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.

RET mutation and increased angiogenesis in medullary thyroid carcinomas

“…The essential roles played by pericytes in vessel sprouting and the maturation and stabilization of new vessels are well established (Baluk et al 2003, Bergers & Song 2005, Ribatti et al 2011, Ribeiro & Okamoto 2015. Collectively, therefore, our findings suggest that RETmut MTCs may be characterized by more intense activation of angiogenesis and that this oncogene exerts particularly powerful effects on the remodeling of the tumoral microvasculature, which may be associated with variations in its function (Eberhard et al 2000, Morikawa et al 2002, Baluk et al 2003, Azzi et al 2013). The differences in angiogenesis state observed between RETmut and RASmut tumors are difficult to explain since RAS itself is activated by RET.…”

Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment

“…However, the tumour vasculatures are often immature and leaky in comparison to the normal vasculature [129]. The peri-vascular niche also overlaps with the metastatic niche.…”

TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity

“…VEGF-C and epiregulin (Ereg) are both known to induce angiogenesis by promoting endothelial cell proliferation (24,25). Furthermore, VEGF-C also induces vessel permeability (26). Interestingly, their expression was even further potentiated in hypoxia (Fig.…”