Mathematical Modeling and Simulation of Tumor-Induced Angiogenesis in Retinal Hemangioblastoma

ABSTRACT Retinal Hemangioblastoma (RH) is the most frequent manifestation of the von Hippel-Lindau syndrome (VHL), a rare disease associated with the germline mutation of the von Hippel-Lindau protein (pVHL). An emblematic feature of RH is the high vascularity, which is explained by the overexpression of angiogenic factors (AFs) arising from the pVHL impairment. The introduction of Optical Coherence Tomography Angiography (OCTA) allowed observing this feature with exceptional detail. Here, we combine OCTA images and a mechanistic model to investigate tumor growth and vascular development in a patient-specific way. We derived our model from the agreed pathology for RH and focused on the earliest stages of tumor-induced angiogenesis. Our simulations closely resemble the medical images, proving the capability of our model to recapitulate vascular patterning in actual patients. Our results also suggest that angiogenesis in RH occurs upon reaching a critical dimension (around 200 μm), followed by the rapid formation of stable vascular networks. These findings open a new perspective on the crucial role of time in antiangiogenic therapy in RH, which has resulted in ineffective control. Indeed, it might be that when RH is diagnosed, angiogenesis is already too advanced to be effectively targeted with any effective means. Moreover, our simulations suggest that vascularization in RH is not a continuous process but an inconstant development with long, stable phases and rapid episodes of vascular sprouting. AUTHOR SUMMARY Tumor-induced angiogenesis is a survival strategy commonly exploited by solid tumors to access further nutrients and sustain their growth. The recent introduction of Optical Coherence Tomography Angiography (OCTA) enables scientists and physicians to observe vascular patterning in the retina, non-invasively and with unprecedented detail. Here, we exploit direct observations on a vascular retinal tumor, Retinal Hemangioblastoma (RH), and a mathematical model to investigate the earliest stages of tumor-induced angiogenesis. Our simulations closely match reality and provide critical insights into the role of time in anti-angiogenic therapy for this neoplasm.