Abstract
In order to metastasize, cancer cells must undergo phenotypic transition from an anchorage-dependent form to a motile form via a process referred to as epithelial to mesenchymal transition. It is currently unclear whether metastatic cells emerge late during tumor progression by successive accumulation of mutations, or whether they derive from distinct cell populations already present during the early stages of tumorigenesis. Similarly, the selective pressures that drive metastasis are poorly understood. Selection of cancer cells with increased proliferative capacity and enhanced survival characteristics may explain how some transformations promote a metastatic phenotype. However, it is difficult to explain how cancer cells that disseminate can emerge due to such selective pressure, since these cells usually remain dormant for prolonged periods of time. In the current study, we have used in silico modeling and simulation to investigate the hypothesis that mesenchymal-like cancer cells evolve during the early stages of primary tumor development, and that these cells exhibit survival and proliferative advantages within the tumor microenvironment. In an agent-based tumor microenvironment model, cancer cell agents with distinct sets of attributes governing nutrient consumption, proliferation, apoptosis, random motility, and cell adhesion were allowed to compete for space and nutrients. These simulation data indicated that mesenchymal-like cancer cells displaying high motility and low adhesion proliferate more rapidly and display a survival advantage over epithelial-like cancer cells. Furthermore, the presence of mesenchymal-like cells within the primary tumor influences the macroscopic properties, emergent morphology, and growth rate of tumors.
Highlights
Cancer progression is typically described as a multi-step process whereby normal replicating cells undergo a series of progressive mutations that lead to dysregulated proliferation, local invasion, and metastatic dissemination (Fidler and Kripke, 1977; Hanahan and Weinberg, 2000)
In the current report, we used an in silico model to demonstrate that cancer cells with a mesenchymal-like phenotype have a survival and proliferative advantage in the microenvironment of an avascular tumor (Figure 7)
Our model shows that tumor morphology is determined by the properties of individual cancer cells and by nutrient distribution
Summary
Cancer progression is typically described as a multi-step process whereby normal replicating cells undergo a series of progressive mutations that lead to dysregulated proliferation, local invasion, and metastatic dissemination (Fidler and Kripke, 1977; Hanahan and Weinberg, 2000). Metastasis was thought to depend on cancer cells which emerge late in the course of disease progression This view has recently been challenged by data from gene expression profiling and reports that metastatic cells disseminate early during primary tumor progression (Bacac and Stamenkovic, 2008; Eyles et al, 2010). The early acquisition of a metastatic phenotype is probably facilitated by epithelial to mesenchymal transition (EMT) of cancer cells (Gavert and Ben-Ze’ev, 2010), a process which normally occurs during embryogenesis (Kalluri and Weinberg, 2009). EMT-like processes are likely to drive the acquisition of a metastatic phenotype by cancer cells (Kalluri, 2009; Gavert and Ben-Ze’ev, 2010) and tumor-infiltrating immune cells have been shown to favor these changes (Santisteban et al, 2009; Toh et al, 2011; Bonde et al, 2012). The factors which promote EMT and drive dissemination of metastatic cells during early cancer progression remain uncertain
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