Tuesday February 24 2009
Cancerous bowel cells seen in colorectal cancer
The Daily Express has reported on a gene that can “turn off” cancer. The identification of the ATOH1 gene “could open the door to revolutionary new treatments” says the newspaper, referring to new research that has found 'turning on' the gene could suppress bowel cancer in mice and humans, plus eye tumours in fruit flies.
These thorough studies have identified a role for ATOH1 in suppressing tumours across species. They have also suggested ways to treat some cancers in humans. It is worth noting that only two types of human cancer were investigated: colorectal cancer and the very rare Merkel cell carcinoma.
The ATOH1 gene may not be involved in other human cancers, and therefore may not be the “master switch” for all cancers as implied in the headlines of some of the newspapers. Further studies in humans will be needed to determine whether drugs that can 'turn up' the action of the ATOH1 gene can help treat people with colorectal cancers who have reduced expression of this gene. It is probably better to view this study as one that improves our understanding of cancer, rather than one that will quickly lead to new treatments of all cancers.
Where did the story come from?
Dr Wouter Bossuyt from the research institute VIB in Belgium and colleagues from elsewhere in Belgium and the US carried out this research, which was published as two studies in the peer-reviewed online journal PLoS Biology.
Numerous organisations supported the research, including the European Molecular Biology Organization, FWO, the Foundation against Cancer, the American Cancer Society and the National Institutes of Health in the US.
What kind of scientific study was this?
The two studies included animal experiments on mice and fruit flies, plus laboratory studies on human tissue. These studies looked at the role in tumour formation played by the ATOH1 gene in humans, and the equivalent genes in mice (Atoh1) and fruit flies (Ato).
When cells become cancerous, they often lose characteristics that mark them out as particular types of cells with specific functions. The ATOH1 gene and its equivalents contains the instructions for making a protein that can switch on the action of certain other genes that tell cells to develop into specific types of cells and to stop dividing, a process called differentiation.
In particular, the ATOH1 gene is involved in differentiation of cells in the peripheral nervous system (the nerves that lie outside of the brain and spinal cord), as well as cells lining the colon (epithelium). The researchers thought that switching off this gene might lead to cells losing their specific characteristics, and might make them more susceptible to becoming cancerous.
In fruit flies, the Ato gene is involved in differentiation of cells in the eye. The researchers took fruit flies that had been genetically engineered to be susceptible to developing eye tumours. They then looked at whether the development of eye tumours was affected by either switching off the Ato gene, or increasing the activity of the Ato gene (essentially 'switching up the volume' of this gene). They also looked at what biochemical pathways in the cells were affected by the Ato gene.
In their second study, the researchers looked at the role of ATOH1 in tumour formation in human tissues and mouse models of cancer. In mammals, two aggressive cancers develop from tissues where ATOH1 controls cell differentiation: Merkel cell carcinoma (MCC, a rare form of skin cancer) and colorectal cancer (CRC). They also looked at what happened when they genetically engineered mice to lack the Atoh1 gene in their intestines and treated them with chemicals that can induce colon cancer.
The researchers also looked at whether either copy of the ATOH1 gene (people usually have two copies) was switched off or absent in human MCC and CRC cells grown in the laboratory, and taken directly from patients (42 CRC patients and four MCC patients). When a copy of a 'tumour suppressor' gene is lost in a cell, this cell is more susceptible to becoming cancerous if the only remaining copy is itself lost, damaged by mutation or made less active ('switched down') by the cell. The researchers therefore looked at whether the remaining copy of the ATOH1 gene in cells that had lost one copy had been mutated or 'switched down'.
The researchers finally looked at the effects of either treating human MCC and CRC cells grown in the laboratory by re-introducing an active Atoh1 gene into the cell lines or using a drug that can increase activity of genes that had been switched down in this way.
What were the results of the study?
In their fruit fly study the researchers found that when introducing an overactive Ato gene into flies susceptible to eye tumours it almost completely stopped the development of eye tumours. Conversely, switching off the Ato gene in these flies led to an increase in the number of eye tumours.
When treated with a colon-cancer-inducing chemical those mice lacking the Atoh1 gene in their intestines were more susceptible to developing abnormal precancerous growths called polyps than normal mice.
The researchers found that the ATOH1 gene was less active in 70% of human CRC tumours than in normal colon tissue. Two of the four MCC samples showed lower ATOH1 gene activity than normal tissue. Lower ATOH1 gene activity appeared to be associated with more aggressive forms of both cancers. The researchers found that at least one copy of the ATOH1 gene was missing in about half of the CRC and MCC cancer tissue tested. Two human CRC and MCC cell lines grown in the laboratory also lacked one copy of the ATOH1 gene.
In the 24 tumour samples that had lost one copy of the ATOH1 gene, the researchers did not find any mutations in the remaining copy. However, they did find evidence that in the majority of samples the remaining copy had been altered so that its activity was reduced.
The researchers found that when they treated CRC cells in the laboratory with a drug that can 'turn up' activity of genes altered in this way, it increased activity of the ATOH1 gene eight-fold.
Introducing an active mouse Atoh1 gene into human MCC and CRC cells grown in the laboratory slowed down their division and caused them to undergo cell death.
What interpretations did the researchers draw from these results?
The researchers conclude that ATOH1 is acting as a tumour suppressor gene protecting against colorectal cancer and Merkel cell carcinoma. Loss of function of this gene is likely to occur early in the development of these types of cancer.
They say that their data suggest that screening for changes in ATOH1 (activity, loss or 'switching down') may be useful in early detection of CRC and MCC. It may also be useful in making treatment decisions, as there are drugs that can help 'turn up' gene expression.
What does the NHS Knowledge Service make of this study?
These thorough studies have identified a role for ATOH1 in tumour suppression across species. They have also suggested ways in which these problems might be treated.
It is worth noting that only two types of human cancer were investigated, colorectal cancer and Merkel cell carcinoma, and the latter form is very rare. The ATOH1 gene may not be involved in other human cancers, and therefore may not be the “master switch” for all cancers as has been implied in the headlines of some of the newspapers.
Further studies in humans will be needed to determine whether drugs that can 'turn up' expression of the ATOH1 gene can help treat people with colorectal cancers that have reduced expression of this gene.