No one wanted these mice.
Fresh out of the National Institute of Health (NIH), the mice — bred without the mesothelia protein found on the outside of the cell — were going to waste until Sharon Stack, professor of biochemistry at Notre Dame and a director for the Harper Cancer Research Institute, asked one of her researchers to do a project with them.
With the help of the previously unwanted NIH mice, assistant research professor Tyvette Hilliard has found an important link between mesothelin and ovarian cancer that can be used to help cancer patients in the future.
“Principal investigators are so quick to say, ‘Oh, this little side project, that should be an easy publication,’” Hilliard explained. “That easy publication turns into years and years of work.”
Hilliard discovered that when she injected the mice with ovarian cancer cells, smaller collections of cancer cells were produced. There was also a significant decrease in the number of metastatic tumors formed throughout the abdomen.
Hilliard’s results, published in the International Journal of Molecular Sciences and titled “Host Mesothelin Expression Increases Ovarian Cancer Metastasis in the Peritoneal Microenvironment,” point back to a previously studied potential link between ovarian cancer and the overproduction of the mesothelin protein.
Ovarian cancer has a relatively low survival rate compared to other cancers of the female reproductive system. This is due to its tendency to spread to other areas of the body early in development and due to the lack of early detection methods.
Studying the ease with which ovarian cancer spreads is essential to increasing the prognosis, Stack said, noting that ovarian cancer spreads in a unique manner due to its location.
“Most tumors will bore into a blood vessel and get in and circulate through the vasculature, and then come out at a distant site and metastasize that way, but ovarian tumors don’t,” she said. “The cancer cells are shed off the tumor on the ovary or the fallopian tube.”
The cancer cells float around in what’s called ascites fluid that surrounds the organs in the abdominal cavity. Stack explained that this buildup of fluid in women with ovarian cancer helps the cancer cells spread around and stick to many different internal organs — specifically adhering to the mesothelin layer of cells.
“Even in the mouse [without mesothelin], we still do see some tumor implantation,” Stack said.
She described that like with a lot of things in nature, the remaining tumor implantation can be explained by compensatory mechanisms — if one pathway is blocked, the cells will adapt and find a different way to survive.
Determining the connection between the mesothelin protein and the decreased tumor load in ovarian cancer was the easy part, Hilliard said. The hard part was understanding the why.
“Our hypothesis was correct. But then you want to know why this is happening,” Hilliard said. “The why was the hardest part.”
She said she tried many different techniques to determine the cause of the decreased tumor load that was observed in the mice. Eventually, she said she determined that something about the cancer cells’ adhesion proteins changes when mesothelia is not present, and the cells are then unable to stick to the portion of the organs that they would have previously been able to attach to.
Hilliard said she hopes to investigate this mechanism further in future studies.
Stack said her hope is that this study will help identify mesothelin as a potential drug target to prolong the lives of women with recurrent ovarian tumors.
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