Paradigm shift: now targeting dormant as well as growing cancer cells

A key to controlling stem cell behaviour that is responsible for the spread of bowel cancer has been discovered by an international team of investigators led by researchers at the University of Melbourne.
Imminent anti-cancer treatments currently being trialled as a result of these findings will benefit patients with a range of cancers including bowel cancer.
This innovative approach will help to arrest cancers in patients by targeting both growing and dormant cancer cells. Targeting dormant cells will be a major advance as conventional therapies and treatments primarily target only growing cancer cells.
“The problem with bowel cancer is that when a patient presents, the cancer is usually advanced and will already have spread to other parts of the body, most commonly the liver. The cancer cells in these ‘secondary’ sites can sit dormant for years before starting new cancer growth,” says Melbourne cancer researcher Elizabeth Vincan.
The approach of this research was to identify a molecule that is expressed on both actively growing and dormant cancer cells in order to target the primary tumour in the bowel and dormant cancer cells in secondary organs.
“I think of laboratories around the world each searching for different pieces of the puzzle, and it was like finding a piece of that puzzle,” Professor Vincan says.
“We knew from previous research that a gut stem cell known as Lgr5+ is involved in initiating cancer growth. The Lgr5+ stem cell needs growth factors like proteins to maintain its unique properties as a stem cell, in order to orchestrate events like regenerating the gut lining or epithelium after it is damaged. Proteins such as the one known as Wnt control cell function by binding to a cell surface receptor. Those receptors are known as Frizzled,” Professor Vincan says.
“We knew that Lgr5+ stem cells need Wnt but the cell surface Frizzled receptor that binds Wnt was not known. There are ten Frizzled receptors. We now know from our study that Frizzled7 is the one that is important in Lgr5+ stem cells and is the one to target in cancer,” she added.
These findings, published in the journal Stem Cell Reports identify the ‘key’, Frizzled 7, to controlling stem cell behaviour that results in the spread of cancer.
“What we found was if you knocked out Frizzled7 while the cells were in a dormant state they weren’t able to restart the tumour growth. The aim is to try to get those cells while they are sitting there and not growing.”
“Most people don’t die of primary bowel cancer. Conventional therapies and treatments have poor outcomes for bowel cancer patients because by the time they are diagnosed, the cancer cells have spread to secondary organs and can sit there, undetected, until something triggers them to form a cancer again, and that is what people die of,” Professor Vincan says.
Bowel cancer is the second most common cancer in Australia (Cancer Council of Australia). Globally there were 1.4 million new cases and 694,000 deaths from bowel cancer in 2012 alone (World Health Organization).
“The next piece of the puzzle is how to target Frizzled7 and develop anti-Frizzled7 antibody treatments that can be used in combination with other current therapies. We are collaborating with scientists internationally who are currently trialling imminent antibody treatments.
“It represents a shift in the targeted management of cancers.”
Professor Vincan has a long-standing interest in Wnt signalling and was the convenor of the first international meeting on it and the first EMBO workshop held in Australia in 2014. EMBO is an organisation of leading researchers which promotes excellence in the life sciences.
“Professor Hans Clevers, who also collaborated on this research, delivered the EMBO keynote speech. He spoke about his discovery of Lgr5 as a stem cell marker and the advances this discovery has made to regenerative medicine and anti-cancer treatment,” Professor Vincan says.
An exciting consequence of this EMBO Wnt meeting is that Professor Clevers will be in Melbourne on sabbatical later this year.
Professor Elizabeth Vincan is Head of the Cancer Biology Laboratory in the Department of Anatomy and Neuroscience, University of Melbourne and Victorian Infectious Diseases Reference Laboratory at the Doherty Institute.
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