Researchers have identified how inactive cancer cells are kept dormant, until they are awoken and form fatal cancer metastases.
Despite successful treatment of the primary tumour, metastatic disease can resurface in many cancer patients. Several studies have shown that there are a population of cancer cells that disseminate from the primary tumour, surviving systemic therapy and initiating future metastases. Persistent disseminated tumour cells (DTCs) can enter into dormancy, which accounts for the unpredictable timing of metastasis. It also acts as a major barrier to a long-lasting cure. However, the exact trigger that switches cells from dormancy to outgrowth remains unclear.
Dormant DTCs contain multiple genetic abnormalities. Yet, they are often unable to reinitiate tumour growth for extended periods of time. This implies that the microenvironment within distant sites is the dominant force for the timing of metastatic progression. This also highlights the potential of targeting the microenvironment to prevent dormant DTCs from awakening. Nonetheless, to implement such therapies researchers require a better understanding of the nature of tissue-specific switches that control the outgrowth of DTCs.
In a recent study, published in Nature, researchers used mouse models and human tissue samples to determine how cancer cells remained dormant or awoke to form metastases. They specifically explored the different tissue-specific microenvironments that impact the progression of breast cancer in the liver. This is a frequent site of metastasis and often associates with a poor prognosis.
The team found that two cells in particular played a key role in this transition. The first cell type was the natural killer cell. The researchers found a selective increase in natural killer cells that sustained dormancy through interferon-γ signalling. The other cell type was the hepatic stellate cell, which influences natural killer cells. When hepatic stellate cells are activated, they inhibit these immune cells, thus allowing the cancer cells to awaken from hibernation.
First author Dr. Anna Correia, explained:
“There can be various reasons why hepatic stellate cells are activated; for example, chronic inflammation in the body or persistent infection,”
These results open the door to several possible methods of preventing metastasis. For example, experts can use immunotherapy that increases the number of natural killer cells and thus maintains the dormant state of the cancer cells. Alternatively, the use of inhibitors to prevent hepatic stellate cells from paralysing natural killer cells. While therapies exist, researchers still need to clinically test them.
Professor Mohamed Bentires-Alj, group leader at the Department of Biomedicine at the University of Basel and University Hospital Basel, expressed:
“The next stage on the long road to an established treatment will be to show that stimulating natural killer cells prevents metastasis in human patients. We are currently looking for ways to finance this next step and are already in discussion with our clinical collaborators at the University Hospital Basel.”
Image credit: By Mohammed Haneefa Nizamudeen – canva