The risk of dying from cancer increases when it migrates from the original site (metastasis). Researchers from the University of Copenhagen have identified a physiological mechanism that can help to predict the risk of metastasis and might also be manipulated to prevent it.
Metastasis is the migration of cancer from the primary tumour to other tissues – often with fatal consequences. The new cancer sites are called metastases.
Cancer can migrate to any site in the body, forming metastases in the lungs, kidneys and liver that develop in these organs.
Danish researchers have identified a fascinating mechanism that determines how easily cancer can metastasize.
The researchers hope that this mechanism can be used diagnostically in the future to determine each person’s risk of cancer metastasizing to specific organs – even before a tumour is formed.
In addition, the researchers will also investigate whether this mechanism can be used therapeutically to inhibit metastasis.
“As we develop more and more organ-specific treatments for cancer, our discovery may help to determine which treatments a person should receive to optimally protect vulnerable organs from metastasis,” says a researcher behind the new study, Janine Erler, Professor, Biotech Research & Innovation Centre (BRIC), University of Copenhagen.
The research has been published in Nature Materials.
Softer membranes prevent metastasis
Janine Erler, Raphael Reuten and other colleagues studied the architecture of basement membranes, which surround all cells and blood vessels.
These basement membranes have varying degrees of stiffness, and new research shows that stiffer basement membranes enable cancer cells to migrate more easily across the membrane and enter the bloodstream and metastasize. Conversely, a softer barrier membrane reduces metastasis.
“Basement membranes are the frontline barrier to metastasis. We therefore knew that they are important for keeping cancer cells in check, but we did not know that their stiffness is the major determining factor,” explains Janine Erler.
Stiff basement membranes increase the risk of dying from cancer
The researchers investigated basement membranes using computer models, animal models and genetic data from people with cancer.
All these studies confirmed that basement membrane stiffness affects metastasis.
“This provides insight into how easily cancer can metastasize to various organs for each individual even before tumours form,” says Janine Erler.
The researchers identified a protein, netrin-4, that is associated with the stiffness of the basement membranes.
Levels of netrin-4 were a key regulator of basement membrane stiffness. More netrin-4 within the basement membrane means a softer barrier, resulting in reduced cancer cell invasion, which is associated with improved survival.
Mice that produced no netrin 4 were more prone to metastasis
The researchers used a genetic mouse model that produced no netrin-4 anymore. Tumours metastasized much more easily in these mice than in mice with normal levels of netrin-4.
Interestingly, injecting netrin-4 into mice reduced the risk of metastasis.
“The more netrin-4 molecules, the softer the basement membrane, so cells have more difficulty in breaching the basement membrane. This keeps the cancer cells encapsulated. We are now investigating the therapeutic and diagnostic potential of our results, and we may investigate whether drugs can increase netrin-4 levels among people with cancer to minimize the risk of metastasis during cancer treatment,” explains Janine Erler.
The researchers further confirmed the relationship between high netrin-4 levels and softness as well as good survival by analysing genetic data from people with cancer.
“Our findings open up a whole new way of understanding cancer and potentially paves the way for some novel therapeutic opportunities for preventing cancer from metastasizing,” says Janine Erler.
