An imaging-based computational model for simulating angiogenesis and tumour oxygenation dynamics

作者：Adhikarla Vikram; Jeraj Robert

来源：Physics in Medicine and Biology, 2016, 61(10): 3885-3902.

DOI：10.1088/0031-9155/61/10/3885

• computational model
• vasculature
• angiogenesis
• imaging-based modelling
• tumour hypoxia
• tumour growth
• anti-angiogenic therapy

Tumour growth, angiogenesis and oxygenation vary substantially among tumours and significantly impact their treatment outcome. Imaging provides a unique means of investigating these tumour-specific characteristics. Here we propose a computational model to simulate tumour-specific oxygenation changes based on the molecular imaging data. Tumour oxygenation in the model is reflected by the perfused vessel density. Tumour growth depends on its doubling time (T-d) and the imaged proliferation. Perfused vessel density recruitment rate depends on the perfused vessel density around the tumour (sMVD(tissue)) and the maximum VEGF concentration for complete vessel dysfunctionality (VEGF(max)). The model parameters were benchmarked to reproduce the dynamics of tumour oxygenation over its entire lifecycle, which is the most challenging test. Tumour oxygenation dynamics were quantified using the peak pO(2) (pO(2peak)) and the time to peak pO(2) (t(peak)). Sensitivity of tumour oxygenation to model parameters was assessed by changing each parameter by 20%. t(peak) was found to be more sensitive to tumour cell line related doubling time (similar to 30%) as compared to tissue vasculature density (similar to 10%). On the other hand, pO(2peak) was found to be similarly influenced by the above tumour-and vasculature-associated parameters (similar to 30-40%). Interestingly, both pO(2peak) and t(peak) were only marginally affected by VEGFmax (similar to 5%). The development of a poorly oxygenated (hypoxic) core with tumour growth increased VEGF accumulation, thus disrupting the vessel perfusion as well as further increasing hypoxia with time. The model with its benchmarked parameters, is applied to hypoxia imaging data obtained using a [Cu-64] Cu-ATSM PET scan of a mouse tumour and the temporal development of the vasculature and hypoxia maps are shown. The work underscores the importance of using tumour-specific input for analysing tumour evolution. An extended model incorporating therapeutic effects can serve as a powerful tool for analysing tumour response to anti-angiogenic therapies.

• 出版日期2016-5-21