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Beyond the bladder: Understanding rare cancers of the upper urinary tract

26 May 2022

Dr Andrew Mason

York Against Cancer Research Fellow in Cancer Informatics

Jack Birch Unit for Molecular Carcinogenesis, The University of York

Beyond the bladder: understanding rare cancers of the upper urinary tract

Bladder cancer is not a rare disease. Quite a succinct summary for Bladder Cancer Awareness Month, but an important one to reiterate. Bladder cancer typically comes in the top 10 of all cancer diagnoses, with over 10,000 cases diagnosed last year (2021) in the UK alone.

As with all cancers, bladder cancer is not a single disease but has multiple layers of classification. These describe where the cancer started, how much cancer cells have diverged from their healthy state, and how the tumour is behaving in the body. In developed nations, over 90% of bladder cancers are urothelial carcinoma (UC), also known as  “transitional cell carcinoma” (TCC). These cancers form from urothelial cells which line the inside of the bladder – the ones directly exposed to the toxins, viruses and potential carcinogens found in urine. However, urothelium is not only found within the bladder, but extends up to the base of the kidneys via the ureters (the pipes connecting each kidney to the bladder). “Upper tract” urothelial carcinoma (UTUC) is a genuinely rare cancer, typically reporting fewer than 500 diagnoses per year in the UK.



As a rare cancer, UTUC is even more poorly studied than urothelial carcinoma of the bladder, so any bladder cancer treatments are simply “applied up”. In many ways this is a fair clinical assumption. UTUCs start from the same type of cell (just in a different location), tumours look the same under a microscope, and the mutations, risk factors and average patient profiles are very similar too. Outcomes, however, are not similar. People typically present at a much later stage with UTUC (likely due to fewer obvious symptoms) and surgery (removal of the affected ureter and kidney) is the standard of care. Even with this radical intervention, over a third of patients will go on to develop a subsequent cancer in the bladder. Consequently, 5-year UTUC survival is ~40%, compared to the 80-90% seen in bladder cancer.

So why the difference in outcome? Is this just a result of later diagnosis with UTUC? In short, no – the difference remains even if you only consider late stage invasive disease. So what makes UTUC different?

Whilst urothelium is found all the way from the kidney to the bladder, the cells of the upper and lower urinary tract actually come from two independent parts of a developing embryo. The bladder forms as an offshoot of the gut, whereas the kidney develops separately and then sends the ureter out and down, eventually connecting with the bladder and sealing it off. We hypothesised that these different developmental origins, still readily detectable in adult urothelium, may drive differences between the two related cancers which could be exploited therapeutically.



This is where our expertise in the York Against Cancer-funded Jack Birch Unit at The University of York comes to the fore. We have grown cells of healthy upper tract and bladder urothelium and used multiple high-throughput sequencing approaches, high-resolution images and electrophysiological studies to identify inherent differences. Most research groups focus solely on the cancer, which doesn’t allow you to understand the normal, healthy state. Thanks to the support of York Against Cancer, we are able to generate these new, unique data to answer these specific research- and clinically-relevant questions, whilst also making use of large, publicly-available cancer datasets.

This study revealed two major results which may eventually impact how we treat urothelial carcinoma from different parts of the urinary tract. First, cells from the upper tract and bladder get to the same functional endpoint in the lab, but do so using different machinery. This means that bladder-specific treatments may not be effective in the upper tract. Second, and very definitely not what we expect, we found that almost 10% of bladder cancers in one of the largest internationally-used datasets were actually derived from urothelial cells which started in the ureter, not the bladder. This may be vitally important for treatment, but also reveals a new mechanism for how cancers establish in the bladder.

As a research unit we are focusing on understanding early initiators of urothelial carcinoma, with the eventual aim of directing personalised medicine and identifying strategies for cancer prevention. This work would not be possible without the long-term support of York Against Cancer.