Researchers at the Indiana University Melvin and Bren Simon Comprehensive Cancer Centre have found that depleting a clotting protein made by the liver could slow down pancreatic cancer.

The research, recently published in Gastroenterology and led by Melissa L. Fishel, PhD, shows that reducing fibrinogen in mouse models shrinks primary pancreatic ductal adenocarcinoma (PDAC) tumours and reduces their ability to metastasise to the liver.

Fibrinogen is cleaved to fibrin following injury and is a primary structural component of blood clots.

Fibrinogen is deposited on pancreatic tumours and contributes to their growth and environment in which the tumour grows.

"It's well known that pancreatic cancer patients have some of the highest rates of blood clots or deep-vein thrombosis, or DVTs," said Fishel, an associate professor of paediatrics and the Myles Brand Scholar in Cancer Research at the IU School of Medicine.

"We wanted to understand whether the proteins involved in blood coagulation and clotting are driving the disease or are a byproduct of the disease." Fishel is also a researcher at the Herman B Wells Centre for Paediatric Research and co-leader of the Cancer Biology and Microenvironment research programme at the cancer centre.

Pancreatic cancer is known to have a dense, fibrotic microenvironment rich in cancer-associated fibroblasts and a matrix of proteins including fibrin.

These fibroblasts are recruited and build a matrix that supports tumour cells.

In healthy pancreas tissue, researchers found very little evidence of fibrin deposition, but on pancreatic tumour samples, fibrin was abundantly deposited.

Using two different methods to deplete fibrinogen in mouse models, the researchers demonstrated that tumours grew smaller and produced far fewer liver metastases.

"When fibrin was not there, we saw a dramatic reduction in primary tumour size as well as liver lesions," Fishel said.

"When pancreatic cancer spreads to the liver the patient prognosis is grim, so we were very excited by the possibility of reducing that tumour burden and metastasis."

The study used multiple tumour cell models, including two derived from IU patient samples and developed by the cancer centre's Pancreatic Cancer Working Group.

To determine whether fibrin in the bloodstream contributed to cancer spreading, researchers also used tumour models that resulted in sites of metastasis in the liver or lung, similar to what is observed in human patients.

They found no difference in metastatic growth with or without fibrinogen, suggesting the protein impacts the tumour cells in the pancreas to alter tumour behaviour and aggressiveness.

"Something about not having fibrin in the primary pancreatic tumour site really changes those tumour cells, so they are either less likely to leave the pancreas or are somehow unable to make a liver lesion," Fishel said.

Since the body needs fibrinogen to prevent excessive bleeding, Fishel said the goal is not to eliminate the protein entirely in patients.

"Since levels of fibrinogen are elevated in pancreatic cancer, the idea would be to return it to baseline — not to zero," Fishel said.

"We believe that could be clinically manageable."

Next steps for this research include combining fibrinogen-targeted approaches with chemotherapy or emerging pancreatic cancer therapies, since reducing fibrinogen led to delayed disease progression — not a cure — in the mouse models.

"Now we want to understand what fibrin is turning on or off in the tumour so we can combine treatments to make them more effective," Fishel said.

The research was conducted as part of the Pancreatic Cancer Stromal Reprogramming Consortium, a multi-site national collaboration aimed at accelerating discoveries in pancreatic cancer.

Source: Indiana University