title: Cellular Hierarchy as a Determinant of Tumor Sensitivity to Chemotherapy.
abstract: Chemotherapy has been shown to enrich cancer stem cells in tumors. Recently, we demonstrated that administration of chemotherapy to human bladder cancer xenografts could trigger a wound-healing response that mobilizes quiescent tumor stem cells into active proliferation. This phenomenon leads to a loss of sensitivity to chemotherapy partly due to an increase in the number of tumor stem cells, which typically respond to chemotherapy-induced cell death less than more differentiated cells. Different bladder cancer xenografts, however, demonstrate differential sensitivities to chemotherapy, the basis of which is not understood. Using mathematical models, we show that characteristics of the tumor cell hierarchy can be crucial for determining the sensitivity of tumors to drug therapy, under the assumption that stem cell enrichment is the primary basis for drug resistance. Intriguingly, our model predicts a weaker response to therapy if there is negative feedback from differentiated tumor cells that inhibits the rate of tumor stem cell division. If this negative feedback is less pronounced, the treatment response is predicted to be enhanced. The reason is that negative feedback on the rate of tumor cell division promotes a permanent rise of the tumor stem cell population over time, both in the absence of treatment and even more so during drug therapy. Model application to data from chemotherapy-treated patient-derived xenografts indicates support for model predictions. These findings call for further research into feedback mechanisms that might remain active in cancers and potentially highlight the presence of feedback as an indication to combine chemotherapy with approaches that limit the process of tumor stem cell enrichment.Cancer Res; 77(9); 2231-41. ©2017 AACR.
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Irvine, California.|Department of Mathematics, University of California, Irvine, California.
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Rodriguez-Brenes
authors.affiliation: Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Antonina V
authors.initials: AV
authors.lastname: Kurtova
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Irvine, California.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Dun L Duncan Cancer Center, Baylor College of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Martha
authors.initials: M
authors.lastname: Mims
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. dwodarz@uci.edu kc1@bcm.edu.|Dun L Duncan Cancer Center, Baylor College of Medicine, Baylor College of Medicine, Houston, Texas.|Scott Department of Urology, Center for Cell Gene and Therapy, Baylor College of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Keith Syson
authors.initials: KS
authors.lastname: Chan
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Irvine, California. dwodarz@uci.edu kc1@bcm.edu.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wodarz
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008962:Models, Theoretical; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays