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'Schwarzenegger' tumor mutation more difficult to treat

By
Stephen Feller
Although doctors can use drugs to melt fibrosis and allow blood to flow properly through tissues, overly aggressive pancreatic tumors cause so much fibrosis the drugs have little benefit or make the condition worse, researchers found in a recent study. Photo by Sebastian Kaulitzki/Shutterstock
Although doctors can use drugs to "melt" fibrosis and allow blood to flow properly through tissues, overly aggressive pancreatic tumors cause so much fibrosis the drugs have little benefit or make the condition worse, researchers found in a recent study. Photo by Sebastian Kaulitzki/Shutterstock

SAN FRANCISCO, April 19 (UPI) -- Fibrosis -- the stiffening of tissue -- around pancreatic cancer tumors is worse in patients with a particular genetic mutation, making treatment more difficult, researchers found in a recent study.

Researchers at the University of California San Francisco found so-called "Schwarzenegger tumors" are significantly more aggressive, and cause more fibrosis of surrounding tissue, making patient prognosis worse.

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A genetic mutation causes tumors to stiffen, worsening the thickening of surrounding tissue. This fibrosis can then exert pressure on blood vessels, making drug delivery more difficult and preventing immune cells from entering the tissue to attack the tumor.

Roughly 15 to 20 percent of pancreatic adenocarcinoma, or PDAC, patients have a mutation to the SMAD4 gene, which is known to weaken protein signaling, causing the increased fibrosis. The fibrosis causes tissue tension, which activates more inflammation and results in more aggressive tumors.

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Not fully understanding how to stop fibrosis -- several drugs have failed in trials -- has made treating PDAC with existing fibrosis-melting drugs more difficult for patients with the mutation, the researchers said.

"The problem is that no one's been looking at these physical factors at all," Dr. Valeria Weaver, a professor of surgery, anatomy and bioengineering and therapeutic sciences, said in a press release. "Tissue mechanics change how tumors behave, and cancer genes impact the mechanics. It's a really important concept to have in our arsenal."

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For the study, published in the journal Nature Medicine, the researchers examined human tumor samples for evidence of fibrosis and heightened tumor aggressiveness. Tumors with weakened TGF-β signaling were more likely to show worse signs of fibrosis and were likely more deadly.

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The researchers then studied mouse models of the cancer, finding similar patterns, and that weakened TGF-β signaling boosts the activity of a gene called Stat3 -- which produces molecules that stiffen connective tissue. The increased tissue and tumor tension activates genes that induce inflammation and increase aggression. This finding was then confirmed in the human PDAC cells, the researchers report.

"We found that individuals with these 'Schwarzenegger tumors' have a particularly poor prognosis and will require a different approach to treatment, one that should begin as early as possible," Weaver said. "We're hopeful that these patients' highly contractile tumor cells may be detectable with non-invasive imaging -- making it easier to identify them and guide their treatment without costly genetic tests."

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