New research in mice reveals "previously unknown" molecules that pancreatic cancer cells use to shape the environment around the tumors and enable them to spread.
Most of the time, the condition has already progressed to an advanced stage by the time doctors diagnose it.
According to some estimates, the average 5-year survival rate for pancreatic cancer is around 8%.
Often, the cancer silently spreads to other organs before detection, which can lower the survival rate to 3%.
However, not all pancreatic cancers metastasize. New research aimed to investigate why some pancreatic tumors spread while others remain confined to the pancreas.
Paul Timpson — head of the Invasion and Metastasis Laboratory at the Garvan Institute of Medical Research in Darlinghurst, Australia — led the new research together with Thomas Cox, who is the leader of the Matrix and Metastasis Group at the same institute.
Timpson and Cox set out to compare the tissue around the tumors in pancreatic cancers that had metastasized with that of those that hadn't. This tissue bears the name of "matrix," and its role is to hold various cells together.
Using a mouse model, the researchers examined subtypes of fibroblasts associated with cancer and the way they interacted with pancreatic cancer cells. Fibroblasts create collagen and are a key part of building the extracellular matrix.
They have published the results of their investigation in the journal Nature Communications.
Perlecan 'educates' the tumor environment
The team used mass spectrometry analysis to examine the molecular interactions between metastatic tumor fibroblasts and pancreatic cancer cells and the interaction between nonmetastatic fibroblasts and cancer cells.
"What we discovered is a previously unknown set of matrix molecules that aggressive pancreatic cancer cells use to shape the tissue around them, in order to both protect them from chemotherapy and enable easier escape around the body," says Cox.
A "key component of this prometastatic environment," the research revealed, is a protein called perlecan. Perlecan binds several growth factors, as well as matrix components including collagen, together.
To further elucidate the role of perlecan in promoting tumor spread, the researchers used a mouse model of aggressive pancreatic cancer and edited the rodents' genes so that they have less perlecan.
Depleting perlecan made the tumors more vulnerable to chemotherapy and stopped the tumors from spreading. This prolonged the survival of the mice.
Furthermore, the researchers believe that cancer fibroblasts use perlecan to "educate" the environment around them, helping cancer cells spread faster.
First study author Claire Vennin, a postdoctoral fellow, further explains the findings:
"Our results suggest that some pancreatic cancer cells can 'educate' the fibroblasts in and around the tumor. This lets the fibroblasts remodel the matrix and interact with other, less aggressive cancer cells in a way that supports the cancer cells' ability to spread."
"This means that in a growing tumor, even a small number of aggressive metastatic cells — a few bad apples — can help increase the spread of other, less aggressive cancer cells."
Therefore, the study authors suggest that perlecan and the environment surrounding the tumor are valid targets in the fight against pancreatic tumors.
"Most cancer therapies today aim to target cancer cells themselves. The environment of tumors is a potential untapped resource for cancer therapy and one which we intend to explore further," says Timpson.
"We believe that there would be important benefit in targeting the fibroblasts of a tumor in combination with targeting the cancer cells themselves with chemotherapy," adds Vennin.
"If we can specifically target the aggressive fibroblasts in [people] harboring precise genetic changes, we can make them more susceptible to our currently approved treatments, which would significantly change how we treat this aggressive cancer," she concludes.