Cells with certain mutations work in a very sophisticated way to promote the development of cancer. Researchers from Amsterdam UMC have discovered this. They have managed to unravel the diabolical mechanism of how cells in the intestines manage to grow into tumors. They write about it Nature from June 2.
“It’s a new trick”, say Professor of Molecular Oncology Louis Vermeulen and PhD student Sanne van Neerven. “We know that cancer cells divide faster or are much tougher than healthy cells. But that’s not the whole story. We show that there is a third way to crowd out healthy cells. They are, as it were, cheating and using a kind of ‘poison’ to disable healthy cells.”
lining of the gut
Every week the inner lining of the intestine (the epithelium, a thin layer of cells) is replaced by fresh cells. “That is necessary because there is literally a lot of ‘shit’ going by, so to speak. The layer must be constantly renewed, otherwise digestion will go wrong”, explains Van Neerven. The source of the continuously renewing layer are the so-called stem cells. These are cells that are ready to grow into a cell with a specific function, in this case a cell for the inner lining of the intestine. “The stem cells are hidden in folds invisible to the eye in the intestinal wall, a crypt. They are safe and protected there. From the crypt, the stem cells can supply fresh cells that will line the inner lining of the gut.”
Folk goats
Because the inner wall of the intestine divides so quickly, the chance of the development of mutations and indirectly therefore also the risk of cancer is greater. “This is the reason that the risk of colon cancer is relatively high and that you can call it a public disease,” says Van Neerven.
Colon cancer occurs when the stem cells have a specific mutation, for those in the know an APC mutation. In 80 percent of cases, this is the onset of colon cancer. Cells with this mutation tend to crowd out the healthy stem cells, which is the first trigger for colon cancer. What is new in the Nature study is that Van Neerven and Vermeulen have unraveled how the altered stem cells manage to displace the healthy stem cells.
Supercompetition
Until now it was assumed that mutated cells gain the upper hand because they divide much faster or survive much longer than the non-mutated cells. Vermeulen explains: “Our research shows that there is another important mechanism. We call this super competition. The mutated cells make proteins that paralyze the healthy cells. Basically a kind of poison that disables the healthy cells. You can really call that cheating.”
It has previously been shown in biology that cells with these types of substances start to proliferate, but according to Vermeulen and Van Neerven this is the first time that this mechanism has been demonstrated in cancer in mammals. That justified a publication in the top scientific journal Nature. This knowledge is especially useful for colorectal cancer, but may also be useful for other forms of cancer in which the APC mutation plays a role.
The new insight may soon be used in practice, says Vermeulen. “It turns out that an existing drug, lithium – a widely used and inexpensive drug for patients with severe mood swings – can thwart cheating of the mutated stem cells in laboratory animals. Lithium arms the healthy cells against the toxins from the mutated cells. Mice we gave this drug did not develop colon cancer despite the mutation.”
Too extensive job
It is not possible to check everyone whether they happen to have that APC mutation in the intestinal cells, that is too extensive a task. But the knowledge is useful in people with a hereditary form of colon cancer (Familiare adenomatous polyposis or FAP), who have a congenital APC mutation. Last month, Vermeulen and Van Neerven received a large grant from the Dutch Cancer Society (KWF) to study together with gastrointestinal liver doctor Evelien Dekker whether lithium can inhibit the development of cancer in FAP patients.
This research is supported by the Oncode Institute and the New York Stem Cell Foundation, to which Louis Vermeulen is also associated. The study was also made possible with support from the European Research Council, Worldwide Cancer Research and KWF Kankerbestrijding.
Source: Amsterdam UMC
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