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Role of Collagen in Pancreatic Cancer Development


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Type I collagen produced by cancer-associated fibroblasts may not promote cancer development, but instead, may play a protective role in controlling pancreatic cancer progression. This new understanding supports novel therapeutic approaches that bolster collagen rather than suppress it, according to a report published by Chen et al in Cancer Cell.

The study found that collagen works in the tumor microenvironment to stop the production of immune signals, called chemokines, that lead to suppression of the antitumor immune response. When collagen is lost, chemokine levels increase, and the cancer is allowed to grow more rapidly.

“Collagen has been the most highly studied component of the tumor microenvironment for decades, but its precise role has remained unclear,” said senior study author Raghu Kalluri, MD, PhD, Chair of Cancer Biology at The University of Texas MD Anderson Cancer Center. “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.”

Raghu Kalluri, MD, PhD

Raghu Kalluri, MD, PhD

Study Findings

Collagen, the most abundant protein in the human body, is produced by a class of cells called fibroblasts and is found mostly in bones, tendons, and skin. The protein also tends to accumulate in and around tumors during cancer development and growth, leading researchers to hypothesize that it helps promote tumor growth, metastasis, or drug resistance, explained Dr. Kalluri.

To investigate these possibilities and clarify the role of collagen, the research team created a mouse model in which collagen is not produced by cancer-associated fibroblasts during pancreatic cancer development. After genetically deleting collagen from these cells, called myofibroblasts, more than 50% of the total collagen was absent in the tumor microenvironment.

With collagen reduced, pancreatic cancer growth accelerated, and the overall survival of the mice significantly decreased, suggesting that collagen plays an important role in blocking cancer progression.

The researchers looked further to understand how collagen was impacting tumor development. In tumors with reduced collagen, the cancer cells produced higher levels of chemokines known to attract myeloid-derived suppressor cells, a type of immune cell that dampens antitumor immune response.

Indeed, the researchers found that collagen-deficient tumors had more myeloid-derived suppressor cells present and fewer immune cells, such as T cells and B cells, that could mount an effective antitumor response. Interestingly, blocking chemokine signaling activity with targeted therapies reversed the immune profile in these tumors and slowed tumor progression, bringing it back to a level similar to that of controls.

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.
— Raghu Kalluri, MD, PhD

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“This was somewhat surprising, because we think of pancreatic cancer as a cancer with poor immune surveillance—with an immunosuppressive tumor microenvironment,” said Dr. Kalluri. “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.”

Noting that pancreatic cancer is one of the most aggressive tumor types with poor outcomes overall, Dr. Kalluri acknowledged that collagen by itself may not be a particularly effective defense mechanism, but it shows that our bodies are doing what they can to control cancer development.

The challenge now, said Dr. Kalluri, is to identify a therapeutic strategy to fix those brakes, by increasing collagen levels or boosting collagen’s downstream effects to further strengthen the antitumor response. Exploring these strategies will be the focus of future work.

Disclosure: This research was supported by the Cancer Prevention & Research Institute of Texas and the National Cancer Institute. For full disclosures of the study authors, visit cell.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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