Slowing the spread of an insidious cancer
By the time pancreatic cancer is diagnosed, it’s almost always at a late stage of disease. The cancer is insidious; tumor cells hide deep inside the body, betraying no symptoms until after the cancer has spread to other organs.
According to new research from a team led by Ellen Puré of the School of Veterinary Medicine, one way to tackle pancreatic cancer may be to slow its spread. The researchers have identified a protein that, when eliminated in mice with the disease, extended survival and reduced metastasis.
“We thought that by targeting this protein, we would see a big change in the primary tumor, and, while we do see a delay, the big change was in the metastasis,” says Puré, the study’s senior author and chair of the Department of Biomedical Science at Penn Vet. “It looks like this protein might be a druggable target, so we’re hoping that with some additional follow-up work, it’s something that we’ll see go into patients.”
Puré and colleagues in the cancer biology field have come to recognize that, for a cancer to grow, changes must occur not only in cells that will become the tumor, but also in the surrounding tissues—what is known as the stroma. This study of the tumor microenvironment has become a focus of the Penn Vet Cancer Center, which Puré directs.
The stroma is sometimes referred to as the “soil” in which cancers grow; the right conditions will either allow a tumor to grow or keep it from rooting.
From earlier work, Puré’s team knew that the collagen-cleaving enzyme FAP, or fibroblast activation protein, played a role in shaping the physical nature of the stroma, and influenced tumor growth in lung and colon cancer.
In the current work, published in the Journal of Clinical Investigation Insight, the researchers sought to ascertain FAP’s role in pancreatic cancer, a tumor type that is dominated by connective tissue.
It became clear the protein was important for driving cancer: In tissue samples from human patients, higher FAP levels correlated with poorer prognoses. And in a mouse model, abolishing FAP expression delayed the onset of disease by five weeks and prolonged the animals’ overall survival by 36 days.
Drilling deeper into the mechanism of action, the researchers found that FAP-depleted tumors had more signs of necrosis, a form of cell death, and greater infiltration of white blood cells, suggesting that FAP may normally act to prevent the immune system from controlling tumors.
What was even more striking, however, was that eliminating FAP reduced the spread of cancer from the pancreas to other organs. Puré says it was this effect that makes FAP such an enticing therapeutic target.
“By targeting FAP with a drug, we may be able to slow down the spread of the cancer by treating distal tissues that you don’t even realize are getting ready to accept tumor cells, a phenomenon referred to as treating premetastatic niches,” she says. “That is the hope.”