Researchers from the Abramson Cancer Center of the University of Pennsylvania report in Nature why the liver is the most common site of metastatic disease. The research shows that hepatocytes coordinate myeloid cell accumulation and liver fibrosis (the thickening and scarring of tissue) which increases the organ’s susceptibility to cancer cells.
"While it is well known that the liver is a common site of cancer spread, the underpinnings of how this occurs have largely remained elusive. Our study identifies hepatocytes as major initiators of this process and show several key steps in this process." explains Gregory L. Beatty, corresponding author of the study.
"Understanding this biology is the first step toward knowing how to disrupt it. If we can prevent the liver from being supportive of cancer spread, that could have major implications for patients as metastasis is the major cause of cancer-related death."
What are hepatocytes?
Hepatocytes are parenchymal cells that comprise the main unit of the liver and are responsible for most of the organ’s metabolic functions.
Study approach and findings
Using a mouse model of pancreatic ductal adenocarcinoma (PDAC) (the most common type of pancreatic cancer) the researchers demonstrated that the cytokine interleukin-6 (IL-6) is secreted by fibroblast cells located within the pancreatic tumor microenvironment.
IL-6 travels via the bloodstream to the liver and binds to its receptor located on the surface of the hepatocyte. Once bound, the IL-6–receptor complex initiates the expression and subsequent phosphorylation of a protein called STAT3. In the mice with cancerous tumors almost all hepatocytes showed STAT3 activation, whereas less than two percent of mice without tumors displayed activated (phosphorylated) STAT3.
Phosphorylated STAT3 triggers the production of serum amyloid A (SAA) proteins that trigger two specific processes when secreted from the cells:
- Attraction of myeloid cells which dampen the immune response
- Activation of hepatic stellate cells which deposit extracellular matrix material (this acts as an anchor and sustenance to cancer cells)
These changes create what is known as a “pro-metastatic niche”. The team showed that it is possible to inhibit the process by blocking the signaling components (IL-6, STAT3, SAA proteins), disrupting the signaling pathway. This limited the cancer’s ability to metastasize to the liver.
The team were also able to demonstrate, through a collaboration with investigators at the Mayo Clinic Arizona and other Penn colleagues, that patients with liver metastases originating from the pancreas, as well as other types of primary tumor (lung, colorectal) had an elevated level of SAA proteins in the bloodstream.
IL-6 was also shown to initiative changes in the liver even in the absence of a tumor, suggesting that any condition resulting in increased levels of IL-6 could affect the liver’s susceptibility to cancer. The team believe that therapies specifically targeting hepatocytes could hold potential as a method to prevent metastasis to the liver.
Beatty touches on next steps: "We have found that hepatocytes are major orchestrators of a niche environment in the liver that can support cancer spread. However, it is not yet clear how to resolve this niche once it is formed. This is important because our data indicate that the niche can form very early during cancer development. So, we are currently studying how to reverse the niche and investigating its role in defining treatment outcomes. We hope that this research will uncover new therapeutic opportunities for patients."
- Lee, J. W., et al. Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature (2019) DOI: 10.1038/s41586-019-1004-y
- Maitra, A. Molecular envoys aid cancer spread. News and Views. Nature (2019) DOI: 10.1038/d41586-019-00710-z