Cancer cells are addicts and, thanks to new research, we are now a step closer to preventing them getting their next fix and even, potentially, stopping them in their tracks.
It has long been known that rapidly dividing tumour cells have a prodigious appetite for sugar, in the form of glucose, to fuel their runaway growth. That predilection has been exploited to detect tumours, which preferentially take up a radio-labelled glucose analogue that lights up on a nuclear scan.
The logical next step is a tantalising one: starve the tumour cells of glucose and you might just bring the big C to its knees.
Not so fast. While glucose is targeted in some cancer treatments, healthy cells also use it as fuel, and so a blanket approach of glucose deprivation can hurt them, too. Hence the search for a selective means of robbing cancer cells of their precious nutrient.
Research led by Koji Itahana, from the Cancer and Stem Cell Biology Program at Duke-NUS Medical School in Singapore, published in Science Signaling, offers up two promising new targets for that endeavour.
Leveraging the fact that some cancers are more sensitive to glucose denial than others, the team isolated a line of cancer cells that succumbed to glucose starvation within just 10 hours. Switching focus to their more robust counterparts, they found cells able to resist the enforced famine maintained higher levels of intracellular glucose.
The researchers showed, for the first time, those tiny amounts of glucose had a signalling function which prevented calcium influx and a cascade of molecular changes culminating in cell death.
Both types of cells were then subjected to a two-pronged attack with STF-31, a compound that inhibits glucose transport into cells, and thapsigargin, which ramps up the level of calcium in cells. Cells that had that extra glucose in the tank shrugged off the assault, while those that held more meagre reserves went to the wall.
Picking off those relatively depleted tumour cells could, the researchers say, be a winning strategy.
“Because these phenomena are not seen in normal/healthy cells, this inability of some tumours to maintain intracellular glucose levels could be an unappreciated Achilles’ heel that might be therapeutically targeted,” they write.
“A molecular signature of cancers with reduced ability to maintain intracellular glucose would help develop that strategy for clinical application.”
A team led by Hans Wandall, from the Department of Cellular and Molecular Medicine at the University of Copenhagen, has found that an enzyme responsible for attaching sugar to proteins in colon cells is overactive in gut cancer.
The findings suggest that when the enzyme, called GalNAc-T6, attaches sugars called glycans to bowel cells, it promotes cell adhesion and the formation of tubular structures characteristic of bowel cancer. That process, say the researchers, helps refine another target for cancer treatment.
“Glycans add an additional context layer that could help us create more specific interventions,” says Wandall.
These findings might prompt some to wonder if a low sugar “ketogenic” diet could help in cancer.
Australian experts have stressed that healthy cells are also starved of sugar, unhelpful for a body fighting disease, and that wily cancer cells will just break down fats to make sugar anyway.
Nonetheless, studies have investigated ketogenic diet as an adjuvant treatment in a range of cancers, including ovarian, breast, stomach, brain and lung. The results, however, are not encouraging.
A recent review lamented that studies of limited number, with less than rigorous design, “contribute to a poor overall quality of evidence and limit the ability to draw evidence-based conclusions.”
Paul Biegler is a philosopher, physician and Adjunct Research Fellow in Bioethics at Monash University. He received the 2012 Australasian Association of Philosophy Media Prize and his book The Ethical Treatment of Depression (MIT Press 2011) won the Australian Museum Eureka Prize for Research in Ethics.
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