Abstract
The cancer stem cell hypothesis suggests that tumors contain a small population of cancer cells that have the ability to undergo symmetric self-renewing cell division. In tumors that follow this model, cancer stem cells produce various kinds of specified precursors that divide a limited number of times before terminally differentiating or undergoing apoptosis. As cells within the tumor mature, they become progressively more restricted in the cell types to which they can give rise. However, in some tumor types, the presence of certain extra- or intracellular signals can induce committed cancer progenitors to revert to a multipotential cancer stem cell state. In this paper, we design a novel mathematical model to investigate the dynamics of tumor progression in such situations, and study the implications of a reversible cancer stem cell phenotype for therapeutic interventions. We find that higher levels of dedifferentiation substantially reduce the effectiveness of therapy directed at cancer stem cells by leading to higher rates of resistance. We conclude that plasticity of the cancer stem cell phenotype is an important determinant of the prognosis of tumors. This model represents the first mathematical investigation of this tumor trait and contributes to a quantitative understanding of cancer.
Highlights
Many different cell types within a tumor have been considered to have tumorigenic potential and possess the ability to cause cancers in secondary recipients
This hypothesis has been shown consistent with data from such diverse cancer types as chronic and acute myeloid leukemias [2,3], breast cancer [4], colorectal cancer [5], mesenchymal neoplasms [6], head and neck squamous cell carcinoma [7], and pancreatic cancer [8]
In the following we investigate the effects of a variety of hypothetical drugs that target different cells within the differentiation hierarchy. Note that these scenarios describe idealized treatments which exert the specified effects onto cancer cells; these scenarios serve as examples of the dynamics of the system during drug treatment
Summary
Many different cell types within a tumor have been considered to have tumorigenic potential and possess the ability to cause cancers in secondary recipients. The cancer stem cell hypothesis suggests that only a small subpopulation of tumor cells has that potential [1]. This hypothesis has been shown consistent with data from such diverse cancer types as chronic and acute myeloid leukemias [2,3], breast cancer [4], colorectal cancer [5], mesenchymal neoplasms [6], head and neck squamous cell carcinoma [7], and pancreatic cancer [8]. The investigation of cancer stem cells in melanoma, has led to controversial findings. The frequency of tumor cells positive for stem cell-like markers in breast cancer varies according to the stage and subtype of the tumor [11]
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