From culprit to ally

New research indicates that collagen formation may be a part of the body’s defenses against cancer, at least according to studies involving the pancreas. The researchers plan to explore the effect in other collagen-rich tumor types as well.

HOUSTON—While the news that things once thought to be benign can in fact be carcinogenic is hardly welcome, but hearing the reverse—that something once thought to promote disease is actually actively benevolent—is the definition of a pleasant surprise. A research team at the University of Texas MD Anderson Cancer Center recently shared one such surprise, having debunked a theory that type I collagen plays a role in cancer development,

Instead, they report that it helps to control disease progression—at least in pancreatic cancer. Their work, detailed in a paper titled “Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer,” appeared in Cancer Cell in March.

“The basis for our work was that in pancreatic cancer, one of the major components that accumulates in the tumor is collagen,” Dr. Raghu Kalluri, chair of cancer biology at MD Anderson and senior author of the paper, told DDN. “It accumulates in large amounts and it’s known to be responsible to make pancreatic tumors very rigid and full of stromal material. Our question was whether this material is really helping cancer progression or in some way doing something else associated with the microenvironment. Now, the collagen that accumulates in pancreatic tumors is made mainly by fibroblasts that also come in large numbers in pancreatic tumors; it can also be made in small amounts by endothelial cells and cancer cells, but generally speaking, fibroblasts are the major cell type that makes collagen.”

The researchers worked to pinpoint the effect of collagen on cancer by engineering a mouse model whose myofibroblasts—cancer-associated fibroblasts—do not produce collagen during pancreatic cancer development. As a result, more than 50 percent of the total collagen disappeared from the tumor microenvironment, and pancreatic cancer growth accelerated while overall mouse survival dropped sharply. Further examination revealed that cancer cells generate higher levels of chemokines that attract myeloid-derived suppressor cells (MDSCs), immune cells that inhibit the anticancer immune response. The collagen-deficient mouse tumors presented with more MDSCs and fewer immune cells such as T or B cells. On the reverse, when chemokine signaling activity was blocked, it reversed the tumors’ immune profiles and slowed tumor progression.

“This was somewhat surprising because we think of pancreatic cancer as a cancer with poor immune surveillance, with an immunosuppressive tumor microenvironment,” Kalluri said. “However, this study shows that the immune system actually is controlling pancreatic tumor growth to some extent, and we see an even more detrimental immune suppressive tumor microenvironment when collagen is lost.”

While the team focused on pancreatic cancer first, as it is known to be the most collagen-rich tumor type, Kalluri says they’re interested in seeing if their results are specific to just pancreatic tumors, noting that breast, kidney, colon, and liver cancer are also collagen-rich. In addition, he comments that another avenue of continued research is to explore if it might be possible to promote collagen production in tumors to help slow the spread of cancer. 

“I would say that for pancreatic cancer, slowing down cancer progression would be of great value because it’s such a rapid tumor,” Kalluri remarked. “So having that feature combined with maybe chemotherapy or other modalities would definitely be a wonderful combination therapy.”

“Collagen has been the most highly studied component of the tumor microenvironment for decades, but its precise role has remained unclear,” he added. “Now, we understand that it is part of a cancer defensive strategy of the body. If we can better understand that strategy, even if it may be suboptimal, we can work to shore up our body’s natural defenses to have therapeutic impact.”

The University of Texas MD Anderson Cancer Center https://www.mdanderson.org/