Can we prevent cancer spreading from the bowels?
BDRF funded a research project at the University of Leicester led by Dr Meera Chauhan, Medical Oncology Registrar.
Dr Chauhan recently presented the results of her trial at the European Society for Medical Oncology 2019 held in Barcelona.
The project which was titled: “Changes in circulating biomarkers of metastatic colorectal cancer when targeting platelet tumour cell interactions with anti-platelet therapy”
Colorectal cancer cells spread by entering the bloodstream and circulating around the body. These circulating cancer cells can leave the blood and start growing in a distant organ. Within the bloodstream, cancer cells interact with cells called platelets.
Platelets normally help the blood to clot when there has been an injury. Research demonstrates that the interaction between cancer cells and platelets helps the spread of cancer.
Drugs which block platelets (anti-platelets) are used as a treatment for heart attacks. Anti-platelet drugs could also block the interaction between platelets and circulating cancer cells and potentially reduce the spread of colorectal cancer.
The team investigated this in a clinical trial where colorectal cancer patients and healthy volunteers took two anti-platelet drugs (Aspirin and Ticagrelor).
Blood samples were collected during treatment to investigate how the drugs change the interactions between circulating cancer cells and platelets. Cancer cells are known to produce and release large amounts of free DNA into the bloodstream. The amount of free DNA and circulating cancer cells were measured from blood samples and could be used as markers to show how a treatment is working.
Measuring these marker levels in trial blood samples, they sought to investigate how they change with anti-platelet treatment.
Plasma levels of cfDNA (cell free DNA)have been reported to be altered in cancer, pregnancy, and in sepsis, but our understanding of how cfDNA levels may vary is still limited.
In addition, there have been very few studies investigating how different drugs might affect cfDNA levels, and it is not known how anti-platelet agents might affect cfDNA levels in the circulation of healthy donors, or in individuals with CRC. The results of this small study affirm that patients with metastatic colorectal cancer have elevated plasma levels of cfDNA. We found that in healthy donors, single anti-platelet agents resulted in increased cfDNA levels, similar to that seen in cancer patients, suggesting that the use of plasma cfDNA levels as a single biomarker in the screening of ‘healthy’ individuals for disease is insufficient, potentially giving false-positive tests, and therefore requires additional plasma biomarkers, such as length of cfDNA copies, and detection of gene-specific transcripts or DNA sequences to give a more informative picture.
This conclusion is supported by the fact that the levels of cfDNA were unchanged in response to anti-platelet drugs in the CRC patients, suggesting additonal cfDNA measurements are required to monitor changes due to medication.
Another approach to monitoring disease progression is through study of CTCs. Tumour cells within the circulation may change to become more likely to attach to a new site and form a new tumour there. This change may also mean that there are changes in the types of proteins that they have on their outer surface.
We found that samples from our patients with metastatic cancer had variable levels of vimentin, a protein involved with cell movement and attachment, and low expression of EpCAM, reflecting CTCs with a more metastatic behaviour.
We conclude that although EpCAM is a useful tool in analysing CTCs, its use as the initial identifier of CTCs is limited, possibly only identifying a subset of cells, and potentially masking the presence of CTCs that have different surface proteins.
Further research in this area is needed to assess the optimal method to ensure isolation of all populations of CTCs, regardless of metastatic status, and to identify a panel of key surface proteins that will be robust biomarkers for assessment of CTCs, and which allow an advance in our understanding and interpretation of how these change in response to different drugs.
In addition, further validation is required to understand the potential benefits and limitations of cfDNA as a diagnostic and therapeutic indicator in CRC.
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