Cancer spread mechanism probed

Behind the Headlines

Tuesday January 25 2011

Cancer cells can multiply and spread throughout the body

We will soon have a “cure for most cancers”, the Daily Express has reported. The newspaper claims that scientists are close to providing the "holy grail" of cancer cures, which will be available within a few years.

The scientists in question were in fact much more cautious when reporting their own research, which was a laboratory study looking at a gene called WWP2 that is present in all cells. The gene can produce a group of different proteins that in turn regulate other proteins that normally prevent tumours from spreading in different ways. The researchers hope eventually to modify this process with drugs so that they can cure cancer. However, this was a preliminary laboratory study and no such drug has yet been found. Such a wide-ranging cure is much further away than the headline suggests.

This carefully conducted study was complex and featured a range of tests examining the proteins and genes thought to be involved in the spread of cancers. However, it did not directly model the "spreading" action of cancer cells, and further research must now test how the chemical processes work in real-world settings.

 

Where did the story come from?

The study was carried out by researchers from the School of Biological Sciences at the University of East Anglia. It was supported the Association for International Research, with additional funding from the Big C charity, the British Skin Foundation and the Dunhill Medical Trust. The study was published in the peer-reviewed journal, Oncogene.

Most newspapers have focused on the research’s potential for giving hope to those living with cancer, with The Daily Telegraph and BBC emphasising how the experimental study’s discoveries might improve our understanding of how cancers spread. However, this is very preliminary, basic laboratory research and although it may lead to potential drug targets in the future, it is very early days.

 

What kind of research was this?

This was a cell-culture based laboratory study that investigated a family of related proteins called “ubiquitin ligases” and how they regulate cellular processes. Of interest were one full-length protein called WWP2-FL and two other, shorter forms of the protein. The function of these proteins is to interact with other target proteins and attach a chemical called ubiquitin to them. Once a target protein within a cell has been bound with ubiquitin, it signals to the cell that the protein should be removed.

Within our DNA genes is the code used by the body to produce certain proteins. Some proteins coded for by a single gene can exist in different forms, called isoforms. The researchers looked at whether isoforms of the WWP2 protein interacted in different ways depending on whether they were the full-length or shorter form.

The researchers then looked at whether the interaction between WWP2 and other proteins in the cell would affect the ability of the cells to move. This would have implications for cancer, where cells can then move to other parts of the body and form cancers in other tissues. This process is called metastasis.

 

What did the research involve?

The research involved a number of tests to look at the various pathways and processes that may be involved in the growth and spread of cancerous cells.

The researchers first analysed the DNA sequence of the WWP2 gene to predict whether it could be used to produce proteins of different length. They confirmed their predictions by measuring the length of RNA, a molecule made when a gene produces the protein that it contains information for making.

They used a technique called “immunoprecipitation” to look at which proteins bound to the WWP2 proteins. To do this they took a mixture of proteins found within cells and passed them through a column coated in WWP2 proteins. They then used antibodies to detect which proteins had bound to the WWP2 proteins. The researchers were particularly interested in a group of proteins called “Smad” so they used antibodies that would bind to Smad proteins to look at their actions. They then measured how quickly the Smad proteins were cleared from the cell in the presence of the different forms of WWP2.

Another protein, called transforming growth factor beta (TGFβ), regulates the activation of some genes, including those that produce for the Smad2 and Smad3 proteins. It also regulates a process called “epithelial-mesenchymal transition” (EMT), in which stationary cells are converted into cells that move, a process that has been linked to cancer cell growth and the metastasis process that is key in the spread of cancers.

The researchers also looked at whether the WWP2 proteins switched on genes and examined a cancer cell line that undergoes EMT to see whether the WWP2 proteins affected this process. Finally they looked at what would happen if they blocked the action of the WWP2 gene using a technique called siRNA.

 

What were the basic results?

This research tested several complex biological pathways, providing a number of results on the individual chemical processes that may contribute to the spread of cancerous cells.

The researchers found that there were three different length proteins made from the WWP2 gene: a full-length WWP2 protein called WWP2-FL, and two smaller proteins called WWP2-N and WWP2-C.

They found that, of the different proteins:

  • WWP2-FL was able to bind with Smads 2, 3 and 7
  • WWP2-N bound to Smad3
  • WWP2-C bound to Smad7 

The researchers found that when there was more WWP2 protein in the cell it increased the speed at which Smads 2, 3 and 7 were removed. The acceleration of Smad7 removal was greater than Smads 2 and 3.

They found that the shorter WWP2-N protein affected the activity of the WWP2-FL protein and made it more likely that WWP2-FL would bind ubiquitin to the Smad2 and Smad3, ultimately causing these proteins to be removed more rapidly.

The researchers additionally found that increasing the amount of WWP2-FL in the cells prevented the TGFβ protein from switching on the Smad2 and Smad3 genes. Decreasing the amount of WWP2-FL in cells using siRNA led to an enhancement of TGFβ-dependent switching on of the Smad2 and Smad3 genes.

After the researchers stimulated a cancer cell line with TGFβ, they found that increasing WWP2-FL could affect the EMT process. The WWP2-C and WWP2-FL proteins both featured a similar fragment. Introducing this fragment of protein into cells (by genetic engineering) caused the Smad7 gene to be more active.

 

How did the researchers interpret the results?

The researchers said that elevated TGFβ-signalling activity (which stimulates gene activation and the mobilisation of cells) is associated with the cellular processes of human disease including fibrosis, heart disease and cancer metastasis. They suggest that the WWP2 protein plays a key role in preventing EMT, a process that may be involved in cancer metastasis. They say that part of the WWP2-C protein increases the levels of Smad7 and cite other studies that have shown that Smad7 inhibits EMT.

 

Conclusion

This preliminary study has made progress in understanding how WWP2 proteins interact with Smad proteins and has given some indication of how these interactions may affect cancer metastasis. The research work was done in cell-culture in the laboratory by genetically modifying the cells to either overproduce or not produce the proteins of interest. Further, direct investigation in cancer cells and tumour tissue sample are needed to see the importance of these proteins in cancer.

Some newspapers have correctly pointed out that this research was preliminary in nature, while others have wrongly implied that a cure for cancer will be available soon.

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Edited by NHS Choices