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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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An overview of model simulation results.(A) Variations in the glioma cell oxygen consumption rate, under the assumption of constant functional vascularisation, reveal a critical proliferation rate b* that separates tumour invasive behaviors in different regimes (Model II). (B) Variations in the vaso-occlusion rate reveal a critical proliferation/diffusion ratio Λ+ = b/D for b > b+ that separates tumour invasive behaviors in different regimes (Model III). Colour gradients from low to high represent the increase of glioma cell oxygen consumption and vaso-occlusion. The purple and black wedges/bars represent the corresponding effects on the tumour front speed and infiltration width for increasing/decreasing glioma cell oxygen consumption and vaso-occlusion rates.
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f5: An overview of model simulation results.(A) Variations in the glioma cell oxygen consumption rate, under the assumption of constant functional vascularisation, reveal a critical proliferation rate b* that separates tumour invasive behaviors in different regimes (Model II). (B) Variations in the vaso-occlusion rate reveal a critical proliferation/diffusion ratio Λ+ = b/D for b > b+ that separates tumour invasive behaviors in different regimes (Model III). Colour gradients from low to high represent the increase of glioma cell oxygen consumption and vaso-occlusion. The purple and black wedges/bars represent the corresponding effects on the tumour front speed and infiltration width for increasing/decreasing glioma cell oxygen consumption and vaso-occlusion rates.

Mentions: In this work, we proposed a deterministic mathematical model of glioma growth and invasion that is formulated as a system of reaction-diffusion partial differential equations. Our glioma-vasculature interplay model accounts for the dynamics of normoxic and hypoxic glioma cells based on the Go-or-Grow mechanism which is in turn influenced by the functional tumour vasculature and the concentration of oxygen in the microenvironment. In particular, we focused on the effect of variations in the glioma cell oxygen consumption and vascular occlusion on prognostically-relevant characteristics of tumour invasion, i.e. the front speed and infiltration width. The main model results are summarised in Fig. 5.


Why one-size-fits-all vaso-modulatory interventions fail to control glioma invasion: in silico insights
An overview of model simulation results.(A) Variations in the glioma cell oxygen consumption rate, under the assumption of constant functional vascularisation, reveal a critical proliferation rate b* that separates tumour invasive behaviors in different regimes (Model II). (B) Variations in the vaso-occlusion rate reveal a critical proliferation/diffusion ratio Λ+ = b/D for b > b+ that separates tumour invasive behaviors in different regimes (Model III). Colour gradients from low to high represent the increase of glioma cell oxygen consumption and vaso-occlusion. The purple and black wedges/bars represent the corresponding effects on the tumour front speed and infiltration width for increasing/decreasing glioma cell oxygen consumption and vaso-occlusion rates.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: An overview of model simulation results.(A) Variations in the glioma cell oxygen consumption rate, under the assumption of constant functional vascularisation, reveal a critical proliferation rate b* that separates tumour invasive behaviors in different regimes (Model II). (B) Variations in the vaso-occlusion rate reveal a critical proliferation/diffusion ratio Λ+ = b/D for b > b+ that separates tumour invasive behaviors in different regimes (Model III). Colour gradients from low to high represent the increase of glioma cell oxygen consumption and vaso-occlusion. The purple and black wedges/bars represent the corresponding effects on the tumour front speed and infiltration width for increasing/decreasing glioma cell oxygen consumption and vaso-occlusion rates.
Mentions: In this work, we proposed a deterministic mathematical model of glioma growth and invasion that is formulated as a system of reaction-diffusion partial differential equations. Our glioma-vasculature interplay model accounts for the dynamics of normoxic and hypoxic glioma cells based on the Go-or-Grow mechanism which is in turn influenced by the functional tumour vasculature and the concentration of oxygen in the microenvironment. In particular, we focused on the effect of variations in the glioma cell oxygen consumption and vascular occlusion on prognostically-relevant characteristics of tumour invasion, i.e. the front speed and infiltration width. The main model results are summarised in Fig. 5.

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