Multiscale Modeling of Glioblastoma Suggests that the Partial Disruption of Vessel/Cancer Stem Cell Crosstalk Can Promote Tumor Regression without Increasing Invasiveness

Abstract

Objective In glioblastoma, the crosstalk between vascular endothelial cells (VECs) and glioma stem cells (GSCs) has been shown to enhance tumor growth. We propose a multiscale mathematical model to study this mechanism, explore tumor growth under various initial and microenvironmental conditions and investigate the effects of blocking this crosstalk. Methods We develop a hybrid continuum-discrete model of highly organized, vascularized tumors. VEC-GSC crosstalk is modeled via VEGF production by tumor cells and by secretion of soluble factors by VECs that promote GSC self-renewal and proliferation. Results VEC-GSC crosstalk increases both tumor size and GSC fraction by enhancing GSC activity and neovascular development. VEGF promotes vessel formation, and larger VEGF sources typically increase vessel numbers, which enhances tumor growth and stabilizes the tumor shape. Increasing the initial GSC fraction has a similar effect. Partially disrupting the crosstalk by blocking VEC secretion of GSC promoters reduces tumor size but does not increase invasiveness, which is in contrast to anti-angiogenic therapies, which reduce tumor size but may significantly increase tumor invasiveness. Significance Multiscale modeling supports the targeting of VEC-GSC crosstalk as a promising approach for cancer therapy.

3D Mathematical Modeling of Glioblastoma Suggests That Transdifferentiated Vascular Endothelial Cells Mediate Resistance to Current Standard-of-Care Therapy

“…We assume that viable tumor cells in the hypoxic core (when the nutrient level is below a threshold) produce VEGF. Similar results are obtained where GSCs produce twice as much VEGF as non-GSCs (7). Vessel sprout sites are selected at a constant probability once the VEGF concentration is higher than a threshold.…”

“…We model GBM tumor progression in 3D by solving numerically a multispecies mixture model adapted from (1,4,7). The equations are solved in dimensionless form using the diffusional length of nutrients as the length scale (L), e.g.…”

“…Because of their simplicity, continuum reaction-diffusion equations have been widely used to describe the infiltration of GBM cells in the brain (29–31) and to develop patient-specific therapeutic approaches (32,33). Here, we use a continuum-level multiscale, mixture type model, extending previous work (4,7) to simulate the dynamics of GBM stem, GBM progenitor, transdifferentiated endothelial cells, terminally differentiated, dead cells. The GBM system is coupled to a discrete angiogenesis model from (1), extended to account for cross-talk between GBM cells and the vascular network.…”

Editorial Special Section on Multiscale Cancer Modeling

“…Yan et al [17] present a 3D hybrid model of glioblastoma (GBM) progression and vasculature growth which accounts for the feedback among various cell types considered in a cell lineage, tumor-induced vascularization, and crosstalk between vascular endothelial cells (VECs) and glioma stem cells (GSCs). The VEC-GSC crosstalk was implemented via vascular endothelial growth factor (VEGF), which promotes vessel formation, and a VEC-secreted factor that promotes GSC self-renewal and proliferation.…”

3D Mathematical modeling of glioblastoma suggests that transdifferentiated vascular endothelial cells promote resistance to current standard-of-care therapy.

“…We model GBM tumor progression in 3D by solving numerically a multispecies mixture model adapted from (4,7,9). The equations are solved in dimensionless form using the diffusional length of nutrients as the length scale (L), for example, around 250 mm, and the cell cycle of a GCP, for example, around 24 hours, as the time scale (T).…”