Somatic evolution in cancer

Somatic evolution in cancer

Somatic evolution is the accumulation of mutations in the cells of a body (the soma) during a lifetime, and the effects of those mutations on the fitness of those cells. Somatic evolution is important in the process of aging as well as the development of some diseases, including cancer.

Natural selection in cancer

Cells in pre-malignant and malignant neoplasms (tumors) evolve by natural selectionNowell PC: The clonal evolution of tumor cell populations. Science 1976, 194(4260):23-28.] Merlo LM, Pepper JW, Reid BJ, Maley CC: Cancer as an evolutionary and ecological process. Nat Rev Cancer 2006, 6(12):924-935.] . This accounts for how cancer develops from normal tissue and why it has been difficult to cure. There are three necessary and sufficient conditions for natural selection, all of which are met in a neoplasm:
# There must be variation in the population. Neoplasms are mosaics of different mutant cells with both genetic and epigenetic changes that distinguish them from normal cells.
# That variation must be heritable. When a cancer cell divides, both daughter cells inherit the genetic and epigenetic abnormalities of the parent cell, and may also acquire new genetic and epigenetic abnormalities in the process of cellular reproduction.
# That variation must affect survival or reproduction (fitness). While many of the genetic and epigenetic abnormalities in neoplasms are probably neutral evolution, many have been shown to increase the proliferation of the mutant cells, or decrease their rate of death (apoptosis) Hanahan D., Weinberg R. The hallmarks of cancer. Cell 100, 57–70 (2000).] . (See Hallmarks below)

Cells in neoplasms compete for resources, such as oxygen and glucose, as well as space. Thus, a cell that acquires a mutation that increases its fitness will generate more daughter cells than competitor cells that lack that mutation. In this way, a population of mutant cells, called a clone, can expand in the neoplasm. Clonal expansion is the signature of natural selection in cancer.

Cancer therapies act as a form of artificial selection, killing sensitive cancer cells, but leaving behind resistant cells. Often the tumor will regrow from those resistant cells, the patient will relapse, and the therapy that had been previously used will no longer kill the cancer cells. This selection for resistance is similar to the repeatedly spraying crops with a pesticide and selecting for resistant pests until the pesticide is no longer effective.

Multilevel selection

Cancer is a classic example of what evolutionary biologists call multilevel selection: at the level of the organism, cancer is usually fatal so there is selection for genes and the organization of tissuesCairns J: Mutation Selection and the Natural History of Cancer. Nature 1975, 255: 197-200.] [Pepper JW, Sprouffske K, Maley CC: Animal Cell Differentiation Patterns Suppress Somatic Evolution. PLoS Comput Biol 2007, 3(12):e250. Also see [ commentary] ] that suppress cancer. At the level of the cell, there is selection for increased cell proliferation and survival, such that a mutant cell that acquires one of the hallmarks of cancer (see below), will have a competitive advantage over cells that have not acquired the hallmark. Thus, at the level of the cell there is selection for cancer.


Pre-Nowell & Cairns

The earliest ideas about neoplastic evolution come from Boveri [Manchester, K. L. Theodor Boveri and the origin of malignant tumours. Trends Cell Biol 5, 384-7 (1995).] who proposed that tumors originated in chromosomal abnormalities passed on to daughter cells. In the decades that followed, cancer was recognized as having a clonal origin associated with chromosomal aberrations [Makino, S. Further evidence favoring the concept of the stem cell in ascites tumors of rats. Ann N Y Acad Sci 63, 818-30 (1956).] [Hauschka, T. S. The chromosomes in ontogeny and oncogeny. Cancer Res 21, 957-74 (1961).] [Levan, A. & Biesele, J. J. Role of chromosomes in cancerogenesis, as studied in serial tissue culture of mammalian cells. Ann N Y Acad Sci 71, 1022-53 (1958).] [de Grouchy, J. & de Nava, C. A chromosomal theory of carcinogenesis. Ann Intern Med 69, 381-91 (1968).] . Advances in cytogenetics facilitated discovery of chromosome abnormalities in neoplasms, including the Philadelphia chromosome in chronic myelogenous leukemia [Nowell and Hungerford J. Natl Cancer Inst 1960; 25:85] and translocations in acute myeloblastic leukemia [Rowley in 1973 (Ann Genet 1973; 16:109] .Sequences of karyotypes replacing one another in a tumor were observed as it progressed [Ford, C. E. & Clarke, C. M. Cytogenetic evidence of clonal proliferation in primary reticular neoplasms. Can Cancer Conf 5, 129-146 (1963).] Yosida, T. H. Relation between Chromosomal Alteration and Development of Tumors. Japanese Journal of Genetics 41, 439-451 (1966).] [de Grouchy, J., de Nava, C., Cantu, J. M., Bilski-Pasquier, G. & Bousser, J. Models for clonal evolutions: a study of chronic myelogenous leukemia. Am J Hum Genet 18, 485-503 (1966). ] . Researchers hypothesized that cancer evolves in a sequence of chromosomal mutations and selection [de Grouchy, J. Cancer and the evolution of species: a ransom. Biomedicine 18, 6-8 (1973).] [Ryser, H. J. Chemical carcinogenesis. N Engl J Med 285, 721-34 (1971).] and that therapy may further select clones [de Grouchy, J. & de Nava, C. A chromosomal theory of carcinogenesis. Ann Intern Med 69, 381-91 (1968).] .

Knudson, Cairns, and Nowell

In 1971, Knudson published the 2-hit hypothesis for mutation and cancer based on statistical analysis of inherited and sporadic cases of retinoblastoma [Knudson AG, Jr.: Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971, 68(4): 820-823.] . He postulated that retinoblastoma developed as a consequence of two mutations; one of which could be inherited or somatic followed by a second somatic mutation. Cytogenetic studies localized the region to the long arm of chromosome 13, and molecular genetic studies demonstrated that tumorigenesis was associated with chromosomal mechanisms, such as mitotic recombination or non-disjunction, that could lead to homozygosity of the mutation [Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Gallie BL, Murphree AL, Strong LC, White RL: Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 1983, 305(5937):779-784.] . The retinoblastoma gene was the first tumor suppressor gene to be cloned in 1986.

Cairns hypothesized a different, but complementary, mechanism of tumor suppression in 1975 based on tissue architecture to protect against selection of variant somatic cells with increased fitness in proliferating epithelial populations, such as the intestine and other epithelial organs [Cairns J: Mutation Selection and the Natural History of Cancer. Nature 1975, 255: 197-200.] . He postulated that this could be accomplished by restricting the number of stem cells for example at the base of intestinal crypts and restraining the opportunities for competition between cells by shedding differentiated intestinal cells into the gut. The essential predictions of this model have been confirmed although mutations in some tumor suppressor genes, including CDKN2A (p16), predispose to clonal expansions that encompass large numbers of crypts in some conditions such as Barrett’s esophagus. He also postulated an immortal DNA strand that is discussed at Immortal DNA strand hypothesis.

Nowell synthesized the evolutionary view of cancer in 1976 as a process of genetic instability and natural selection. Most of the alterations that occur are deleterious for the cell, and those clones will tend to go extinct, but occasional selectively advantageous mutations arise that lead to clonal expansions. This theory predicts a unique genetic composition in each neoplasm due to the random process of mutations, genetic polymorphisms in the human population, and differences in the selection pressures of the neoplasm’s microenvironment. Interventions are predicted to have varying results in different patients. More importantly, the theory predicts the emergence of resistant clones under the selective pressures of therapy. Since 1976, researchers have identified clonal expansionsBrash, D. E., Zhang, W., Grossman, D. & Takeuchi, S. Colonization of adjacent stem cell compartments by mutant keratinocytes. Semin Cancer Biol 15, 97-102 (2005).] [Braakhuis, B. J., Leemans, C. R. & Brakenhoff, R. H. Expanding fields of genetically altered cells in head and neck squamous carcinogenesis. Semin Cancer Biol 15, 113-20 (2005).] Maley, C. C. et al. Selectively advantageous mutations and hitchhikers in neoplasms: p16 lesions are selected in Barrett's esophagus. Cancer Res 64, 3414-27 (2004).] [Habuchi, T. Origin of multifocal carcinomas of the bladder and upper urinary tract: molecular analysis and clinical implications. Int J Urol 12, 709-16 (2005).] [Franklin, W. A. et al. Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis. J Clin Invest 100, 2133-7 (1997).] [Brentnall, T. A. et al. Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. Gastroenterology 107, 369-78 (1994).] and genetic heterogeneityTsao, J. L. et al. Genetic reconstruction of individual colorectal tumor histories. Proc Natl Acad Sci U S A 97, 1236-41 (2000).] Gonzalez-Garcia, I., Sole, R. V. & Costa, J. Metapopulation dynamics and spatial heterogeneity in cancer. Proc Natl Acad Sci U S A 99, 13085-9 (2002).] Harada, T. et al. Interglandular cytogenetic heterogeneity detected by comparative genomic hybridization in pancreatic cancer. Cancer Res 62, 835-9 (2002).] Murphy, D. S. et al. Characterization of extensive genetic alterations in ductal carcinoma in situ by fluorescence in situ hybridization and molecular analysis. J Natl Cancer Inst 87, 1694-704 (1995).] Castro, M. A., Onsten, T. T., de Almeida, R. M. & Moreira, J. C. Profiling cytogenetic diversity with entropy-based karyotypic analysis. J Theor Biol 234, 487-95 (2005).] Barrett, M. T. et al. Evolution of neoplastic cell lineages in Barrett oesophagus. Nature Genetics 22, 106-9 (1999).] within many different types of neoplasms.

omatic evolution in progression

Genetic heterogeneity in neoplasms

It is known that there are multiple levels of genetic heterogeneity that are associated with cancer, including single nucleotide polymorphism (SNP) Hu W, Feng Z, Ma L, Wagner J, Rice JJ, Stolovitzky G, Levine AJ: A single nucleotide polymorphism in the MDM2 gene disrupts the oscillation of p53 and MDM2 levels in cells. Cancer Res. 2007, 67(6):2757-65. ] , sequence mutations , Microsatellite shifts and instability Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, Compton C, Mayer RJ, Bertagnolli MM, Boland CR: Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 2004, 64(9):3014-21. ] , Loss of heterozygosity (LOH) , Copy number variation (detected both by Comparative Genomic Hybridization (CGH) , and array CGH Kallioniemi A: CGH microarrays and cancer. Curr Opin Biotechnol. 2008, 19(1):36-40. ] , and karyotypic variations including chromosome structural aberrations and aneuploidy ; ; Duesberg P, Rausch C, Rasnick D, Hehlmann R: Genetic instability of cancer cells is proportional to their degree of aneuploidy.Proc Natl Acad Sci U S A. 1998, 95(23):13692-7. ] ; Heng HH, Stevens JB, Liu G, Bremer SW, Ye KJ, Reddy PV, Wu GS, Wang YA, Tainsky MA, Ye CJ: Stochastic cancer progression driven by non-clonal chromosome aberrations. J Cell Physiol. 2006a, 208(2):461-72. ] , Heng HH, Bremer SW, Stevens J, Ye KJ, Miller F, Liu G, Ye CJ: Cancer progression by non-clonal chromosome aberrations. J Cell Biochem. 2006b, 98(6):1424-35. ] . Studies of this issue have focused mainly at the gene mutation level, as copy number variation, LOH and specific chromosomal translocations are explained in the context of gene mutation. It is thus necessary to integrate multiple levels of genetic variation in the context of complex system and multilevel selection.

System instability is a major contributing factor for genetic heterogeneity Ye CJ, Liu G, Bremer SW, Heng HH: The dynamics of cancer chromosomes and genomes. Cytogenet Genome Res. 2007, 118(2-4):237-46. ] . For the majority of cancers, genome instability is reflected at the chromosomal level and is referred to as chromosome instability or CIN Lengauer C, Kinzler KW, Vogelstein B: Genetic instabilities in human cancers. Nature. 1998, 396(6712):643-9. ] . Genome instability is also referred to as an enabling characteristic for achieving endpoints of cancer evolution . Traditionally, many of the somatic evolutionary studies have been focused on clonal expansion, as recurrent types of changes can be traced to illustrate the evolutionary path based on available methods. Recent studies from both direct DNA sequencing and karyotype analysis illustrate the importance of the high level of heterogeneity in somatic evolution. For the formation of solid tumors, there is an involvement of multiple cycles of clonal and non-clonal expansion Heng HH, Stevens JB, Liu G, Bremer SW, Ye KJ, Reddy PV, Wu GS, Wang YA, Tainsky MA, Ye CJ: Stochastic cancer progression driven by non-clonal chromosome aberrations. J Cell Physiol. 2006a, 208(2):461-72. ] , Heng HH: Cancer genome sequencing: the challenges ahead. Bioessays. 2007, 29(8):783-94. ] . Even at the typical clonal expansion phase, there are significant levels of heterogeneity within the cell population, however, most are under-detected when mixed populations of cells are used for molecular analysis. In solid tumors, a majority of gene mutations are not recurrent types Bielas JH, Loeb KR, Rubin BP, True LD, Loeb LA: Human cancers express a mutator phenotype. Proc Natl Acad Sci U S A. 2006, 103(48):18238-42. ] , and neither are the karyotypes Heng HH, Stevens JB, Liu G, Bremer SW, Ye KJ, Reddy PV, Wu GS, Wang YA, Tainsky MA, Ye CJ: Stochastic cancer progression driven by non-clonal chromosome aberrations. J Cell Physiol. 2006a, 208(2):461-72. ] , Ye CJ, Liu G, Bremer SW, Heng HH: The dynamics of cancer chromosomes and genomes. Cytogenet Genome Res. 2007, 118(2-4):237-46. ] These analyses offer an explanation for the findings that there are no common mutations shared by most cancers Wood LD, Parsons DW, Jones S, Lin J, Sjöblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B: The genomic landscapes of human breast and colorectal cancers. Science. 2007, 318(5853):1108-13.] .

omatic evolution by epigenetics

The state of a cell may be changed epigenetically, in addition to genetic alterations. The best understood epigenetic alterations in tumors are the silencing or expression of genes by changes in the methylation of CG pairs of nucleotides in the promoter regions of the genes. These methylation patterns are copied to the new chromosomes when cells replicate their genomes and so methylation alterations are heritable and subject to natural selection. Methylation changes are thought to occur more frequently than mutations in the DNA, and so may account for many of the changes during neoplastic progression (the process by which normal tissue becomes cancerous), particularly in the early stages. Epigenetic changes in progression interact with genetic changes. For example, epigenetic silencing of genes responsible for the repair of mutations in the DNA (e.g. MLH1 and MSH2) results in an increase of genetic mutations.

Clonal expansions

One common feature of neoplastic progression is the expansion of a clone with a genetic or epigenetic alteration. This may be a matter of chance, but is morely likely due to the expanding clone having a competitive advantage (either a reproductive or survival advantage) over other cells in the tissue. Since clones often have many genetic and epigenetic alterations in their genomes, it is often not clear which of those alterations cause a reproductive or survival advantage and which other alterations are simply hitchhikers or passenger mutations (see Glossary below) on the clonal expansion.

Clonal expansions are most often associated with the loss of the p53 (TP53) or p16 (CDKN2A/INK4a) tumor suppressor genes. In lung cancer, a clone with a p53 mutation was observed to have spread over the surface of one entire lung and into the other lung [Franklin WA, Gazdar AF, Haney J, Wistuba, II, La Rosa FG, Kennedy T, Ritchey DM, Miller YE: Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis. J Clin Invest 1997, 100(8):2133-2137.] .In bladder cancer, clones with loss of p16 were observed to have spread over the entire surface of the bladder [Czerniak B, Chaturvedi V, Li L, Hodges S, Johnston D, Roy JY, Luthra R, Logothetis C, Von Eschenbach AC, Grossman HB et al: Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer. Oncogene 1999, 18(5):1185-1196.] [Majewski T, Lee S, Jeong J, Yoon DS, Kram A, Kim MS, Tuziak T, Bondaruk J, Lee S, Park WS et al: Understanding the development of human bladder cancer by using a whole-organ genomic mapping strategy. Lab Invest 2008, 88(7):694-721.] . Similarly, large expansions of clones with loss of p16 have been observed in the oral cavity [Braakhuis BJ, Leemans CR, Brakenhoff RH: Expanding fields of genetically altered cells in head and neck squamous carcinogenesis. Semin Cancer Biol 2005, 15(2):113-120.] and in Barrett's esophagus. Clonal expansions associated with inactivation of p53 have also appear in skin [Zhang W, Hanks AN, Boucher K, Florell SR, Allen SM, Alexander A, Brash DE, Grossman D: UVB-induced apoptosis drives clonal expansion during skin tumor development. Carcinogenesis 2005, 26(1):249-257.] , Barrett's esophagus, brain [Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML, Cavanee W, Vogelstein B: Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 1992, 355(6363):846-847.] , and kidney [Bardeesy N, Beckwith JB, Pelletier J: Clonal expansion and attenuated apoptosis in Wilms' tumors are associated with p53 gene mutations. Cancer Res 1995, 55(2):215-219.] .Further clonal expansions have been observed in the stomach [McDonald SA, Greaves LC, Gutierrez-Gonzalez L, Rodriguez-Justo M, Deheragoda M, Leedham SJ, Taylor RW, Lee CY, Preston SL, Lovell M et al: Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology 2008, 134(2):500-510.] , bladder [Lee S, Jeong J, Majewski T, Scherer SE, Kim MS, Tuziak T, Tang KS, Baggerly K, Grossman HB, Zhou JH et al: Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia. Proc Natl Acad Sci U S A 2007, 104(34):13732-13737.] , colon [McDonald SA, Preston SL, Greaves LC, Leedham SJ, Lovell MA, Jankowski JA, Turnbull DM, Wright NA: Clonal expansion in the human gut: mitochondrial DNA mutations show us the way. Cell Cycle 2006, 5(8):808-811.] , lung [Park IW, Wistuba, II, Maitra A, Milchgrub S, Virmani AK, Minna JD, Gazdar AF: Multiple clonal abnormalities in the bronchial epithelium of patients with lung cancer. J Natl Cancer Inst 1999, 91(21):1863-1868.] , hematopoietic (blood) cells [Tiu R, Gondek L, O'Keefe C, Maciejewski JP: Clonality of the stem cell compartment during evolution of myelodysplastic syndromes and other bone marrow failure syndromes. Leukemia 2007, 21(8):1648-1657.] , and prostate [Mehra R, Tomlins SA, Yu J, Cao X, Wang L, Menon A, Rubin MA, Pienta KJ, Shah RB, Chinnaiyan AM: Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer. Cancer Res 2008, 68(10):3584-3590.] .

These clonal expansions are important for at least two reasons. First, they generate a large target population of mutant cells and so increase the probability that the multiple mutations necessary to cause cancer will be acquired within that clone. Second, in at least one case, the size of the clone with loss of p53 has been associated with an increased risk of a pre-malignant tumor becoming cancerous [Maley CC, Galipeau PC, Li X, Sanchez CA, Paulson TG, Blount PL, Reid BJ: The combination of genetic instability and clonal expansion predicts progression to esophageal adenocarcinoma. Cancer Res 2004, 64(20):7629-7633.] . It is thought that the process of developing cancer involves successive waves of clonal expansions within the tumor [Beerenwinkel N, Antal T, Dingli D, Traulsen A, Kinzler KW, Velculescu VE, Vogelstein B, Nowak MA: Genetic progression and the waiting time to cancer. PLoS Comput Biol 2007, 3(11):e225.] .

Phylogenetic analyses

Phylogenetics may be applied to cells in tumors to reveal the evolutionary relationships between cells, just it is used to reveal evolutionary relationships between organisms and species. Shibata, Tavare and colleagues have exploited this to estimate the time between the intiation of a tumor and its detection in the clinic. Louhelainen et al. have used parsimony to reconstruct the relationships between biopsy samples based on loss of heterozygosity [Louhelainen J, Wijkstrom H, Hemminki K: Initiation-development modelling of allelic losses on chromosome 9 in multifocal bladder cancer. Eur J Cancer 2000, 36(11):1441-1451.] . Phylogenetic trees should not be confused with oncogenetic trees [Desper R, Jiang F, Kallioniemi O-P, Moch H, Papadimitriou CH, Schaffer AA: Inferring tree models for oncogenesis from comparative genome hybridization data. J Comput Biol 1999:37-51.] , which represent the common sequences of genetic events during neoplastic progression and do not represent the relationships of common ancestry which are essential to a phylogeny.

Adaptive Landscapes

An adaptive landscape is a hypothetical topological landscape upon which evolution is envisioned to take place. It is similar to Wright's fitness landscape [Wright S. Evolution in mendelian populations. Genetics, 16, 97-159 (1931)] [Wright S. Evolution and genetics of populations. Vol. 2, University of Chicago Press (1969)] in which the location of each point represents the genotype of an organism and the altitude represents the fitness of that organism in the current environment. However, unlike Wright's rigid landscape, the adaptive landscape is pliable. It readily changes shape with changes in population densities and survival/reproductive strategies used within and among the various species.

Wright’s shifting balance theory of evolution combines genetic drift (random sampling error in the transmission of genes) and natural selection to explain how multiple peaks on a fitness landscape could be occupied or how a population can achieve a higher peak on this landscape. This theory, based on the assumption of density-dependent selection as the principle forms of selection, results in a fitness landscape that is relatively rigid. A rigid landscape is one that does not change in response to even large changes in the position and composition of strategies along the landscape.

In contrast to the fitness landscape, the adaptive landscape is constructed assuming that both density and frequency-dependent selection is involved (selection is frequency-dependant when the fitness of a species depends not only on that species strategy, but on the strategy of all other species). As such, the shape of the adaptive landscape can change drastically in response to even small changes in strategies and densities [Nowak M. and Sigmund K. Evolutionary dynamics of biological games. Science 303, 793-799 (2004)] .

The flexibility of adaptive landscapes provide several ways for natural selection to cross valleys and occupy multiple peaks without having to make large changes in their strategies. Within the context of differential or difference equation models for population dynamics, an adaptive landscape may actually be constructed using a Fitness Generating Function [Vincent T. L. and Brown J. S. Evolutionary game theory, natural selection, and Darwinian dynamics. Cambridge University Press 2005] . If a given species is able to evolve, it will, over time, “climb” the adaptive landscape toward a fitness peak through gradual changes in its mean phenotype according to a strategy dynamic that involves the slope of the adaptive landscape. Because the adaptive landscape is not rigid and can change shape during the evolutionary process, it is possible that a species may be driven to maximum, minimum, or saddle point on the adaptive landscape. A population at a global maximum on the adaptive landscape corresponds an evolutionarily stable strategy (ESS) and will become dominant, driving all others toward extinction. Populations at a minimum or saddle point are not resistant to invasion, so that the introduction of a slightly different mutant strain may continue the evolutionary process toward unoccupied local maxima.

The adaptive landscape provides a useful tool for studying somatic evolution as it can describe the process of how a mutant cell evolves from a small tumor to an invasive cancer. Understanding this process in terms of the adaptive landscape may lead to the control of cancer through external manipulation of the shape of the landscape [Vincent T. L. and Gatenby R. A. An evolutionary model for initiation, promotion,and progression in carcinogenesis. International Journal of Oncology 32, 729-737 (2008)] Maley CC, Reid BJ, Forrest S: Cancer prevention strategies that address the evolutionary dynamics of neoplastic cells: simulating benign cell boosters and selection for chemosensitivity. Cancer Epidemiol Biomarkers Prev 2004, 13(8):1375-1384.] .

The Hallmarks of Cancer as evolutionary adaptations in a neoplasm

In their landmark paper, The Hallmarks of Cancer, Hanahan and Weinberg suggest that cancer can be described by a small number of underlying principles, despite the complexities of the disease. The authors describe how tumor progression proceeds via a process analogous to Darwinian evolution, where each genetic change confers a growth advantage to the cell. These genetic changes can be grouped into six "hallmarks", which drive a population of normal cells to become a cancer. The six hallmarks are:
# self-sufficiency in growth signals
# insensitivity to antigrowth signals
# evasion of apoptosis
# limitless replicative potential
# sustained angiogenesis, and
# tissue invasion and metastasis. Genetic instability is defined as an “enabling characteristic” that facilitates the acquisition of other mutations due to defects in DNA repair.

The hallmark "self-sufficiency in growth signals" describes the observation that tumor cells produce many of their own growth signals and thereby no longer rely on proliferation signals from the micro-environment. Normal cells are maintained in a nondividing state by antigrowth signals, which cancer cells learn to evade through genetic changes producing "insensitivity to antigrowth signals". A normal cell initiates programmed cell death (apoptosis) in response to signals such as DNA damage, oncogene overexpression, and survival factor insufficiency, but a cancer cell learns to "evade apoptosis", leading to the accumulation of aberrant cells. Most mammalian cells can replicate a limited number of times due to progressive shortening of telomeres; virtually all malignant cancer cells gain an ability to maintain their telomeres, conferring "limitless replicative potential". As cells cannot survive at distances of more than 100 μm from a blood supply, cancer cells must initiate the formation of new blood vessels to support their growth via the process of "sustained angiogenesis". During the development of most cancers, primary tumor cells acquire the ability to undergo "invasion and metastasis" whereby they migrate into the surrounding tissue and travel to distant sites in the body, forming secondary tumors.

The pathways that cells take toward becoming malignant cancers are variable, and the order in which the hallmarks are acquired can vary from tumor to tumor. The early genetic events in tumorigenesis are difficult to measure clinically, but can be simulated according to known biology [Spencer S.L., Gerety R.A., Pienta K.J., Forrest S. Modeling Somatic Evolution in Tumorigenesis. PLoS Computational Biology 2(8), e108 (2006).] . Macroscopic tumors are now beginning to be described in terms of their underlying genetic changes, providing additional data to refine the framework described in The Hallmarks of Cancer.

omatic evolution in therapeutic resistance

Therapeutic resistance has been observed in virtually every form of therapy, from the beginning of cancer therapy [Chabner BA & Roberts TG, Jr. (2005) Timeline: Chemotherapy and the war on cancer. Nat. Rev. Cancer 5(1):65-72.] . In most cases, therapies appear to select for mutations in the genes or pathways targeted by the drug. A common cytotoxic chemotherapy used in a variety of cancers, 5-flurouracil (5-FU), targets the TYMS pathway and resistance can evolve through the evolution of extra copies of TYMS, thereby diluting the drug's effect [Wang TL, Diaz LA, Jr., Romans K, Bardelli A, Saha S, Galizia G, Choti M, Donehower R, Parmigiani G, Shih Ie M et al: Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Proc Natl Acad Sci U S A 2004, 101(9):3089-3094.] .

Resistance to BCR-ABL targeting drugs

In the case of Gleevec (Imatinib), which targets the BCR-ABL fusion gene in chronic myeloid leukemia, resistance often develops through a mutation that changes the shape of the binding site of the drug [Gorre ME, Sawyers CL: Molecular mechanisms of resistance to STI571 in chronic myeloid leukemia. Curr Opin Hematol 2002, 9(4):303-307.] [Roche-Lestienne C, Preudhomme C: Mutations in the ABL kinase domain pre-exist the onset of imatinib treatment. Semin Hematol 2003, 40(2 Suppl 2):80-82.] . Sequential application of drugs can lead to the sequential evolution of resistance mutations to each drug in turn [Shah NP, Skaggs BJ, Branford S, Hughes TP, Nicoll JM, Paquette RL, Sawyers CL: Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. J Clin Invest 2007, 117(9):2562-2569.] .

Resistance to EGFR targeting drugs

Gefitinib(Iressa) and Erlotinib (Tarceva) are epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors used for non-small cell lung cancer patients whose tumors have somatic mutations in EGFR. However, most patients eventually become resistant to these drugs. Two major mechanisms of acquired resistance have been discovered in patients who have developed clinical resistance to Gefitinib or Erlotinib [Engelman, J.A., Janne, P.A. Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. Clin Cancer Res 14, 2895-2899 (2008).] : point mutations in the EGFR gene targeted by the drugs [Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005, 352(8):786-792.] , and amplification of MET, another receptor tyrosine kinase, which can bypass EGFR to activate downstream signaling in the cell. In an initial study, 22% of tumors with acquired resistance to Gefitinib or Erlotinib had MET amplification [Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J et al: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007, 316(5827):1039-1043.] . To address these issues, clinical trials are currently assessing irreversible EGFR inhibitors (which inihibit growth even in cell lines with mutations in EGFR), the combination of EGFR and MET kinase inhibitors, and Hsp90 inihibitors (EGFR and MET both require Hsp90 proteins to fold properly). Additionally, taking repeated tumor biopsies from patients as the develop resistance to these drugs would help to understand the tumor dynamics.

Resistance to selective estrogen receptor modulator drugs

Selective Estrogen Receptor Modulators (SERMs) are a commonly used adjuvant therapy in estrogen-receptor positive (ERα+) breast cancer and a preventive treatment for women at high risk of the disease. There are several possible mechanisms of SERM resistance, though the relative clinical importance of each is debated. These include [Ring A & Dowsett M. Mechanisms of tamoxifen resistance. Endocrine-Related Cancer. 11:643-658 (2004)] [Osborne CK. Tamoxifen in the treatment of breast cancer. NEJM. 339(22):1609-1618 (1998)] :
*Loss of estrogen receptor alpha (ERα) [Encarnación CA, Ciocca DR, McGuire WL, Clark GM, Fuqua SA, Osborne CK. Measurement of steroid hormone receptors in breast cancer patients on tamoxifen. Breast Cancer Res Treat. 26(3):237-46. (1993)]
**Although this may be a mechanism of resistance in a minority of women, most ERα+ tumors that become resistant to SERMS remain ERα+ [Johnston SR, Saccani-Jotti G, Smith IE, Salter J, Newby J, Coppen M, Ebbs SR, Dowsett M. Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer. Cancer Res. 55(15):3331-8. (1995)]
*Increrased relative expression of ERβ compared to ERα
*Interference/cross-talk with growth factor signaling pathways such as EGFR/HER2
*Mutations in estrogen receptors
*Alterations in co-regulatory proteins
**Interactions between the SERM, ER, and co-regulatory proteins may influence whether the SERM acts as an estrogen antagonist or as an estrogen agonist.
*Reduced metabolic activation of tamoxifen [Jordan VC and O'Malley BW. Selective strogen-receptor modulators and antihormonal resistance in breast cancer. Journal of Clinical Oncology. 25(36):5815-5824 (2007)]
**Polymorphisms in CYP2D6 show variable rates of conversion of tamoxifen to its activated, anti-estrogenic form [Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD. CYP2D6 polymorphisms and the impact on tamoxifen therapy. J Pharm Sci. 96(9):2224-31. (2007)]

Resistance to anti-androgen therapy

Most prostate cancers derive from cells that are stimulated to proliferate by androgens. Most prostate cancer therapies are therefore based on removing or blocking androgens. Mutations in the androgen receptor (AR) have been observed in anti-androgen resistant prostate cancer that makes the AR hypersensitive to the low levels of androgens that remain after therapy [Taplin ME, Bubley GJ, Ko YJ, Small EJ, Upton M, Rajeshkumar B, Balk SP: Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res 1999, 59(11):2511-2515.] . Similarly, extra copies of the AR gene (amplification) have been observed in anti-androgen resistant prostate cancer [Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen R, Palmberg C, Palotie A, Tammela T, Isola J, Kallioniemi OP: In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 1995, 9(4):401-406.] . These additional copies of the gene are thought to make the cell hypersensitive to low levels of androgens and so allow them to proliferate under anti-androgen therapy.

Resistance to radiotherapy

Resistance to radiotherapy is also commonly observed. However, to date, comparisons of malignant tissue before and after radiotherapy have not been done to identify genetic and epigenetic changes selected by exposure to radiation. In gliomas, a form a brain cancer, radiation therapy appears to select for stem cells [Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006, 444(7120):756-760.] , though it is unclear if the tumor returns to the pre-therapy proportion of cancer stem cells after therapy or if radiotherapy selects for an alteration that keeps the glioma cells in the stem cell state.


Mapping between common terms from cancer biology and evolutionary biology

* Driver mutation = a mutation that gives a selective advantage to a clone in its microenvironment, either through increasing its survival or reproduction. Driver mutations tend to cause clonal expansions.
* Passenger mutation = a mutation that has no effect on the fitness of a clone but may be associated with a clonal expansion because it occurs in the same genome with a driver mutation. This is known as a hitchhiker in evolutionary biology.
* Clone = a set of cells that all descend from a common ancestor cell. A clone is usually distinguished through inheritance of a distinctive genetic lesion (mutation) that occurred in the ancestor cell.
* Neoplastic progression = the somatic evolutionary process by which normal tissue changes into malignant (cancerous) tissue.


External links

* [ Santa Fe Institute working group on evolution in cancer]
* [ Darryl Shibata's lab, focusing on research in evolution in cancer and somatic evolution]
* [ Carlo Maley's lab, focusing on reserach in evolution in cancer]
* [ John Pepper's research in somatic evolution]
* [ The Seattle Barrett's Esophagus Research Program]

ee also

*Cancer research
*Natural Selection

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