A mix of cancerous and normal cells alters interactions with the immune system.
by Mohit Kumar Jolly June 24 2014, 3:01pm CDT
Pancreatic cancer is one of the most lethal cancers, with the survival period after diagnosis being only four to six months. The main reason for the poor prognosis is that chemotherapy, which has had some success in extending lives for patients with other cancers, doesn’t seem to slow down pancreatic cancer.
People had thought that this failure was caused by the tissue that surrounds the tumor, called the stroma, blocking the delivery of chemotherapy drugs to the tumor. A new study, published in Cancer Cell, raises questions about this idea. It shows that rather than supporting tumor progression, the stroma inhibits the progression by recruiting the body’s immune system to attack the tumor.
All tumors are composed of a mix of cancerous and normal cells. But pancreatic cancer is unusual in that only around 10 percent of the cells in the tumor are cancerous, the lowest proportion in any cancer. The remaining 90 percent is stroma that consists of cells known as myofibroblasts.
In keeping with this distinctive property of pancreatic cancer, a previous study had indicated that the stroma can act as a physical barrier to keep chemotherapy drugs away from the tumor. This finding triggered a slew of clinical trials that combined chemotherapy with “stromal depletion therapy”—that is, removing the stroma from the tumor. However, these trials had to be stopped abruptly when patients receiving this combination therapy were found to have an accelerated tumor progression when compared to patients who only received chemotherapy.
In a new study, Raghu Kalluri and his colleagues at MD Anderson Cancer Center may have found an explanation for these disappointing results.
Using mice, Kalluri and colleagues showed that the depletion of myofibroblasts—the major component of stroma—at any stage of pancreatic cancer does not improve the efficiency of chemotherapy. Instead, tumors grow more aggressively. This indicated to Kalluri that the stroma could inhibit the tumor rather than promote its growth.
“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 in a statement. “This supportive tissue that is 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. It is like having a car with weak yet functioning brakes vs having one with no brakes."
Dump me not just yet
It is not all bad news for this cancer therapy, however. Kalluri found that tumors with less stroma had higher levels of CTLA-4, a protein that is responsible for slowing down the immune system response. When these tumors were treated with ipilumimab, a drug that blocks CTLA-4, survival time of the mice increased by 60 percent compared to the untreated control mice.
This is a shot in the arm for cancer immunotherapy—therapies that enable the body’s immune system to fight cancer directly—which was named the Breakthrough of the Year in 2013 by the journal Science. This sort of therapy might be more effective in pancreatic cancer patients where CTLA-4 is blocked. It’s also possible that a combination of immunotherapy and stromal depletion therapy might be more effective for pancreatic cancer patients with dense stroma.
The development offers hope for patients with a disease in which only seven out of 100 patients survive for five years after being diagnosed.
Mohit Kumar Jolly is a graduate student in cancer systems biology at Rice University. This article was first published on The Conversation.
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