Supportive tissue in tumors hinders pancreatic cancer

Fibrous tissue long suspected of making pancreatic cancer worse actually supports an immune attack that slows tumor progression but cannot overcome it, scientists have reported.

"This supportive tissue that's abundant in pancreatic cancer tumors is not a traitor as we thought, but rather an ally that is fighting to the end. It's a losing battle with cancer cells, but progression is much faster without their constant resistance," said study senior author Raghu Kalluri, PhD, MD, chair of Cancer Biology at The University of Texas MD Anderson Cancer Center in Houston. "It's like having a car with weak yet functioning brakes vs. having one with no brakes."

The team's findings, reported in Cancer Cell (2014; doi:10.1016/j.ccr.2014.04.005), point to a potential new avenue for guiding treatment, including immunotherapy, and offer an explanation for the failure of a promising combination drug approach in clinical trials.

"Cancer is one form of tissue injury. When our defense system detects damaged cells it sends soldiers to contain and repair the damage," Kalluri said. "When it cannot remove the damaged cells and repair the injured area, our defensive fibrotic response tries to put a boundary around it, to contain it and prevent it from spreading."

Pancreatic cancer is resistant to treatment and only about 7% of patients survive for 5 years. An estimated 46,420 new US cases will be diagnosed in 2014 and 39,590 people will die of the disease.

Kalluri and colleagues used genetically engineered mouse models that allowed depletion of tissue-repair cells called myofibroblasts in pancreatic cancer. Myofibroblasts compose a major portion of supportive tissue called stroma and also produce collagen, which serves as a scaffold for wound-healing and tissue regeneration. Up to 90% of a pancreatic tumor can consist of fibrotic support tissue.

When the scientists depleted myofibroblast production in mice with either early or later-stage pancreatic ductal adenocarcinoma, their tumors became much more invasive, aggressive, and lethal.

"We did these experiments thinking that we would show the importance of myofibroblasts and fibrosis in pancreas cancer progression, but the results went completely against that hypothesis," Kalluri said.

Since myofibroblasts and collagen are thought to block chemotherapy, the team treated their myofibroblast-depleted mice with gemcitabine, the standard treatment for pancreas cancer. The drug did not have any effect on the disease course or improve survival.

The team's analysis of pancreatic tumors from 53 patients showed low levels of tumor myofibroblasts are associated with decreased survival.

Study findings are consistent with pathologic evidence that tumors with more fibrotic tissue more closely resemble normal pancreas tissue, indicating a better prognosis for patients, even though lab experiments indicated those tumors should be more aggressive, explained co-author Anirban Maitra, MD.

The researchers set up a new experiment using ipilimumab, a drug that blocks CTLA-4 and frees T cells to attack tumors.

Mice with depleted myofibroblasts who were treated with ipilimumab to stifle CTLA-4 had an average survival increase of 60% compared with untreated control mice and those with either depleted myofibroblasts or treated with ipilimumab alone.

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