Vascular permeability and drug delivery in cancers

Abstract

The endothelial barrier strictly maintains vascular and tissue homeostasis, and therefore modulates many physiological processes such as angiogenesis, immune responses, and dynamic exchanges throughout organs. Consequently, alteration of this finely tuned function may have devastating consequences for the organism. This is particularly obvious in cancers, where a disorganized and leaky blood vessel network irrigates solid tumors. In this context, vascular permeability drives tumor-induced angiogenesis, blood flow disturbances, inflammatory cell infiltration, and tumor cell extravasation. This can directly restrain the efficacy of conventional therapies by limiting intravenous drug delivery. Indeed, for more effective anti-angiogenic therapies, it is now accepted that not only should excessive angiogenesis be alleviated, but also that the tumor vasculature needs to be normalized. Recovery of normal state vasculature requires diminishing hyperpermeability, increasing pericyte coverage, and restoring the basement membrane, to subsequently reduce hypoxia, and interstitial fluid pressure. In this review, we will introduce how vascular permeability accompanies tumor progression and, as a collateral damage, impacts on efficient drug delivery. The molecular mechanisms involved in tumor-driven vascular permeability will next be detailed, with a particular focus on the main factors produced by tumor cells, especially the emblematic vascular endothelial growth factor. Finally, new perspectives in cancer therapy will be presented, centered on the use of anti-permeability factors and normalization agents.

Keywords: VE-cadherin; VEGF; endothelial barrier; permeability; tumor angiogenesis.

Figure 1

Transcellular and paracellular pathways in endothelial cells. The passage of cells and macromolecules through the endothelial barrier can occur through transcellular (vesicular vacuolar organelles) or paracellular (tight and adherens junctions) pathways. Gap junctions ensure water and ion transport. Moreover, endothelial cells are anchored and connected to the extracellular matrix (ECM) through integrin-based adhesion complexes, namely focal adhesions.

Figure 2

VE-cadherin adhesive complex. VE-cadherin mediates the adhesion between endothelial cells in calcium-dependent manner. VE-cadherin is constituted of an extracellular domain, which allows homophilic interaction in trans. The transmembrane domain participates to lateral clustering in cis. The intracellular domain of VE-cadherin binds p120-catenin (p120), and β-catenin (β-cat), which participates to VE-cadherin membrane retention. Actin cytoskeleton is anchored to VE-cadherin via α-catenin (α-cat) or plakoglobin (plako). In addition, VE-cadherin can bind VEGF-R2 (vascular endothelial growth factor receptor 2) and VE-PTP (vascular endothelial phosphotyrosine phosphatase).

Figure 3

Endothelial barrier in normal and tumor vessels. The endothelial barrier structure differs in normal (A) and tumor (B) blood vessels. Contrary to normal vessels, the tumor vasculature pattern is extremely disorganized and anarchic, presents morphological and structural difference, i.e., weak association between endothelial cells, abnormal shapes of pericytes, lack of smooth muscles, as well as basal membrane modification.

Figure 4

Molecular pathways involved in VEGF-endothelial permeability. VEGF-A stimulation induces VEGF-R2 dimerization and the sequential activation of Vav2, Rac, and PAK, through Src. This results in the serine phosphorylation of VE-cadherin by PAK, and its subsequent internalization into clathrin-coated pits. VEGF can also trigger the tyrosine phosphorylation of VE-cadherin and of its binding partners β-catenin (β-cat) and p120, in a Src-dependent fashion. In addition, VEGF-A decreases the VE-cadherin/p120-catenin association and promotes VE-cadherin endocytosis. VEGF-A also induces the phosphorylation of myosin light chains (MLC), which produces stress fibers that exert tension on intercellular junctions, thus weakening cell–cell contacts. Finally, VEGF-A stimulation causes the dissociation of VE-PTP/VE-cadherin and triggers loss of adhesion and permeability increase.

Figure 5

Signaling pathways of anti-permeability factors. The most relevant anti-permeability factors are angiopoietin-1 (Ang1), sphingosine-1-phosphate (S1P), and fibroblast growth factor (FGF). Ang1 activation of its cognate receptor, Tie2, elicits a signaling pathway and promotes Src sequestration; thus hindering VEGF-A signaling and VE-cadherin internalization. S1P signaling maintains vascular integrity by modulating VE-cadherin internalization, cytoskeletal rearrangement, barrier enhancement and integrity, through its cognate receptor S1P1R. FGF maintains the integrity of the VE-cadherin/p120-catenin complex, thus stabilizing VE-cadherin at the membrane.