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Identification of Novel Molecular Markers for Detection of Gastric Cancer Cells in the Peripheral Blood Circulation Using Genome-Wide Microarray Analysis

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Identification of Novel Molecular Markers for Detection of Gastric Cancer Cells in the Peripheral Blood Circulation Using Genome-Wide Microarray Analysis EXPERIMENTAL AND THERAPEUTIC MEDICINE 2: 705-713, 2011 Identification of novel molecular markers for detection of gastric cancer cells in the peripheral blood circulation using genome-wide microarray analysis NOBUYUKI MATSUMURA, HITOSHI ZEMBUTSU, KOJI YAMAGUCHI, KAZUAKI SASAKI, TETSUHIRO TSURUMA, TOSHIHIKO NISHIDATE, RYUICHI DENNO and KOICHI HIRATA First Department of Surgery, Sapporo Medical University, School of Medicine, Hokkaido 060-0061, Japan Received March 8, 2011; Accepted April 5, 2011 DOI: 10.3892/etm.2011.252 Abstract. Although metastasis or relapse is a leading cause Introduction of death for patients with gastric cancer, the hematogenous spread of cancer cells remains undetected at the time of initial Gastric cancer causes approximately 800,000 deaths therapy. The development of novel diagnostic molecular worldwide per year and is still one of the leading causes of marker(s) to detect circulating gastric cancer cells is an issue cancer-related death in the world (1). Most gastric cancers at of great clinical importance. We obtained peripheral blood an early stage can be cured by surgical resection; however, samples from 10 patients with gastric cancer who underwent patients with advanced gastric cancers have worse prognosis laparotomy and 4 healthy volunteers. Microarray analysis than those with early stage disease (2). Although metastasis consisting of 30,000 genes or ESTs was carried out using or relapse is the main cause of death for patients with gastric eight gastric cancer tissues and normal gastric mucosae. We cancer (3), the hematogenous spread of malignant cells selected 53 genes up-regulated in gastric cancer compared remains undetected at the time of initial therapy. During to normal gastric mucosae from our microarray data set, the development of cancer, tumor cells may detach from the and, among these, identified five candidate marker genes primary tumor and disseminate into the lymph system and/ (TSPAN8, EPCAM, MMP12, MMP7 and REG3A) which or blood circulation, and grow in the bone marrow, liver, were not expressed in peripheral blood mononuclear cells kidney and other organs, which is called micrometastasis (4). (PBMCs) from 4 healthy volunteers. We further carried out Micrometastasis is barely detected by routine biochemical semi-quantitative nested reverse transcription-polymerase and histopathological assays or graphical methods, such as chain reaction (RT-PCR) for HRH1, EGFR, CK20 and CEA X-ray, CT and MRI (3). Detection of circulating tumor cells at in addition to the five newly identified genes using PBMCs the mRNA level [reverse transcription-polymerase chain reac- of patients with gastric cancer, and found that expression of tion (RT-PCR)] in blood samples of patients with cancer could one or more genes out of the nine was detected in 80% of serve as a unique and easy diagnostic tool to predict cancer the patients with gastric cancer. Moreover, the numbers of recurrence and to monitor treatment effectiveness (5-7). genes expressed in PBMCs were ≤2 and ≥2 in all vascular However, molecular marker(s) that detect circulating gastric invasion-negative cases and in 5 of 6 positive cases, respec- cancer cells for routine clinical use have not yet been identi- tively, showing significant differences between the two groups fied. Hence, the development of novel diagnostic molecular (P=0.041). Nested RT-PCR analysis for the set of nine marker marker(s) to detect circulating gastric cancer cells is an issue genes using PBMCs may provide the potential for detection of of great clinical importance. circulating gastric cancer cells prior to metastasis formation Carcinoembryonic antigen (CEA) is a well-known tumor in other organs. marker and has been used to detect small amounts of adeno- carcinoma cells in the blood, peritoneal wash or other body fluids (8-12). However, the expression of CEA mRNA is not specific to cancer cells and often produces false-positive results (13). Profiling of gene expression patterns on genome-wide microarrays enables investigators to perform comprehensive Correspondence to: Professor Koichi Hirata, First Department of characterization of molecular activities in cancer cells (14-17). Surgery, Sapporo Medical University, School of Medicine, Hokkaido 060-0061, Japan Systematic analysis of expression levels for thousands of genes E-mail: [email protected] is also a useful approach for identifying molecular markers to detect small amounts of circulating cancer cells (18). In this Key words: microarray, gastric cancer, molecular marker, nested study, we identified genes whose expression had been altered RT-PCR, peripheral blood during gastric carcinogenesis using genome-wide information obtained from 8 cases on a microarray consisting of 30,000 transcribed elements. Based on the results of the microarray 706 MATSUMURA et al: MOLECULAR MARKERS FOR DETECTION OF GASTRIC CANCER CELLS Table I. Characteristics of patients included in the nested was added to each sample of total RNA according to the RT-PCR analysis of PBMCs. manufacturer's instructions. Parameters No. of patients Analysis of microarray. Total RNA was extracted from each gastric tissue using TRIzol according to the manufacturer's Gender (male:female) 5:5 instructions. To guarantee the quality of RNAs, total RNA Age range (average), in years 41-82 (61.9) extracted from the residual tissue of each case was electro- Depth of tumor invasion (T1:T2:T3:T4) 1:6:2:1 phoresed on a denaturing agarose gel, and the quality was Lymph node metastasis (N0:N1:N2:N3) 4:3:2:1 confirmed by the presence of rRNA bands. After treatment Distant metastasis (M0:M1) 10:0 with DNase I, T7-based RNA amplification was carried out as described previously with a few modifications (19). Using Liver metastasis (H0:H1) 10:0 5 µg of total RNA from each tissue sample as starting mate- Peritoneal metastasis (P0:P1) 9:1 rial, one round of amplification was performed; the amount Peritoneal lavage cytology (CY0:CY1) 9:1 of each amplified RNA (aRNA) was measured by a spectro- Stage (I:II:III:IV) 4:1:2:3 photometer. A mixture of normal gastric mucosae from 8 Lymphatic invasion (ly0:ly1-3) 2:8 patients was prepared as a universal control and was amplified Vessel invasion (v0:v1-3) 4:6 in the same manner; 2.5 µg of aRNAs from each cancerous tissue and from the control was reversely transcribed in the presence of Cy5-dCTP and Cy3-dCTP, respectively (15). AceGene 30K-1 Chip Version (Hitachi Software Engineering Co., Japan) was used for microarray analysis. The procedures assay, we identified five candidate genes for the specific for hybridization, washing, photometric quantification of detection of circulating gastric cancer cells at the mRNA signal intensities of each spot and normalization of data were level. We suggest that such information may lead ultimately to according to the manufacturer's instructions. To normalize the improve the prognosis of patients with gastric cancers. amount of mRNA between tumors and controls, the fluores- cence intensities of Cy5 (gastric cancer) and Cy3 (control) for Materials and methods each target spot were adjusted so that the mean Cy5/Cy3 ratio of 30,000 genes equaled 1. Genes were categorized into three Blood and tissue samples. Blood samples were obtained from groups according to the cancer/normal ratio of their mean 10 patients with gastric cancer who underwent laparotomy signal intensity: up-regulated (expression ratio >5.0), down- and 4 healthy volunteers after obtaining informed consent. regulated (expression ratio <0.2) and unchanged expression Heparinized blood samples (5 ml) from the 10 patients with (expression ratio between 0.2 and 5.0). gastric cancer were obtained from a peripheral artery through a catheter used for monitoring arterial blood pressure during Semi-quantitative RT-PCR. To validate the result of the surgical operation. Peripheral venous blood was obtained microarray analysis, we examined the expression levels of from 4 healthy volunteers for control after discarding the the genes up-regulated in gastric cancer by means of semi- initial 10 ml of blood to protect the mixture from epithelial quantitative RT-PCR analysis. Total RNAs (3 µg) extracted cells. Clinicopathological characteristics of the 10 patients are from each cancerous tissue and normal gastric mucosa shown in Table I. Clinical stage of each patient was judged were reversely transcribed for single-stranded cDNAs using according to the Union for International Cancer Control oligo(dT)12-18 primer with Superscript II reverse transcriptase (UICC) TNM classification. Among the 10 patients with (Life Technologies, Inc.). Each single-stranded cDNA was gastric cancer, 8 primary gastric cancer tissues and corre- diluted for subsequent PCR amplification. A housekeeping sponding non-cancerous gastric mucosae from surgically gene, GAPDH, served as the internal control. The PCR reac- resected tissues were obtained at Sapporo Medical University tion was conducted at 95˚C for 5 min, and then for 30 cycles at and Douto Hospital after each patient had provided informed 95˚C for 30 sec, 60˚C for 30 sec and 72˚C for 1 min followed consent. The samples that had been confirmed histologically by 72˚C for 10 min, in the Gene Amp PCR System 9700 as gastric adenocarcinoma were used for microarray study. (Perkin-Elmer Applied Biosystems, Foster City, CA, USA). These samples were immediately frozen and stored at -80˚C. All cancer tissues were obtained from the margin of the tumor Nested RT-PCR using blood samples. We performed nested mass, while non-cancerous tissues were obtained from corre- RT-PCR using total RNAs extracted from PBMCs to accu- sponding normal mucosae of the same stomach. This study rately examine mRNA levels of the candidate marker genes. was approved by the Ethics Committee of Sapporo Medical Initially, RT-PCR was carried out as described above. In University, School of Medicine, Hokkaido, Japan. nested RT-PCR, 1 ml of the initial PCR product, 4 ml of 10X PCR buffer, 200 mmol/l dNTP mixture, 0.2 mmol/l primers RNA extraction of blood samples.
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