Early Research May Unlock How Pancreatic Cancer Metastasizes to the Liver

Key Points

  • The team thinks solitary cancer cells have already spread to the liver in many patients well before they go to surgery to have their primary tumor removed.
  • When ER stress was blocked, the DCCs became more typical pancreatic cancer cells and were then eliminated by the immune system. 
  • Dr. Fearon and his team theorize that when T cells in the liver are suppressed after surgery due to stress and impaired nutrition, the DCCs begin to divide and pancreatic cancer metastases become apparent.

Douglas Fearon, MD, Professor at Cold Spring Harbor Laboratory, and colleagues may have discovered how pancreatic cancer metastasizes to the liver following surgery, as reported by Pommier et al in Science.

“This discovery is significant because for patients who undergo pancreatic cancer surgery, there is typically a period lasting up to 2 weeks during which T cells are depleted, owing to a surge in postoperative stress hormone (cortisol) levels,” Dr. Fearon said. “If we can keep those cortisol levels down, we might be able to stop the cancer from metastasizing.”

Early Research

Working with mice that model pancreatic ductal adenocarcinoma, Dr. Fearon's team discovered that the immune system controls the spread of isolated, solitary dormant cancer cells in the liver of animals that have primary pancreas tumors. These quiescent cancer cells in the liver don't divide—but they can be activated under certain conditions and proliferate to become clinically relevant metastases. 

The team thinks solitary cancer cells have already spread to the liver in many patients well before they go to surgery to have their primary tumor removed. They are likely carried there by the bloodstream, having been shed by the primary tumor. Dr. Fearon estimates that in a typical patient, 14 million cancer cells pass through the liver every day. The immune system kills most of the cancer cells deposited in the liver.  However, there are some latent, nondividing solitary cancer cells—called disseminated cancer cells (DCCs)—that are left behind after the escape attack by the immune system has killed all the other cancer cells that are capable of growing. The immune system ignores the DCCs because they lack certain cell surface features that mark them for removal. 

Dr. Fearon's team showed that DCCs have a particular abnormality that makes them invisible to the immune system, called ER stress. This refers to a flaw that enables unfolded proteins to clog the organelle of the cell called the endoplasmic reticulum. This ER stress is what enables DCCs to escape destruction by the immune system. When ER stress was blocked, the DCCs became more typical pancreatic cancer cells and were then eliminated by the immune system. 

In mice that model this condition, metastases soon appeared in the liver. The affected mice were now like patients who, following surgery, lacked metastatic liver lesions but bore a burden of DCCs—cells which, after a period of latency, became seeds of a metastasis. Dr. Fearon theorizes that it is during such postoperative periods that DCCs, already present in the liver, lose their immunity and begin to divide in patients who go on to develop metastasis.

Based upon these findings, Dr. Fearon and his team theorize that when T cells in the liver are suppressed after surgery due to stress and impaired nutrition, the DCCs begin to divide and pancreatic cancer metastases become apparent.

Dr. Fearon is currently planning to test whether this postoperative stress can be medically managed and lead to less early relapses following surgery, and therefore improved outcomes for patients.

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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