Exploring the roads to colon cancer

JNI Oncology Lectures

Speaker: Louis Vermeulen (Academic Medical Center Amsterdam)

Subject: Stem cell dynamics in homeostasis and cancer of the gut

Location: Erasmus MC Rotterdam

Date: Wednesday, 23.03.2016, 11:00-12:00

Author: Edgar Schönfeld

The inner lining of the  intestine has a surface area of circa 250 m2 and is completely renewed every 7 to 10 days. The high turnover rate might partially explain why colorectal cancer is one of the most common types of cancer. New tissue is continuously generated by intestinal stem cells (ISCs) that are located at the bottom of the intestinal crypts. However, the ISC population is not very static. For instance, ISCs can transition between a highly proliferative and a quiescent phenotype. Of particular importance here is the fact, that ISCs are constantly replaced by neighboring ISCs. The dynamics of this ‘birth-and-death’ process can be visualized by a technique called ‘lineage tracing’. Thereby an ISCs is labeled via the incorporation of a marker, such as a fluorescent protein, which will be expressed by the progenitors of the cell. Figure 1 shows the arrangement of ISCs in a cross-section of the bottom of an intestinal crypt. Imagine an initial situation in which each of these cells is labeled with a different marker. Over time, each ISC will either replace a neighbor or will be replaced itself. The result of this stochastic process is that one ISC will eventually replace all the other cells with its copies (this is called ‘fixation’).

ISCs

Figure 1: A schematic representation of the gradual replacement of ISCs by neighboring cells, leading to the fixation of one ISC phenotype.

The cells of origin of colorectal cancer are known to have stem-cell-like properties. With this in mind, Vermeulen and colleagues established a connection between ISC dynamics and the development of colorectal cancer. The dynamics of ISC birth and replacement are governed by several parameters, such as N and λ, representing the number of functional stem cells and the replacement rate measured in stem cells/day, respectively. Vermeulen et al. determined N to be 5 and λ to be 0.1 in the small intestine [1]. Under normal conditions, each ISC has a chance of 0.5 of replacing a neighbor, and a fixation-chance of 1/N. Hereby, we speak of ‘neutral drift’. Subsequently, the researchers went on to examine the effect of mutations in the APC tumor suppressor gene and the K-ras oncogene on the dynamics of this system. Of note, these two genes play a central role in the so-called adenoma-carcinoma sequence, a model stating among others that loss of APC must occur before activation of K-ras in order to induce colorectal cancer. Tumorigenesis is thought to be an evolutionary multistep process, in which the cell population with the greatest selective advantage will eventually dominate in the tumor. Indeed, Vermeulen and colleagues found that an APC or K-ras mutation endows ISCs with a selective advantage with regard to the observed replacement dynamics: While a normal ISC has a chance of 50% of replacing a neighbor, the chance rises up to 79% for APC negative and to 78% for K-ras positive ISCs. In addition, they found that loss of TP53, a gene that is mutated in 50% of all human cancers, does not alter the chance of replacing a neighbor, except in the case of colitis (inflammation of the colon lining). The chance of fixation can be calculated as follows: Pfix=(1-(1-0.PR)/PR)/(1-((1-PR)/PR)N), resulting in a fixation chance of ca 73% for a K-ras or APC mutation (where N=5 and PR= chance of replacing a neighboring cell).
As a consequence of this research, we should look out for drugs that can restore the balance in favor of normal ISCs.

 

[1] Vermeulen L, Morrissey E, van der Heijden M, Nicholson AM, Sottoriva A, Buczacki S, Kemp R, Tavaré S, Winton DJ. Defining stem cell dynamics in models of intestinal tumor initiation. Science. 2013 Nov 22;342(6161):995-8.

 

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