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Wednesday, October 16, 2013

How Aspirin may Work to Improve Survival in Colon Cancer Patients

Posted by Prahallad Panda on 5:56 PM Comments


It has been seen that aspirin may help in suppressing colon cancer, apart from its’ well known protection to the patients of coronary artery disease. But, the mechanism of such protective effect is elusive till now.
A group of researchers from Amsterdam, The Netherlands postulate that aspirin exert its’ effect via interaction of the body’s immune system on the tumour cells expressing Human Leukocyte Antigen class I (HLA class I).
Endoscopic image of colon cancer identified in...
Endoscopic image of colon cancer identified in the sigmoid colon on screening colonoscopy for Crohn's disease (Photo credit: Wikipedia)


HLA class I are cell-surface proteins produced by a collection of genes involved in the functioning of the immune system.
Human Leukocyte Antigen (HLA) class I molecules are of major importance for cell-mediated anti-tumor immune responses. Expression of HLA class I/β2-microglobulin (β2-m) complexes carrying tumour-specific peptides is a prerequisite for adaptively matured cytotoxic T cells (CTLs) to be able to recognize tumour cells.
HLA class I antigens are encoded by a family of highly polymorphic genes, with each allele responsible for a different repertoire of antigen presentation. Thus, even the loss of a single allele could potentially allow the escape from an antigen-specific anti-tumour response. Loss of expression of HLA class I molecules has been frequently reported for colorectal tumours.
Aspirin prevents clot formation in the body and it is believed that platelets help in distant spread of cancer by shielding the cancer cells from immune cells.
Aspirin could help to ‘unmask’ those tumour cells by attacking the platelet shield, so that the immune cells can detect and eliminate them.

Aspirin-3D
Aspirin-3D (Photo credit: Wikipedia)

Dr Reimers and her colleagues used tissue microarray technology to investigate the pattern of protein expression in colon cancer patients whose aspirin use after cancer diagnosis was known and who were registered with the Eindhoven Cancer Registry between 1998 and 2007.
They studied 999 colon cancers to look at HLA class I expression, and expression of the COX-2 enzyme. They also extracted DNA from 663 tumours to look for mutations in the PIK3CA gene. Both COX-2 expression and PIK3CA mutations are known to be involved in the onset of cancer.
They found that low dose (80mg a day) aspirin use after diagnosis improved survival only in patients with tumours expressing HLA class I.
Those who used aspirin with HLA class I expression were half as likely to die during the average four years of follow-up as patients who did not use aspirin.
This effect of aspirin was not seen in patients without HLA class I expression. Therefore, HLA class I might serve as a predictive biomarker to help identify patients who would benefit from aspirin therapy after diagnosis.
The results showed that there was no difference in the effect of aspirin in relation to COX-2 (Cyclooxygenase)  expression and PIK3CA (Phosphatidylinositol 3-kinase) mutation.
Until now it was assumed that COX-2 expression or PIK3CA gene mutation played a role in the effectiveness of aspirin use. Patients with aspirin use after diagnosis with strong COX-2 expressing tumours had the same survival benefit as tumours with weak COX-2 expression.
On the other hand, aspirin has a preventive effect on colonic polyp formation, which is believed to be precursor to the colonic cancer.
The researchers believe that aspirin may be acting on two different pathways in colon cancer: one in the preventive setting and the other through the control of metastasis – the spread of cancer to other parts of the body from its primary site.
The first pathway is thought to be due to its’ preventive action on PIK3CA mutations and COX-2 expression, thereby limiting the formation of polyp, which are often the forerunners of cancer.
The second pathway, it seems, is more involved in preventing metastasis, by influencing the platelets in the bloodstream. It may be that the interaction of platelets with HLA positive tumour cells circulating in the blood promotes the metastatic potential of these cells. Aspirin interferes with this interaction, thereby decreasing the risk of metastatic disease and colon cancer-related death.
The researchers say that more evidence from larger studies and clinical trials is required to support their findings. Some randomised clinical trials have started in the UK and one in Asia – a multi-centre prospective randomised controlled phase III trial of aspirin use in colorectal cancer patients, called the ASCOLT study.




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