Emergence of cyclic hypoxia and the impact of PARP inhibitors on tumor progression Conte, Martina Cabeza Fernández, Vanesa Oliver, F. Javier Alarcón, Tomás Soler Vizcaino, Juan Segundo umor hypoxia is a dynamic phenomenon marked by fluctuations in oxygen levels across both rapid (seconds to minutes) and slow (hours to days) time scales. While short hypoxia cycles are relatively well understood, the mechanisms behind longer cycles remain largely unclear. In this paper, we present a novel mechanistic mathematical model that explains slow hypoxia cycles through feedback loops involving vascular expansion and regression, oxygen-regulated tumor growth, and toxic cytokine production. Our study reveals that, for the emergence of slow hypoxia cycles, endothelial cells must adapt by decreasing receptor activation as ligand concentration increases. Additionally, the interaction between tumor cells and toxic cytokines influences frequency and intensity of these cycles. By examining the effects of pharmacological interventions, specifically poly (ADP-ribose) polymerase inhibitors, we also demonstrate how targeting cell proliferation can help regulate oxygen levels. Our findings enhance the understanding of hypoxia regulation and suggest PARP proteins as promising therapeutic targets. 2024-11-18T11:20:27Z 2024-11-18T11:20:27Z 2024-10-22 journal article Conte, M. et. al. npj Syst Biol Appl 10, 122 (2024). [https://doi.org/10.1038/s41540-024-00453-2] https://hdl.handle.net/10481/97004 10.1038/s41540-024-00453-2 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Springer Nature