Cancer stem cell, niche and EGFR decide tumor development and treatment response: A bio-computational simulation study

• Published in: Journal of theoretical biology Vol. 269; no. 1; pp. 138 - 149
• Main Authors: Zhu, Xiuwei, Zhou, Xiaobo, Lewis, Michael T., Xia, Ling, Wong, Stephen
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 21.01.2011
• Subjects: apoptosis; Breast cancer; breast neoplasms; Cell Division; Cell Proliferation; Compartment method; Computer Simulation; Humans; Mathematical model; mathematical models; Models, Biological; Neoplasm Recurrence, Local - pathology; Neoplasms - enzymology; Neoplasms - pathology; Neoplasms - therapy; Neoplastic Stem Cells - enzymology; Neoplastic Stem Cells - pathology; niches; Precancerous Conditions - enzymology; Precancerous Conditions - pathology; Precancerous Conditions - therapy; probability; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction; Signaling pathway; Stem Cell Niche - pathology; stem cells; Tumor Burden; tyrosine; Tyrosine kinase inhibitors; Compartment method; Breast cancer; Signaling pathway; Mathematical model; Tyrosine kinase inhibitors
• ISSN: 0022-5193; 1095-8541
• DOI: 10.1016/j.jtbi.2010.10.016

Recent research in cancer biology has suggested the hypothesis that tumors are initiated and driven by a small group of cancer stem cells (CSCs). Furthermore, cancer stem cell niches have been found to be essential in determining fates of CSCs, and several signaling pathways have been proven to play a crucial role in cellular behavior, which could be two important factors in cancer development. To better understand the progression, heterogeneity and treatment response of breast cancer, especially in the context of CSCs, we propose a mathematical model based on the cell compartment method. In this model, three compartments of cellular subpopulations are constructed: CSCs, progenitor cells (PCs), and terminal differentiated cells (TCs). Moreover, (1) the cancer stem cell niche is, considered by modeling its effect on division patterns (symmetric or asymmetric) of CSCs, and (2) the EGFR signaling pathway is integrated by modeling its role in cell proliferation, apoptosis. Our simulation results indicate that (1) a higher probability for symmetric division of CSC may result in a faster expansion of tumor population, and for a larger number of niches, the tumor grows at a slower rate, but the final tumor volume is larger; (2) higher EGFR expression correlates to tumors with larger volumes while a saturation function is observed, and (3) treatments that inhibit tyrosine kinase activity of EGFR may not only repress the tumor volume, but also decrease the CSCs percentages by shifting CSCs from symmetric divisions to asymmetric divisions. These findings suggest that therapies should be designed to effectively control or eliminate the symmetric division of CSCs and to reduce or destroy the CSC niches.