Researching some cancers is much harder than others, especially where these cancers are uncommon. Ideally we need large numbers of patients in a study in order to see patterns in the data. In bone tumours (which are rare but very debilitating cancers affecting adolescent humans) there have been few advances in treatment strategies in the last 30 years. This is because osteosarcoma (bone tumour) datasets are very small.

At Bristol Vet School, Dr Grace Edmunds and her collaborators [1] believe that dogs can provide the answer to the problem of rare cancers.

Since dogs have a unique genetic architecture (they come in breeds of all shapes and sizes), we find that certain breeds are predisposed to certain cancers. Rottweilers, for example, have more than ten times the risk of bone cancer compared with crossbreeds. This means that vets see a lot more bone tumours than human doctors, and we have much bigger datasets to work with.

We can sequence the DNA of Rottweilers to find the genes that increase bone cancer risk in dogs and people. We can also look dog bone tumour samples, to find out what happens to a bone cell when it becomes a cancer, and what treatments might be effective. We know that dog bone tumours are very similar to human ones, so all of our findings will help both humans and dogs with cancer.

The beauty of these studies is that they can be done using leftover dog blood or biopsies that would otherwise be thrown away, so that clinical waste becomes useful research material without any additional procedures for our veterinary patients.

View Grace's profile

View the osteosarcoma infographic

This work is funded by Bristol Veterinary School, Elizabeth Blackwell Institute (via a Wellcome Trust ISSF) and the University of Bristol Cancer Research Fund.

[1] Prof Matt Smalley and Prof Rachel Errington (both Cardiff University), Dr Dan O’Neill (Royal Vet College), Dr Helen Winter (Bristol Royal Infirmary).

‌Excerpt from a VetCompass infographic quantifying breed risk of osteosarcoma (bone cancer)

What can dogs teach us about human cancer? image caption: Grace with a Rhodesian Ridgeback, one at-risk breed for osteosarcoma

Bristol investigators, under lead investigator Professor Richard Martin based in Bristol Medical School, led the world’s largest randomised prostate cancer screening trial which demonstrated that prostate-specific-antigen (PSA) testing does not reduce prostate cancer mortality but over-detects indolent- and under-detects lethal-cancers. The CAP Trial (Cluster randomised trial of PSA testing for prostate cancer) involved almost 600 GP practices in the UK and included more than 400,000 men, comparing those who were invited to have a one-off PSA test with those who weren’t. You can watch a video describing the project and read about the results from the trial. 

These findings underpinned the UK’s prostate cancer ‘no screening’ policy, reducing unnecessary NHS costs estimated at £1 billion a year and the USA’s shared decision-making recommendations in 2018. 

Those invited to have a one-off PSA test and who were diagnosed with localised prostate cancer took part in a treatment trial called ProtecT. This trial investigates the effectiveness of three treatments for men diagnosed with localised prostate cancer. Led by Professor Jenny Donovan in Bristol Medical School, it is the only randomised trial comparing active monitoring, prostatectomy and radiotherapy for prostate cancer, showing high 10-year survival irrespective of treatment and changing The National Institute for Health and Care Excellence (NICE) guidance (NG131, last updated 2021), helping reduce overtreatment from 28% (2006-12) to 4% (2018-2019) (see www.npca.org.uk/reports).

A serendipitous meeting at a conference initiated an interdisciplinary collaboration. Dr Emma Vincent and Dr Caroline Bull, both University of Bristol, were interested in the link between lipid metabolites and renal cell carcinoma, a type of kidney cancer. They had found that higher circulating levels of high-density lipoprotein (HDL) cholesterol in the blood was associated with the disease. These data were generated using a technique in genetic epidemiology called Mendelian randomization, which utilises large genetic data sets from populations. Dr Celeste Simon from the University of Pennsylvania happened to visit Emma and Caroline’s poster at the Keystone Tumour Metabolism Conference and revealed she had made a similar observation but using a completely different research discipline. Celeste’s group had used laboratory-based methods in cancer cell biology to discover that renal cell carcinoma cells were dependent on taking up HDL cholesterol for their growth and survival, implicating the HDL receptor as a novel therapeutic target for treating kidney cancer.

This chat over a poster led to a joint publication which appeared in the journal Cancer Discovery in 2021: Riscal R, Bull CJ, Mesaros C et al. Cholesterol Auxotrophy as a Targetable Vulnerability in Clear Cell Renal Cell Carcinoma. 

This paper shows how different disciplines, in this case genetic epidemiology and cancer cell biology, can complement each other. The methodologies are very different, yet the results support each other extremely well. Taking this interdisciplinary approach to writing the paper appealed to the journal and the reviewers and gives strength to the conclusions. This collaboration into renal cell carcinoma continues. 

The team created an animation which explains the results in accessible language. 

Gliomas are brain tumours that initiate in the brain’s glial cells, which are the supporting cells of the brain and spinal cord. Common symptoms include headaches, seizures, nausea, memory problems or changes in personality, and weakness, vision problems or speech problems which can get progressively worse.

Brain tumours are classified according to grade; this grade, on a scale of 1 to 4, reflects the severity of the tumour. Grade 1 and 2 gliomas are non-cancerous (benign) and tend to grow quite slowly; grade 3 and 4 are cancerous (malignant), grow quickly, and are more difficult to treat.

Correctly identifying high-grade gliomas during surgery can potentially improve removal of the growth and survival of the patient. Gliolan is a safe medicinal powder which contains the active substance 5-aminolevulinic acid hydrochloride, or 5-ALA. It can be given orally to adult patients with malignant glioma prior to surgery, and is absorbed by cells in the body where it is converted into fluorescent chemicals, in particular a substance called protoporphyrin IX (PPIX). Since glioma cells take up more of the 5-ALA and convert it more rapidly into PPIX, higher levels of PPIX accumulate in the cancer cells than in normal tissue. This means that the neurosurgeon can turn down the lights in surgery, turn on the ultraviolet lights and visualise the high-grade glioma which glows pink – otherwise known as ‘pink drink’. This enables the surgeon to see the tumour more clearly during brain surgery and to remove it more accurately, sparing healthy brain tissue.

Kathreena Kurian, Professor of Neuropathology and Head of Bristol’s Brain Tumour Research Centre, assessed samples on the trial study on 5-ALA. 5-ALA is now NICE approved and is given to all UK patients with suspected high-grade glioma.

The breast is a unique organ as it mostly develops after birth during puberty and pregnancy.  A woman’s reproductive history, including timing of puberty, menopause, and child-bearing status, can influence their risk of developing breast cancer later in life. For example, observational studies suggest that pubertal and pregnancy-induced breast development represent crucial windows in breast cancer susceptibility. Our research is focused on better understanding how changes in normal breast cell behaviours during these hormone-driven events can influence breast cancer risk.

The group, which includes Dr Bethan Lloyd-Lewis, a Vice Chancellor's Research Fellow based in the University of Bristol's School of Cellular and Molecular Medicine,  uses several complementary tools to study mammary (breast) epithelial cell behaviours during normal and abnormal breast development. These include growing human or mouse mammary cells in organotypic three-dimensional (3D) cultures to model breast development in response to reproductive hormones and growth signals. We combine this with advanced microscopy which allows us to visualise the behaviours of mammary cells in 3D, and in real time, in response to changing exposures.

To complement our laboratory work, we also collaborate with the University of Bristol Medical Research Council (MRC) Integrative Epidemiology Unit to apply genetic epidemiology techniques that utilise large genetic data sets from human populations to investigate how early life exposures (e.g. childhood body mass index, or BMI) and reproductive timing may influence breast cancer risk. Ultimately, combining these two different scientific disciplines may lead to improved approaches for breast cancer prevention and early detection.

Image shows normal (in red) and tumour (in green) mammary epithelial cells grown in 3D organoid culture in the lab. Image provided by Dr Lloyd-Lewis. 

When the body encounters an infectious agent such as a virus or bacterium, comes up close with irritants such as chemical agents or uv light, or finds damaged cells in its tissues, its first reaction is protection. The affected area becomes inflamed: painful, itchy, swollen - like a sunburn or an allergic reaction to stinging nettles. Inflammation is the body’s way of getting rid of damaged and dead cells and beginning the repair process.

In the case of cancer cells, the inflammatory response can go two ways: it can either kill newly born cancer cells, or nurture them. We don’t yet know how these inflammatory cells find and interact with these cancer cells, and how the cancer cells go on to multiply in tissues (creating a malignant tumour).

Here at the University of Bristol Professor Paul Martin and his team have identified some of the first signals that attract these inflammatory, or immune, cells to the early cancer cells. Inflammatory cells feasting on pre-tumour cells have been filmed; but it was also observed that pre-tumour cells with no interaction with immune cells grow at a slower rate. This suggests it is the immune cells that deliver the growth signals to the pre-tumour cells. We have now shown that one of these growth signals is prostaglandin, a hormone-like substance that plays an important role with a range of bodily functions including inflammation.

This observation may explain recent studies that have shown how low-dose aspirin can hold off the onset of gut and other cancers – because it blocks prostaglandin synthesis.

We think that local inflammation might drive the formation of polyps – the precursors of most bowel cancers – and we’re working with cancer clinician Dr Tom Creed, to investigate.

We’re also investigating the inflammatory response of wounds as they heal after surgery by watching – using zebrafish models - how the natural inflammatory response of a wound attracts immune cells to nearby newly transformed cancer cells, and what the consequences of that might be.

The inflammatory response - Why Zebrafish? image caption: These fish are invaluable in our cancer research because they’re translucent, which means we are able to watch – live, in realtime – the interactions between cancer cells and immune cells. It is impossible to watch these interactions in tissues that aren’t translucent, and by watching the interplay between cells we’re able to better understand the role inflammation has in cancer cell growth.