protein discovered that helps tumor evade body defenses and stimulates angiogenesis

[Lani]

and her2 is involved:
USC researchers investigate protein that protects tumors [Eureka News Service]
A protein that allows breast cancer cells to evade the body's natural immune responses could be a target of future cancer therapies, according to a study by scientists from the Keck School of Medicine of the University of Southern California.

The study, published in the July 1 issue of the American Journal of Pathology, is the first to identify how EphB4 - a protein that sits on the surface of cells - functions.

"The important aspect of this study is that . if we turn the protein [EphB4] off, the tumor cells die, which means that its function helps the cancer cells survive," says Parkash S. Gill, MD, a professor of medicine in the Keck School and the study's senior author.

The scientists used a fluorescent dye attached to the protein's antibody to reveal the protein's location on the tumor cells.

"The first step was to identify whether it's there [on cancer cells] and how often," he explained. "We found that it was present on 60 percent of the tumors . and it's expressed from the very first stage of the cancer formation."

The next step was to determine EphB4's purpose. What the scientists discovered was that EphB4 serves as a sentry, guarding the tumor cells from any defenses the body deploys to attack them.

"There are means in the body to kill tumor cells," Gill says. "[If] you block those then you give the cells the opportunity to survive and grow." Not only did EphB4 block those defenses, but it helped the cancer cells flourish by issuing a call for more blood vessels - the biological equivalent of food for the tumor.

"The tumor cell carrying this protein . on its surface communicates with blood vessels nearby," Gill says. "It sends the signal for more blood vessels to grow. One key item for any cancer to grow is to include more blood vessels."

The goal of a future anti-cancer therapy would be to block the protein, essentially knocking out one of the tumor cell's guardians. A similar approach was used to develop Herceptin, one of the first biological treatments for breast cancer. Herceptin targets the her2 protein, which is found on the surface of tumor cells about 20 percent of the time, says Gill.

The her2 protein played a role in this study as well. That protein, along with several of its cousins, was found to activate EphB4, he said. "There are certain growth factors that can make this particular protein (EphB4) go up," Gill says. "We are learning more about how this protein is turned on and off in a cancer cell."


ABSTRACT: Receptor Tyrosine Kinase EphB4 Is a Survival Factor in Breast Cancer [American Journal of Pathology; Subscribe; Sample]
EphB4, a member of the largest family of receptor tyrosine kinases, is normally expressed on endothelial and neuronal cells. Although aberrant expression of EphB4 has been reported in several human tumors, including breast cancer, its functional significance is not understood. We report here that EphB4 is expressed in 7 of 12 (58%) human breast cancer specimens and 4 of 4 (100%) breast tumor cell lines examined. Overexpression of EphB4 in breast cancer cells was driven by gene amplification and by the erbB family of receptors via activation of Janus tyrosine kinase-signal transducers and activators of transcription and protein kinase B. The aberrantly expressed receptor was phosphorylated by its natural ligand, EphrinB2, and signaled via the protein kinase B pathway. Targeted knockdown of EphB4 expression by small interference RNA (and antisense oligodeoxynucleotides (ODNs)) led to dose-dependent reduction in cell survival, increased apoptosis, and sensitization to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Antisense ODN-mediated EphB4 knockdown resulted in reduced tumor growth in a murine tumor xenograft model. Antisense ODN-treated tumors were 72% smaller than control tumors at 6 weeks, with an 86% reduction in proliferating cells, 15-fold increase in apoptosis, and 44% reduction in tumor microvasculature. Our data indicate that biologically active EphB4 functions as a survival factor in breast cancer and is a novel target for therapy.