Evolutionary dynamics and significance of multiple subclonal mutations in cancer

Beckman, Robert A.; Loeb, Lawrence A.

doi:10.1016/j.dnarep.2017.06.002

Cited by 16 publications

(11 citation statements)

References 75 publications

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“…Therefore, a strong pluripotency should not be used to dichotomize cancer cells into CSC and non-CSC groups. It is true that in cancers many cells die at a much higher rate than others due to various stressors, such as insufficient oxygen or nutrient nourishment, or overly severe genetic damage [554,555,835]. The opposite is also true that in a cancer mass some cells' ability of self-renewal via symmetrical division is much more potent than that of the others.…”

Section: Neglecting Immortality Causes Confusion On Cancer Stem Cellsmentioning

confidence: 99%

Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology

Dou¹,

Tong²,

Huang³

et al. 2020

J. Cancer

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Modern research into carcinogenesis has undergone three phases. Surgeons and pathologists started the first phase roughly 250 years ago, establishing morphological traits of tumors for pathologic diagnosis, and setting immortality and autonomy as indispensable criteria for neoplasms. A century ago, medical doctors, biologists and chemists started to enhance "experimental cancer research" by establishing many animal models of chemical-induced carcinogenesis for studies of cellular mechanisms. In this second phase, the two-hit theory and stepwise carcinogenesis of "initiation-promotion" or "initiation-promotion-progression" were established, with an illustrious finding that outgrowths induced in animals depend on the inducers, and thus are not authentically neoplastic, until late stages. The last 40 years are the third incarnation, molecular biologists have gradually dominated the carcinogenesis research fraternity and have established numerous genetically-modified animal models of carcinogenesis. However, evidence has not been provided for immortality and autonomy of the lesions from most of these models. Probably, many lesions had already been collected from animals for analyses of molecular mechanisms of "cancer" before the lesions became autonomous. We herein review the monumental work of many predecessors to reinforce that evidence for immortality and autonomy is essential for confirming a neoplastic nature. We extrapolate that immortality and autonomy are established early during sporadic human carcinogenesis, unlike the late establishment in most animal models. It is imperative to resume many forerunners' work by determining the genetic bases for initiation, promotion and progression, the genetic bases for immortality and autonomy, and which animal models are, in fact, good for identifying such genetic bases.

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Section: Neglecting Immortality Causes Confusion On Cancer Stem Cellsmentioning

confidence: 99%

Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology

Dou¹,

Tong²,

Huang³

et al. 2020

J. Cancer

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“…Moreover, when the oxidative stress state of cells persists from the imbalance of ROS, DNA damage and induction of mutations affect cellular signaling pathways ( 14 , 15 ), leading to the activation of a variety of protein kinases that regulate diverse cellular functions including the cell cycle, survival, migration, angiogenesis, apoptosis and cell death ( 16 ). The infinite cell proliferation capacity of cancer cells has an effect on angiogenesis related mechanisms ( 17 ), which can induce cancer metastasis by promoting cancer progression-associated processes such as proliferation, migration, and tube formation ( 18 ).…”

Section: Relationship Between Ros and Cancermentioning

confidence: 99%

Potential roles of reactive oxygen species derived from chemical substances involved in cancer development in the female reproductive system

2018

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Reactive oxygen species (ROS) are major sources of cellular oxidative stress. Specifically, cancer cells harbor genetic alterations that promote a continuous and elevated production of ROS. While such oxidative stress conditions could be harmful to normal cells, they facilitate cancer cell growth in multiple ways by causing DNA damage and genomic instability, and ultimately by reprogramming cancer cell metabolism. This review provides up to date findings regarding the roles of ROS generation induced by diverse biological molecules and chemicals in representative women’s cancer. Specifically, we describe the cellular signaling pathways that regulate direct or indirect interactions between ROS homeostasis and metabolism within female genital cancer cells.

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“…All tumors contain genetically divergent cells spawned by the evolutionary processes of mutation and selection. In some tumors, genetic heterogeneity arises from a “mutator phenotype” 1 due to mismatch repair (MMR) defects 2 or heterozygous exonuclease domain mutations (EDMs) affecting the leading or lagging strand DNA polymerases (pol), Polε or Polδ 3 – 9 . Since MMR corrects polymerase errors, when MMR and EDM mutations occur together they produce a dramatic increase in the number of unrepaired polymerase errors.…”

Section: Introductionmentioning

confidence: 99%

Rate volatility and asymmetric segregation diversify mutation burden in cells with mutator alleles

et al. 2021

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Mutations that compromise mismatch repair (MMR) or DNA polymerase ε or δ exonuclease domains produce mutator phenotypes capable of fueling cancer evolution. Here, we investigate how combined defects in these pathways expands genetic heterogeneity in cells of the budding yeast, Saccharomyces cerevisiae, using a single-cell resolution approach that tallies all mutations arising from individual divisions. The distribution of replication errors present in mother cells after the initial S-phase was broader than expected for a single uniform mutation rate across all cell divisions, consistent with volatility of the mutator phenotype. The number of mismatches that then segregated to the mother and daughter cells co-varied, suggesting that each division is governed by a different underlying genome-wide mutation rate. The distribution of mutations that individual cells inherit after the second S-phase is further broadened by the sequential actions of semiconservative replication and mitotic segregation of chromosomes. Modeling suggests that this asymmetric segregation may diversify mutation burden in mutator-driven tumors.

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Evolutionary dynamics and significance of multiple subclonal mutations in cancer

Cited by 16 publications

References 75 publications

Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology

Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology

Potential roles of reactive oxygen species derived from chemical substances involved in cancer development in the female reproductive system

Rate volatility and asymmetric segregation diversify mutation burden in cells with mutator alleles

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