The nitty‐gritty of vascular permeability in cancer: targeting blood endothelium to control metastases

Blood vascular permeability is a hallmark of cancer and acts as an active driver of metastatic dissemination. Metastasis accounts for the vast majority of cancer deaths, yet most work has focussed on tumour-intrinsic traits and angiogenesis, while the specific contribution of endothelial barrier regulation to intravasation and extravasation remains underappreciated. In this narrative review, we first summarise the structural and molecular bases of vascular permeability, detailing transendothelial permeability and, in particular, paracellular leakage controlled by endothelial tight junctions, endothelial adherens junctions and the endothelial glycocalyx. The review then dissects how tumour microenvironmental cues, including hypoxia, growth factors, inflammatory cytokines, mechanical stress and endothelial heterogeneity, converge to induce a chronically hyperpermeable, disorganised vasculature that promotes metastatic niche formation. Particular emphasis is placed on SRC proto-oncogene, non-receptor tyrosine kinase (Src)/vascular endothelial (VE)-cadherin signalling driven by vascular endothelial growth factor (VEGF). Finally, we discuss pharmacological strategies aiming not to ablate tumour blood vessels, that is, anti-angiogenesis, but to restore proper control of permeability in order to selectively (re)tighten the endothelial barrier and promote endothelium resilience perturbed by cancer metastasis. All in all, this review argues that targeting vascular permeability represents a promising, underexploited avenue to limit metastasis, both by itself and in conjunction with cytotoxic and immune therapies. Finally, we plead for implementing more predictive, mechanistically sound and clinically relevant in vitro, in vivo and in silico models specific to permeability-driven metastasis, developed in close collaboration between computational scientists, biologists and clinical oncologists in a manner that can be translated to clinical benefit.