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A deeper understanding of the tumor microenvironment (TME) and its role in metabolic activity at different stages of vascularized tumors can provide useful insights into cancer progression and better support clinical assessments. In this study, a robust and comprehensive multi-scale computational model for spatiotemporal transport of F-18 fluorodeoxyglucose (FDG) is developed to incorporate important aspects of the TME, spanning subcellular-, cellular-, and tissue-level scales. Our mathematical model includes biophysiological details, such as radiopharmaceutical transport within interstitial space via convection and diffusion mechanisms, radiopharmaceutical exchange between intracellular and extracellular matrices by glucose transporters, cellular uptake of radiopharmaceutical, as well as its intracellular phosphorylation by the enzyme. Further, to examine the effects of tumor size by varying microvascular densities (MVDs) on FDG dynamics, four different capillary networks are generated by angiogenesis modeling. Results demonstrate that as tumor grows, its MVD increases, and hence, the spatiotemporal distribution of total FDG uptake by tumor tissue changes towards a more homogenous distribution. In addition, spatiotemporal distributions in tumor with lower MVD have relatively smaller magnitudes, due to the lower diffusion rate of FDG as well as lower local intravenous FDG release. Since mean standardized uptake value (SUV mean ) differs at various stages of microvascular networks with different tumor sizes, it may be meaningful to normalize the measured values by tumor size and the MVD prior to routine clinical reporting. Overall, the present framework has the potential for more accurate investigation of biological phenomena within TME towards personalized medicine., (© 2022. The Author(s).)

Emerging evidence shows that endothelial cells are not only the building blocks of vascular networks that enable oxygen and nutrient delivery throughout a tissue but also serve as a rich resource of angiocrine factors. Endothelial cells play key roles in determining cancer progression and response to anti-cancer drugs. Furthermore, the endothelium-specific deposition of extracellular matrix is a key modulator of the availability of angiocrine factors to both stromal and cancer cells. Considering tumor vascular network as a decisive factor in cancer pathogenesis and treatment response, these networks need to be an inseparable component of cancer models. Both computational and in vitro experimental models have been extensively developed to model tumor-endothelium interactions. While informative, they have been developed in different communities and do not yet represent a comprehensive platform. In this review, we overview the necessity of incorporating vascular networks for both in vitro and in silico cancer models and discuss recent progresses and challenges of in vitro experimental microfluidic cancer vasculature-on-chip systems and their in silico counterparts. We further highlight how these two approaches can merge together with the aim of presenting a predictive combinatorial platform for studying cancer pathogenesis and testing the efficacy of single or multi-drug therapeutics for cancer treatment., (Copyright © 2018. Published by Elsevier Inc.)