation of the PIG-A gene (essential to the synthesis of a moiety that interacts with a number of proteins on the cellular surface) in hematopoietic cells. These cells thus lack the proteins usually held in place by this `anchor'. The current hypothesis explaining the disorder suggests that there are two components: (i) hematopoietic stem cells with the characteristic defect are present in the marrow of many if not all normal individuals in very small numbers; (ii) some aplastogenic influence suppresses the normal stem cells but does not suppress the defective stem cells, thus allowing the proportion of these cells to increase. Current research attempts to substantiate this hypothesis, which is clearly based on a Darwinian interpretation: what causes PNH is not only the mutation (necessary as it is), but also a selection force consisting in the destruction of normal bone marrow cells and in a selective survival of mutated cells (13).

Recently, Mori et al. (14) have shown something similar for children's leukemia. They found that the common leukemia fusion genes, TEL-AML1 or AML1-ETO, are present in cord bloods at a frequency that is 100-fold greater than the risk of the corresponding leukemia. Single-cell analysis confirmed the presence of translocations in restricted cell types corresponding to the B lymphoid or myeloid lineage of the leukemias that normally harbor these fusion genes. The frequency of positive cells (10-4 to 10-3) indicates the substantial clonal expansion of a progenitor population.

Paleontology: mutations in cancer do not necessarily represent the fingerprint of a carcinogen
The `fingerprint theory'—at least in its strongest form—implies (i) that cancer is essentially due to mutations, and (ii) that each specific carcinogen leaves a typical signature on DNA (15). However, this interpretation has received rather serious disconfirmation in a study by Denissenko et al. (16). They incubated cells with aflatoxin B1 and then studied the types of DNA adducts induced in p53 (adducts express the amount of a chemical bound to DNA in a specific site). They observed that adducts were mainly in sites different from codon 249, the one that the `fingerprint' theory implicated. In addition, the expected adducts in codon 249 were rapidly repaired (50% in 7 h). Therefore, the possibility that aflatoxin exerts its carcinogenic activity by leaving a signature in a specific codon and with a specific mechanism in p53 was considerably weakened. Nevertheless, some aspects of the fingerprint hypothesis remain valid. Smokers with lung cancer show a pattern of mutations in p53 that is considerably different from that of non-smokers. The same group of Denissenko has shown that in the very same sites of p53, where typical mutations are found in smokers with lung cancer, the carcinogenic chemical benzo[a]pyrene also forms adducts (17).

Extinction of intermediate types
At least in the late stages of carcinogenesis, intermediate cells that carry mutations either undergo further (malignant) transformation or undergo apoptosis.

In conclusion, Table IIIGo shows that similar mechanisms can operate for the adaptation of individuals to changing environments or speciation, and the origin of cancer. The difference is mainly due to the fact that forces that induce adaptation and speciation operate through reproductive fitness, i.e. in the reproductive age of individuals, while environmental pressures after the reproductive age, which modify the ratio between mitosis and apoptosis, may induce neoplastic changes. It is probable, given the various examples we have seen, that such forces mainly come from dietary habits. Dietary habits were crucial in at least two important population genetic changes, (i) the diffusion of malaria and the consequent selection of heterozygotes for sickle-cell disease, and (ii) the diffusion of lactose tolerance. These forces were operating at the level of reproductive fitness. Now we are facing important dietary changes that interact differently with genes, i.e. against a given metabolic background inherited from prehistoric humans. The lack of adaptation to such changes is not sufficiently strong to impair reproductive fitness, but creates an environment for cells that facilitates the selection of mutated clones.


View this table:
[in this window]
[in a new window]
 
Table III. Parallels between evolutionary mechanisms operating on individuals and those operating on cells
 

    Epidemiologic evidence
 Top
 Abstract
 Introduction
 A different view of...
 The Darwinian paradigm of...
 Is cancer due to...
 A new approach to...
 Some relevant hints from...
 Epidemiologic evidence
 Darwinian dynamics of neoplastic...
 Adaptation or speciation?
 References
 
The apparent `fingerprints' observed in cancer cells in conjunction with certain exposures at least in some circumstances may be a manifestation of the selective survival of mutated clones. The specificity of mutations (e.g. the T to G transversions in codon 249 of p53) might be related more to the metabolically altered environment—which exerts a selective pressure—than to the original mutagenic exposures (18). The following are a few tentative examples of how exposures of interest to epidemiologists might be responsible for the selection of clones carrying specific mutations.

  1. Porta et al. (19) have reported that patients with pancreatic cancer had mutations in the ras gene more frequently if they were regular coffee drinkers than non-drinkers. Coffee drinking was equally associated with the two main types of K-ras mutations, i.e. there was no specific association with mutational spectrum. Coffee is known to impair DNA repair; thus, cells with ras mutations (induced by smoking or by other pancreatic carcinogens) might acquire a selective advantage in coffee drinkers through a variety of mechanisms.
  2. Several types of evidence indicate that the Western diet is associated with the chronic stimulation of pancreatic cells that produce insulin and with peripheral insulin resistance. Hyperinsulinemia has been proposed as a risk factor for colon cancer (20) by exerting a proliferative stimulus on colon cells; in fact, it may act by selecting mutated clones.
  3. We have observed that DNA adducts in bladder cells were higher in association with high tumor grades (21), suggesting that cancer development can lead to `tolerance' towards DNA damage, through clonal cell selection.
  4. In the case of liver carcinoma, it has been suggested that the selection of clones with p53 mutations might be due to the action of the hepatitis B virus (16).

These are only a few examples that might become more numerous if research is addressed properly.


    Darwinian dynamics of neoplastic cells
 Top
 Abstract
 Introduction
 A different view of...
 The Darwinian paradigm of...
 Is cancer due to...
 A new approach to...
 Some relevant hints from...
 Epidemiologic evidence
 Darwinian dynamics of neoplastic...
 Adaptation or speciation?
 References
 
On the basis of the evolutionary model that I propose, one can imagine a mathematical approach to carcinogenesis that considers the relationships between cells and their competition for resources. This kind of formalization has been attempted already by Gatenby (22). His model is based on equations that describe the relationships of only two populations, normal and malignant cells, competing for space and other resources:

((1))

((2))
where N1 = cancer cells, N2 = normal cells, R = intrinsic rate of growth of each population, Ki = maximum number of cells that can occupy a tissue in the absence of a competing population and {alpha}ij = coefficient of competition that measures the effects of population i on population j.

In the initial phase of growth of a cancer, approximately N1/K1 = 0 and N2/K2 = 1.

Therefore, equations 1 and 2GoGo become:

((3))

((4))

In the first phases of development the growth of the cancer population only depends on the interaction with the host population, as K1/N2 is negligible.

In the invasive phase, equations 1 and 2GoGo become:

((5))

((6))

In general, an approach based on `Darwinian Dynamics' might prove extremely useful in the study of the different phases of carcinogenesis (23).


    Adaptation or speciation?
 Top
 Abstract
 Introduction
 A different view of...
 The Darwinian paradigm of...
 Is cancer due to...
 A new approach to...
 Some relevant hints from...
 Epidemiologic evidence
 Darwinian dynamics of neoplastic...
 Adaptation or speciation?
 References
 
There is still one aspect, which has remained ambiguous in the preceding overview: whether cancer can be likened to adaptation or to speciation. My proposal is that cancer is more similar to speciation, because its cells have lost many of the characteristics of the normal cell and acquired an invasive tendency that is typical of a new `fit' species; other diseases, by contrast, can be likened to adaptation because the changes at the cellular level are more specific and less disruptive. For example, atherosclerosis and benign tumors are essentially characterized by a proliferation of cells otherwise similar to the cells of origin, and could be interpreted as phenomena of adaptation. Interestingly, exposures that induce cancer are also able to cause atherosclerosis, for example arsenic, polycyclic aromatic hydrocarbons, ionizing radiation and, above all, cigarette smoking (2427). It is worth noting that tumors of the heart or the arteries are extremely rare, indicating that proliferation in these organs does not lead to the malignant phenotype. We have mentioned that the pre-neoplastic events are considered to be polyclonal, i.e. cell proliferation that precedes cancer tends to involve several cell clones. In contrast, the crucial event leading to cancer seems to be the selection and further expansion of a single clone, characterized by a `carcinogenic advantage' (3). Polyclonality seems to be compatible with the hypothesis of adaptation, monoclonality with the hypothesis of clonal expansion of cells that have cumulated many different changes and acquired a new biological personality.


    References
 Top
 Abstract
 Introduction
 A different view of...
 The Darwinian paradigm of...
 Is cancer due to...
 A new approach to...
 Some relevant hints from...
 Epidemiologic evidence
 Darwinian dynamics of neoplastic...
 Adaptation or speciation?
 References
 

  1. Eigen,M. (1992) Steps Towards Life. Oxford University Press, Oxford.
  2. Albertini,R.J. Mechanistic insights from biomarker studies: somatic mutations and rodent/human comparisons following exposure to a potential carcinogen. In Buffler,P. et al. (eds) Mechanisms of Carcinogenesis. IARC Scientific Publications, IARC, Lyon (in press).
  3. Wright,N.A. (2002) Cell proliferation in carcinogenesis. In Alison,M. (ed.) Cancer Handbook. MacMillan Publishers, London.
  4. Wang,T.L., Rago,C., Silliman,N., Ptak,J., Markowitz,S., Willson,J.K., Parmigiani,G., Kinzler,K.W., Vogelstein,B. and Velculescu,V.E. (2002) Prevalence of somatic alterations in the colorectal cancer cell genome. Proc. Natl Acad. Sci. USA, 99, 3076–3080.[Abstract/Free Full Text]
  5. Luebeck,E.G. and Moolgavkar,S.H. (2002) Multistage carcinogenesis and the incidence of colorectal cancer. Proc. Natl Acad. Sci. USA(in press).
  6. Finette,B.A., Homans,A.C., Rivers,J., Messier,T. and Albertini,R.J. (2001) Accumulation of somatic mutations in proliferating T cell clones from children treated for leukemia. Leukemia, 15, 1898–1905.[ISI][Medline]
  7. Vineis,P., Crosignani,P., Sacerdote,C. et al. (1999) Hematopoietic cancer and peptic ulcer: a multicenter case-control study. Carcinogenesis, 20, 1459–1463.[Abstract/Free Full Text]
  8. Neel,J.V., Weder,A.B. and Julius,S. (1998) Type II diabetes, essential hypertension and obesity as `Syndromes of impaired genetic homeostasis': the `thrifty genotype' hypothesis enters the 21st century. Persp. Biol. Med., 42, 44–75.[ISI]
  9. McCully,K.S. (2001) The significance of wheat in the Dakota territory, human evolution, civilization, and degenerative diseases. Persp. Biol. Med., 44, 52–61.[ISI]
  10. Binkova,B., Smerhovsky,Z., Strejc,P., Boubelik,O., Stavkova,Z., Chvatalova,I. and Sram,R.J. (2001) DNA-adducts and atherosclerosis: a study of accidental and sudden death males in the Czech Republic. Mutat. Res., 501, 115–128.[ISI]
  11. Mayr,E. (2001) What Evolution Is. Basic Books, New York.
  12. Jonason,A.S., Kunala,S. Price,G.J. et al. (1996) Frequent clones of p53-mutated keratinocytes in normal human skin. Proc. Natl Acad. Sci. USA, 93, 14025–14029.[Abstract/Free Full Text]
  13. Rosse,W.F. (1996) New insights into paroxysmal nocturnal hemoglobinuria. Curr. Opin. Hematol., 8, 61–67.
  14. Mori,H., Colman,S.M., Xiao,Z., Ford,A.M., Healy,L.E., Donaldson,C., Hows,J.M., Navarrete,C. and Greaves,M. (2002) Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc. Natl Acad. Sci. USA, 99, 8242–8247.[Abstract/Free Full Text]
  15. Hussain,S.O., Hollstein,M. and Harris,C.C. (2000) p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis, molecular epidemiology, and human risk assessment. Ann. N.Y. Acad. Sci., 919, 79–85.[Abstract/Free Full Text]
  16. Denissenko,M.F., Koudriakova,T.B., Smith,L. et al. (1998) The p53 codon 249 mutational hotspot in hepatocellular carcinoma is not related to selective formation or persistence of aflatoxin B1 adducts. Oncogene, 17, 3007–3014.[CrossRef][ISI][Medline]
  17. Denissenko,M.F., Pao,A., Tang,M. and Pfeifer,G.P. (1996) Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science, 274, 430–432.[Abstract/Free Full Text]
  18. Karran,P. and Bignami,M. (1994) DNA damage tolerance, mismatch repair and genomic instability. Bioessays, 16, 833–839.[ISI][Medline]
  19. Porta,M., Malats,N., Alguacil,J. et al. (2000) Coffee, pancreatic cancer, and K-ras mutations: updating the research agenda. J. Epidemiol. Commun. Health, 54, 656–659.[Free Full Text]
  20. Nilsen,T.I. and Vatten,L.J. (2001) Prospective study of colorectal cancer risk and physical activity, diabetes, blood glucose and BMI: exploring the hyperinsulinaemia hypothesis. Br. J. Cancer, 84, 417–422.[CrossRef][ISI][Medline]
  21. Airoldi,L., Magagnotti,C., Coda,R. et al. (2002) Carcinogen-DNA adducts in bladder cancer biopsies, tumor grade and fruit and vegetable intake. Carcinogenesis, 23, 861–866.[Abstract/Free Full Text]
  22. Gatenby,R.A. (1996) Application of competition theory to tumour growth: implications for tumour biology and treatment. Eur. J. Cancer, 32A, 722–726.[CrossRef]
  23. Michod,R.E. (1999) Darwinian Dynamics. Princeton University Press, Princeton.
  24. Wang,C.H., Jeng,J.S., Yip,P.K., Chen,C.L., Hsu,L.I., Hsueh,Y.M., Chiou,H.Y., Wu,M.M. and Chen CJ. (2002) Biological gradient between long-term arsenic exposure and carotid atherosclerosis. Circulation, 105, 1804–1809.[Abstract/Free Full Text]
  25. Li,R., Folsom,A.R., Sharrett,A.R., Couper,D., Bray,M. and Tyroler,H.A. (2001) Interaction of the glutathione S-transferase genes and cigarette smoking on risk of lower extremity arterial disease: the Atherosclerosis Risk in Communities (ARIC) study. Atherosclerosis, 154, 729–738.[CrossRef][ISI][Medline]
  26. Renner,S.M., Massel,D. and Moon,B.C. (1999) Mediastinal irradiation: a risk factor for atherosclerosis of the internal thoracic arteries. Can. J. Cardiol., 15, 597–600.[ISI][Medline]
  27. Doll,R., Peto,R., Wheatley,K., Gray,R. and Sutherland,I. (1994) Mortality in relation to smoking: 40 years' observations on male British doctors. Br. Med. J., 309: 901–911[Abstract/Free Full Text]
  28. Haenszel,W. and Kurihara,M. (1968) Studies of Japanese migrants. I. Mortality from cancer and other diseases among Japanese in the United States. J. Natl Cancer Inst., 40, 43–68.[ISI][Medline]
  29. Burnet,N.G., Johansen,J., Turesson,I., Nyman,J. and Peacock,J.H. (1998) Describing patients' normal tissue reactions concerning the possibility of individualising radiotherapy dose prescriptions based on potential predictive assays of normal tissue radiosensitivity. Int. J. Cancer, 79, 606–613.[CrossRef][ISI][Medline]
Received August 5, 2002; revised September 5, 2002; accepted September 5, 2002.