Ovarian Tumors Metastasize in Blood

Even before a woman learns she has ovarian cancer, the tumor has usually metastasized. A new study shows that the tumor cells spread through the blood and suggests a way to rein them in.

Three years ago, a team led by Ernst Lengyel, MD, PhD, of the University of Chicago in Illinois showed that metastasizing ovarian tumor cells home in on the omentum, a fatty curtain of tissue that covers the organs in the lower part of the abdomen. The standard explanation has been that the migrating cells reach new locations like the omentum by crawling along the peritoneum, the membrane that lines the abdominal cavity and sheathes some of the viscera, or by drifting through the fluid within the peritoneal cavity.

However, ovarian cancer cells also turn up in the blood, suggesting that they spread through the circulatory system, notes Anil Sood, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Sood and his colleagues tested that possibility by sewing together pairs of mice so that they shared a bloodstream. When the researchers injected ovarian cancer cells into the peritoneum or ovary of one mouse in each pair, metastases arose in the animal's omentum. Often, they also appeared in the omentum of its partner. Because the animals don't share their lymphatic circulation and their abdominal cavities are not connected, the ovarian tumor cells must have traveled from one mouse to the other in the blood, the researchers report in Cancer Cell.

The scientists identified one factor that may drive metastasis of ovarian cancer cells: they overproduce ErbB3, a member of the EGFR family that spurs cell proliferation. Sood and his colleagues reduced metastasis to the omentum with an anti-ErbB3 siRNA and with MM-121 (Merrimack Pharmaceuticals), an investigational ErbB3-blocking antibody. The team also discovered that the omentum contains large amounts of neuregulin, which stimulates ErbB3.

Ovarian tumors can metastasize by the traditional routes, but the research shows that “this cancer has the capacity to spread by the blood system,” says Sood. He and his colleagues think that tumor cells can disperse widely in the bloodstream, but they exit the circulation and enter the omentum because of its high levels of neuregulin. They may settle down there or move on and establish metastases elsewhere.

“This study is convincing and has strong data,” says Lengyel. Although there were hints of circulatory metastasis before, “this is the first well-done experimental setup where it was proven,” adds Charles Landen, MD, of the University of Alabama-Birmingham.

Sood says that the results suggest anti-ErbB3 treatments might curtail metastasis of ovarian tumors in patients. Although MM-121 faltered in a previous clinical trial, he notes that study tested the antibody's ability to shrink primary ovarian tumors, not its ability to prevent metastasis. Drugs like trastuzumab (Herceptin; Genentech) that target Her2 (ErbB2) might also work, since ErbB3 can't function unless it pairs up with ErbB2 or another family member.