Differentiated cancer cells may regain stem cell characteristics; however, the effects of such a cellular dedifferentiation on tumoural growth and treatment are currently understudied. Thus, we here extend a mathematical model of cancer stem cell (CSC) driven tumour growth to also include dedifferentiation. We show that dedifferentiation increases the likelihood of tumorigenenis and the speed of tumoural growth, both modulated by the proliferative potential of the non-stem cancer cells (NSCCs). We demonstrate that dedifferentiation also may lead to treatment evasion, especially when a treatment solely targets CSCs. Conversely, targeting both CSCs and NSCCs in parallel is shown to be more robust to dedifferentiation. Despite dedifferentiation, perturbing CSC-related parameters continues to exert the largest relative effect on tumoural growth; however, we show the existence of synergies between specific CSC- and NSCC-directed treatments which cause superadditive reductions of tumoural growth. Overall, our study demonstrates various effects of dedifferentiation on growth and treatment of tumoural lesions, and we anticipate our results to be helpful in guiding future molecular and clinical research on limiting tumoural growth in vivo.

On tumoural growth and treatment under cellular dedifferentiation

The intestinal epithelium is one of the fastest renewing tissues in mammals with an average turnover time of only a few days. It shows a remarkable degree of stability towards external perturbations such as physical injuries or radiation damage. Tissue renewal is driven by intestinal stem cells, and differentiated cells can de-differentiate if the stem cell niche is lost after tissue damage. However, self-renewal and regeneration require a tightly regulated balance to uphold tissue homoeostasis, and failure can lead to tissue extinction or to unbounded growth and cancerous lesions. Here, we present a mathematical model of intestinal epithelium population dynamics that is based on the current mechanistic understanding of the underlying biological processes. We derive conditions for stability and thereby identify mechanisms that may lead to loss of homoeostasis. A key results is the existence of specific thresholds in feedbacks after which unbounded growth occurs, and a subsequent convergence of the system to a stable ratio of stem to non-stem cells. A biologically interesting property of the model is that the number of differentiated cells at the steady-state can become invariant to changes in their apoptosis rate. Moreover, we compare alternative mechanisms for homeostasis with respect to their recovery dynamics after perturbation from steady-state. Finally, we show that de-differentiation enables the system to recover more gracefully after certain external perturbations, which however makes the system more prone to loosing homoeostasis.

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Fischer Mm

Papers

Maintaining and escaping feedback control in hierarchically organised tissue: a case study of the intestinal epithelium