Fibrous tissue that was long suspected of making pancreatic cancer worse actually supports an immune attack that slows tumor progression, though in the end the tumor wins, MD Anderson scientists report.
“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,” says study senior author Raghu Kalluri, Ph.D., M.D., chair of Cancer Biology.
The team’s findings point to a potential new avenue for guiding treatment 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 says. “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.”
Kalluri and colleagues used genetically engineered mouse models that allowed depletion of tissue repair cells called myofibroblasts in pancreatic cancer.
Myofibroblasts comprise 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 be fibrotic support tissue.
When the scientists depleted myofibroblast production in mice, 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 says.
Since myofibroblasts and collagen are thought to block chemotherapy, the team treated their myofibroblast-depleted mice with gemcitabine, the standard treatment for pancreatic cancer. The chemo drug didn’t have any effect on the disease course or improve survival.
These results track those of a major clinical trial that combined a myofibroblast-depleting drug called a hedgehog inhibitor with gemcitabine to treat pancreatic cancer patients. The trial was stopped in 2012 when an interim analysis showed the patients taking the combination had faster disease progression than the control group that took only gemcitabine.
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