surface of one entire lung and into the other lung. in bladder cancer, clones with loss of p16 were observed to have spread over the entire surface of the bladder. likewise, large expansions of clones with loss of p16 have been observed in the oral cavity and in barrett's esophagus. clonal expansions associated with inactivation of p53 have also appear in skin, barrett's esophagus, brain, and kidney. further clonal expansions have been observed in the stomach, bladder, colon, lung, hematopoietic (blood) cells, and prostate. 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. it is thought that the process of developing cancer involves successive waves of clonal expansions within the tumor. field defects longitudinally opened freshly resected colon segment showing a cancer and four polyps. plus a schematic diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of cancer) in this colon segment. the diagram indicates sub-clones and sub-sub-clones that were precursors to the tumors. the term "field cancerization" was first used in 1953 to describe an area or "field" of epithelium that has been preconditioned by (at that time) largely unknown processes so as to predispose it towards development of cancer. since then, the terms "field cancerization" and "field defect" have been used to describe pre-malignant tissue in which new cancers are likely to arise. field defects, for example, have been identified in most of the major areas subject to tumorigenesis in the gastrointestinal (gi) tract. cancers of the gi tract that are shown to be due, to some extent, to field defects include head and neck squamous cell carcinoma (hnscc), oropharyngeal/laryngeal cancer, esophageal adenocarcinoma and esophageal squamous-cell carcinoma, gastric cancer, bile duct cancer, pancreatic cancer, small intestine cancer and colon cancer. in the colon, a field defect probably arises by natural selection of a mutant or epigenetically altered cell among the stem cells at the base of one of the intestinal crypts on the inside surface of the colon. a mutant or epigenetically altered stem cell, if it has a selective advantage, could replace the other nearby stem cells by natural selection. this can cause a patch of abnormal tissue, or field defect. the figure in this section includes a photo of a freshly resected and lengthwise-opened segment of the colon that may represent a large field defect in which there is a colon cancer and four polyps. the four polyps, in addition to the cancer, may represent sub-clones with proliferative advantages. the sequence of events giving rise to this possible field defect are indicated below the photo. the schematic diagram shows a large area in yellow indicating a large patch of mutant or epigenetically altered cells that formed by clonal expansion of an initial cell based on a selective advantage. within this first large patch, a second such mutation or epigenetic alteration may have occurred so that a given stem cell acquired an additional selective advantage compared to the other stem cells within the patch, and this altered stem cell expanded clonally forming a secondary patch, or sub-clone, within the original patch. this is indicated in the diagram by four smaller patches of different colors within the large yellow original area. within these new patches (sub-clones), the process may have been repeated multiple times, indicated by the still smaller patches within the four secondary patches (with still different colors in the diagram) which clonally expanded, until a stem cell arose that generated either small polyps (which may be benign neoplasms) or else a malignant neoplasm (cancer). these neoplasms are also indicated, in the diagram below the photo, by 4 small tan circles (polyps) and a larger red area (cancer). the cancer in the photo occurred in the cecal area of the colon, where the colon joins the small intestine (labeled) and where the appendix occurs (labeled). the fat in the photo is external to the outer wall of the colon. in the segment of colon shown here, the colon was cut open lengthwise to expose the inner surface of the colon and to display the cancer and polyps occurring within the inner epithelial lining of the colon. phylogenetic analyses phylogenetics may be applied to cells in tumors to reveal the evolutionary relationships between cells, just as it is used to reveal evolutionary relationships between organisms and species. shibata, tavare and colleagues have exploited this to estimate the time between the initiation 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. phylogenetic trees should not be confused with oncogenetic trees, which represent the common sequences of genetic events during neoplastic progression and do not represent the relationships of common ancestry that are essential to a phylogeny. for an up-to-date review in this field, see bast 2012. 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 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 principal 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 also 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. 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. 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. 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. 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. clonal evolution and cancer stem cells monoclonal theory of cancer origin the theory about the monoclonal origin of cancer states that, in general, neoplasms arise from a single cell of origin. while it is possible that certain carcinogens may mutate more than one cell at once, the tumor mass usually represents progeny of a single cell, or very few cells. a series of mutations is required in the process of carcinogenesis for a cell to transition from being normal to pre-malignant and then to a cancer cell. the mutated genes usually belong to classes of caretaker, gatekeeper, landscaper or several other genes. mutation ultimately leads to acquisition of the ten hallmarks of cancer. cancer stem cells main article: cancer stem cell the first malignant cell, that gives rise to the tumor, is often labeled a cancer stem cell. the cancer stem-cell hypothesis relies on the fact that a lot of tumors are heterogeneous – the cells in the tumor vary by phenotype and functions. current research shows that in many cancers there is apparent hierarchy among cells. in general, there is a small population of cells in the tumor – about 0.2%–1% – that exhibits stem cell-like properties. these cells have the ability to give rise to a variety of cells in tumor tissue, self-renew indefinitely, and upon transfer can form new tumors. according to the hypothesis, cancer stem cells are the only cells capable of tumorigenesis – initiation of a new tumor. cancer stem cell hypothesis might explain such phenomena as metastasis and remission. the monoclonal model of cancer and the cancer stem-cell model are not mutually exclusive. cancer stem cell arises by clonal evolution as a result of selection for the cell with the highest fitness in the neoplasm. this way, the heterogeneous nature of neoplasm can be explained by two processes – clonal evolution, or the hierarchical differentiation of