Initiation of Colorectal Cancer: Where do the Two Hits Hit?

Komarova, Natalia L.; Wang, Liming

doi:10.4161/cc.3.12.1186

Cited by 41 publications

(33 citation statements)

References 28 publications

(37 reference statements)

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“…This very simple and relatively abstract system is an important case study because it allows a rigorous mathematical description of the ways of evolution in the simple case. It turns out that the results allow understanding of several more complex and more biologically relevant scenarios, including the mutation dynamics in spatial and hierarchically organized cell populations (12)(13)(14)(15).…”

Section: Resultsmentioning

confidence: 99%

Spatial interactions and cooperation can change the speed of evolution of complex phenotypes

Komarova

2014

Proc. Natl. Acad. Sci. U.S.A.

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Complex traits arise from the interactions among multiple gene products. In the case where the complex phenotype is separated from the wild type by a fitness valley or a fitness plateau, the generation of a complex phenotype may take a very long evolutionary time. Interestingly, the rate of evolution depends in nontrivial ways on various properties of the underlying stochastic process, such as the spatial organization of the population and social interactions among cells. Here we review some of our recent work that investigates these phenomena in asexual populations. The role of spatial constraints is quite complex: there are realistic cases where spatial constrains can accelerate or delay evolution, or even influence it in a nonmonotonic fashion, where evolution works fastest for intermediate-range constraints. Social interactions among cells can be studied in the context of the division-of-labor games. Under a range of circumstances, cooperation among cells can lead to a relatively fast creation of a complex phenotype as an emerging (distributed) property. If we further assume the presence of cheaters, we observe the emergence of a fully mutated population of cells possessing the complex phenotype. Applications of these ideas to cancer initiation and biofilm formation in bacteria are discussed.mutations | stochastic modeling C omplex traits depend on several genes and their environments, and arise from the interactions among multiple gene products. Much research has been devoted to inheritance patterns of complex traits (1) and to identifying their genetic makeup (2). Here we will concentrate on the evolutionary process of the emergence of complex traits in asexual populations, and review some of our recent results in this context.In some cases, the evolution of complex traits involves the accumulation of several beneficial mutations. In other cases, however, their evolution requires the accumulation of multiple mutations, each of which is individually neutral or deleterious. A fitness advantage is only attained when all mutations have been acquired (sign epistasis). In such cases, evolution involves the crossing of a fitness valley or fitness plateau (3-5). We can talk about a "fitness foothill" when intermediate mutations are very slightly advantageous compared with the wild type, but not nearly as advantageous as the complex trait (Fig. 1). We will denote by m the number of mutations that need to be accumulated to reach the advantageous complex phenotype. Though recombination can bring together all m mutations within an organism, evolution in asexual populations depends on the sequential accumulation of these mutations within a lineage. The process of sequential accumulation (especially if it involves intermediate deleterious types, such as in the case of fitness valleys) can take a very long evolutionary time. In this paper we discuss how this process and its timing depend on the underlying evolutionary dynamics. In particular, we review recent results on the role of the spatial restrictions inherent in th...

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Section: Resultsmentioning

confidence: 99%

Spatial interactions and cooperation can change the speed of evolution of complex phenotypes

Komarova

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Stated in this form, however, the problem is not sufficiently constrained. In particular, [37,38]). This result becomes intuitive when we look at the proliferative potential of stem cells in specific tissues.…”

Section: Resultsmentioning

confidence: 99%

“…As we discussed in §1, the effectiveness of this protection will depend on the replication capacity of the originally transformed cell as it directly influences the likelihood of acquiring subsequent mutations and of escaping the Hayflick limit itself. Even though the proliferative potential of non-stem cells is limited because they are responsible for the overwhelming majority of cell divisions within a tissue, it can be shown that statistically the accumulation of mutations in non-stem cells is possible [38]. Furthermore, for certain types of cancers, there is evidence that the initiating mutations originate in progenitors (for a review, see [39]).…”

Section: Resultsmentioning

confidence: 99%

Minimizing the risk of cancer: tissue architecture and cellular replication limits

Rodriguez-Brenes

Wodarz

Komarova

2013

J. R. Soc. Interface.

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Normal somatic cells are capable of only a limited number of divisions, which prevents unlimited cell proliferation and the onset of tumours. Cancer cells find ways to circumvent this obstacle, typically by expressing the enzyme telomerase and less often by alternative recombination strategies. Given this fundamental link between cellular replication limits and cancer, it is important to understand how a tissue's architecture affects the replicative capacity of a cell population. We define this as the average number of remaining divisions at equilibrium. The lower the replication capacity, the lower the chances to escape the replication limit during abnormal growth when a tumour develops. In this paper, we examine how the replication capacity is influenced by defining characteristics of cell lineages, such as the number of intermediate cell compartments, self-renewal capability of cells and division rates. We describe an optimal tissue architecture that minimizes the replication capacity of dividing cells and thus the risk of cancer. Interestingly, some of the features that define an optimal tissue architecture have been documented in a variety of tissues, suggesting that they may have evolved as a cancer-protecting strategy in multicellular organisms.

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“…First, it is important to point out the convention that it takes multiple genetic hits to create bona fide cancer [70–72]. In murine models, the consensus is 2–3 hits, while in human settings, it is thought that at least three hits are required to transform cells.…”

Section: Intrinsic Factors Influence Ccosmentioning

confidence: 99%

Refining the role for adult stem cells as cancer cells of origin

White

Lowry

2015

Trends in Cell Biology

120

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Significant progress has been made to identify the cells at the foundation of tumorigenesis, the cancer cell of origin (CCO). The majority of data points towards resident adult stem cells (ASCs) or primitive progenitors as the CCO for those cancers studied, highlighting the importance of stem cells not only as propagators but also as initiators of cancer. Recent data suggest tumor initiation at the CCOs can be regulated through both intrinsic and extrinsic signals and that the identity of the CCOs and their propensity to initiate tumorigenesis is context dependent. In this review, we summarize some of the recent findings regarding CCOs and solid tumor initiation and highlight its relation with bona fide human cancer.

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Initiation of Colorectal Cancer: Where do the Two Hits Hit?

Cited by 41 publications

References 28 publications

Spatial interactions and cooperation can change the speed of evolution of complex phenotypes

Spatial interactions and cooperation can change the speed of evolution of complex phenotypes

Minimizing the risk of cancer: tissue architecture and cellular replication limits

Refining the role for adult stem cells as cancer cells of origin

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