MS-based clinical proteomics: biomarker discovery in men’s cancer

29 October 2010  •  Author(s): Brian Flatley Dept of Chemistry, University of Reading, Reading and Harold Hopkins Dept of Urology, Royal Berkshire NHS Foundation Trust Hospital, Reading and Peter Malone Harold Hopkins Dept of Urology, Royal Berkshire NHS Foundation Trust Hospital, Reading and Rainer Cramer Dept of Chemistry, University of Reading, Reading

Each year, approximately 10,000 men in the UK die as a result of prostate cancer (PCa) making it the third most common cancer behind lung and breast cancer. Worldwide, more than 670,000 men are diagnosed every year with the disease1. Current methods of diagnosis of PCa mainly rely on the detection of elevated prostate-specific antigen (PSA) levels in serum and/or physical examination by a doctor for the detection of an abnormal prostate. PSA is a glycoprotein produced almost exclusively by the epithelial cells of the prostate gland2. Its role is not fully understood, although it is known that it forms part of the ejaculate and its function is to solubilise the sperm to give them the mobility to swim. Raised PSA levels in serum are thought to be due to both an increased production of PSA from the proliferated prostate cells, and a diminished architecture of affected cells, allowing an easier distribution of PSA into the wider circulatory system.

There is much debate as to what constitutes a raised level of PSA in the body. The European Association of Urology guidelines released in 2007 state that there is no universally accepted cut-off value between normal and raised PSA levels in the body. The guidelines further state that many studies are using 4ng/ml as the cut-off point between normal and clinically important PSA levels3 – and this threshold increases with age. Aside from a vague universal threshold limit, the PSA test is not specific to prostate cancer alone. Benign prostate hyperplasia (BPH) and prostatitis can also raise PSA levels in men. Equally, there are reported cases of men with below threshold levels of PSA in serum and organ confined prostate cancer. In 2001, Babaian et al found that a significant number of men with PCa (24.5 per cent of a sample size of 51) had serum PSA levels between 2.5 and 4ng/ml4. The problem with lowering the threshold level of PSA as an indicator for both high and low grade prostate cancer was discussed by Yossepowitch in 20083: the detection sensitivity, i.e. number of men correctly diagnosed with PCa, increases at the expense of a concomitant decrease in detection specificity, i.e. increase in the number of men suffering from ‘inconsequential diseases’ such as BPH and undergoing unnecessary biopsies.

The quest for proteomic biomarkers that could serve as more specific identifiers of prostate cancer has been undertaken by a number of research groups using a variety of biological matrices – plasma, serum, urine and prostate secretion. The glycopeptide metalloproteinase inhibitor 1 was recognised by Diamond et al in 20055 as a possible marker of prostate cancer, because it was down regulated in prostate tissue of cancer patients. Another potential marker, named PCa-24 by Zheng et al, was found only to be expressed in patients with prostate cancer6. They used laser microdissection to extract prostate tumour cells and normal/BHP cells from patients undergoing radical prostatectomy. The cells were lysed open and the proteins were selectively analysed using ProteinChip technology and surface-enhanced laser/desorption ionisation time-of-flight mass spectrometry (SELDI TOF MS). They found a protein peak at m/z 24,782.56 ± 107.27 present in 16 of 17 (94 per cent) prostate carcinoma specimens. However, attempts by the group to identify the protein by mass yielded no results6. TB-15 was also reported as a potential biomarker of prostate cancer, as it was found by Hutchinson et al to be up-regulated in patients suffering from prostate or breast cancer7. The same group developed an ELISA for TB-15 and in a recent publication, they report increased specificity from 49 per cent to 64 per cent in a control group of 209 patients. While this study is a welcome addition to the studies that have been carried out examining possible biomarkers for prostate cancer, it has yet to be developed into a specific and sensitive test that out – performs PSA in terms of a robust biomarker differentiating between clinically relevant prostate cancer and neoplasms which might not require further intervention.

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