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

Irina Kareva,Oliver Dodd,Olga Dashevsky,Abdo Abou-Slaybi,Giannoula Lakka Klement,Jean-Léon Thomas

doi:10.1371/journal.pone.0166655

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.

Highlights

A state of chronic inflammation and active angiogenesis, characteristic of many tumors, has led to tumors often being considered “wounds that never heal” [1]
This earlier work [2] challenged the widely accepted assumption that platelets degranulate and release proteins en masse. We hypothesize that this is a direct consequence of the varying heparin sulfate-binding affinities of stimulators and inhibitors of angiogenesis, and that there is a specific order to the release of angiogenesis regulators from the platelet clots
Using increasing concentration of NaCl as a surrogate for increasing concentration of tissue proteases, our results indicate that platelet-associated angiogenesis regulators may be eluted in sequence corresponding to their heparin-binding affinities

Summary

Introduction

A state of chronic inflammation and active angiogenesis, characteristic of many tumors, has led to tumors often being considered “wounds that never heal” [1]. We need to identify the mechanisms that lead to normal pruning, stabilization and inhibition of vascular sprouting in wound healing, and why these may be absent in tumor angiogenesis. Both the physiological and pathological variants of angiogenesis are regulated by carefully orchestrated, temporally and spatially controlled signals from surrounding tissues, and it is the sum of these signals the leads to sequential release of stimulators and inhibitors of angiogenesis. We have shown previously that angiogenesis regulators are actively, and against a concentration gradient sequestered in platelets [2], and that stimulators and inhibitors of angiogenesis are differentially released [3, 4]

Methods

Results

Conclusion