Cancer cells may be able to avoid destruction by anti-vascular and anti-angiogenesis agents through a cellular stress response that activates a pro-survival protein called GRP78, according to researchers from the Keck School of Medicine of the University of Southern California.
This provides a novel explanation to address the failure of these drugs to meet initial expectations in the battle against the growth and spread of malignant tumors.
In a study published in the July 1 issue of the journal Cancer Research, the USC team of researchers-in collaboration with researchers from the National Cancer Institute and MannKind Corp. of Valencia, Calif.-showed that anti-angiogenesis drugs that target the formation and upkeep of blood vessels can increase levels of a protein called glucose regulated protein 78, which can work to block cell death, or apoptosis. GRP78 is synthesized and found primarily in the cell's endoplasmic reticulum, or ER.
"When you look at the successful cancer therapies, they often lose efficacy over time because of resistance in the tumor cells," notes Amy S. Lee, Ph.D., professor of biochemistry and molecular biology at the Keck School of Medicine, associate director of basic sciences at the USC/Norris Comprehensive Cancer Center, and principal investigator for this research. "The majority of patients today die not from a primary tumor, but from a failure of the body to overcome the development of resistance to the drugs that treat that tumor."
Lee's research sheds light onto why that resistance might develop in the first place. Her study shows that antiangiogenesis drugs, by doing the very job they are supposed to do-starving cells of oxygen and glucose-force tumor cells into a survival mode in which they turn on genes like GRP78 that can help them to both resist and survive the onslaught.
"When a tumor is under the attack of chemotherapy drugs and trying to survive and grow, they turn on this protective mechanism," she says, "In fact, I think it's an innate property of a cancer cell to turn on this survival mechanism, which is used to protect normal cells during stress."
When unopposed, this mechanism can give cancer cells the ultimate victory. "The induction of these protective genes is a survival mechanism that allows a small number of cells to become resistant to the chemotherapy's effects," Lee explains. "Then, when the therapy is withdrawn, these surviving cells flourish."