Public Release: 

Cancer gene drives vascular disorder

American Association for the Advancement of Science


IMAGE: PIK3CA mutations impair blood vessel formation in mouse embryos (upper panels). Here, the mutations improved after treatment with a PI3Kα inhibitor (lower panels). This material relates to a paper that... view more

Credit: P. Castel et al., Science Translational Medicine (2016)

Two research teams have uncovered mutations in a well-known cancer gene that may drive the most common form of blood vessel abnormality, venous malformations, in some patients. The findings pave the way for repurposing cancer therapies being developed to target the gene, known as PIK3CA, for treatment of this vascular disease. Individuals with venous malformations are born with abnormally large and distorted blood vessels that grow over time. These painful and disfiguring lesions can cause bleeding and obstruct organs, such as intestines, muscles, or joints. Current treatments like surgery and sclerotherapy are only partially effective. Defects in the gene TEK are known to cause about half of nonhereditary venous malformations, but the genetic changes responsible for the other half of cases remains elusive. Sandra Castillo et al. and Pau Castel et al. now find that PIK3CA is mutated in about 25% of patients with venous malformations, who also happened to lack TEK alterations.A key regulator of cell growth and survival, the PI3K pathway is known to drive many cancers and overgrowth syndromes. In fact, Castel et al. were originally studying its role in uterine cancer when they noticed that mice harboring Pik3ca mutations developed defective blood vessels that closely resembled venous malformations. Indeed, Castillo et al. designed mice with Pik3ca-activating mutations that also mimicked the human disease, including during mouse embryonic development. Both teams found that the mutation spurred endothelial cells to grow uncontrolled, forming abnormal clusters and faulty blood vessels. Treating the mice with a PI3K inhibitor, including a topical formulation tested by Castillo et al., stunted blood vessel overgrowth. Altogether, the results suggest that repurposing PI3K-inhibiting cancer drugs may offer a potential therapeutic avenue for patients with venous malformations.


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