Using detection of survivin-expressing circulating tumor cells in peripheral blood to predict tumor recurrence following curative resection of gastric cancer

Objective. To explore the application value of circulating tumor cells (CTCs) and circulating free DNA (cfDNA) from peripheral blood in the prognosis of advanced gastric cancer (AGC). Here, we measured CTCs and cfDNA quantity for predicting the outcome of patients. Patients and Methods. Forty-five patients with advanced gastric cancer who underwent neoadjuvant chemotherapy and surgical treatment were enrolled in this study. All patients received neoadjuvant chemotherapy with paclitaxel + S-1 + oxaliplatin (PSOX) regimen, and CTCs and cfDNA of the peripheral blood were detected before and after neoadjuvant therapy. Relationships between the number/type of CTC or cfDNA and the efficacy of neoadjuvant chemotherapy were analyzed. Results. Among 45 patients, 43 (95.6%) were positive, and the positive rate of mesenchymal CTC was increased with the increase in the T stage. The proportion of mesenchymal CTC was positively correlated with the N stage ( P < 0.05 ), and the larger N stage will have the higher proportion of mesenchymal CTC. Patients with a small number of mesenchymal CTC before neoadjuvant chemotherapy were more likely to achieve partial response (PR) with neoadjuvant therapy. Patients with positive CA-199 were more likely to achieve PR with neoadjuvant therapy ( P < 0.05 ). Patients in the PR group were more likely to have decreased/unchanged cfDNA concentration after neoadjuvant therapy ( P = 0.119 ). After neoadjuvant therapy (before surgery), the cfDNA concentration was higher and the efficacy of neoadjuvant therapy (SD or PD) was lower ( P = 0.045 ). Conclusions. Peripheral blood CTC, especially interstitial CTC and cfDNA, has a certain value in predicting the efficacy and prognosis of neoadjuvant chemotherapy in advanced gastric cancer.

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Early detection of biomarkers for circulating tumor cells in Bone marrow and Peripheral blood in a fast-progressing gastric cancer model

10.1101/2020.01.29.925727 ◽

2020 ◽

Author(s):

Prerna Bali ◽

Ivonne Lozano-Pope ◽

Collin Pachow ◽

Marygorret Obonyo

Keyword(s):

Gastric Cancer ◽

Bone Marrow ◽

Early Detection ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Peripheral Blood ◽

Post Infection ◽

Cancer Metastasis ◽

Cancer Model ◽

Emt Markers

AbstractHelicobacter pylori poses one of the greatest risks for development of gastric cancer. We previously established a crucial role for myeloid differentiation primary response 88 (MyD88) in the regulation of Helicobacter-induced gastric cancer. Mice deficient in Myd88 rapidly progressed to neoplasia when infected with H. felis, a close relative of H. pylori. For this study we examined circulating tumor cells (CTCs) by measuring expression of cytokeratins, epithelial to mesenchymal transition (EMT) and cancer stem cell (CSC) markers in in the bone marrow and peripheral blood of gastric cancer models we termed fast (Myd88-/-)- and slow (WT)-“progressors”. We detected cytokeratins CK8/18 as early as 3 months post infection in the fast “progressors”. In contrast, cytokeratins were not detected in slow “progressor” gastric cancer model even after 7 months post infection. Expression of MUC1 was observed in both bone marrow and peripheral blood at different time points suggesting its role in gastric cancer metastasis. Snail, Twist and ZEB were expressed at different levels in bone marrow and peripheral blood. Expression of these EMT markers suggests manifestation of cancer metastasis in the early stages of disease development. Lgr5, CD44 and CD133 were the most prominent CSC markers detected. Detection of CSC and EMT markers along with cytokeratins does reinforce their use as biomarkers for gastric cancer metastasis. This early detection of markers suggests that CTCs leave primary site even before cancer is well established. Thus, cytokeratins, EMT, and CSCs could be used as biomarkers to detect aggressive forms of gastric cancers. This information will be important in stratifying patients for treatment before the onset of severe disease characteristics.

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Preoperative detection of circulating tumor cells in patients with colorectal carcinoma: Correlation with clinicopathologic variables and recurrence.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.10578 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 10578-10578

Author(s):

Hideyasu Sakihama ◽

Nozomi Kobayashi ◽

Tohru Funakoshi ◽

Tatsushi Shimokuni ◽

Shigenori Homma ◽

...

Keyword(s):

Healthy Volunteers ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Peripheral Blood ◽

Tumor Recurrence ◽

Strong Predictor ◽

Depth Of Invasion ◽

Blood Samples ◽

Positive Rate ◽

Colorectal Cancer Patients

10578 Background: The role of circulating tumor cells (CTC) in the management of colorectal cancer patients has not fully established. The aims of this study are to investigate the relationship between the presence of CTC with clinicopathological variables and recurrence by magnetic activated cell sorting (MACS) system. Methods: Peripheral blood samples were collected from 80 patients. Enrichment of CTC was performed by direct immunomagnetic labeling of EpCAM positive cells in peripheral blood. Subsequently, double immunofluorescence for cytokeratin and CD45 was performed to detect CTC. Peripheral blood samples from twenty healthy volunteers were used as controls. Results: Preoperative positive rate of CTC was 35% while specificity was 100%. No CTC was found in peripheral blood from healthy volunteers. No correlation was found between the presence of CTC and location of tumors, grade of differentiation, vessel invasion, lymph node metastasis or TNM stages. On the other hand, the depth of invasion (0% in Tis, 11.1% in T1, 18.2% in T2 and 34.7% in T3+T4, P=0.05) and tumor recurrence (28.2% for initial operation and 88.9% for reoperative surgery for tumor recurrence, P<0.001) closely correlated with the presence of CTC. Preoperative positive rate of CTC among patients who have recurred postoperatively was 75%. Conclusions: Our results indicate that detections of CTCs correlate with the depth of invasion and tumor recurrence. Preoperative presence of CTCs might be a strong predictor for tumor recurrence.

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Detection of circulating tumor cells in peripheral blood from patients with gastric cancer using microRNA as a marker

Journal of Molecular Medicine ◽

10.1007/s00109-010-0617-2 ◽

2010 ◽

Vol 88 (7) ◽

pp. 709-717 ◽

Cited By ~ 102

Author(s):

Hui Zhou ◽

Jun-Ming Guo ◽

Yan-Ru Lou ◽

Xin-Jun Zhang ◽

Fa-De Zhong ◽

...

Keyword(s):

Gastric Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Peripheral Blood

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Clinical significance of circulating tumor cells in peripheral blood from patients with gastric cancer

Cancer ◽

10.1002/cncr.28309 ◽

2013 ◽

Vol 119 (22) ◽

pp. 3984-3991 ◽

Cited By ~ 39

Author(s):

Yoshikazu Uenosono ◽

Takaaki Arigami ◽

Tsutomu Kozono ◽

Shigehiro Yanagita ◽

Takahiko Hagihara ◽

...

Keyword(s):

Gastric Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Clinical Significance ◽

Peripheral Blood

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Detection of viable human circulating tumor cells using telomerase-specific GFP-expressing bioengineered adenovirus in patients with gastric cancer: A feasibility study.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.18 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 18-18

Author(s):

T. Fujiwara ◽

F. Uno ◽

Y. Hashimoto ◽

Y. Shirakawa ◽

T. Nagasaka ◽

...

Keyword(s):

Gastric Cancer ◽

Viral Replication ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Peripheral Blood ◽

Fluorescent Protein ◽

Human Tumor ◽

Blood Leukocytes ◽

Systemic Treatments ◽

Gastric Cancer Patients

18 Background: The presence of circulating tumor cells (CTC) in the peripheral blood is associated with short survival and, therefore, the detection of CTC is clinically useful as prognostic factors of disease outcome and/or surrogate markers of treatment response. Recent technical advances in immunocytometric analysis and quantitative real-time PCR have made possible to detect a few CTC in the blood; however, there is no sensitive assay for detecting viable CTC. We developed a new approach to visually detect live CTC among millions of peripheral blood leukocytes using telomerase-specific replication-selective adenovirus expressing green fluorescent protein (GFP). Methods: We constructed a GFP-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401, TelomeScan). The detection method for viable human CTC in the peripheral blood involves a three-step procedure including the lysis of red blood cells, the subsequent addition of OBP-401 to the cell pellets, and the automated scan under the fluorescent microscope. We analyzed fresh blood samples collected from 37 patients with histologically confirmed gastric cancer. We further assessed the CTC dynamics in patients who were undergoing chemotherapy or surgery to demonstrate the clinical potential of our approach for monitoring treatment responses. Results: OBP-401 increased the signal-to-background ratio as a tumor-specific probe, because the fluorescent signal can be amplified only in viable human tumor cells by viral replication. Although the CTC level varied widely, ranging from 0 to 47 in 5-ml samples, 26 gastric cancer patients (70.3%) had more than one CTC; there was, however, no apparent relationship between CTC counts and TNM stages. Patients who had a recurrence of gastric cancer had decreased CTC counts after systemic chemotherapy. In the patients who underwent surgery, the CTC level dropped after complete resection. Conclusions: This GFP-expressing virus-based method is simple and allows precise enumeration of CTC, which might be useful for monitoring the efficacy of local and systemic treatments. [Table: see text]

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Survivin expression in circulating tumor cells of patients with gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.65 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 65-65

Author(s):

Masanori Terashima ◽

Keiichi Hatakeyama ◽

Yushi Yamakawa ◽

Norihiko Sugisawa ◽

Yuichiro Miki ◽

...

Keyword(s):

Gastric Cancer ◽

Mrna Expression ◽

Real Time ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Peripheral Blood ◽

Survivin Expression ◽

Expression Level ◽

Survivin Mrna ◽

Pcr Targeting

65 Background: Detection of circulating tumor cells (CTC) in peripheral blood is thought to be a promising method to evaluate the extent of minimal residual disease that may be useful for predicting recurrence and for monitoring treatment efficacy. However, unlike breast or lung cancer, little information is available in patients with gastric cancer. Among them, evaluation of survivin, a member of the inhibitor of apoptosis (IAP) family, mRNA expression in peripheral blood appears to be a promising procedure with relative good performance for predicting recurrence after curative resection. In order to evaluate the clinical significance of surviving expression in peripheral blood, we performed real-time RT-PCR analysis using whole blood obtained from patients with gastric cancer. Methods: A total of 95 patients with gastric cancer treated at our cancer center between Nov. 2009 and Aug. 2012 were enrolled in this study. Peripheral blood samples were collected using PAX gene and RNA was isolated using Boom method. After cDNA synthesis, quantitative real-time PCR targeting survivin gene was performed. The relative expression level of survivin mRNA was calculated with actin beta as an internal standard. Correlation between survivin expression and clinicopathologic factors was investigated. Results: Survivin mRNA expression level in peripheral blood ranged from 34.8 to 1889.6, and the median level was 370.3. Survivin mRNA level tended to be higher in patients with T4, N3b, CY1, and Stage IV. There was no significant correlation with histological type, lympho-vascular invasion, or macroscopic type. If we set a cut-off value at 540, survivin was positive in 27 patients (28%). Disease-free survival was significantly worse in survivin positive patients than in negative patients (p=0.0216). Conclusions: Survivin expression in CTC was higher in advanced stage and appears to be a good prognostic marker in patients with gastric cancer. Validation with large sample size should be performed to confirm the significance of survivin in CTC.

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