A protein associated with cancer progression when abundant inside of tumors also unexpectedly regulates the creation of new blood vessels that feed the tumor outside, a research team led by scientists at The University of Texas MD Anderson Cancer Center reports in the August edition of Cancer Cell.
By using a nanoparticle-based gene-silencing system to block production of the protein, the researchers inhibited formation of new blood vessels (angiogenesis) to the tumor and caused a steep reduction in tumor burden in a mouse model of ovarian cancer.
"We've discovered that EZH2 promotes tumor growth by shutting down genes that block formation of new blood vessels," said study senior author Anil Sood, M.D., professor in UT MD Anderson's departments of Gynecologic Oncology and Cancer Biology. "Tumors treated with current anti-angiogenesis drugs eventually progress. This study presents a new mechanism for angiogenesis that opens the door for development of new treatment approaches."
EZH2 is a member of a group of proteins known to repress gene expression. It has been associated with the progression and spread of bladder, breast, prostate and gastric cancers and one type of cancer of the pharynx.
Increased EZH2 is tied to decreased survival for patients
An examination of 180 ovarian cancer tumors found that the protein was overexpressed in the tumor in 66 percent of cases and in the endothelial cells of 67 percent of samples. Endothelial cells line the inside of blood vessels and are crucial to angiogenesis.
Increased expression of the protein in either tumor or endothelial cells was associated with late-stage and high-grade disease and decreased median survival. Patients with increased EZH2 levels in their tumors had a median survival of 2.5 years compared to 7.33 years for those without. For overexpression in the endothelial cells, the difference was 2.33 years versus 8.33 years for those with normal levels.
In a series of lab experiments, the team found that vascular endothelial growth factor (VEGF), a known stimulator of angiogenesis, boosts the level of EZH2 in endothelial cells. EZH2 then silences the vasohibin1 (VASH1) gene, which normally inhibits blood-vessel-formation. Silencing the EZH2 gene in the tumor's endothelial cells reactivates VASH1, reducing angiogenesis and ovarian cancer growth in mice.
Silencing ezh2 reduces tumor weight
The ezh2 gene was targeted separately in tumor cells and in endothelial cells by delivery of small interfering RNA (siRNA) - short snippets of RNA that block gene expression - to mice with one of two strains of ovarian cancer.
* Treating mice with siRNA that silenced ezh2 in the tumor-associated endothelial cells reduced average tumor weight by 62 percent and 40 percent in the two strains of cancer compared with control mice.
* Hitting the gene only in the tumor had little significant effect on tumor burden.