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Why one-size-fits-all vaso-modulatory interventions fail to control glioma invasion: in silico insights

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ABSTRACT

Gliomas are highly invasive brain tumours characterised by poor prognosis and limited response to therapy. There is an ongoing debate on the therapeutic potential of vaso-modulatory interventions against glioma invasion. Prominent vasculature-targeting therapies involve tumour blood vessel deterioration and normalisation. The former aims at tumour infarction and nutrient deprivation induced by blood vessel occlusion/collapse. In contrast, the therapeutic intention of normalising the abnormal tumour vasculature is to improve the efficacy of conventional treatment modalities. Although these strategies have shown therapeutic potential, it remains unclear why they both often fail to control glioma growth. To shed some light on this issue, we propose a mathematical model based on the migration/proliferation dichotomy of glioma cells in order to investigate why vaso-modulatory interventions have shown limited success in terms of tumour clearance. We found the existence of a critical cell proliferation/diffusion ratio that separates glioma responses to vaso-modulatory interventions into two distinct regimes. While for tumours, belonging to one regime, vascular modulations reduce the front speed and increase the infiltration width, for those in the other regime, the invasion speed increases and infiltration width decreases. We discuss how these in silico findings can be used to guide individualised vaso-modulatory approaches to improve treatment success rates.

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Modelling logic and hierarchy.(A) Diagram of the interactions between glioma cells, oxygen availability, functional tumour vasculature and pro-angiogenic factors. (B) From left to right model complexity increases with respect to the interactions between system variables: density of glioma cells ρ(x, t), density of functional tumour vasculature v(x, t) and oxygen concentration σ(x, t). The parameters σ0 and v0 represent constant oxygen concentration and functional tumour vascularisation, respectively. The parameters h2 and g2 are the glioma cell oxygen consumption and vaso-occlusion rates, respectively (see equations (12)–(13).
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f2: Modelling logic and hierarchy.(A) Diagram of the interactions between glioma cells, oxygen availability, functional tumour vasculature and pro-angiogenic factors. (B) From left to right model complexity increases with respect to the interactions between system variables: density of glioma cells ρ(x, t), density of functional tumour vasculature v(x, t) and oxygen concentration σ(x, t). The parameters σ0 and v0 represent constant oxygen concentration and functional tumour vascularisation, respectively. The parameters h2 and g2 are the glioma cell oxygen consumption and vaso-occlusion rates, respectively (see equations (12)–(13).

Mentions: We develop a mathematical model that describes the growth of vascularised gliomas focusing on the interplay between the migration/proliferation dichotomy and vaso-occlusion at the margin of viable tumour tissue. The system variables are the density of glioma cells ρ(x, t) and functional tumour vasculature v(x, t), as well as the concentrations of oxygen σ(x, t) and pro-angiogenic factors a(x, t) in the tumour microenvironment, where and d is the dimension of the system. Figure 2(A) shows a schematic representation of the system interactions and model assumptions, which are summarised as follows:


Why one-size-fits-all vaso-modulatory interventions fail to control glioma invasion: in silico insights
Modelling logic and hierarchy.(A) Diagram of the interactions between glioma cells, oxygen availability, functional tumour vasculature and pro-angiogenic factors. (B) From left to right model complexity increases with respect to the interactions between system variables: density of glioma cells ρ(x, t), density of functional tumour vasculature v(x, t) and oxygen concentration σ(x, t). The parameters σ0 and v0 represent constant oxygen concentration and functional tumour vascularisation, respectively. The parameters h2 and g2 are the glioma cell oxygen consumption and vaso-occlusion rates, respectively (see equations (12)–(13).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120360&req=5

f2: Modelling logic and hierarchy.(A) Diagram of the interactions between glioma cells, oxygen availability, functional tumour vasculature and pro-angiogenic factors. (B) From left to right model complexity increases with respect to the interactions between system variables: density of glioma cells ρ(x, t), density of functional tumour vasculature v(x, t) and oxygen concentration σ(x, t). The parameters σ0 and v0 represent constant oxygen concentration and functional tumour vascularisation, respectively. The parameters h2 and g2 are the glioma cell oxygen consumption and vaso-occlusion rates, respectively (see equations (12)–(13).
Mentions: We develop a mathematical model that describes the growth of vascularised gliomas focusing on the interplay between the migration/proliferation dichotomy and vaso-occlusion at the margin of viable tumour tissue. The system variables are the density of glioma cells ρ(x, t) and functional tumour vasculature v(x, t), as well as the concentrations of oxygen σ(x, t) and pro-angiogenic factors a(x, t) in the tumour microenvironment, where and d is the dimension of the system. Figure 2(A) shows a schematic representation of the system interactions and model assumptions, which are summarised as follows:

View Article: PubMed Central - PubMed

ABSTRACT

Gliomas are highly invasive brain tumours characterised by poor prognosis and limited response to therapy. There is an ongoing debate on the therapeutic potential of vaso-modulatory interventions against glioma invasion. Prominent vasculature-targeting therapies involve tumour blood vessel deterioration and normalisation. The former aims at tumour infarction and nutrient deprivation induced by blood vessel occlusion/collapse. In contrast, the therapeutic intention of normalising the abnormal tumour vasculature is to improve the efficacy of conventional treatment modalities. Although these strategies have shown therapeutic potential, it remains unclear why they both often fail to control glioma growth. To shed some light on this issue, we propose a mathematical model based on the migration/proliferation dichotomy of glioma cells in order to investigate why vaso-modulatory interventions have shown limited success in terms of tumour clearance. We found the existence of a critical cell proliferation/diffusion ratio that separates glioma responses to vaso-modulatory interventions into two distinct regimes. While for tumours, belonging to one regime, vascular modulations reduce the front speed and increase the infiltration width, for those in the other regime, the invasion speed increases and infiltration width decreases. We discuss how these in silico findings can be used to guide individualised vaso-modulatory approaches to improve treatment success rates.

No MeSH data available.


Related in: MedlinePlus