Normal Wound Healing and Tumor Angiogenesis as a Game of Competitive Inhibition

Authored by Irina Kareva, Abdo Abou-Slaybi, Oliver Dodd, Olga Dashevsky, Giannoula Lakka Klement

Date Published: 2016

DOI: 10.1371/journal.pone.0166655

Sponsors: United States National Institutes of Health (NIH)

Platforms: NetLogo

Model Documentation: Other Narrative Mathematical description

Model Code URLs: Model code not found

Abstract

Both normal wound healing and tumor angiogenesis are mitigated by the sequential, carefully orchestrated release of growth stimulators and inhibitors. These regulators are released from platelet clots formed at the sites of activated endothelium in a temporally and spatially controlled manner, and the order of their release depends on their affinity to glycosaminoglycans (GAG) such as heparan sulfate (HS) within the extracellular matrix, and platelet open canallicular system. The formation of vessel sprouts, triggered by angiogenesis regulating factors with lowest affinities for heparan sulfate (e.g. VEGF), is followed by vessel-stabilizing PDGF-B or bFGF with medium affinity for HS, and by inhibitors such as PF-4 and TSP-1 with the highest affinities for HS. The invasive wound-like edge of growing tumors has an overabundance of angiogenesis stimulators, and we propose that their abundance out-competes angiogenesis inhibitors, effectively preventing inhibition of angiogenesis and vessel maturation. We evaluate this hypothesis using an experimentally motivated agent-based model, and propose a general theoretical framework for understanding mechanistic similarities and differences between the processes of normal wound healing and pathological angiogenesis from the point of view of competitive inhibition.

Tags

cancer Cells Platelet hemostatic functions Endothelial growth-factor Alpha-granule proteins Heparin affinity Release Endostatin Stroma