Abstract
Random mutations and epigenetic alterations provide a rich substrate for microevolutionary phenomena to occur in proliferating epithelial tissues. Genetic diversity resulting from random mutations in normal cells is critically important for understanding the genetic basis of oncogenesis. However, evaluation of the cell-specific role of individual (epi-)genetic alterations in living tissues is extremely difficult from a direct experimental perspective. For this purpose, we have developed a single cell model to describe the fate of every cell in the uterine epithelium and to simulate occurrence of the first cancer cell. Computational simulations have shown that a baseline mutation rate of two mutations per cell division is sufficient to explain sporadic endometrial cancer as a rare evolutionary consequence with an incidence similar to that reported in SEER data. Simulation of the entire oncogenic process has allowed us to analyze the features of the tumor-initiating cells and their clonal expansion. Analysis of the malignant features of individual cancer cells, such as de-differentiation status, proliferation potential, and immortalization status, permits a mathematical characterization of malignancy at the single cell level and a comparison of intra-tumor heterogeneity between individual tumors. We found, under the conditions specified, that cancer stem cells account for approximately 7% of the total cancer cell population. Therefore, our mathematical modeling describes the genetic diversity and evolution in a normal cell population at the early stages of oncogenesis and characterizes intra-tumor heterogeneity. This model has explored the role of accumulation of a large number of genetic alterations in oncogenesis as an alternative to traditional biological approaches emphasizing the driving role of a small number of genetic mutations. A quantitative description of the contribution of a large set of genetic alterations will allow the investigation of the impact of environmental factors on the growth advantage of and selection pressure on individual cancer cells for tumor progression.
Highlights
An evolutionary model has been established to describe the entire process of tumor development in colorectal cancer with detailed molecular mechanisms for the stepwise oncogenic progression driven by sequential accumulation of several genetic mutations (Fearon and Vogelstein, 1990; Jones et al, 2008a)
This rate can be approximately translated into about two to three mutations per cell per division. This reported mutation rate of two to three random mutations per cell per generation would produce billions of mutations in the proliferating uterine epithelial tissue and may be sufficient to explain the large number of genetic mutations uncovered in human tumors (Gallo et al, 2012; Kuhn et al, 2012; Liang et al, 2012). These studies have not found a significant difference in the mutation rate between normal and transformed cells (Elmore et al, 1983; Araten et al, 2005; Jones et al, 2008a), indicating that the genetic diversity universally reported in cancer cell populations may be present in normal cell populations as well, serving as fertile ground for evolution at the earliest stage of oncogenesis
ANALYSIS OF THE MEDIAN PROPERTIES OF TUMORS FORMED BY tumor-initiating cancer cell (TICC) AND tumor-initiating cancer stem cell (TICSC) We extend the above analysis to 500 tumors generated from TICCs
Summary
An evolutionary model has been established to describe the entire process of tumor development in colorectal cancer with detailed molecular mechanisms for the stepwise oncogenic progression driven by sequential accumulation of several genetic mutations (Fearon and Vogelstein, 1990; Jones et al, 2008a). This reported mutation rate of two to three random mutations per cell per generation would produce billions of mutations in the proliferating uterine epithelial tissue and may be sufficient to explain the large number of genetic mutations uncovered in human tumors (Gallo et al, 2012; Kuhn et al, 2012; Liang et al, 2012) These studies have not found a significant difference in the mutation rate between normal and transformed cells (Elmore et al, 1983; Araten et al, 2005; Jones et al, 2008a), indicating that the genetic diversity universally reported in cancer cell populations may be present in normal cell populations as well, serving as fertile ground for evolution at the earliest stage of oncogenesis. Genetic mutations in normal cells can provide significant genetic diversity for subsequent selection, allowing for a unique, albeit extremely rare, consequence: a cell may escape the typical fate of normal cells and become immortalized
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