title: Normal Wound Healing and Tumor Angiogenesis as a Game of Competitive Inhibition.
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.
authors.affiliation: Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America.|Mathematical, Computational and Modeling Sciences Center, Arizona State Univ, Tempe, Arizona, United States of America.
authors.forename: Irina
authors.initials: I
authors.lastname: Kareva
authors.affiliation: Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Abdo
authors.initials: A
authors.lastname: Abou-Slaybi
authors.affiliation: Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America.|Massachusetts Institute of Technology, Boston, Massachusetts, United States of America.
authors.forename: Oliver
authors.initials: O
authors.lastname: Dodd
authors.affiliation: Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America.|Dept. of Medical Oncology, Dana-Farber Cancer Institute, Dept. of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Olga
authors.initials: O
authors.lastname: Dashevsky
authors.affiliation: Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America.|Pediatric Hematology Oncology, Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America.|Sackler School of Graduate Biomedical Sciences at Tufts University, Boston, Massachusetts, United States of America.
authors.forename: Giannoula Lakka
authors.initials: GL
authors.lastname: Klement
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001792:Blood Platelets / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010978:Platelet Factor 4 / Q000378:metabolism; D011485:Protein Binding; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing
chemical_list: D016222:Fibroblast Growth Factor 2; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D010978:Platelet Factor 4; D020574:Proto-Oncogene Proteins c-sis; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A