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.

Effect of feedback regulation on stem cell fractions in tissues and tumors: understanding chemo-resistance in bladder cancer

“…Chemotherapy-induced death of more differentiated cells resulted in a wound healing type response that is mediated by PGE2 and that resulted in the activation and proliferation of CSCs during treatment. A mathematical model of these treatment dynamics confirmed that this wound-healing response could contribute to the amplification of the CSC population during chemotherapy [11]. At the same time, however, the model showed that this CSC enrichment was not maintained following cessation of therapy.…”

“…At the same time, however, this interesting observation has brought up a number of questions that can best be answered by using mathematical models to interpret the data. Mathematical modeling [11] suggested that the wound-healing response alone cannot result in CSC enrichment that is sustained beyond the treatment phase, and hence cannot ex- When considering a specific model, as has been done in much of the literature so far, results can depend on the particular mathematical formulation of feedback interactions. These particular formulations are typically arbitrary, and the same biological processes can often be described by somewhat different mathematical terms, which can impact model predictions and thus lead to robustness issues.…”

“…To gain analytical insights, we reduced the complexity of the lineage differentiation pathway to include only stem cells and differentiated cells, ignoring intermediate transit amplifying cell populations with limited self-renewal capacity. Our previous work included models that explicitly took into account transit amplifying cells [11], and the relationship between the presence of negative feedback on stem cell division and the occurrence of stem cell enrichment remained qualitatively the same [41]. Other modeling approaches have treated the cell differentiation pathway as a continuous process using partial differential equations, rather than considering discrete cell sub-populations [42].…”

“…In other words, the positive feedback wound-healing response alone could not account for a pronounced reduction in the response to chemotherapy during the next cycle following an off-therapy phase. This situation changed when we added negative feedback from differentiated cells onto the division rate of stem cells in the mathematical model [11]. We found that in this case, the enriched stem cell fractions were predicted to be maintained in the long term during the off-treatment phase.…”

“…The present study provides a solid theoretical basis for implicating the presence of feedback regulatory loops as a determinant of responses to cancer therapy. This adds to the mathematical literature quantifying the role of feedback regulation for tissue and tumor dynamics [11,13,[15][16][17][18][19][20][21][22][23][24], and builds upon the wider mathematical literature concerned with the dynamics of hierarchically structured cell populations, e.g. [25][26][27][28][29][30][31] and stem cell fractions [32].…”