One of the many reasons that cancer is so difficult to treat is its ability to hijack normal cellular components and switch them from useful to deadly. Cancer can therefore turn vital, natural cell types against the body.
As Dr. Aine McCarthy, Cancer Research UK’s senior science information officer, says, “Some cancers are incredibly difficult to treat and can use the body’s own cells to help them grow, evade treatment, and spread around the body. Researchers have been trying to unlock the secrets behind this for many years.”
The findings of the most recent study in this field, carried out by researchers at the University of Southampton, are published this week in the Journal of the National Cancer Institute.
An example of the repurposing of the body’s biological mechanisms involves fibroblasts. Normally, these cells make a range of products, such as collagen and elastic fibers, helping to fix organs and cells together. However, cancer can utilize these cells for its own purpose, turning them into cancer-associated fibroblasts (CAFs).
Investigating cancer-associated fibroblasts
CAFs support a tumor as it grows and can help it spread. Earlier studies carried out at the University of Southampton have demonstrated that increased CAF levels are associated with poorer survival rates in a number of cancers, including bowel and head and neck cancers.
They have also shown that CAFs protect cancer cells from chemotherapy and suppress the immune system’s anti-cancer response.
The relationship between CAF levels and survival could make them a potential target for pharmacological intervention. To date, however, attempts to interact with them have been unsuccessful.
Medical News Today spoke with lead researcher Prof. Gareth Thomas, who is chair of experimental pathology at the University of Southampton. He told us about his previous research into CAFs in a range of cancer types.
“I think what surprised us was the fact that there is a common mechanism that regulates the formation of CAFs in multiple cancer types. […] This common mechanism suggests that we can adopt a similar strategy for targeting the cells in different types of cancer.”
Recently, Prof. Thomas and his team embarked on a new project looking at the potential of a specific enzyme, called NOX4, to interrupt CAFs. This enzyme is essential for the conversion of fibroblasts into CAFs.
The team demonstrated that by blocking NOX4, the size of tumors in mice was reduced by up to 50 percent.
The drug that blocks NOX4 is currently being developed to treat organ fibrosis, which is a condition characterized by the formation of excessive fibrous connective tissue. If follow-up studies go well, it might be a useful medication to be taken alongside existing cancer treatments.
“By looking at many types of cancer, we have identified a common mechanism responsible for CAF formation in tumors. These cells make cancers aggressive and difficult to treat, and we can see exciting possibilities for targeting CAFs in many patients who don’t respond well to existing therapies.”
Prof. Gareth Thomas
The future of CAF research
Of course, there is much to learn about CAFs and how they operate, so this is by no means the end of the story. MNT asked Prof. Thomas about the fresh questions that had been generated by his recent research.
He informed us that, to date, little is known about CAFs. Although it has been shown that the “myofibroblastic CAF subtype is associated with aggressive cancers,” there are presumably a number of CAF subtypes, all of which could have different functions that need to be unpicked.
Prof. Thomas is currently involved in a study involving the collection of cells directly from patients with head and neck cancers; the plan is “to identify different CAF subtypes and examine their similarity between different cancer types.”
Additionally, Prof. Thomas talked to MNT about new questions that have opened up about the importance of the immune system in this process. The team found that when tumors have high levels of CAF, there is a significant reduction in immune response.
“This suggests that CAF may be a mechanism by which cancers evade the immune response, an important consideration given the current interest in immunotherapy. Our experiments in murine models have confirmed this, and we have recently shown (unpublished) that targeting CAF through NOX4 inhibition can improve the immune response to anti-cancer vaccination.”
He told MNT that they recently received funding from Cancer Research UK to examine “the effect of combining chemotherapy or immunotherapy with NOX4 suppression” in mice.
The team is casting its net wide: they are also investigating another enzyme pathway involved in the generation of CAFs alongside NOX4.
Although there is much to learn about CAFs and their role in cancer, the hunt is on and Prof. Thomas and his team are leading from the front.