June 22, 2007

Genes Turned on in Tumor-Associated Blood Vessels

IStylized 3D illustration of blood vessels

A team of researchers at NIH's National Cancer Institute (NCI) has uncovered a set of genes that are turned on, or expressed, at high levels only in the blood vessels that feed tumors. These genes, and the proteins they encode, are potential targets for novel drugs that could selectively cut off a tumor's blood supply.

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 forms of cancer, this carefully regulated process becomes imbalanced, and blood vessel growth is redirected toward supplying nutrients and oxygen to feed diseased tissue. Blocking angiogenesis requires a delicate balance, however, 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.

An NCI research team led by Dr. Brad St. Croix, head of the Tumor Angiogenesis Section at NCI’s Center for Cancer Research 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 vessel growth. The researchers chose to analyze cells derived from mouse liver, because the liver can be induced to sprout new blood vessels during regeneration after partial surgical removal.

The team reported in the June 2007 issue of the journal Cancer Cell that, by comparing the gene expression profiles of endothelial cells from regenerating liver to those derived from tumor-bearing livers, they 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, which encodes a protein located on the cell surface.

To determine if the mouse findings were relevant to human cancers, the researchers first confirmed that CD276 is expressed in endothelial cells derived from human colorectal cancer. They then examined CD276 protein patterns and found high levels of the protein in tumor-associated blood vessels from colon, lung, breast, esophageal and bladder cancers. They also saw higher levels of the protein in 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,” St. Croix says. “Therefore, it may be an important target for the development of new drugs that can selectively home in on blood vessels associated with disease.”

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