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SILAC-based quantitative proteomic analysis of gastric cancer secretome.

ABSTRACT: Gastric cancer is a commonly occurring cancer in Asia and one of the leading causes of cancer deaths. However, there is no reliable blood-based screening test for this cancer. Identifying proteins secreted from tumor cells could lead to the discovery of clinically useful biomarkers for early detection of gastric cancer.A SILAC-based quantitative proteomic approach was employed to identify secreted proteins that were differentially expressed between neoplastic and non-neoplastic gastric epithelial cells. Proteins from the secretome were subjected to SDS-PAGE and SCX-based fractionation, followed by mass spectrometric analysis on an LTQ-Orbitrap Velos mass spectrometer. Immunohistochemical labeling was employed to validate a subset of candidates using tissue microarrays.We identified 2205 proteins in the gastric cancer secretome of which 263 proteins were overexpressed greater than fourfold in gastric cancer-derived cell lines as compared to non-neoplastic gastric epithelial cells. Three candidate proteins, proprotein convertase subtilisin/kexin type 9 (PCSK9), lectin mannose binding 2 (LMAN2), and PDGFA-associated protein 1 (PDAP1) were validated by immunohistochemical labeling.We report here the largest cancer secretome described to date. The novel biomarkers identified in the current study are excellent candidates for further testing as early detection biomarkers for gastric adenocarcinoma.

SUBMITTER: Marimuthu A

PROVIDER: S-EPMC3804263 | biostudies-other | 2013 Jun

REPOSITORIES: biostudies-other

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SILAC-based quantitative proteomic analysis of gastric cancer secretome.

Marimuthu Arivusudar A Subbannayya Yashwanth Y Sahasrabuddhe Nandini A NA Balakrishnan Lavanya L Syed Nazia N Sekhar Nirujogi Raja NR Katte Teesta V TV Pinto Sneha M SM Srikanth Srinivas M SM Kumar Praveen P Pawar Harsh H Kashyap Manoj K MK Kashyap Manoj K MK Maharudraiah Jagadeesha J Ashktorab Hassan H Smoot Duane T DT Ramaswamy Girija G Kumar Rekha V RV Cheng Yulan Y Meltzer Stephen J SJ Roa Juan Carlos JC Chaerkady Raghothama R Prasad T S Keshava TS Harsha H C HC Chatterjee Aditi A Pandey Akhilesh A

Proteomics. Clinical applications 20130521 5-6

<h4>Purpose</h4>Gastric cancer is a commonly occurring cancer in Asia and one of the leading causes of cancer deaths. However, there is no reliable blood-based screening test for this cancer. Identifying proteins secreted from tumor cells could lead to the discovery of clinically useful biomarkers for early detection of gastric cancer.<h4>Experimental design</h4>A SILAC-based quantitative proteomic approach was employed to identify secreted proteins that were differentially expressed between neo ...[more]

PMID: 23161554

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Project description:BackgroundA wide range of response rates have been reported in HER2-positive gastric cancer (GC) patients treated with trastuzumab. Other HER2-targeted therapies for GC have yet to show efficacy in clinical trials. These findings raise question about the ability of standard HER2 diagnostics to accurately distinguish between GC patients who would and would not benefit from anti-HER2 therapies.Patients and methodsGC patients (n = 237), including a subset from the Trastuzumab in GC (ToGA) trial were divided into three groups based on HER2 status and history of treatment with standard chemotherapy or chemotherapy plus trastuzumab. We applied mass spectrometry-based proteomic analysis to quantify HER2 protein expression in formalin-fixed tumor samples. Using HER2 expression as a continuous variable, we defined a predictive protein level cutoff to identify which patients would benefit from trastuzumab. We compared quantitated protein level with clinical outcome and HER2 status as determined by conventional HER2 diagnostics.ResultsQuantitative proteomics detected a 115-fold range of HER2 protein expression among patients diagnosed as HER2 positive by standard methods. A protein level of 1825 amol/µg was predicted to determine benefit from the addition of trastuzumab to chemotherapy. Trastuzumab treated patients with HER2 protein levels above this cutoff had twice the median overall survival (OS) of their counterparts below the cutoff (35.0 versus 17.5 months, P = 0.011). Conversely, trastuzumab-treated patients with HER2 levels below the cutoff had outcomes similar to HER2-positive patients treated with chemotherapy. (Progression-free survival = 7.0 versus 6.5 months: P = 0.504; OS = 17.5 versus 12.6 months: P = 0.520). HER2 levels were not prognostic for response to chemotherapy.ConclusionsProteomic analysis of HER2 expression demonstrated a quantitative cutoff that improves selection of GC patients for trastuzumab as compared with current diagnostic methods.

Dataset Information

SILAC-based quantitative proteomic analysis of gastric cancer secretome.

Publications

SILAC-based quantitative proteomic analysis of gastric cancer secretome.

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