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. 2016 Dec 9;11(12):e0166655.
doi: 10.1371/journal.pone.0166655. eCollection 2016.

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

Irina Kareva  1   2 , Abdo Abou-Slaybi  1 , Oliver Dodd  1   3 , Olga Dashevsky  1   4 , Giannoula Lakka Klement  1   5   6
Affiliations

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

Irina Kareva et al. PLoS One. .

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Release of angiogenesis regulators from platelets is sequential.
The activity of tissue proteases such as heparinase, which is an enzyme that cleaves heparan sulfate from the cell membranes, is simulated by increased concentrations of NaCl. As shown in a, b and c, higher concentrations of NaCl are required for the release of growth factors with higher heparan sulfate affinities, going from VEGF (a) to PDGF-B (b) to PF-4 and TSP-1 (c). The observed plateau in PF-4 was due to the detection limit of the PF-4 ELISA. The predicted shape of the curve in the absence of ELISA detection limit is shown as a dotted red line. Fig 1D shows an overlay of each protein with PDGF-B divided by 10, PF-4 divided by 50 and TSP-1 divided by 100. Each experiment was repeated 3 times in technical duplicate.
Fig 2
Fig 2. A snapshot of the proposed agent-based model.
(A) Model initialization. The grid is populated by cells, which are characterized by pre-determined number of binding sites. The color changes in the microenvironments represent heparinase concentration. Darker patches correspond to higher concentrations of heparinase; lighter patches correspond to lower levels of heparinase. (B) After the simulation has begun, the growth factors LA, MA and HA mode randomly throughout the grid. Once they encounter a cell with free binding sites (red crosses), they occupy them, and thereby decreasing the number of available sites (numbers by the cell agents decreases, reflecting the number of available sites). Growth factors become cleaved depending on the current concentration of heparinase in the corresponding microenvironment. The NetLogo code for this model is attached in Supporting Information.
Fig 3
Fig 3. Simulation of cytokine release during normal wound healing.
Angiogenesis regulators bound to a heparin sulfate moiety in platelet clots are eluted using incremental concentrations of sodium chloride as a surrogate for tissue proteases. The experimentally observed release of growth factors appears to suggest that angiogenesis regulators are released in order of their affinity for heparan sulfate, with VEGF having the lowest affinity, and PF-4 and TSP-1 the highest.
Fig 4
Fig 4. Summary of simulations for normal and pathological angiogenesis.
The simulation of cytokine profiles in normal wound healing (A) is distinctly different from the cytokine profiles during tumor angiogenesis (B-F). In order to simulate tumor angiogenesis, a number of scenarios were explored: The release of 1 additional low affinity cytokine released into the model microenvironment per run (B); 1 additional low affinity (LA) and 1 medium affinity (MA) (C); 2 LA and1MA (D); 5LA and 1MA (E); and 5LA, 1MA and 1HA (F). The combination of continuous presence of LA and MA may be suggestive of continued formation of new, but leaky vessels.
Fig 5
Fig 5. Schematic representation of the proposed mechanism underlying normal wound healing, pathological angiogenesis and differences in both dormant and progressive tumors.
See this image and copyright information in PMC

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