Carbonic Anhydrase I as a New Plasma Biomarker for Prostate Cancer

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Abstract

Serum prostate-specific antigen (PSA) levels ranging from 4 to 10 ng/mL is considered a diagnostic gray zone for detecting prostate cancer because biopsies reveal no evidence of cancer in 75% of these subjects. Our goal was to discover a new highly specific biomarker for prostate cancer by analyzing plasma proteins using a proteomic technique. Enriched plasma proteins from 25 prostate cancer patients and 15 healthy controls were analyzed using a label-free quantitative shotgun proteomics platform called 2DICAL (2-dimensional image converted analysis of liquid chromatography and mass spectrometry) and candidate biomarkers were searched. Among the 40,678 identified mass spectrum (MS) peaks, 117 peaks significantly differed between prostate cancer patients and healthy controls. Ten peaks matched carbonic anhydrase I (CAI) by tandem MS. Independent immunological assays revealed that plasma CAI levels in 54 prostate cancer patients were significantly higher than those in 60 healthy controls ( P = 0.022, Mann-Whitney U test). In the PSA gray-zone group, the discrimination rate of prostate cancer patients increased by considering plasma CAI levels. CAI can potentially serve as a valuable plasma biomarker and the combination of PSA and CAI may have great advantages for diagnosing prostate cancer in patients with gray-zone PSA level.

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Most cited references 23

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Carbonic anhydrases as targets for medicinal chemistry.

Claudiu Supuran, Andrea Scozzafava (2007)

Carbonic anhydrases (CAs, EC 4.2.1.1) are zinc enzymes acting as efficient catalysts for the reversible hydration of carbon dioxide to bicarbonate. 16 different alpha-CA isoforms were isolated in mammals, where they play crucial physiological roles. Some of them are cytosolic (CA I, CA II, CA III, CA VII, CA XIII), others are membrane-bound (CA IV, CA IX, CA XII, CA XIV and CA XV), CA VA and CA VB are mitochondrial, and CA VI is secreted in saliva and milk. Three acatalytic forms are also known, the CA related proteins (CARP), CARP VIII, CARP X and CARP XI. Representatives of the beta-delta-CA family are highly abundant in plants, diatoms, eubacteria and archaea. The catalytic mechanism of the alpha-CAs is understood in detail: the active site consists of a Zn(II) ion co-ordinated by three histidine residues and a water molecule/hydroxide ion. The latter is the active species, acting as a potent nucleophile. For beta- and gamma-CAs, the zinc hydroxide mechanism is valid too, although at least some beta-class enzymes do not have water directly coordinated to the metal ion. CAs are inhibited primarily by two classes of compounds: the metal complexing anions and the sulfonamides/sulfamates/sulfamides possessing the general formula RXSO(2)NH(2) (R=aryl; hetaryl; perhaloalkyl; X=nothing, O or NH). Several important physiological and physio-pathological functions are played by CAs present in organisms all over the phylogenetic tree, related to respiration and transport of CO(2)/bicarbonate between metabolizing tissues and the lungs, pH and CO(2) homeostasis, electrolyte secretion in a variety of tissues/organs, biosynthetic reactions, such as the gluconeogenesis and ureagenesis among others (in animals), CO(2) fixation (in plants and algae), etc. The presence of these ubiquitous enzymes in so many tissues and in so different isoforms represents an attractive goal for the design of inhibitors with biomedical applications. Indeed, CA inhibitors are clinically used as antiglaucoma drugs, some other compounds being developed as antitumour agents/diagnostic tools for tumours, antiobesity agents, anticonvulsants and antimicrobials/antifungals (inhibitors targeting alpha- or beta-CAs from pathogenic organisms such as Helicobacter pylori, Mycobacterium tuberculosis, Plasmodium falciparum, Candida albicans, etc.).

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Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination. Enhancement of specificity with free PSA measurements.

W Catalona, D S Smith, D Ornstein (1997)

To determine the detection rate of prostate cancer in a screening population of men with prostate-specific antigen (PSA) concentrations of 2.6 to 4.0 ng/mL and a benign prostate examination, to assess the clinicopathological features of the cancers detected, and to assess the usefulness of measuring the ratio of free to total PSA to reduce the number of prostatic biopsies. A community-based study of serial screening for prostate cancer with serum PSA measurements and prostate examinations. University medical center. A total of 914 consecutive screening volunteers aged 50 years or older with serum PSA levels of 2.6 to 4.0 ng/mL who had a benign prostate examination and no prior screening tests suspicious for prostate cancer, 332 (36%) of whom underwent biopsy of the prostate. Cancer detection rate, clinical and pathological features of cancers detected, and specificity for cancer detection using measurements of percentage of free PSA. Cancer was detected in 22% (73/332) of men who underwent biopsy. All cancers detected were clinically localized, and 81% (42/52) that were surgically staged were pathologically organ confined. Ten percent of the cancers were clinically low-volume and low-grade tumors, and 17% of those surgically staged were low-volume and low-grade or moderately low-grade tumors (possibly harmless). Using a percentage of free PSA cutoff of 27% or less as a criterion for performing prostatic biopsy would have detected 90% of cancers, avoided 18% of benign biopsies, and yielded a positive predictive value of 24% in men who underwent biopsy. There is an appreciable rate of detectable prostate cancer in men with serum PSA levels of 2.6 to 4.0 ng/mL. The great majority of cancers detected have the features of medically important tumors. Free serum PSA measurements may reduce the number of additional biopsies required by the lower PSA cutoff.

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Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening.

Simon Smith, Joseph Basler, William Catalona … (1993)

To determine whether prostate-specific antigen (PSA)-based screening alters the proportion of organ-confined prostate cancers detected. A prospective, nonrandomized, serial PSA-based screening trial (follow-up from 6 to 37 months), and a concurrent comparison group. General community outpatient screening program based at a university center. The study group consisted of 10,251 men aged 50 years and older (mean and median age, 63 years; mean and median age of patients who underwent biopsies, 66 years) who presented to a prostate cancer screening program and consented to phlebotomy. The comparison group consisted of 266 concurrently studied private patients in the same age range (mean and median age, 68 years) who were referred for prostatic ultrasonography and biopsy because of an abnormal digital rectal examination (DRE). Proportion detected with clinically or pathologically advanced prostate cancer. The men were divided into three groups: the comparison group, the initial PSA-based screening group, and the serial PSA-based screening group. The proportions of prostate cancers detected that were clinically or pathologically advanced were as follows: comparison group, 57% (27/47); initial PSA-based screening group, 37% (91/244); and serial PSA-based screening group, 29% (37/129). Screened patients had a lower proportion of advanced cancers than the comparison group (chi 2 [2] = 12.3; P = .002); this advantage was observed principally in patients younger than 70 years. Surgical staging revealed that the cancer was microscopically focal and well differentiated (possibly latent cancer) in 2.5% (1/40) of the nonscreened group, 2.9% (7/244) of the initially screened group, and 7.8% (10/129) of the serially screened group (generalized Fisher's Exact Test, P = .08). Screening based on PSA identifies some men with prostate cancer who have a significantly increased proportion of organ-confined tumors compared with those detected through evaluation for an abnormal DRE alone.

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Author and article information

Journal

Journal ID (nlm-ta): ISRN Oncol

Journal ID (iso-abbrev): ISRN Oncol

Journal ID (publisher-id): ISRN.ONCOLOGY

Title: ISRN Oncology

Publisher: International Scholarly Research Network

ISSN (Print): 2090-5661

ISSN (Electronic): 2090-567X

Publication date Collection: 2012

Publication date (Electronic): 19 November 2012

Volume: 2012

Electronic Location Identifier: 768190

Affiliations

¹Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

²Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

³New Frontiers Research Laboratories, Toray Industries, Inc., 10-1 Tebiro, Kanagawa, Kamakura 248-8555, Japan

⁴Bio Science Department, Research and Development Center, Mitsui Knowledge Industry Co., Ltd., 2-7-14 Higashinakano, Nakano-Ku, Tokyo 164-8555, Japan

⁵Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

Author notes

*Masaya Ono: masono@ 123456ncc.go.jp

Academic Editors: A. E. Bilsland, B. Comin-Anduix, G. Ferrandina, and S. Holdenrieder

Article

DOI: 10.5402/2012/768190

PMC ID: 3506895

PubMed ID: 23213568

SO-VID: db6a9aad-4151-42ee-ab8c-b101a5bac5b7

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This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 17 September 2012

Date accepted : 2 October 2012

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Carbonic Anhydrase I as a New Plasma Biomarker for Prostate Cancer

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Karger: Oncology

Most cited references 23

Carbonic anhydrases as targets for medicinal chemistry.

Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination. Enhancement of specificity with free PSA measurements.

Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening.

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