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Anti-angiogenic mechanism in cornea may find applications in cancer treatment
Researchers hope that the same mechanisms that keep the cornea clear of blood vessels may help stunt the growth of tumors.
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A recent discovery that shed light on the mechanism that keeps the cornea free of blood vessels may also have implications for cancer research, according to an investigator.
A team of researchers including Reza Dana, MD, MSc, MPH, recently found that vascular endothelial growth factor receptors present in the corneal epithelium prevent the growth of blood vessels in the cornea. Dr. Dana spoke with Ocular Surgery News about the implications their findings may have in the treatment of cancer.
He said what they expect is that the cornea’s anti-angiogenic properties may yield a method of stunting fast-growing tumors that need blood vessels in order to develop.
“Our hope on the one hand is to pursue these investigations and applications for pathological angiogenesis in the eye and, second, to convey this important message to the scientific community and then to collaborate with groups that are interested in oncology and management of cancer to hopefully develop these therapeutic tools,” Dr. Dana said.
Anti-angiogenic effect
Dr. Dana said clinicians have observed for many years that the epithelium of the cornea seems to have an inherent anti-inflammatory and anti-angiogenic affect.
“Whenever a cornea, for example from some autoimmune problem, does not have its epithelium, it is much more susceptible to growth of blood vessels and inflammation,” Dr. Dana explained. “Conversely, whenever the epithelium grew back or we put epithelium on the cornea to help it heal, the inflammation readily goes down, the growth of blood vessels stops, in fact, it regresses.”
Although this phenomenon has been observed clinically, Dr. Dana said, physicians have not known why it occurred.
Dr. Dana and colleagues observed that a number of types of vascular endothelial growth factor receptors are present in the cornea. In particular, he said, VEGFR-3 is present at high levels.
This was an unexpected finding. These receptors are found in the lymphatic system and in the endothelium of proliferating blood vessels, driving pathological angiogenesis. VEGF-C and VEGF-D bind VEGFR-2 and VEGFR-3 in order to promote blood vessel growth or drive pathological angiogenesis, respectively, he said.
“We hypothesized, given our clinical observations, that the reason the cornea is free of blood vessels is that by expressing VEGFR-3 in an unusual place, the corneal epithelium, acts as a Sink Mechanism by binding all the VEGF=C and =D that is around and preventing VEGF=C and D to bind VEGFR-2, which is the receptor that promotes pathological angiogenesis. This thereby prevents the growth of blood vessels, which require VEGFR-2 to be bound,” he explained.
Dr. Dana said the high expression of VEGF-3 in the corneal epithelium is ectopic, in that one would not expect to find it there.
“Of course, in this case, the expression by the cornea of the receptor is where it belongs because it is physiologically relevant,” he said. “It is ectopic in that it is not where one would normally expect to find it, which is on the endothelium of blood vessels and lymphatics.”
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Image: Dana R |
The applications
Dr. Dana explained that this finding could have applications for both ophthalmology and oncology, as well as efforts to modify wound healing.
“There are a lot of applications that we can develop from this work,” he said. “Therapeutically, in the cornea and possibly the retina, one might employ high level of expression of VEGFR-3 to act as a decoy or sink mechanism to prevent pathological angiogenesis by binding the growth factor.”
The finding could have applications in reversing corneal blindness, the second leading cause of blindness in the world, Dr. Dana said.
“We can do the same thing with tissues around tumors,” he said. “Tumors require a lot of blood vessels, and we can, for example, induce the expression of this receptor around tumors to choke off their blood supply.”
Dr. Dana said he and his colleagues hope this ophthalmic discovery will lead to wide applications in medicine.
“I think this only adds to the literature of seminal findings in ophthalmology that have been shown to be critical for the larger field of biomedicine,” he said. “The eye is a wonderful model for studying basic biological mechanisms that are important for both disease and normal physiology elsewhere in the body. This is a great example of how tissues themselves can regulate, self-regulate if you will, pathological mechanisms from taking hold in them.
For more information:
- Reza Dana, MD, MSc, MPH, can be reached at 20 Staniford St., Boston, MA 02114; 617-912-7404; fax: 617-912-0117; e-mail: reza_dana@meei.harvard.edu.
Reference:
- Cursiefen C, Chen L, et al. Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision. Proc Natl Acad Sci U S A. 2006;103:11405-11410.
- Katrina Altersitz is an OSN Staff Writer who covers all aspects of ophthalmology.