role of HKa, ferritin in angiogenesis revealed (?new antiangiogenic treatments?)

[Lani]

Dr. Judah Folkman, pioneer and advocate of antiangiogenic therapy, theorized that utilizing just one antiangiogenic therapy against cancer might not suffice as it could mutate (or another clone outcompete the rest) which switched to utilizing another angiogenic substance to fuel growth. At the time of his lectures more than a dozen such substances had been discovered as I recall. The story may be even more complicated, or perhaps more easily treatable if one takes interactions into account.

It seems that angiogenic substances may not act alone. Here ferritin, a form of the body's iron storage, combines with HKa, a natural antiangiogenic substance in the body, to cause angiogenesis.

Blood protein may hold key to stopping tumor growth in cancer patients
[Eureka News Service]
WINSTON-SALEM, N.C. - A recent discovery by researchers at Wake Forest University School of Medicine could clear the way for a new drug that inhibits tumor growth in cancer patients and could potentially help in the healing of wounds.
The discovery stems from a study, recently published in the Proceedings of the National Academy of Sciences of the United States of America, in which researchers looked at angiogenesis - the body's formation of new blood vessels from existing blood vessels - and how some blood proteins are involved in that process and affect blood vessel growth.
Researchers found that a protein called ferritin binds to and cripples the ability of another blood protein, called HKa, to shut down blood vessel growth. Because new blood vessels supply a steady stream of nutrients and oxygen that are essential for tumor growth, researchers found that the binding of the two proteins actually assists in new blood vessel formation by removing HKa's influence and therefore promotes tumor growth.
The finding led researchers to the hypothesis that if they can somehow prevent the binding of ferritin and HKa, it will allow HKa to prevent new blood vessel growth and therefore block the growth of tumors.
The finding also has possible implications for wound care. In order to heal, wounds need blood vessel growth. It is therefore possible that by increasing the binding of ferritin to HKa, one could increase the rate at which a serious wound heals.
"It's been known for a long time that levels of ferritin are increased in people with tumors, but it's never been understood why that happens," said Suzy V. Torti, Ph.D., the study's lead investigator, an associate professor of biochemistry and an expert in iron biology at the School of Medicine. "Ferritin appears to play an important role in blood vessel formation. Further, the interaction between ferritin and HKa may represent a new area of interest for possible drug development."
For the study, researchers injected mice with prostate cancer cells to determine how ferritin and HKa affected the formation of new blood vessels.
The mice injected with the cancer cells grew tumors. But when researchers mixed HKa with the tumor cells, the HKa inhibited blood vessel formation. When researchers added ferritin to the mixture of HKa and cancer cells, however, the ferritin restored blood vessel formation, allowing the tumors to grow again.
"Blood vessels can either be helpful, for example in wound healing, or they can be harmful, for example by favoring tumor growth," Torti said. "Our new finding is that the interaction between ferritin and HKa can influence blood vessel formation. This finding could serve as the basis for strategies to either inhibit or stimulate blood vessels. This opens up a new realm of potential ways to treat tumors or other conditions that depend on new blood vessel formation."
The research team, supported by a National Institutes of Health grant, has begun work to develop an anti-tumor drug based on their findings.
Lan G. Coffman, Ph.D., Derek Parsonage, Ph.D., Ralph D'Agostino Jr., Ph.D., and Frank M. Torti, M.D., M.P.H, all of the Wake Forest University School of Medicine, also collaborated on the study.
ABSTRACT: Regulatory effects of ferritin on angiogenesis
[Proceedings of the National Academy of Sciences]
Angiogenesis, the synthesis of new blood vessels from preexisting vessels, plays a critical role in normal wound healing and tumor growth. HKa (cleaved high molecular weight kininogen) is an endogenous inhibitor of angiogenesis formed by the cleavage of kininogen on endothelial cells. Ferritin is a protein principally known for its central role in iron storage. Here, we demonstrate that ferritin binds to HKa with high affinity (Kd 13 nM). Further, ferritin antagonizes the antiangiogenic effects of HKa, enhancing the migration, assembly, and survival of HKa-treated endothelial cells. Effects of ferritin were independent of its iron content. Peptide mapping revealed that ferritin binds to a 22-aa subdomain of HKa that is critical to its antiangiogenic activity. In vivo, ferritin opposed HKa's antiangiogenic effects in a human prostate cancer xenograft, restoring tumor-dependent vessel growth. Ferritin-mediated regulation of angiogenesis represents a new angiogenic regulatory pathway, and identifies a new role for ferritin in cell biology.