Metastasis enablers: Findings could unlock new ovarian cancer treatments
Research from the lab of Pamela Kreeger, an associate professor of biomedical engineering at the University of Wisconsin-Madison, has identified one way ovarian cancer cells appear to successfully spread.The work, detailed in a paper published May 8, 2018, in Cancer Research, could lead to new therapies to curb metastasis of these tumors. Kreeger is a BMES member.
“Like most cancers, it's not the primary tumor that's usually the problem. It's the spread of the tumor to nearby organs that leads to serious complications,” Kreeger said in a university article. “So if you can slow that process down, it's possible the patient will live longer and/or have a better quality of life.”
In studying high-grade serous ovarian cancer, the most common but also most aggressive type, Kreeger, postdoctoral fellow and BMES member Molly Carroll and other lab members have teased out how one type of immune cells helps cancer cells attach in the peritoneal cavity, enabling metastasis. Higher levels of these immune cells, called alternatively activated macrophages, are associated with worse outcomes. But the question remained: Do these macrophages encourage metastasis?
To find out, Kreeger's team created a micro-culture device that allowed them to bring together the key players: macrophages, cancer cells and mesothelial cells, which line the peritoneal cavity. Experiments revealed macrophages increase tumor cell attachment to the mesothelial cells—by making the mesothelial cells stickier.
“For me that was one of those scientific ‘ah ha' moments—the interactions between the normal cells in our body can influence metastasis. In other words, it's not all about the tumor cell,” says Kreeger.
But which of the 25 proteins the team detected in the co-culture device was responsible for this effect? Computational modeling revealed the culprit: The macrophages produce a protein called MIP-1β, which causes the mesothelial cells to produce more of an adhesion protein called P-selectin. That, in turn, allows the cancer cells to stick.
A preliminary experiment in mice validated those results, while human samples—obtained through collaborators in the UW-Madison School of Medicine and Public Health—showed that patients with ovarian cancer had higher levels of MIP-1β and P-selectin.
The good news: There are already several existing drugs, developed for other diseases, that could prove useful. Maraviroc, which is used to treat HIV, inhibits the receptor for MIP-1β, while two different drugs that target P-selectin are in clinical trials for blood disorders.
“We're interested in pursuing multiple avenues, because it's possible one will work better than another,” says Kreeger, whose group has filed a provisional patent on the findings with the Wisconsin Alumni Research Foundation. “It's also possible one will have more tolerable side effects than another.”
Kreeger will use a recently awarded grant from the Rivkin Center for Ovarian Cancer to further validate the findings in long-term experiments in mice in order to set the stage for pre-clinical testing of drug treatments.
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