Oncoproteomics is the study of proteins and their interactions in a cancer cell by proteomic technologies. Proteomic research first came to the fore with the introduction of two-dimensional gel electrophoresis. At the turn of the century, proteomics has been increasingly applied to cancer research with the wide-spread introduction of mass spectrometry and proteinchip. There is an intense interest in applying proteomics to foster an improved understanding of cancer pathogenesis, develop new tumor biomarkers for diagnosis, and early detection using proteomic portrait of samples. Oncoproteomics has the potential to revolutionize clinical practice, including cancer diagnosis and screening based on proteomic platforms as a complement to histopathology, individualized selection of therapeutic combinations that target the entire cancer-specific protein network, real-time assessment of therapeutic efficacy and toxicity, and rational modulation of therapy based on changes in the cancer protein network associated with prognosis and drug resistance. Besides, oncoproteomics is also applied to the discovery of new therapeutic targets and to the study of drug effects. In pace with the successful completion of the Human Genome Project, the wave of proteomics has raised the curtain on the postgenome era. The study of oncoproteomics provides mankind with a better understanding of neoplasia. In this article, the discovery of cancer biomarkers in recent years is reviewed. The challenges ahead and perspectives of oncoproteomics for biomarkers development are also addressed. With a wealth of information that can be applied to a broad spectrum of biomarker research projects, this review serves as a reference for biomarker researchers, scientists working in proteomics and bioinformatics, oncologists, pharmaceutical scientists, biochemists, biologists, and chemists.

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Contribution of oncoproteomics to cancer biomarker discovery

Many cancer patients are diagnosed at a stage in which the cancer is too far advanced to be cured, and most cancer treatments are effective in only a minority of patients undergoing therapy. There is thus a tremendous opportunity to improve the outcome for people with cancer by enhancing detection and treatment approaches, and biomarker is instrumental in making that transition. A biomarker is defined as any characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological response to a therapeutic intervention. A cancer biomarker is any substance that is measured biologically and associated with an increased risk of cancer. These indicators could include a broad range of biochemical entities, such as nucleic acids, proteins, carbohydrates, lipids, small metabolites, whole cells or biophysical characteristics of tissues. Because of the heterogeneity among diseases and patients, recharacteri­zation of cancer in pathophysiological terms via biomarker is a key to the future of medicine. Detection of cancer biomarkers can be accomplished by a wide variety of methods, ranging from biochemical anal­ysis of blood or tissue samples to biomedical imaging. There has been much interest in biomarkers of cancer risk in predicting future patterns of neoplasm, especially as cancer treatment has made such positive strides in the last few years. Successful development of cost effective tests has a profound impact on how cancer is detected, diagnosed, and treated; thus, could reduce the economic burden of cancer.

Cancer Biomarkers (An Overview)

The aim of the study was to report the diagnostic performance of total prostate-specific antigen (tPSA) and free prostate-specific antigen ratio (%fPSA). The diagnostic performances of tPSA and %fPSA were evaluated in 3�4 men by ROC curves, sensitivity, specificity and diagnostic odds ratio calculations. One hundred and sixty-two patients were diagnosed as prostate cancer (PCa) and 202 as normal. The median tPSA levels and %fPSA ratios differed significantly, 11.1� ng/mL and 11 versus �.51 ng/mL and 20 in PCa and normal groups, respectively. At tPSA levels between 4-10 ng/mL; area under curve (AUC)%fPSA was greater than AUCtPSA. 1� as a cut off value of %fPSA was the optimum choice revealing a sensitivity of 0.703, a specificity of 0.�5� and diagnostic odds ratio of 4.254(95% CI 2.157- 8.39 ). %fPSA ratio is an expedient screening marker in PCa. In our laboratory, at tPSA levels between 410 ng/mL, %fPSA ratio of 1� offers a preferable diagnostic performance. [Turk J Cancer 2009;39(1):18-25]

http://www.turkjcancer.org/pdf/pdf_TJC_504.pdf

Performance of total prostate specific antigen and free prostate specific antigen ratio for screening prostate cancer in a Turkish population

Asthma is a common, heterogeneous condition where current treatment options are limited to a ‘one size fits all’ approach. Biological therapies targeting specific components of the Type 2 inflammatory pathway are emerging as potential alternatives for those who are inadequately controlled on current treatment options. Biomarkers, such as serum periostin, can be used in clinical settings to identify potential responders to these treatments.  The aim of this research was to investigate the epidemiology of periostin and its ability to predict important clinical outcomes in asthma.  Six studies were conducted: two cohort studies observing the change to periostin after bone and dental injury in non-asthmatic adults; a cohort study investigating reference ranges of periostin in Chinese adults with and without asthma; two longitudinal studies measuring the change in periostin in asthmatic adults with stable and unstable disease; and a longitudinal cohort study investigating the association between periostin and risk of exacerbation.  There was a biphasic response of serum periostin after bone injury. This was particularly marked after joint replacement surgery where periostin fell within 48 hours by a ratio of geometric means 0.80 (95% CI 0.75 to 0.86) before rising to a maximum level at eight weeks with a ratio of geometric means 1.89 (95% CI 1.77 to 2.02). There was no significant change to periostin after simple or surgical tooth extractions with a maximal ratio of geometric means of 1.02 (95% CI 0.95 to 1.10). Serum periostin was higher in Chinese non-asthmatic adults versus Caucasian non- asthmatic adults, mean periostin 57 ng/ml and 49.7 ng/ml respectively, difference (95% CI) 8.2 (5.8 to 10.6) ng/ml. Serum periostin remained stable in adults with well- controlled asthma with an intra-class coefficient for variation of 0.93. In unstable asthma, there was a decrease in serum periostin one week after the start of a severe exacerbation and treatment with systemic corticosteroids, with a ratio of geometric means 0.86 (95% CI 0.82 to 0.92) before stabilising four weeks later. Finally, adults with mild to moderate asthma with low baseline levels of periostin were more likely to have a severe asthma exacerbation with a hazard ratio (95% CI) 0.62 (0.35 to 1.09) per 0.693 ng/ml increase of log periostin.  In conclusion, serum periostin showed significant biphasic variation in response to bone injury, the magnitude and duration of which was proportional to bone size. Whilst this pattern was not replicated in adults undergoing dental surgery, it suggests that serum periostin can be affected by non-asthma related conditions. Periostin demonstrated higher mean values in Chinese adults than in Caucasian adults, indicating ethnicity-specific reference ranges may be required if it were to become a clinical biomarker. Intra-participant variability of serum periostin was low in a homogenous group of well controlled, moderate to severe asthmatic adults, but there was wide variability between individuals in this group suggesting that factors other than asthma are likely to affect serum periostin levels. Serum periostin was suppressed during and after treatment for a severe exacerbation for up to four weeks.  This is likely due to the exacerbation and/or its treatment, suggesting the interpretation of periostin as a biomarker for response to biological therapies should not occur within four weeks of a severe exacerbation. The reported positive association between periostin and risk of severe exacerbation in populations with severe eosinophilic asthma does not extend to a general population of mild to moderate asthmatics, in which an inverse associated was observed.  Serum periostin may be useful in predicting treatment responsiveness of patients to monoclonal antibody therapy directed against IL-4Rα, IL-13 and IgE. However, it may be difficult to use as a biomarker clinically, as numerous non-asthma related factors, such as bone injury and ethnicity, have been shown to significantly affect serum levels, making interpretation difficult.

Periostin - A biomarker in adults with asthma

The increased expression of fatty acid binding protein 4 (FABP4) and 5 (FABP5) play a crucial role in promoting tumorigenicity and metastasis of prostate cancer. FABP4 was suggested to be a therapeutic target for metastasis of prostate cancer. FABP5 was also proven to be a prognostic marker and potential treatment target. In contrast to numerous studies conducted to investigate the crucial role of FABP4 and FABP5 in prostate cancer, investigations on the possible involvement of other FABPs in the malignant progression of prostate cancer are rare. To find out whether any other FABP family proteins can also be used as diagnostic or prognostic markers for prostate cancer as FABP5, we measured the mRNA levels of 10 FABPs in benign and malignant prostate cell lines. Results showed that FABP4, FABP5, FABP6, FABP9 and FABP12 exhibited clearly higher levels in all tested malignant cell lines compared to their levels in the benign PNT-2 cells. Although, FABP4 and FABP5 have been associated with human prostate cancer as revealed in studies of our group and other groups, the finding of potential roles of FABP6, FABP9 and FABP12 have not been addressed. FABP12 is the most recently discovered member and no antibody was available for this candidate, thus FABP12 will be studied in a separate project of the group. Thereafter we assessed the expression status of FABP6 and FABP9 in both human prostate cell lines and tissues at the protein level. FABP6 protein was overexpressed only in 1 of the 5 malignant cell lines and its immunohistological staining intensities were not significantly different between the benign and the malignant prostate tissues. In contrast, FABP9 protein was highly expressed in highly malignant cell lines PC-3 and PC3-M, but its level in the benign PNT-2 and other malignant cell lines was not detectable. When analysed in an archival set of human prostate tissues, immunohistological staining intensity for FABP9 was significantly higher in carcinomas than in benign cases and the increase in FABP9 was significantly correlated with reduced patient survival times. Moreover, the increased level of staining for FABP9 was significantly associated with the increased joint Gleason scores (GS) and androgen receptor index (AR). Suppression of FABP9 expression in highly malignant PC3-M cells inhibited their invasive potential, but did not affect their growth rate, anchorage-independent growth and migration rate. Our results suggest that FABP9 is a valuable prognostic marker to predict the outcomes of prostate cancer patients, perhaps by playing an important role in prostate cancer cell invasion.

Expression of FABP6 and FABP9 in prostate cancer and their relationship to malignant progression

Introduction [corrected] PSA is the most important tumor marker in all solid tumor, indispensable in the management of prostate cancer. Screening for prostate cancer is still not recomended, although performed in many countries, which introduced questions about the usefulnes of PSA in detection of prostate cancer. The PSA treshold has also been changed, the value of PSA derivatives revised. Whether such changes are applicable in non scrrened population is questionable. Aim of this study was to evaluate the predictive value of PSA, free/ total PSA and PSA density in our non screened population. Patients and methods TRUS guided prostate biopsy was performed in 579 patients. The number of cores was 6-12. Mean age of the patients was 67.5 years (30-90). PSA was ranging from 0.41 to 2250 (mean 38.6 ng/ml, median: 11.95, SD 140,45). Digitorectal examination was considered positive in 351 patients. Free PSA was measured in 352 patients with the index ranging from 0.02 to 0.88 (mean free/total PSA: 0.14, median: 0.13). The volume of the prostate was measured in all patients according the prostate ellipsoid model, and PSA density calculated according to the formula PSA/PV. Patients were stratified in 6 groups according to PSA value (I: PSA ng/ml, II: PSA 2.5-4, III: PSA 4-10, IV: PSA 10-20, V: PSA: 20 to 50, Group 6: PSA 50). Results Non homogenicity of the patients can be seen through the wide range of PSA which was from 0.4 to 2025). Prostate cancer was diagnosed in 233 pts (40.2%). As expected, the probability of detecting cancer was raised with PSA (p), and was extremely rare in pts with PSA below 4 ng/ml. PSA, free/total PSA, volume of the prostate and PSA density were significantly different according to the presence of cancer. Most of our patients had PSA between 4 and 20 ng/ml. Predictive value of PSA was 20.6% for pts with PSA from 4 to 10 and 32.7% for those with PSA from 10 to 20 ng/ml. Sensitivity, specificity, positive and negative predictive values for different cut off's of PSA (4, 10 and 20) was performed. The best results were obtained for PSA cut off of 10 ng/ml. In the group of patient with PSA, PSA density more reliable than free/total PSA index. Conclusion PSA is still valuable marker for detection of prostate cancer in our non screened population. According to our results PSA treshold should not be lowered below 4 ng/ml. PSA density is a reliable PSA derivative, free/total PSA index having less importance in pts with PSA below 20 ng/ml.

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The predictive value of PSA in diagnosis of prostate cancer in non screened population.

Muscle invasive bladder cancer is usually treated by radical cystectomy, but in some selected cases with solitary tumor with appropriate localization partial cystectomy can be the treatment of choice achieving long term results with bladder preservation. We reviewed records of 11 patients which were treated in 5 year period from June 2002 to June 2007. by partial cystectomy according to the size of the tumor, localization, histology, multifocality, pathological and clinical stage, sex, and age. Male: female ratio was 6:5, mean age of the patients being 64.9 years. All patients bur one had solitary lesions located in the bladder dome in 4, on lateral sides in 5,2 patients had a tumor in diverticulum. TCC gr II was diagnosed 6 pts, TCC gr III in 5. One patient died in a year from disease progression, one from other reason, while all other patients are alive and disease free, the longest disease free interval being 3 years. Bladder capacity is adequate in all patients resulting in good quality of life .Our results suggest that in selected patients cancer control can be achieved with partial cystectomy.

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S. Cerovic

Papers

The predictive value of PSA in diagnosis of prostate cancer in non screened population.

The role of partial cystectomy in treatment of muscle invasive bladder cancer.