Abstract
Tumor angiogenesis is regulated by pro- and anti-angiogenic factors. Anti-angiogenic agents target the interconnected network of angiogenic factors to inhibit neovascularization, which subsequently impedes tumor growth. Due to the complexity of this network, optimizing anti-angiogenic cancer treatments requires detailed knowledge at a systems level. In this study, we constructed a tumor tissue-based model to better understand how the angiogenic network is regulated by opposing mediators at the extracellular level. We consider the network comprised of two pro-angiogenic factors: vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2), and two anti-angiogenic factors: thrombospondin-1 (TSP1) and platelet factor 4 (PF4). The model’s prediction of angiogenic factors’ distribution in tumor tissue reveals the localization of different factors and indicates the angiogenic state of the tumor. We explored how the distributions are affected by the secretion of the pro- and anti-angiogenic factors, illustrating how the angiogenic network is regulated in the extracellular space. Interestingly, we identified a counterintuitive result that the secretion of the anti-angiogenic factor PF4 can enhance pro-angiogenic signaling by elevating the levels of the interstitial and surface-level pro-angiogenic species. This counterintuitive situation is pertinent to the clinical setting, such as the release of anti-angiogenic factors in platelet activation or the administration of exogenous PF4 for anti-angiogenic therapy. Our study provides mechanistic insights into this counterintuitive result and highlights the role of heparan sulfate proteoglycans in regulating the interactions between angiogenic factors. This work complements previous studies aimed at understanding the formation of angiogenic complexes in tumor tissue and helps in the development of anti-cancer strategies targeting angiogenesis.
Highlights
Angiogenesis, the growth of new blood microvessels from pre-existing microvasculature, plays a crucial role in tumor development (Hanahan and Weinberg, 2011)
With the baseline secretion rates, the model predicts that the pro-angiogenic factors (VEGF and fibroblast growth factor 2 (FGF2)) and anti-angiogenic factors (TSP1 and platelet factor 4 (PF4)) have significantly different distribution patterns in tumor tissue (Figure 3)
The model predicts that 23% of total FGF2 is in a signaling form bound to FGFR1:cell-surface heparan sulfate proteoglycans (cHSPG) dimers
Summary
Angiogenesis, the growth of new blood microvessels from pre-existing microvasculature, plays a crucial role in tumor development (Hanahan and Weinberg, 2011). Single-agent anti-angiogenic therapies that target a particular angiogenic factor in the network were the first angiogenesis-inhibiting therapies studied These include antibodies or small molecules targeting pro-angiogenic factors (Abdalla et al, 2018) and peptide mimetics of anti-angiogenic factors (Jeanne et al, 2015). These single-agent anti-angiogenic therapies showed limited success in the clinic due to toxicity, low efficacy, or the development of resistance (Wehland et al, 2012; Vasudev and Reynolds, 2014). These drawbacks have promoted efforts to develop combination therapies administering multiple antiangiogenic agents that simultaneously target various angiogenic species in the network (Alessi et al, 2009; Kim et al, 2009; Uronis et al, 2013; van Beijnum et al, 2015)
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