The small intestine as a model for evaluating adult tissue stem cell drug targets<sup>1</sup>

Potten, Christopher S; Booth, Catherine; Hargreaves, Danielle F

doi:10.1046/j.1365-2184.2003.00264.x

Cited by 106 publications

(102 citation statements)

References 29 publications

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“…So far many authors tended to concentrate on studying the stem cells, as the most likely targets of cancer initiation. 7 Our results suggest that differentiated cells may be as important for initial stages of colon cancer.…”

Section: Introductionmentioning

confidence: 71%

“…5 It is widely believed that the relevant target cells for the first mutation are the colonic stem cells. 6,7,[9][10][11][12][13] The argument usually goes in the following way. 14 If the first mutation happened in a proliferative daughter cell, it would be washed away before the second hit has a chance to confer a significant phenotypic change.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Komarova¹,

Wang²

2004

Cell Cycle

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Section: Introductionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

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

Komarova¹,

Wang²

2004

Cell Cycle

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“…Thus, the observed difference in the incidence of the two cancers (PC and CRC) could mainly arise from a difference in X , the number of susceptible stem cells, or from a difference in the mutation rates μ 0(1) , or both. The human colon has ≈2×10 7 crypts (48), each maintained by a number of adult colonic stem cells. Nicolas et al (49) have estimated the number of such stem cells to be between 8 and 20 cells, although their findings also allow larger numbers.…”

Section: Discussionmentioning

confidence: 99%

Age-specific incidence of cancer: Phases, transitions, and biological implications

Meza

Jeon

Moolgavkar

et al. 2008

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

144

183

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The observation that the age-specific incidence curve of many carcinomas is approximately linear on a double logarithmic plot has led to much speculation regarding the number and nature of the critical events involved in carcinogenesis. By a consideration of colorectal and pancreatic cancers in the Surveillance Epidemiology and End Results (SEER) registry we show that the log-log model provides a poor description of the data, and that a much better description is provided by a multistage model that predicts two basic phases in the age-specific incidence curves, a first exponential phase until the age of ≈60 followed by a linear phase after that age. These two phases in the incidence curve reflect two phases in the process of carcinogenesis. Paradoxically, the early-exponential phase reflects events between the formation (initiation) of premalignant clones in a tissue and the clinical detection of a malignant tumor, whereas the linear phase reflects events leading to initiated cells that give rise to premalignant lesions because of abrogated growth/differentiation control. This model is consistent with Knudson's idea that renewal tissue, such as the colon, is converted into growing tissue before malignant transformation. The linear phase of the age-specific incidence curve represents this conversion, which is the result of recessive inactivation of a gatekeeper gene, such as the APC gene in the colon and the CDKN2A gene in the pancreas.colorectal | pancreatic | multistage carcinogenesis | neoplastic progression | Knudson's "two-hit" hypothesis T he precise shape of the age-specific incidence of various cancers, especially of nonembryonal solid tumors, and what information can be gleaned from their behavior, is still subject to scientific debate. A widely held view, put forward independently by Muller (1) and Nordling (2) and which reflects the basis of the Armitage-Doll model (3), conceives the stepwise progression of normal cells to cancer as a multistage process involving a number of rate-limiting (epi)genetic events. When viewed at the population level, this assumption uniquely defines the mathematical shape of the age-specific incidence of a cancer, also reflecting the assumed number of rate-limiting events. Indeed, at some level of mathematical approximation (see, e.g., ref. 4), the sequential nature of such a multistep process imposes a power-law behavior, that is, the age-specific incidence of cancers that arise as a consequence of several rate-limiting genomic alterations is predicted to increase with a power of age that is one less than the number of events necessary for malignant transformation. Although it is generally recognized that the carcinogenic process is more complicated and possibly punctuated by selection of advantageous mutations and clonal expansions (5), the qualitative power-law behavior of the age-specific cancer incidence is still considered a reasonable approximation for many cancers and continues to be invoked to argue for or against the importance of specific biological events in car...

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“…Using the mutation rate per base pair per generation (26) of 5 × 10 −10 , the rate of inactivation of APC is 2.4 × 10 −6 per cell per generation. A typical human colon is ∼1.5 m long and has about 10 8 stem cells, each of which divides roughly once every week (40). In the clinical studies (37,38), the authors only measure the number and size of polyps in the last 20 cm of the colon; the effective rate of APC inactivation in this part of the colon is ∼32 per stem cell generation, i.e., we estimate that 32 new polyps are initiated per week in this section of the colon.…”

mentioning

confidence: 99%

Accumulation of driver and passenger mutations during tumor progression

Božić

Antal

Ohtsuki

et al. 2010

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

756

829

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Major efforts to sequence cancer genomes are now occurring throughout the world. Though the emerging data from these studies are illuminating, their reconciliation with epidemiologic and clinical observations poses a major challenge. In the current study, we provide a mathematical model that begins to address this challenge. We model tumors as a discrete time branching process that starts with a single driver mutation and proceeds as each new driver mutation leads to a slightly increased rate of clonal expansion. Using the model, we observe tremendous variation in the rate of tumor development-providing an understanding of the heterogeneity in tumor sizes and development times that have been observed by epidemiologists and clinicians. Furthermore, the model provides a simple formula for the number of driver mutations as a function of the total number of mutations in the tumor. Finally, when applied to recent experimental data, the model allows us to calculate the actual selective advantage provided by typical somatic mutations in human tumors in situ. This selective advantage is surprisingly small-0.004 AE 0.0004-and has major implications for experimental cancer research.genetics | mathematical biology

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The small intestine as a model for evaluating adult tissue stem cell drug targets¹

Cited by 106 publications

References 29 publications

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

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

Age-specific incidence of cancer: Phases, transitions, and biological implications

Accumulation of driver and passenger mutations during tumor progression

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The small intestine as a model for evaluating adult tissue stem cell drug targets1

Cited by 106 publications

References 29 publications

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

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

Age-specific incidence of cancer: Phases, transitions, and biological implications

Accumulation of driver and passenger mutations during tumor progression

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The small intestine as a model for evaluating adult tissue stem cell drug targets¹