Evolution and phenotypic selection of cancer stem cells.
Cells of different organs at different ages have an intrinsic set of kinetics that dictates their behavior. Transformation into cancer cells will inherit these kinetics that determine initial cell and tumor population progression dynamics. Subject to genetic mutation and epigenetic alterations, cancer cell kinetics can change, and favorable alterations that increase cellular fitness will manifest themselves and accelerate tumor progression. We set out to investigate the emerging intratumoral heterogeneity and to determine the evolutionary trajectories of the combination of cell-intrinsic kinetics that yield aggressive tumor growth. We develop a cellular automaton model that tracks the temporal evolution of the malignant subpopulation of so-called cancer stem cells(CSC), as these cells are exclusively able to initiate and sustain tumors. We explore orthogonal cell traits, including cell migration to facilitate invasion, spontaneous cell death due to genetic drift after accumulation of irreversible deleterious mutations, symmetric cancer stem cell division that increases the cancer stem cell pool, and telomere length and erosion as a mitotic counter for inherited non-stem cancer cell proliferation potential. Our study suggests that cell proliferation potential is the strongest modulator of tumor growth. Early increase in proliferation potential yields larger populations of non-stem cancer cells(CC) that compete with CSC and thus inhibit CSC division while a reduction in proliferation potential loosens such inhibition and facilitates frequent CSC division. The sub-population of cancer stem cells in itself becomes highly heterogeneous dictating population level dynamics that vary from long-term dormancy to aggressive progression. Our study suggests that the clonal diversity that is captured in single tumor biopsy samples represents only a small proportion of the total number of phenotypes.
Center of Cancer Systems Biology, GRI, Tufts University School of Medicine, Boston, Massachusetts, United States of America; College of Inter-faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Warsaw, Poland.
Jan
J
Poleszczuk
Center of Cancer Systems Biology, GRI, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
Philip
P
Hahnfeldt
Center of Cancer Systems Biology, GRI, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
Heiko
H
Enderling
D001706:Biopsy; D049109:Cell Proliferation; D019295:Computational Biology; D018450:Disease Progression; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000473:pathology / Q000503:physiopathology; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D010641:Phenotype