All living things tend to develop a way of surviving in an unfavorable environment. Cancer cells do this when confronted with disease-fighting drugs.
A new study, led by clinician and scientist Catherine O’Brien of the Princess Margaret Cancer Center, shows that cancer cells become dormant and enter a “drug-tolerant persistent (DTP)” state. ” when exposed to chemotherapy and targeted agents.
While DTPs have been shown to exist in a number of cancers, there is little understanding of the mechanisms that drive this state in response to those therapies.
According to the magazine Cell, This tolerance is known as “diapause”, which occurs in undifferentiated cells that have not yet matured and cancer cells use it to resist.
In order to further characterize DTP status, the team developed experimental models of colon cancer. “When treated with chemotherapy, we found that all cells within the tumor were capable of entering that state and that this phenomenon was not limited to a subpopulation of cells,” O’Brien explained. “Once the treatment was over, the cells started to grow again.”
The researchers were interested in examining what biological mechanisms were responsible for driving this response. Using high-throughput gene sequencing technologies, they found that during the DTP state, cancer cells displayed gene expression profiles similar to those that certain animals use during development when faced with inappropriate environmental conditions, called diapause. During this, the growth of an embryo is suspended until the threat is removed.
The authors also found that slow-growing DTP cancer cells are functionally similar to embryos in diapause, where both depend on a cellular mechanism called autophagy, a process by which cells digest themselves during periods of starvation to survive.
They went further, showing that by treating tumors with autophagy inhibitors, cancer cells were less likely to enter the DTP state and escape chemotherapy.
“Here we demonstrate for the first time how cancer cells have adopted an evolutionarily conserved mechanism to survive treatment,” said O’Brien. “New therapeutic strategies targeting cancer cells in the DTP state hinder their ability to enter that slow-cycling state and will be essential in addressing treatment failure and relapse.
“It seems that cancer cells have cunningly chosen this state for their survival,” he said.
Catherine O’Brien is a Senior Scientist at the Princess Margaret Cancer Center, a General Surgeon at the University Health Network, Toronto General and Western Hospitals. She is also an Associate Professor in the Department of Surgery at the University of Toronto. She also holds the chair in translational research in colorectal cancer. Her focuses are to identify the molecular pathways that drive tumor growth in this disease, with the ultimate goal of using this knowledge to find better treatment options.
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