Connexin hemichannel induced vascular leak suggests a new paradigm for cancer therapy

Abstract

a b s t r a c tIt is 40 years since cancer growth was correlated with neovascularisation. Anti-angiogenic drugs remain at the forefront of cancer investigations but progress has been disappointing and unexpected toxicities are emerging. Gap junction channels are implicated in lesion spread following injury, with channel blockers shown to improve healing; in particular preventing vascular disruption and/or restoring vascular integrity. Here we briefly review connexin roles in vascular leak and endothelial cell death that occurs following acute wounds and during chronic disease, and how connexin channel regulation has been used to ameliorate vascular disruption. We then review chronic inflammatory disorders and trauma in the eye, concluding that vascular disruption under these conditions mimics that seen in tumours, and can be prevented with connexin hemichannel modulation. We apply this knowledge to tumour vessel biology, proposing that contrary to current opinion, these data suggest a need to protect, maintain and/or restore cancer vasculature. This may lead to reduced tumour hypoxia, promote the survival of normal cells, and enable improved therapeutic delivery or more effective radiation therapy.

Gap junctions and cancer: communicating for 50 years

“…ATP release and modulation of Ca 2+ concentrations regulate cell proliferation in a variety of cell types 154-156 , and inappropriate hemichannel opening may underlie some hyperproliferative disorders such as hidrotic ectodermal dysplasia 157 . Hemichannel functions have also been linked to vascular disruption and haemorrhage within tumours 158 , and recently Cx43 hemichannels of osteocytes are involved in suppression of breast cancer cell growth and bone metastasis 159 . However, the link between hemichannels and cancer is difficult to conclusively establish as most reagents that block gap junction channels also block connexin hemichannels making assignment of functional consequences specifically to hemichannel functions problematic 160 .…”

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

“…These changes in Cx43 will have physiological consequences. In HUVECs and other ECs, TNFα, IL-1β or oxidized LDL promote apoptosis, inhibit cell growth and inhibit barrier function; however, they also promote Cx43 expression and formation of gap junctions (73)(74)(75). Inhibition of Cx43 expression and gap junctions inhibit apoptosis, promote proliferation and maintain barrier function.…”

Connexin channel and its role in diabetic retinopathy

“…Therefore, the hemichannel-blocking peptides are postulated to be developed into potential treatment alternatives for injury, inflammatory and chronic disease. The role of Cx43 hemichannels has drawn significant attention, especially in the pathogenesis of chronic inflammation in the eye (Zhang et al, 2014). They hypothesize that vascular disruption mimics that seen in tumor and can be prevented with the modulation of connexin hemichannels and further suggest that maintaining or restoring cancer vasculature, in contrast to current opinion, leads to reduced tumor hypoxia and promotes the survival of normal cells.…”