Cellular hierarchy as a determinant of tumor sensitivity to chemotherapy

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, leading to a loss of sensitivity to chemotherapy. Different bladder cancer xenografts, however, demonstrate differential sensitivities to chemotherapy, the basis of which is not understood. Using mathematical models, we show here 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. Our model predicted a weaker response to therapy if negative feedback from differentiated tumor cells inhibited the rate of tumor stem cell division. If this negative feedback was less pronounced, treatment response was predicted to be enhanced. Negative feedback on the rate of tumor cell division promoted 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 indicated support for model predictions. These findings call for further research into feedback mechanisms that might remain active in cancers, and they highlight the presence of feedback as an indication to potentially combine chemotherapy with approaches that limit the process of tumor stem cell enrichment.

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