Connexin hemichannel induced vascular leak suggests a new paradigm for cancer therapy
Jie Zhang1, Simon J O'Carroll2, Kimiora Henare3
1Department of Ophthalmology and New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Abstract:
It 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.
Insights
Targeting tumor blood vessels with anti-angiogenic drugs has yielded disappointing results. This study suggests protecting, not blocking, tumor vasculature using connexin channel modulation may improve cancer therapy and patient outcomes.
Area of Science:
- Oncology
- Vascular Biology
- Cellular Biology
Background:
- Neovascularization is crucial for tumor growth, yet anti-angiogenic therapies have shown limited success and emerging toxicities.
- Gap junction channels and connexins play roles in vascular integrity, wound healing, and inflammatory diseases.
- Vascular disruption in chronic eye conditions shares similarities with tumor vasculature.
Purpose of the Study:
- To review the role of connexins in vascular leak and endothelial cell death.
- To explore the potential of connexin hemichannel modulation in preventing vascular disruption.
- To propose a novel therapeutic strategy of protecting tumor vasculature.
Main Methods:
- Review of existing literature on connexins, vascular biology, and anti-angiogenic therapies.
- Analysis of vascular disruption in wound healing, ocular diseases, and cancer.
- Application of findings from non-cancerous conditions to tumor vessel biology.
Main Results:
- Connexin channel blockers can improve healing by preventing vascular disruption and restoring vascular integrity.
- Vascular changes in chronic inflammatory eye disorders resemble those in tumors.
- Connexin hemichannel modulation can prevent vascular disruption in ocular conditions.
Conclusions:
- Current anti-angiogenic strategies targeting tumor vasculature may be misguided.
- Protecting and restoring tumor vasculature, rather than inhibiting it, could be a beneficial therapeutic approach.
- Modulating connexin hemichannels offers a potential strategy to improve cancer treatment efficacy by reducing hypoxia and enhancing drug/radiation delivery.
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