Targeting non-cancerous cells to tackle cancer

New research conducted by scientists at Queen’s University Belfast suggests that treating the non-cancerous tissue around a tumour could offer a more effective treatment approach than treating only the tumour. The team, whose findings have been published in the European Molecular Biology Organization Journal, found that surrounding non-cancerous tissue, or stroma, plays an important role in allowing cancerous cells to spread.

This discovery could result in novel techniques for the treatment of cancer. By targeting and treating the stroma, scientists could inhibit the spread of cancer to healthy, non-cancerous cells. Although the scientists’ attentions were focused on throat and cervical cancers, they are hopeful that this principle could be extended across the field of oncology.

The research was funded by the Wellcome Trust, the Experimental Cancer Medicine Centre and the United States’ National Institutes of Health, and it was supported by the Northern Ireland Biobank. The team, led by Belfast’s Professor Dennis McCance, found that when the Retinoblastoma protein (Rb) in healthy stroma is activated, the expansion of tumours is halted. Whilst previous research has demonstrated the role that Rb plays in regulating the growth of cancer cells from within tumours, Professor McCance and his colleagues have explored how the protein operates within healthy tissue.

I spoke to Professor McCance to find out more about how the new approach that he has identified might bolster the fight against cancer. I began by asking him whether or not he had expected the stroma to play such a prominent role in regulating the spread of cancer.

"Probably not as much as it does," he replied. "Following the publication of our paper, two reports from the United States showed very similar findings. I think that it’s now clear that stroma plays a major role in the biology of cancer. I guess that I was surprised at our initial findings but I think that in combination with the American papers, we have identified a general phenomenon. Normal tissue seems to affect tumours in many different ways. We just don’t yet know all of the permutations."

I asked Professor McCance to explain more about targeting the stroma whilst simultaneously treating the tumour. As he explained, a dual approach based on his research could prove to be an effective cancer treatment method.

"If you identify the pathway that is signalling and upregulating these growth factors, you could inhibit it with drugs," he said. "There may be targets within this pathway that are susceptible to certain drugs, and you could tailor your drugs to hit those targets. It would probably be a good strategy not only to target the tumour directly, but also the normal tissue surrounding the tumour. I think that this approach could offer a more efficient and beneficial technique for getting rid of cancers."

The Rb protein has been identified as a key player in the regulation of cancer expansion both in tumours and in healthy surrounding tissues. I asked Professor McCance how much he and his colleagues understood about the relationship between the Retinoblastoma protein and the spread of cancerous cells.

"We examined throat and cervical cancers, and we found that in the normal cells surrounding a tumour, this protein is switched off," he explained. "However, when we looked at healthy tissues further away, we saw that the Rb protein was switched on. It is only around the immediate vicinity of the tumour that Rb is deactivated, and this leads to an increase in the P13-kinase pathway. That is the cause of the increase in the keratinocyte growth factor – the one that is upregulated. This is then secreted from fibroplasts in the normal tissue and binds to receptors on the cancerous tissue. A signal for the upregulation of metalloproteases is then released and these proteases actually chew away at the healthy tissue so that the cancer can advance.

"We have very clearly mapped this pathway in vitro, and it appears that this pathway is upregulated in head, neck and cervical cancers. The growth factor seems to be stimulating these proteases, which are essential for the advancement of cancerous cells into normal tissue."

Although Professor McCance’s team studied cancers of the throat and cervix, he is confident that his findings could find applications in the treatment of other cancers as well. As he explained, whilst the specifics might be slightly different in each case, the approach of targeting the stroma as well as the tumour could prove universally effective.

"I think that all cancers, regardless of their location, will exhibit interaction between the normal stroma and the tumour cell," said Professor McCance. "The mechanism by which the normal cells react might be different - and we would have to delineate the relevant pathways in each type of cancer - but I think that the interaction that we have identified is going to be universal. We just need to identify the pathways in the normal tissue that are important for sending signals to the tumour. It may be that the pathway that we have looked at is applicable to other cancers, but I’m sure that it won’t be applicable to all of them. It will be a case of going through and finding the relevant pathways in each cancer."

I concluded our conversation by asking Professor McCance about his research plans for the future.

"We want to find out what is inactivating this Rb protein in the normal tissue," he explained. "I would guess that it is something that the tumour cell is expressing and excreting, because I think that there has to be a two-way flow of information. In light of this, we are currently trying to find the signal being transmitted by the tumour cell that is responsible for inactivating the fibroblasts. I don’t think that this could be a genetic inactivation. I don’t think that it’s a mutation in those cells. Instead, I think that it is something that the tumour cells are sending out; a signal that is being transmitted to the normal cells. This is what we are currently working to identify."

It seems then that Professor McCance’s research has come full circle. After breaking away from traditional research approaches and concentrating on the healthy surrounding stroma, his team are focusing once again on the tumours themselves. However, the deeper understanding of the relationship between healthy and cancerous tissues that has been gained by this study could lead to the development of new weapons in the fight against cancer.