Dr Bernardo Tavora
Nature has published a new paper by Dr Bernardo Tavora, former postdoctoral researcher in Professor Kairbaan Hodivala-Dilke's Adhesion & Angiogenesis laboratory.
This paper links blood vessel function with cancers' ability to become resistant to chemotherapeutic drugs, and pinpoints a key molecule in this unwanted defence.
The team have found that blood vessels can protect cancer cells from chemotherapy and radiotherapy, and targeting the protein FAK could be key to breaking down this resistance and make cancer treatments more effective.
Dr Tavora said:
“This work shows that sensitivity to cancer treatment is related to our own body mistakenly trying to shield the cancer from cell-killing effects caused by radiotherapy and chemotherapy.
“Although taking out FAK from blood vessels won’t destroy the cancer by itself, it can remove the barrier cancer uses to protect itself from treatment.”
You can find out more about this work from Bernardo and Prof. Hodivala-Dilke in the Cancer Research UK blog and podcast coverage linked below.
When we use chemotherapy – cell-damaging drugs that are given in a dose high enough to kill cancer cells but cause minimal side-effects in the patient – we tend to encounter two problems:
1) the patient's cancer is resistant to treatment or the treatments we have offer no benefit, or
2) the patient’s cancer acquires resistance to the treatment over time and this leads to relapse.
Given this common factor, understanding chemoresistance is important if we are to overcome these challenges and design better treatment programmes. It is the DNA inside cells’ nuclei that is altered and causes both cancer and chemoresistance, so we must look at the DNA to find out how, and how we can overcome it.
To date, most groups have only studied tumour cells in models of drug resistance. But here the collaborative team of scientists at BCI in the Centre for Tumour Biology and the Centre for Haemato-Oncology, we know that cancer could be better characterised as an organ that responds to the body’s environment; so in this paper the team have asked, does the tumour microenvironment play a role in chemoresistance?
Know your enemy
Understanding tumour angiogenesis – blood vessel growth into tumours – requires that we investigate cells that make up blood vessels, which includes endothelial cells. A protein called FAK has been the focus of several projects in the Hodivala-Dilke lab in recent years; it is a “signalling” protein; one that communicates with many other proteins, acting as a “hub” for signals coming into and leaving the cell.
Some of these signalling molecules released from cells cause other cells to grow and divide and are known as cytokines. FAK controls the release of some cytokines from endothelial cells – could it be passing instructions to nearby tumour cells to help them resist treatments?
What’s the intelligence?
Tumour blood vessel endothelial cells (red),
surrounded by tumour cell nuclei (blue and green).
Red blood cells (green shapes) are visible
in the centre of the blood vessel .
The group used a genetic model to find out if and how FAK was helping tumour cells to survive therapies. Their model allows FAK deletion specifically in endothelial cells at chosen times.
They found that deleting FAK in blood vessel endothelial cells increased melanoma and lung tumour cell DNA damage and cell death after radiation and chemotherapy, as well as overall survival, suggesting that FAK in blood vessels provides tumour cells with some protection against these lines of attack.
Importantly, FAK was deleted after cancers were already established in the model and did not affect blood vessel function, unlike results seen when it is deleted before cancer growth begins. So it seemed that the effect was due to FAK’s influence on the local blood vessel environment, rather than a change of blood vessel function.
Dr Kat Arney, Cancer Research UK’s science communications manager, said:
“This exciting research may have cracked how healthy cells in the blood vessels are protecting against cancer treatments. This pre-clinical research gives real hope that we can boost the effectiveness of cancer medicine and sensitise cancers to the drugs we have.”
Human lymphoma samples were also studied in collaboration with Professor John Gribben, which revealed a correlation between high endothelial FAK levels and patients whose disease progressed or relapsed following chemotherapy. This finding provides a second line of evidence to suggest that FAK could be protecting tumour cells.
Perhaps we need to think of the blood vessels less as inert pipes and more as active biological structures with a local influence. In the future maybe we can design treatments that both change vessel function and endothelial effects on tumour cells themselves, via cytokines. Since they are sent outside cells, they could be easier to target than genes or proteins that remain within cells.
Drug testing is usually performed in vitro (outside the body, in the lab), in in vivo (living) models, short-term and on tumour cells rather than whole cancers. We need in vivo testing to look at cancer in its environmental context, but better models are required – including spontaneous cancers and orthotopics (cancer grown in the relevant organ sites).
There is still much to learn about this phenomenon, dubbed angiocrine signalling.
What exactly is the role of the blood vessel tissue, the endothelium?
What is the molecular basis behind this form of protection beyond what has been uncovered here (so far the team has identified NFκB signalling as important in the process)?
What are the effects in different cancers and with different types of drugs?
These are preliminary results, but more are likely to emerge soon in this exciting new field of interest.
B. Tavora, L. E. Reynolds, S. Batista, F. Demircioglu, I. Fernandez, T. Lechertier, D. M. Lees, P. P. Wong, A. Alexopoulou, G. Elia, A. Clear, A. Ledoux, J. Hunter, N. Perkins, J. G. Gribben, K. M. Hodivala-Dilke. (2014) Nature. doi:10.1038/nature13541
Cancer Research UK Press Release
QMUL - New drug target can break down cancer's barrier against treatment
The Times (£) - Cancer cells protected by patient's body
Express.co.uk - Breakthrough in treatment of cancer cells
Herald Scotland - Molecule link to protecting cancerous cells
Yahoo! News - Molecule removal helps fight cancer
Nursing Times - Blood molecule may 'reduce effectiveness of cancer treatment'
Western Daily Press - Chemotherapy may be more effective without focal adhesion kinase molecule