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Finding extracellular vesicle biomarkers for oesophageal cancer early detection

Extracellular vesicles (EVs) are entities secreted by cells that can be involved in cell-to-cell communication. They contain messenger proteins and other molecules, which act like ‘instructions’ to recipient cells.  EVs contain proteins both on their inside and outside.

All cells, including cancer cells, release EVs.  EVs from different cell types have slightly different compositions of proteins, which give them the ‘characteristics’ of their parent cell.

Members of the Goberdhan’s lab have previously shown that EVs released by colorectal cancer cells contain different protein when they are subjected to certain types of stress, such as certain nutrient deficiencies.  These ‘switched’ EVs change recipient cell behaviour, for example, increasing cancer cell growth. Researchers can potentially exploit these differences in EV protein composition to define distinct EV sub-populations: a helpful step towards their use as multi-protein biomarkers.

Dr Jennifer Allen and Ms Karen Billington from the Goberdhan lab are now applying this concept to the early detection of oesophageal cancer. Barrett’s Oesophagus is a pre-cancerous condition whereby oesophageal cells become damaged. Over time the damage can increase and cancer can develop.

Monitoring patients with Barrett’s Oesophagus is in place to try and identify when cancer has developed, however this is done through invasive and costly endoscopy, which may miss cancer in the very early stages. There is a need to identify when Barrett’s Oesophagus has progressed using less-invasive methods that can be used more regularly, so that cancer can be caught earlier.

Jen and Karen are investigating the potential of using EV proteins as biomarkers, which could be identified though simple blood tests. They are using different types of cells – such as normal oesophagus cells, Barrett’s Oesophagus cells and Oesophageal cancer cells – to compare the proteins found on the EVs released by each of these cell types.

The team is working with Dr Elizabeth Bird-Lieberman, a Gastroenterology Consultant at the JR Hospital, to collect blood samples from patients with Barrett’s Oesophagus, to see if EV information could be extracted and tested through simple blood tests – such as that being developed by Prof Jason Davis.

The aim is to identify a handful of proteins via proteomic analysis, that allows them to differentiate EVs from oesophageal cancer cells. If the protein biomarkers associated with the more cancerous cell lines can be detected in patient blood samples, Barrett’s Oesophagus patients could then be routinely tested for specific EV proteins that indicate the presence of parent cancer cells. This simple test could be carried out much more regularly than endoscopy surveillance and would enable earlier detection and treatment of oesophageal cancer in these patients.

Colorectal cancer cell extracellular vesicles. These two vesicles have become deflated and have the characteristic cup-shaped morphology caused by preparation for electron microscopy. Images generated by Dr John Mason (DPAG) and Dr Errin Johnson (EM Facility Manager, Dunn School).

About the study

The Goberdhan lab members are interested in intracellular signalling and cell communication. Their major focus is on how this goes wrong in cancer and other major human diseases. Specifically, they investigate:

  1. The role of amino acid sensing and stress-induced signalling in regulating cellular growth and intercellular communication involving exosomes.
  2. The regulation of exosome formation and heterogeneity by intracellular signalling pathways and membrane trafficking.
  3. The effect of exosome signalling on recipient cell behaviour and cancer progression, particularly in response to microenvironmental stresses applied to exosome-secreting cells.

 

This study is funded by the CRUK Early Detection Primer Award.

How chemotherapy impacts the body

Current standard cancer treatments, such as chemotherapy and radiotherapy, can have lasting effects on the body. Chemotherapy for example is associated with many side effects, such as nausea and anaemia, due to the impact of the toxins on healthy tissue as well as the tumour.

Neoadjuvant therapy, whereby therapies are administered before the main treatment, to help reduce the size of a tumor or kill cancer cells that have spread, has previously been suggested to contribute to changes in the composition of a patient’s body. This includes reduction in muscle mass (or ‘sarcopenia’) which is a natural result of aging, but in those with cancer it can lead to some post-operative complications and other diseases further down the line.

A new study from Mr Nick Maynard, Oxford University Hospitals Trust, has assessed the changes in muscle mass in gastro-oesophageal cancer patients, to better understand the long-lasting impact therapies have on the body and if it can be used to predict the risk of post-op complications. From a sample of 199 patients, they observed a decrease in skeletal mass in all individuals, with 91 participants losing more than 5% of their original skeletal mass. Those with a high rate of muscle mass depletion were generally male and significantly older, i.e. over the age of 67 years old.

50% of patients in the study experienced post-operative complications, such as pneumonia, with 13% having severe complications. However, Nick and the team observed that this was not related to the patient’s loss of skeletal mass.

Fortunately, this means that patients undergoing surgery for oesophageal cancer with large reductions in muscle mass are not necessarily at an increased risk of post-operative complications. Whilst these results do not produce any new method for predicting post-op complications, as sarcopenia did not determine the frequency of post-op complications in the sampled patients, they provide a deeper understanding of how neoadjuvant therapies can impact the body. This is important as post-operative loss of muscle mass has been previously associated with a lower survival rate for oesophageal cancer patients, so this will help to inform clinicians which patients may need to be more closely monitored.

First Huaxi SCU-Oxford Forum on Gastrointestinal Cancer

As part of the 110th Anniversary celebrations for the founding of Sichuan University (SCU), members of the Sichuan University (West China Hospital)-Oxford University Gastrointestinal Cancer Centre attended the first Centre Forum on Gastrointestinal Cancer at SCU. In attendance was an internationally known faculty of researchers who explored basic, translational and clinical aspects of colorectal, oesophageal and gastric cancer in a series of plenary lectures. See the full event agenda here.

The event built on the expertise of leading faculty members from Sichuan and Oxford University, complemented by international experts who are recognized leaders in their respective fields.

The lectures provided state of art updates on clinical management and insights into the biology of these tumour types and how this information can be exploited to identify new disease markers and therapeutic targets.

The forum attracted over 5,000 clinicians virtually from across China, representing all of the specialties involved in the management of GI cancer and basic scientists with an interest in translational and precision cancer medicine and is considered a great success.

Many thanks to the superb technical team who assured that all zoom delivered lectures were delivered with perfect clarity.

It gives the Centre great pleasure to announce that they will hold the second Huaxi  SCU-Oxford Forum on Gastrointestinal Cancer in Queens College Oxford in early September 2021, in partnership with collaborators from the University of Oslo, with whom they have formed the Colorectal Cancer Network.

QResearch researchers collaborate on two major cancer projects

The Department of Primary Care and Health Sciences recently announced that researchers in the Primary Care Epidemiology Group are joining two landmark projects to combine healthcare data and artificial intelligence to improve cancer diagnosis.

Led by Professor Julia Hippisley-Cox, the team will utilise the QResearch database of routinely collected electronic patient health records for studies on lung and oesophageal cancer diagnosis.

The two projects, announced today as part of a £13m investment from UKRI through their industrial strategy challenge fund, brings together different strengths from academia, charities, digital health and diagnostics companies.

Both projects are part-funded by Cancer Research UK.

DELTA, led by the University of Cambridge, will help to diagnose oesophageal cancer, which has increased 6-fold since the 1990s. Just 15% of people will survive for 5 years or more – often because it’s diagnosed too late.

Barrett’s oesophagus, a condition that can turn into cancer of the oesophagus, is more common in patients who suffer with heartburn. By using a new test for patients with heartburn, called the ‘Cytosponge’, the project aims to diagnose up to 50% of cases of oesophageal cancer earlier, leading to improvements in survival, quality of life and economic benefits for the NHS.

Professor Hippisley-Cox’s team are leading on the clinical epidemiology element of this research programme. The researchers will interrogate the QResearch database with the aim of developing a risk prediction algorithm that will be able to identify those individuals at highest risk of oesophageal cancer for further investigation.

DART (The Integration and Analysis of Data Using Artificial Intelligence to Improve Patient Outcomes with Thoracic Diseases), led by the University of Oxford, will accelerate lung cancer diagnosis, increasing the likelihood that treatment will be successful. See the full story on this announcement here.

Academics, NHS clinicians, the Roy Castle Lung Cancer Foundation and industrial partners (Roche Diagnostics, GE Healthcare, Optellum) will work with the NHS England Lung Health Checks programme to combine clinical, imaging and molecular data for the first time using artificial intelligence algorithms.

Professor Hippisley-Cox’s team will link to data from primary care to better assess risk in the general population to refine the right at-risk individuals to be selected for screening. It is hoped that this research will define a new set of standards for lung cancer screening to increase the number of lung cancers diagnosed at an earlier stage, when treatment is more likely to be successful. Find out more about this project here.

The QResearch database is one of the largest clinical research databases in Europe, covering 35 million patients from 1,500 GP practices throughout the UK. It includes longitudinal data collected over 25 years that is linked at an individual patient level to Hospital Episode Statistics (HES), mortality data and cancer registration (more details here), making it an extremely rich resource for cancer research.

Dr Eileen Parkes joins Oxford Cancer

Eileen brings research into the body’s innate immune response to cancer and how we can harness these pathways to develop novel clinical treatments

Tackling oesophageal cancer early detection challenges through AI

Dr Sharib Ali specialises in the applications of AI to early oesophageal cancer detection

Oesophageal Cancer Focus Month: DPhil Spotlight – Pek Kei Im (Becky)

We talk to DPhil student Becky Im about her investigations into oesophageal cancer risks in Asian populations

Developing and Integrating Multi-modal Techniques to Predict Oesophageal and Gastric Cancer Behaviour