Study discovers how pancreatic cancer spreads to the liver

May 18, 2015, Weill Cornell Medical College
MIF-expressing pancreatic cancer exosomes induce/prepare liver metastasis. Pancreatic cancer exosomes induce liver fibrosis (fibronectin, green) and immune cells (macrophages, red) accumulate. Credit: Dr. Bruno Costa da Silva and Dr. David Lyden

An international team led by Weill Cornell Medical College investigators has illuminated the precise molecular steps that enable pancreatic cancer to spread to the liver—the event that makes the most common form of the disease lethal. By understanding this process, investigators say their discovery can lead to targeted treatments that delay metastasis, and could offer clinicians a new biomarker to test for the earliest signs of pancreatic cancer.

The study, published May 18 in Nature Cell Biology, focuses on the role of small, spherical tumor-secreted packages, called exosomes, which contain tumor-derived proteins, in preparing a liver microenvironment fertile for metastasis.

Nearly 49,000 people in the United States will be diagnosed with pancreatic cancer, and more than 40,000 of them will succumb to it, according to estimates from the American Cancer Society. Pancreatic cancers are among the most lethal cancers—only six percent of patients survive five years after diagnosis, with the median survival rate being just six months.

"What makes this cancer so lethal is that patients don't generally become symptomatic—and as such aren't diagnosed—until the cancer is very advanced and treatment options are limited," said senior author Dr. David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology and a professor of pediatrics in the Department of Pediatrics at Weill Cornell Medical College.

In the study, the investigators recreated the environment for pancreatic cancer using mouse models and discovered that exosomes were finding their way to the liver during the cancer's earliest stages. Once in the liver, the exosomes were taken up by resident immune cells, called Kupffer cells. This process changed the Kupffer cells' gene expression and protein composition, and educated them to produce a powerful protein. This protein, in turn, affected the behavior of a group of cells, inducing . Liver fibrosis is an overly exuberant wound healing process that can interfere with normal liver function, and creates a microenvironment auspicious for tumor seeding and growth.

When investigating how exosomes exerted these effects on liver cells, Dr. Lyden and his team found that pancreatic cancer exosomes contain a protein called macrophage migration inhibitory factor (MIF). When the investigators eliminated MIF from exosomes, they noticed that they had prevented the creation of a fibrotic, tumor-supporting environment in the liver.

This infographic illustrates the precise molecular steps that enable pancreatic cancer to spread to the liver. Credit: Weill Cornell Medical College

"In mouse models of pancreatic cancer progression, exosomes containing MIF are released in circulation prior to the onset of a recognized and can 'educate' the liver, inducing fibrosis," said first authorDr. Bruno Costa Silva, an instructor of cell and developmental biology in pediatrics at Weill Cornell. "Our findings suggest that a microenvironment ripe for metastasis is generated at an earlier stage of the disease than previously recognized."

Once they understood this process, the investigators attempted to block each individual step in this sequence."Disrupting just one part of the process at any point of the circuit decreased metastasis, a discovery that could lead to the development of multi-targeted therapies that could prolong patients' lives," said Dr. Lyden, who also has appointments in the Sandra and Edward Meyer Cancer Center and the Gale and Ira Drukier Institute for Children's Health. Dr. Lyden and his team conduct their research in the Children's Cancer and Blood Foundation labs at Weill Cornell.

Dr. Lyden and his team also found that MIF is highly expressed in exosomes circulating in patients who have advanced pancreatic cancer. When they examined pancreatic cancer blood samples, the scientists discovered that exosomal MIF was much higher in patients who went on to develop liver metastasis than in those who escaped it. They say this protein signature could be used to predict which patients would then go on to develop metastatic disease. These discoveries were made possible by an international collaboration between researchers at Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center, University of Nebraska Medical Center, University of Pennsylvania and Oslo University Hospital.

Since five percent of patients diagnosed with pancreatitis—a disease characterized by inflammation—go on to develop pancreatic cancer, the investigators believe MIF could also serve as a biomarker for clinicians to monitor disease progression. Dr. Lyden and his team are currently testing whether measuring MIF levels in exosomes isolated from patients' blood can accurately estimate the risk of pancreatic cancer in patients with non-malignant pancreatic lesions. This type of "liquid biopsy" could allow the clinicians to initiate treatments, such as surgical resection, earlier in patients at risk, preventing disease progression.

Explore further: Uncovering new functions of a gene implicated in cancer growth opens new therapeutic possibilities

More information: Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver, DOI: 10.1038/ncb3169

Related Stories

Uncovering new functions of a gene implicated in cancer growth opens new therapeutic possibilities

April 29, 2015
Weill Cornell Medical College researchers have shown for the first time that a gene previously implicated in blood vessel formation during embryonic development and tumor growth also induces immune suppression during tumor ...

Promising new strategy to halt pancreatic cancer metastasis

March 2, 2015
Pancreatic cancer and its metastases might have their days numbered, according to a study published in The Journal of Experimental Medicine.

What makes pancreatic cancer so aggressive? New study sheds light

January 15, 2015
New research from the University of Michigan Comprehensive Cancer Center helps explain why pancreatic cancer is so lethal, with fewer than a third of patients surviving even early stage disease.

Cancerous tumors deliver pro-metastatic information in secreted vesicles

May 29, 2012
Cancer researchers have known for well over a century that different tumor types spread only to specific, preferred organs. But no one has been able to determine the mechanisms of organ specific metastasis, the so-called ...

Researchers identify gene that pushes normal pancreas cells to change shape

February 20, 2015
A research team led by investigators from Mayo Clinic's campus in Jacksonville, Florida, and the University of Oslo, Norway, have identified a molecule that pushes normal pancreatic cells to transform their shape, laying ...

Recommended for you

A small, daily dose of Viagra may reduce colorectal cancer risk

March 19, 2018
A small, daily dose of Viagra significantly reduces colorectal cancer risk in an animal model that is genetically predetermined to have the third leading cause of cancer death, scientists report.

Cancer comes back all jacked up on stem cells

March 19, 2018
After a biopsy or surgery, doctors often get a molecular snapshot of a patient's tumor. This snapshot is important - knowing the genetics that cause a cancer can help match a patient with a genetically-targeted treatment. ...

Researchers create a drug to extend the lives of men with prostate cancer

March 16, 2018
Fifteen years ago, Michael Jung was already an eminent scientist when his wife asked him a question that would change his career, and extend the lives of many men with a particularly lethal form of prostate cancer.

Machine-learning algorithm used to identify specific types of brain tumors

March 15, 2018
An international team of researchers has used methylation fingerprinting data as input to a machine-learning algorithm to identify different types of brain tumors. In their paper published in the journal Nature, the team ...

Higher doses of radiation don't improve survival in prostate cancer

March 15, 2018
A new study shows that higher doses of radiation do not improve survival for many patients with prostate cancer, compared with the standard radiation treatment. The analysis, which included 104 radiation therapy oncology ...

Joint supplement speeds melanoma cell growth

March 15, 2018
Chondroitin sulfate, a dietary supplement taken to strengthen joints, can speed the growth of a type of melanoma, according to experiments conducted in cell culture and mouse models.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

not rated yet May 18, 2015
Make the cancer inherit environment-sparing conduct, be happy.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.