Body Fluid Proteomics for Biomarker Discovery: Lessons from the Past Hold the Key to Success in the Future

Good, David W.; Thongboonkerd, Visith; Novák, Jan; Bascands, Jean-Loup; Schanstra, Joost P.; Coon, Joshua J.; Dominiczak, Anna F.; Mischak, Harald

doi:10.1021/pr070529w

Cited by 222 publications

(188 citation statements)

References 53 publications

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“…Body fluids have been shown to be excellent media for biomarker discovery (10). Because ascites fluid contains many cells of tumor origin in addition to other soluble growth factors that have been associated with invasion and metastasis (11,12), this fluid contains the secretome of ovarian cancer cells while reflecting other microenvironmental factors of the malignancy.…”

mentioning

confidence: 99%

Mining the Ovarian Cancer Ascites Proteome for Potential Ovarian Cancer Biomarkers

Kuk

Kulasingam

Gunawardana

et al. 2009

Molecular & Cellular Proteomics

112

111

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Current ovarian cancer biomarkers are inadequate because of their relatively low diagnostic sensitivity and specificity. There is a need to discover and validate novel ovarian cancer biomarkers that are suitable for early diagnosis, monitoring, and prediction of therapeutic response. We performed an in-depth proteomics analysis of ovarian cancer ascites fluid. Size exclusion chromatography and ultrafiltration were used to remove high abundance proteins with molecular mass >30 kDa. After trypsin digestion, the subproteome (<30 kDa) of ascites fluid was determined by two-dimensional liquid chromatography-tandem mass spectrometry. Filtering criteria were used to select potential ovarian cancer biomarker candidates. By combining data from different size exclusion and ultrafiltration fractionation protocols, we identified 445 proteins from the soluble ascites fraction using a two-dimensional linear ion trap mass spectrometer. Among these were 25 proteins previously identified as ovarian cancer biomarkers. After applying a set of filtering criteria to reduce the number of potential biomarker candidates, we identified 52 proteins for which further clinical validation is warranted. Our proteomics approach for discovering novel ovarian cancer biomarkers appears to be highly efficient because it was able to identify 25 known biomarkers and 52 new candidate biomarkers that warrant further validation. Molecular & Cellular Proteomics 8:661-669, 2009.Accounting for ϳ3% of all new cancer cases in 2008 (1) with a 1 in 59 (1.7%) lifetime probability of developing the disease, ovarian cancer is the most lethal gynecological malignancy deeming 5-6% of all cancer deaths (1). Hidden deep within the pelvis, ovarian cancer is relatively asymptomatic in early stages, and because of the lack of adequate screening, ovarian cancer has resulted in the majority of cases being presented with late stage disease in association with a low 5-year survival rate of 25-40%. When presented at an early stage, the 5-year survival rate exceeds 90% and most patients are cured by surgery alone (2). Although the most widely used serum marker for ovarian cancer is carbohydrate antigen 125 (CA125), 1 its utility as a screening marker is limited because of its high false positive rates and elevation in other malignancies such as uterine, fallopian, colon, and gastric cancer (3, 4) as well as in non-malignant conditions such as pregnancy and endometriosis (5). These reasons alone demonstrate the need and immediate benefit in using biomarkers with increased sensitivity and specificity for early diagnosis, prognosis, or monitoring of ovarian cancer.Many advanced stage ovarian cancer patients exhibit rapid growth of intraperitoneal tumors along with abdominal distention as a result of accumulation of ascites fluid in the peritoneal cavity. Mechanistically ascites formation occurs as malignant cells secrete proteins, growth factors, and cytokines that cause neovascularization, angiogenesis, increased fluid filtration, and/or lymphatic obstruction (6 -8) resulting...

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mentioning

confidence: 99%

Mining the Ovarian Cancer Ascites Proteome for Potential Ovarian Cancer Biomarkers

Kuk

Kulasingam

Gunawardana

et al. 2009

Molecular & Cellular Proteomics

112

111

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“…Besides the expected circulatory proteins, this archive also contains specific tumour-secreted proteins, normal tissue-and plasma-proteins digested by tumour-secreted proteases, and proteins produced by local and distant responses to the tumour [11,28,29]. Moreover, whole blood is an easy to sample, readily accessible matrix that allows repeated collection, thereby augmenting the clinical relevance of candidate blood-borne biomarkers [28,30].…”

Section: Protein Profiling Of Serum and Plasmamentioning

confidence: 99%

“…CSF is specific for the central nervous system [77], contains less total protein than serum and provides a low fluid-volume-to-organ ratio, thereby augmenting biomarker discovery [30]. As collection of CSF by invasive lumbar puncture is not applicable to healthy controls, this matrix has thus far only been investigated for prognostic purposes.…”

Section: Prognostic Protein Profiling Studiesmentioning

confidence: 99%

Clinical proteomics in breast cancer: a review

Gast

Schellens

Beijnen

2008

Breast Cancer Res Treat

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Breast cancer imposes a significant healthcare burden on women worldwide. Early detection is of paramount importance in reducing mortality, yet the diagnosis of breast cancer is hampered by the lack of an adequate detection method. In addition, better breast cancer prognostication may improve selection of patients eligible for adjuvant therapy. Hence, new markers for early diagnosis, accurate prognosis and prediction of response to treatment are warranted to improve breast cancer care. Since proteomics can bridge the gap between the genetic alterations underlying cancer and cellular physiology, much is expected from proteome analyses for the detection of better protein biomarkers. Recent technical advances in mass spectrometry, such as matrix-assisted laser desorption/ ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and its variant surface-enhanced laser desorption/ ionisation (SELDI-) TOF MS, have enabled highthroughput proteome analysis. In the current review, we give a comprehensive overview of the results of expression proteomics (i.e. protein profiling) research performed in breast cancer using these two platforms. Many protein peaks have been reported to bear significant diagnostic, prognostic or predictive value, however, only few candidate markers have been structurally identified yet. In addition, although of pivotal importance in preventing overfitting of data and systematic bias by pre-analytical parameters, validation of biomarker candidates by other, quantitative, methods and/or in new populations is very limited. Moreover, none of the identified candidate biomarkers has been investigated for their utility as breast cancer markers in large, prospective, clinical settings. As such, the candidate biomarkers discussed in this overview have not been validated sufficiently to be used for clinical patient care. Nonetheless, regarding the promising results up to now, MALDI-and SELDI-TOF MS protein profiling studies could eventually fulfil the great promise that protein biomarkers have for improving cancer patient outcome, provided that these studies are performed with adequate statistical power and analytical rigour.

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“…While the latter method is best suited for the identification of large proteins, the former is more applicable for peptides and small proteins and gives a more accurate definition of the potential biomarkers. As outlined recently, any biomarker should be defined by its accurate molecular composition (39). The identification of a theoretical protein based on a few tryptic fragments may be quite misleading, as it generally does not allow accounting for posttranslational modifications, which may in fact confer »biomarker quality« to the protein: glycated albumin may serve as a biomarker for diabetes, while albumin precursor, which would be defined as biomarker based on several tryptic peptides, certainly does not (40).…”

Section: Bottom-up and Top-down Proteomicsmentioning

confidence: 99%

Urinary Proteome Analysis using Capillary Electrophoresis Coupled to Mass Spectrometry: A Powerful Tool in Clinical Diagnosis, Prognosis and Therapy Evaluation

Mischak¹,

Schiffer²,

Zürbig³

et al. 2009

Journal of Medical Biochemistry

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Kratak sadr`aj: Analiza proteoma je postala je mo}no sredstvo za de{ifrovanje (pato)fiziolo{kih procesa, {to je za rezultat imalo uspostavljanje oblasti klini~ke proteomike. Jedan od glavnih ciljeva je otkrivanje biomarkera oboljenja iz tkiva i telesnih te~nosti. Zbog ogromne slo`enosti pro teoma, pri proteomskoj analizi zasnovanoj na masenoj spektrometriji potrebno je izvr{iti separaciju. U radu su opisane prednosti i ograni~enja proteomske analize pri separaciji proteina putem dvodimenzionalne gel elektroforeze, te~ne hromatografije, SELDI i kapilarne elektroforeze (KE), sa fokusom na KE-MS. KE-MS omogu}ava separaciju i detekciju proteoma male molekularne te`ine u biolo{kim te~nostima uz visoku reproducibilnost i preciznost u samo jednom koraku radnog postupka i za kratko vreme. Po{to pojedina~ni senzitivni i specifi~ni biomarkeri mo`da i ne postoje, strategija za premo{}ivanje te dijagnosti~ke praznine pomera se sa detekcije pojedina~nog analita na simultanu analizu vi{e analita koji zajedno ~ine obrazac specifi~an za dato oboljenje. Takvi pristupi, me|utim, nose sa sobom dodatne izazove, koje }emo predstaviti u ovom radu. Pored izbora odgovaraju}ih tehnolo{kih platformi, neophodan je visok nivo standar dizacije proteomskih merenja i obrade podataka kako bi se vr{ilo profilisanje proteoma. U tom pogledu, zahtevi koji se ti~u nacrta studija, izbora primeraka uzoraka, analize proteomskih podataka i klini~ke evaluacije trebalo bi da budu razmotreni pre izvo|enja proteomske studije.Klju~ne re~i: klini~ka proteomika, kapilarna elektro foreza, masena spektrometrija, biomarker, urin Summary: Proteome analysis has emerged as a powerful tool to decipher (patho)physiological processes, resulting in the establishment of the field of clinical proteomics. One of the main goals is to discover biomarkers for diseases from tissues and body fluids. Due to the enormous complexity of the proteome, a separation step is required for mass spectrometry (MS)-based proteome analysis. In this review, the advantages and limitations of protein separation by two-dimensional gel electrophoresis, liquid chromatography, surface-enhanced laser desorption/ionization and capillary electrophoresis (CE) for proteomic analysis are described, focusing on CE-MS. CE-MS enables separation and detection of the small molecular weight proteome in biological fluids with high reproducibility and accuracy in one single processing step and in a short time. As sensitive and specific single biomarkers generally may not exist, a strategy to overcome this diagnostic void is shifting from single analyte detection to simultaneous analysis of multiple analytes that together form a disease-specific pattern. Such approaches, however, are accompanied with additional challenges, which we will outline in this review. Besides the choice of adequate technological platforms, a high level of standardization of proteomic measurements and data processing is also necessary to establish proteomic profiling. In this regard, demands concerning study design, choice of specimens, ...

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Body Fluid Proteomics for Biomarker Discovery: Lessons from the Past Hold the Key to Success in the Future

Cited by 222 publications

References 53 publications

Mining the Ovarian Cancer Ascites Proteome for Potential Ovarian Cancer Biomarkers

Mining the Ovarian Cancer Ascites Proteome for Potential Ovarian Cancer Biomarkers

Clinical proteomics in breast cancer: a review

Urinary Proteome Analysis using Capillary Electrophoresis Coupled to Mass Spectrometry: A Powerful Tool in Clinical Diagnosis, Prognosis and Therapy Evaluation

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