You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: Evolution and Phenotypic Selection of Cancer Stem Cells}
Article:
Abstract:
Cells of different organs at different ages have an intrinsic set of kinetics that dictates their behavior. Transformation into cancer cells will inherit these kinetics that determine initial cell and tumor population progression dynamics. Subject to genetic mutation and epigenetic alterations, cancer cell kinetics can change, and favorable alterations that increase cellular fitness will manifest themselves and accelerate tumor progression. We set out to investigate the emerging intratumoral heterogeneity and to determine the evolutionary trajectories of the combination of cell-intrinsic kinetics that yield aggressive tumor growth. We develop a cellular automaton model that tracks the temporal evolution of the malignant subpopulation of so-called cancer stem cells( CSC), as these cells are exclusively able to initiate and sustain tumors. We explore orthogonal cell traits, including cell migration to facilitate invasion, spontaneous cell death due to genetic drift after accumulation of irreversible deleterious mutations, symmetric cancer stem cell division that increases the cancer stem cell pool, and telomere length and erosion as a mitotic counter for inherited non-stem cancer cell proliferation potential. Our study suggests that cell proliferation potential is the strongest modulator of tumor growth. Early increase in proliferation potential yields larger populations of non-stem cancer cells( CC) that compete with CSC and thus inhibit CSC division while a reduction in proliferation potential loosens such inhibition and facilitates frequent CSC division. The sub-population of cancer stem cells in itself becomes highly heterogeneous dictating population level dynamics that vary from long-term dormancy to aggressive progression. Our study suggests that the clonal diversity that is captured in single tumor biopsy samples represents only a small proportion of the total number of phenotypes.
Introduction:
Human organs and tissues are comprised of cells that have evolved to maintain functionality and integrity. Cells of different organs and ages have different traits, such as migration rate, turnover time, proliferation potential and lifespan until senescence. While fetal diploid cell strains in culture demonstrate a large number of divisions before mitotic arrest and culture degeneration( 50 ± 10 population doublings, termed the “Hayflick Limit”[1–3]), hematopoietic progenitors may undergo about 20–30 divisions[4], and colonic crypt progenitors complete only four to six divisions before getting washed off at the top of the crypt[3]. Repopulation of the tissue is assured by tissue stem cells that sit on top of a cellular hierarchy[5, 6]. In a physiological setting, stem cells are predominantly non-mitotic to prevent malignant transformation[7] and only enter the mitotic cycle when tissue repopulation is required[8–10]. The transit-amplifying offspring of a stem cell may undergo multiple divisions to produce a population of cells that differentiate into tissue-specific cells with determined function and lifespan. The potencies of tissue stem cells and transit-amplifying cells vary with tissue type and age. Transformation may occur at any time in all tissue compartments, but the ability of transformed cells to initiate and sustain pathologic tumor growth requires certain kinetic properties including longevity, migration potential, self-renewal and differentiation capacity. These traits are comparable to physiologic stem cells, and cancer cells with such properties have been termed cancer stem cells causing a long and active discussion about the cell of origin of tumor[5, 11, 12]. Intestinal cancer may be initiated by a transformed stem cell[13], but a transformed progenitor cell with acquired stem-like traits is more likely in myeloid malignancies and NF1- and PDGF-driven glioblastoma[14, 15]. The set of kinetics in the initial cancer stem cell, however, is initially close to that of the untransformed cell. The kinetics will be inherited by the descendent cells yielding tumor population dynamics ranging from microscopic dormancy to aggressive tumor growth[16]. It is conceivable that the variation in kinetics of cells in different positions of the tissue hierarchy and at different ages gives rise to many trait combinations unfavorable for progression[17]. Inferior cancer cell trait combinations could, at least in part, explain the increasing observations of pathologic but non-advancing lesions[18, 19]. Trait fitness, mutation and evolution may augment our understanding why tumors may be more prevalent in certain organs at a specific age range[20]. Regardless of kinetics at time of transformation, cells are subject to mutations, which enables evolution of and selection for more aggressive traits. For example, during mitosis the daughter cells inherit telomeres, the non-coding replicative protective ends of the DNA[21]. Telomeres get shortened during mitosis[22], which offers a quantitative visualization of the remaining cellular proliferation potential[22, 23]. Abnormally increased or decreased telomerase activity[24] in cancer stem cells lengthens or shortens telomeric DNA that defines the number of cell divisions for non-stem cancer cell progeny[25, 26].
Discussion:
It becomes increasingly appreciated that tumors are heterogeneous populations of cells with different traits and fates. An intrinsic difference in tumor initiation and propagation potential led to a classification of cancer stem cells( CSC) and non-stem cancer cells( CC) in the majority of hematologic and solid tumors[12, 32–34]. The transformed cells that lead to the initial CSC inherit kinetic properties of their somatic cell of origin, which may be significantly varying at different ages and between organs. Different cell kinetics result in different overall tumor population dynamics ranging from population level dormancy to aggressive growth and invasion[17]. Agent-based models are well suited to simulate individual cell dynamics and estimate tumor progression dependencies on single cell kinetics. We have identified a set of orthogonal cell kinetics that include cell migration rate, proliferation potential, spontaneous cell death, and symmetric cancer stem cell division. In a cancer stem cell-driven tumor, proliferation potential and spontaneous cell death have been shown to non-monotonically modulate overall tumor progression[16, 30, 31] while increased cell migration and symmetric CSC division always lead to accelerated tumor growth[27, 35]. The complex interplay of these participating dynamics, however, requires a more elegant investigation of which combinations of simultaneously evolving kinetics yield the most aggressive tumor clones. While parameter evolution yields predominantly fast growing tumors, early unfavorable mutation events may ultimately push tumor dynamics into dwarfed tumor growth or long-term dormancy. Our study suggests that cell proliferation potential is the strongest modulator of tumor growth. Early increase in proliferation potential yields larger populations of CC that compete with CSC and thus inhibit CSC division[16, 30]. Conversely, a reduction in proliferation potential decreases intratumoral competition and enables accelerated CSC pool expansion and further evolution. Interestingly, short telomeres indicative of short-lived cancer cells with limited proliferation capacity have indeed been observed in malignant tumor population[26, 36], lending further support that limiting the number of CC progeny promotes parental CSC expansion and tumor growth. Phenotypes that eventually dominate the tumor developed relatively late indicating that the chosen initial parameter values were suboptimal for tumor progression despite previous observations of relatively fast growth[17]. Successfully evolving tumors exhibit a heterogeneous distribution of phenotypes with different sub-clones dominating local expansion. This confirms clinical observations of intratumoral heterogeneity and branched evolution with spatially distinct genetic profiles[37]. The spatial heterogeneity of cell traits also leads to a large variation in CSC fraction in biopsy samples, offering yet another angle to the ongoing discussion about the proportion of tumorigenic subpopulations in tumors[38–41]. Furthermore, our work suggests that the so-called sub-population of cancer stem cells is in itself heterogeneous. Whilst some CSC will initiate immediate growth, other CSC will form microscopic tumors that may remain dormant for prolonged periods of time. Indeed, a variety of individual human derived malignant cancer cell lines can each be carefully divided into sub-clones that form fast-growing tumors or stable disease for many months before initiating rapid growth[42–44]. The model presented here is a complex but simple approach for measuring continuous intratumoral CSC evolution. For computational convenience we have limited our study to a two-dimensional model. A previous analysis in a similar cell interaction model has shown that two-dimensional cellular automata qualitatively mimic three-dimensional tumor growth dynamics[45]. The presented results assumed a mutation rate of 50%; other mutation rates yield qualitatively similar results on a different time scale with smaller mutation rates yielding slower growing tumors( S1 Fig). To first understand the trajectories of intratumoral evolution, we limited the study to stem and non-stem cancer cells and ignored tumor environmental factors that will exert external selection pressure on the tumor population and shape parameter fitness values accordingly[46, 47]. Future developments of this model may include local tumor-environmental interactions or globally-informed modulations by the host immune system. To further increase complexity, bi-directional plasticity of phenotypes via CSC differentiation and CC de-differentiation may be considered[48–51], which will contribute to increased biological realism of tumor evolution dynamics.
We present an in silico computational model of tumor growth and evolution according to the cancer stem cell hypothesis . Inheritable traits of cells may be genetically or epigenetically altered , and traits that confer increased fitness to the cell will be selected for on the population level . Phenotypic evolution yields aggressive tumors with large heterogeneity , prompting the notion that the cancer stem cell population per se is highly heterogeneous . Within aggressive tumors cancer stem cells with low tumorigenic potential may be isolated . Simulations of our model suggest that the cells harvested in core needle biopsies represent less than 10% of the phenotypic heterogeneity of the total tumor population . Dependent on the cells captured in the sample , xenografted tumors may exhibit aggressive growth or long-term dormancy—dynamics that may suggest opposing treatment approaches for the same tumor when translated into clinical decision-making .