Researchers have discovered that collagen is key for the ability of tumour cells to enter a dormant life cycle, with huge implications for future cancer treatments.
Why do tumour cells want to be dormant?
Metastasis is a process in which cancer cells spread from their place of origin to other areas around the body. This results in the formation of tumours in new organs and tissues. Unfortunately, metastasis can occur many years after a primary tumour is removed from a patient. This is possible due to the ability of cancer cells to become dormant, which makes them undetectable by the body. In dormancy, cells do not proliferate.
Most deaths from cancer are due to metastases or the consequences of their treatment. Therefore, uncovering exactly how cancer cells remain dormant is hugely important. It is a critical step in the journey towards curing cancer.
Investigating the extracellular matrix
To discover what drives dormancy, a team from Mount Sinai began by looking at the extracellular matrix (ECM) of tumour cells. The ECM is a protein network that surrounds cells to provide structural and biochemical support. Previous studies had shown that signals from the ECM are what instruct cancer cells to remain dormant. However, the precise nature of these interactions was not known until now.
The researchers used cutting-edge technology in order to visualise dormant cancer cells in real time within a living mouse. By using the imaging techniques, which included intravital two-photon microscopy, the team were able to see how the ECM of the tumour cells changed between dormant and malignant states.
The role of collagen in dormant tumour cells
Comparisons between the ECM of dormant and proliferative cells revealed that dormant cells have a lower level of linearly oriented collagen fibres. In fact, an increase in fibre alignment was found to be characteristic of proliferative cells and those escaping dormancy.
Due to this observation, the team decided to investigate collagen in the ECM further. Analysis between dormant and malignant cells found that the dormant cells have an ECM highly enriched in collagen compared to the proliferative cells. More specifically, type III collagen was the most abundant type of collagen. It was present at much higher levels in the dormant cells than the malignant cells. This suggested that type III collagen was playing a role in keeping those cells in dormancy.
To test this hypothesis, the researchers enriched the environment of highly proliferative cells with type I, III, and IV collagen. Amazingly, they found that the enrichment with type III collagen specifically forced the cells back into dormancy and prevented the formation of tumours. Additionally, only 20% of mice treated with type III collagen relapsed. In comparison, 80% of mice in the control group relapsed.
In addition, the team reduced the ability of dormant cells to produce type III collagen. This resulted in the cells exiting their dormant state and becoming proliferative once again. This suggests that a certain threshold level of collagen is required in the ECM for cancer cells to remain dormant.
Implications for cancer treatment
Overall, this study discovered that enriching the microenvironment of cells for type III collagen activated dormancy and suppressed tumour growth. This discovery is extremely exciting, as it suggests a potential method for preventing metastasis. More studies will have to be done, including clinical trials, but the researchers are hopeful that their work will pave the way for future cancer treatments.
“Our findings have potential clinical implications and may lead to a novel biomarker to predict tumour recurrences, as well as a therapeutic intervention to reduce local and distant relapses,” senior author Jose Javier Bravo-Cordero said. “This intervention aimed at preventing the awakening of dormant cells has been suggested as a therapeutic strategy to prevent metastatic outgrowth. As the biology of tumour dormancy gets uncovered and new specific drugs are developed, a combination of dormancy-inducing treatments with therapies that specifically target dormant cells will ultimately prevent local recurrence and metastasis and pave the way to cancer remission.”
Photo by National Cancer Institute on Unsplash