Dr Ahmad Waseem
Research has appeared in the open access journal PLoS ONE
which suggests a new catalyst for tumour growth in the form of an interaction between two genes. Funded by the Facial Surgery Research Foundation, Saving Faces, it is hoped that the study will eventually lead to new targeted treatments for many of the most common cancers.
Forkhead box protein M1, encoded by the FOXM1 gene, has become infamous since the discovery of its association with almost all types of human cancer. On the other hand, the gene for the protein keratin 15 (K15) was thought to be merely a biomarker for normal stem cells.
Because we have used so many different methods, we think this link is genuine and does exist in living cells and tissues. We believe that it is a direct interaction, because otherwise the kind of signal we saw in quantitative PCRs would not have been possible.
Dr Ahmad Waseem
However, the somewhat surprising results of this research indicate what is believed to be a direct link between K15 and FOXM1. The researchers believe this may be responsible for the uncontrolled stem cell replication that leads to the growth of cancerous tissue.
I spoke to Dr Ahmad Waseem, Reader in Oral Biology at Queen Mary, University of London and lead author of the study, in order to learn more about how this connection was established and why its implications may be very far-reaching…What did your research find and why did this come as a surprise?
We have been working on FOXM1 and K15 for quite some time now. FOXM1, we have shown, is a growth-promoting factor, and that is why it is induced in almost all cancers that we have studied. Most of its targets are growth-related proteins, but K15 is not related to growth; it is a stem cell marker. It came as a surprise when my colleague Dr Muy-Teck Teh who studied FOXM1 in cancer found that a cancer-causing gene could influence a stem cell marker. We jointly published this discovery a couple of years ago, which later led to the ‘Molecule of the Year 2010’ award being assigned to FOXM1. Since then, we have focused on the mechanism of how FOXM1 hijacks stem cells to induce cancer initiation.
Considering as a whole all the data that we have collected in the last four to five years, it does make perfect sense. Cancer is a disease of stem cells – we know that stem cell behaviour is changed in cancer – and we know that FOXM1 is a cancer-causing gene. Finding a linkage between a stem cell marker and a cancer-causing gene is actually very exciting, because it suggests that FOXM1 could modify or modulate the behaviour of stem cells by affecting the level of K15 in the cells.
This link is suggestive of a sort of first step in the process by which FOXM1 can initiate carcinogenesis (the formation of cancerous cells or cancer tissue). The reason we were so excited is because we were not expecting this link.How was the link established between FOXM1 and K15?
As I said, we have been working on this for quite some time, and over this time we have established a number of techniques. Empirically we have found that whenever FOXM1 increases due to disease, this is accompanied by relatively high levels of K15. We elevated FOXM1 artificially using a process called retro-virus transduction. When we did that we found that K15 levels were very high in those cells where the level of FOXM1 had been elevated. In this way we established a link, but we could not say for certain that it was a direct rather than an indirect effect.
In this study, we showed a direct interaction between the FOXM1 gene and the K15 protein using chromatin immuno-precipitation, which necessitates the use of the quantitative polymerase chain reaction (PCR). So we used a whole set of cell and molecular biology techniques to establish the link.How much do we know about the mechanisms at work here?
Because we have used so many different methods, we think this link is genuine and does exist in living cells and tissues. We believe that it is a direct interaction, because otherwise the kind of signal we saw in quantitative PCRs would not have been possible. We now know that the binding of FOXM1 protein to the promoter region of the K15 gene appears to activate K15 gene expression.What might be the implications of this discovery?
Although this is only a linkage, it is a very important one because we know that FOXM1 can regulate the level of K15 and thereby change the behaviour of stem cells. In the field we call it ‘stemness’. This is the extent to which a stem cell retains its ability to replicate itself and differentiate into specialised cells. Some stem cells have more potential than others; they are possessed of more or less stemness.
K15 can change the behaviour of stem cells by changing stemness, and if that is the case then we can also modulate or change this activity. In theory, at least, this could mean bringing stemness back to normal by nullifying the effect of FOXM1. We think the next step is to work on inactivating or suppressing the activity of FOXM1, which would in turn influence the stemness of stem cells by suppressing K15 expression.Does this apply to all cancers?
It applies to most epithelial cancers. 95 per cent of cancers are epithelial in origin, so this would apply to most of the more common cancers.