A Model for Spheroid versus Monolayer Response of SK-N-SH Neuroblastoma Cells to Treatment with 15-Deoxy-PGJ₂

Abstract

Researchers have observed that response of tumor cells to treatment varies depending on whether the cells are grown in monolayer, as in vitro spheroids or in vivo. This study uses data from the literature on monolayer treatment of SK-N-SH neuroblastoma cells with 15-deoxy-PGJ 2 and couples it with data on growth rates for untreated SK-N-SH neuroblastoma cells grown as multicellular spheroids. A linear model is constructed for untreated and treated monolayer data sets, which is tuned to growth, death, and cell cycle data for the monolayer case for both control and treatment with 15-deoxy-PGJ 2. The monolayer model is extended to a five-dimensional nonlinear model of in vitro tumor spheroid growth and treatment that includes compartments of the cell cycle (G 1, S, G 2/M) as well as quiescent (Q) and necrotic (N) cells. Monolayer treatment data for 15-deoxy-PGJ 2 is used to derive a prediction of spheroid response under similar treatments. For short periods of treatment, spheroid response is less pronounced than monolayer response. The simulations suggest that the difference in response to treatment of monolayer versus spheroid cultures observed in laboratory studies is a natural consequence of tumor spheroid physiology rather than any special resistance to treatment.

Targeting Cellular DNA Damage Responses in Cancer: An In Vitro-Calibrated Agent-Based Model Simulating Monolayer and Spheroid Treatment Responses to ATR-Inhibiting Drugs

“…The observation that anti-cancer drug responses vary between in vitro monolayer, in vitro spheroid and in vivo models has also been addressed in a mathematical study by Wallace et al, who used ODE models to simulate neuroblastoma treated with 15-Deoxy- in monolayers and spheroids (Wallace et al. 2016 ). Similar to our modelling approach (Fig.…”

Targeting cellular DNA damage responses in cancer: Anin vitro-calibrated agent-based model simulating monolayer and spheroid treatment responses to ATR-inhibiting drugs

“…In order to realistically simulate in vivo tumours, effects of the host’s immune system can furthermore be incorporated in the model. The observation that anti-cancer drug responses vary between in vitro monolayer, in vitro spheroid and in vivo models has also been addressed in a mathematical study by Wallace et al ., who used ODE models to simulate neuroblastoma treated with 15-Deoxy- PGJ 2 in monolayers and spheroids (Wallace et al, 2016). Similar to our modelling approach (Figure 1), the authors used in vitro data to calibrate a monolayer model, and thereafter extended the model to incorporate spheroid features in order to simulate spheroid dynamics.…”

Cell-Cycle Synchronization Prior to Radiotherapy: A Mathematical Model of the Use of Gemcitabine on Melanoma Xenografts

“…To represent a spheroid culture, the model used in this study retains the parameters for the cell cycle determined from the monolayer experimental data and adds quiescent and necrotic compartments. In addition, the model incorporates the cytokine, tumor necrosis factor alpha (TNF-α), which is produced by the necrotic core and induces apoptosis in proliferating cells as described by Wallace et al and He et al [24,33]. Spheroid growth data are taken from Browning et al [34].…”