NCI Researchers Discover Genes that are Turned on at High Levels in Tumor-Associated Blood Vessels of Mice and Humans
News Jun 12, 2007
A team of researchers at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), has uncovered a set of genes that are turned on, or expressed, at high levels only in the blood vessels that feed tumors in mice and humans.
These genes, and the proteins they encode, are important new potential targets for novel drugs that could selectively cut off a tumor's blood supply without affecting the blood vessels of healthy tissues, overcoming one of the major concerns of current anticancer therapies targeted at blood vessel growth.
The findings are published in the June 2007 issue of the journal Cancer Cell. "These results offer new insights into what is an important aspect of tumor development," said NCI Director John E. Niederhuber, M.D.
"How blood vessels grow, intertwined with normal tissue in a tumor's microenvironment, is not just an area of scientific interest; it's a research field that is continuing to develop potentially potent and specific anticancer agents that cut off the tumor from a vital support system."
The growth of blood vessels, a process known as angiogenesis, is a normal process in the body that is essential for organ growth and repair. In many diseases, including most forms of cancer, this carefully regulated process becomes imbalanced, and normal blood vessel growth is redirected toward supplying nutrients and oxygen to feed diseased tissue, destroy normal tissues, and in the case of cancer, allow tumor cells to escape and travel to distant sites in the body.
Researchers have tried to stop disease-related angiogenesis by identifying the molecules that stimulate blood vessel and developing new drugs to block their action.
However, blocking angiogenesis requires a delicate balance between tumor and normal cells as most angiogenesis-related molecules are also critical for normal blood vessel growth in the body - for example, during menstruation, pregnancy, or tissue repair. Thus, drugs that target critical angiogenesis molecules can cause a wide range of unintended side effects in healthy tissue.
The NCI research team, led by Brad St. Croix, Ph.D., head of the Tumor Angiogenesis Section at the NCI's Center for Cancer Research (CCR) in Frederick, Md., set out to discover the molecular differences between tumor-associated and normal angiogenesis to identify potential new drug targets. St. Croix and his colleagues focused on endothelial cells, which line the inner surface of blood vessels and are critical for new vascular growth.
The researchers chose to analyze endothelial cells derived from mouse liver, because the liver can be induced to sprout new blood vessels when regenerating itself following partial surgical removal. By comparing the gene expression profiles of endothelial cells from regenerating liver to those derived from tumor-bearing livers, the researchers found 13 distinct genes that were selectively overexpressed (turned on to a greater degree than other genes) during disease-related angiogenesis.
Among the genes identified was CD276, a gene that encodes a protein located on the cell surface, as well as other known and previously undescribed genes.
To determine if the mouse findings were relevant to human cancers, the researchers then examined CD276 expression patterns in endothelial cells derived from cancer patients. They found that the CD276 protein was overexpressed in tumor-associated blood vessels from colon, lung, breast, esophageal and bladder cancers.
In addition, the protein was also found to be frequently overexpressed by the tumor cells themselves, indicating that a suitable inhibitory molecule might be able to deliver a double blow - one to the tumor cells themselves and the other to the blood vessels that feed them.
"These studies demonstrate that CD276 is overexpressed in the blood vessels of a variety of human cancers," says St. Croix. "Therefore, it may be an important target for the development of new drugs that can selectively home in on blood vessels associated with disease."