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Lin X, Han T, Xia Q, Cui J, Zhuo M, Liang Y, Su W, Wang L, Wang L, Liu Z, Xiao X. CHPF promotes gastric cancer tumorigenesis through the activation of E2F1. Cell Death Dis 2021; 12:876. [PMID: 34564711 PMCID: PMC8464597 DOI: 10.1038/s41419-021-04148-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 08/16/2021] [Accepted: 09/09/2021] [Indexed: 01/06/2023]
Abstract
Chondroitin polymerizing factor (CHPF) is an important glycosyltransferase involved in the biosynthesis of chondroitin sulfate. However, the relationship between CHPF and gastric cancer has not been fully investigated. CHPF expression in gastric cancer tissues was detected by immunohistochemistry and correlated with gastric cancer patient prognosis. Cultured gastric cancer cells and human gastric epithelial cell line GES1 were used to investigate the effects of shCHPF and shE2F1 on the development and progression of gastric cancer by MTT, western blotting, flow cytometry analysis of cell apoptosis, colony formation, transwell and gastric cancer xenograft mouse models, in vitro and in vivo. In gastric cancer tissues, CHPF was found to be significantly upregulated, and its expression correlated with tumor infiltration and advanced tumor stage and shorter patient survival in gastric cancer. CHPF may promote gastric cancer development by regulating cell proliferation, colony formation, cell apoptosis and cell migration, while knockdown induced the opposite effects. Moreover, the results from in vivo experiments demonstrated that tumor growth was suppressed by CHPF knockdown. Additionally, E2F1 was identified as a potential downstream target of CHPF in the regulation of gastric cancer, and its knockdown decreased the CHPF-induced promotion of gastric cancer. Mechanistic study revealed that CHPF may regulate E2F1 through affecting UBE2T-mediated E2F1 ubiquitination. This study showed, for the first time, that CHPF is a potential prognostic indicator and tumor promoter in gastric cancer whose function is likely carried out through the regulation of E2F1.
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Affiliation(s)
- Xiaolin Lin
- Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Ting Han
- Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Qing Xia
- Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Jiujie Cui
- Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Meng Zhuo
- Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Yiyi Liang
- Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Wenyu Su
- Department of Gastroenterology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai, 200127, China
| | - Lisha Wang
- Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA
| | - Liwei Wang
- Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| | - Zebing Liu
- Department of Pathology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| | - Xiuying Xiao
- Department of Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
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Chen W, Zhang J, Fu H, Hou X, Su Q, He Y, Yang D. KLF5 Is Activated by Gene Amplification in Gastric Cancer and Is Essential for Gastric Cell Proliferation. Cells 2021; 10:cells10051002. [PMID: 33923166 PMCID: PMC8152363 DOI: 10.3390/cells10051002] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/12/2021] [Accepted: 04/21/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is the third leading cause of cancer death worldwide. In this study, we tried to clarify the function of KLF5 in gastric cancer. Copy number variation (CNV) and the expression of KLF5 were interrogated in public datasets. The clinical significance of KLF5 amplification and gene expression in gastric cancer were evaluated. The function of KLF5 in cell proliferation was studied in gastric cancer cell lines and organoids. We found that KLF5 amplification mainly occurred in the chromosome instable tumors (CIN) and was significantly associated with TP53 mutation. In addition, higher KLF5 expression correlated with more locally invasive gastric cancer and higher T stage. Next, a KLF5 gene expression signature was curated. The genes in the signature were involved in cell development, cell cycle regulation, cell death, suggesting potential roles played by KLF5. Functional studies using siRNAs revealed that KLF5 was essential for the proliferation of gastric cancer cells. Finally, using gastric organoid models, we revealed that the proliferation of organoids was significantly inhibited after the down regulation of KLF5. Our study revealed that KLF5 was amplified and over-expressed in gastric cancer, and it may play an oncogene-like role in gastric cancer by supporting cell proliferation.
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Affiliation(s)
- Wei Chen
- Center for Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; (W.C.); (J.Z.); (H.F.); (X.H.)
- Department of Pathology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, China
| | - Jian Zhang
- Center for Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; (W.C.); (J.Z.); (H.F.); (X.H.)
| | - Huafeng Fu
- Center for Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; (W.C.); (J.Z.); (H.F.); (X.H.)
- Laboratory of Surgical Department, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Xun Hou
- Center for Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; (W.C.); (J.Z.); (H.F.); (X.H.)
| | - Qiao Su
- Animal Experiment Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
- Correspondence: (Q.S.); (Y.H.); (D.Y.)
| | - Yulong He
- Center for Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; (W.C.); (J.Z.); (H.F.); (X.H.)
- Digestive Medicine Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, China
- Correspondence: (Q.S.); (Y.H.); (D.Y.)
| | - Dongjie Yang
- Center for Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; (W.C.); (J.Z.); (H.F.); (X.H.)
- Correspondence: (Q.S.); (Y.H.); (D.Y.)
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Yan C, Song X, Wang S, Wang J, Li L. Knockdown of PDIA6 Inhibits Cell Proliferation and Enhances the Chemosensitivity in Gastric Cancer Cells. Cancer Manag Res 2020; 12:11051-11062. [PMID: 33173338 PMCID: PMC7646476 DOI: 10.2147/cmar.s267711] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 10/10/2020] [Indexed: 12/14/2022] Open
Abstract
Background Protein disulfide isomerase A6 (PDIA6), a member of the disulfide isomerase (PDI) family, has been reported to be closely associated with progression of various cancers. However, the specific effects of PDIA6 on gastric cancer (GC) remain unclear. In this study, we investigated the expression pattern and biological functions of PDIA6 in GC. Materials and Methods The CCK-8 assay was carried out to examine cell proliferation and cisplatin cytotoxicity. The Western blot analysis was used to measure the protein expression of PDIA6, Wnt3a and β-catenin. The xenograft tumor assay was performed to evaluate the in vivo effect of PDIA6 on GC cell proliferation and chemoresistance. Results PDIA6 was significantly elevated in GC tissues and cell lines. Down-regulation of PDIA6 inhibited GC cell proliferation and chemoresistance to cisplatin while up-regulation of PDIA6 promoted the proliferation and chemoresistance of GC cells. Besides, PDIA6 regulated the chemosensitivity of GC cells to cisplatin in vivo. Mechanically, PDIA6 served as a regulator of the Wnt/β-catenin signaling pathway by affecting the protein expression of Wnt3a and β-catenin in GC cells. Additionally, Wnt activator reversed the inhibitory effect of PDIA6 knockdown on cisplatin resistance in GC cells. Conclusion These findings provided new insight into the potential role of PDIA6 as a promising target for drug resistance in GC chemotherapy.
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Affiliation(s)
- Chao Yan
- Department of Radiation Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, People's Republic of China
| | - Xiaolei Song
- Intervention Department, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, People's Republic of China
| | - Su Wang
- Department of General Surgery, Qingdao Chengyang People's Hospital, Qingdao 266109, People's Republic of China
| | - Jinhai Wang
- Gastroenterology Department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, People's Republic of China
| | - Lu Li
- Gastroenterology Department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, People's Republic of China
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Park JH, Park M, Park SY, Lee YJ, Hong SC, Jung EJ, Ju YT, Jeong CY, Kim JY, Ko GH, Hah YS, Jeong SH. ERH overexpression is associated with decreased cell migration and invasion and a good prognosis in gastric cancer. Transl Cancer Res 2020; 9:5281-5291. [PMID: 35117894 PMCID: PMC8797358 DOI: 10.21037/tcr-20-1498] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 07/08/2020] [Indexed: 12/23/2022]
Abstract
Background The enhancer of rudimentary homolog (ERH) protein is implicated in transcriptional regulation, cell cycle progression, and malignancy. We previously conducted a proteomics analysis using gastric cancer (GC) tissues and identified ERH as a biomarker candidate. The aim of this study was to investigate whether ERH may be useful as a prognostic marker for GC. Methods Surgically resected GC tissue specimens were obtained from 327 patients who underwent gastrectomy at Gyeongsang National University Hospital. Immunohistochemistry (IHC) was used to validate ERH as a prognostic marker in these tissues. SNU601 and MKN74 cells with siRNA-mediated knockdown of ERH expression and ERH-overexpressing SNU601 and MKN74 knock-in cells were used for analysis of ERH function. Results ERH was overexpressed in stomach cancer tissues compared with normal tissues according to proteomics analysis (n=29, P<0.01) of patient samples. Based on IHC, patients with tumors overexpressing ERH had lower T stage and lower TNM stage classifications, lower cancer recurrence rates and longer survival times than did patients with tumors showing low expression of ERH (P=0.04). In vitro, forced expression of ERH significantly decreased GC cell migration and invasion, and depletion of ERH triggered GC cell migration and invasion but had no effect on proliferation in vitro. Conclusions The findings from the present study show that ERH is associated with decreased cancer cell migration and invasion, suggesting that overexpression of ERH may serve as a marker of good prognosis for patients with GC.
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Affiliation(s)
- Ji-Ho Park
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Korea
| | - Miyeong Park
- Department of Anesthesiology, Gyeongsang National University Changwon Hospital, Changwon, Korea
| | - Sun Yi Park
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Korea
| | - Young-Joon Lee
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Korea
| | - Soon-Chan Hong
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Korea
| | - Eun-Jung Jung
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Korea
| | - Young-Tae Ju
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Korea
| | - Chi-Young Jeong
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Korea
| | - Ju-Yeon Kim
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Korea
| | - Gyung Hyuck Ko
- Department of Pathology, School of Medicine, Gyeongsang National University, Jinju, Korea
| | - Young-Sool Hah
- Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, Korea
| | - Sang-Ho Jeong
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Korea
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Rational design of small molecule RHOA inhibitors for gastric cancer. THE PHARMACOGENOMICS JOURNAL 2020; 20:601-612. [PMID: 32015453 DOI: 10.1038/s41397-020-0153-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 01/21/2020] [Accepted: 01/23/2020] [Indexed: 11/08/2022]
Abstract
Previously, we identified Ras homologous A (RHOA) as a major signaling hub in gastric cancer (GC), the third most common cause of cancer death in the world, prompting us to rationally design an efficacious inhibitor of this oncogenic GTPase. Here, based on that previous work, we extend those computational analyses to further pharmacologically optimize anti-RHOA hydrazide derivatives for greater anti-GC potency. Two of these, JK-136 and JK-139, potently inhibited cell viability and migration/invasion of GC cell lines, and mouse xenografts, diversely expressing RHOA. Moreover, JK-136's binding affinity for RHOA was >140-fold greater than Rhosin, a nonclinical RHOA inhibitor. Network analysis of JK-136/-139 vs. Rhosin treatments indicated downregulation of the sphingosine-1-phosphate, as an emerging cancer metabolic pathway in cell migration and motility. We assert that identifying and targeting oncogenic signaling hubs, such as RHOA, represents an emerging strategy for the design, characterization, and translation of new antineoplastics, against gastric and other cancers.
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Dai X, Zhang X, Yu J. Clinicopathological features and Borrmann classification associated with HER2-positive in primary gastric cancer. Clin Exp Gastroenterol 2019; 12:287-294. [PMID: 31303779 PMCID: PMC6605773 DOI: 10.2147/ceg.s212895] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 05/27/2019] [Indexed: 12/19/2022] Open
Abstract
PURPOSE Human epidermal growth factor receptor 2 (HER2) assesment is important for patients with advanced gastric cancer (GC) to determine trastuzumab therapy is being considered. A study was performed to evaluate the rate of HER2 positivity in patients with primary gastric cancer and to assess the relationship between HER2-positive and Borrmann classification. PATIENTS AND METHODS Four hundred and sixty-one patients with gastric or gastroesophageal junction cancer were confirmed as having adenocarcinoma between 2005 and 2016. HER2 status was assessed using immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH). Tissues were considered to be HER2-positive when assessment revealed either an IHC score of 3+ or IHC score 2+ accompanied by a positive FISH result. RESULTS The HER2-positive rate was significantly higher in men than in women (19% vs 9%; p=0.006). In our study, HER2-positive gastric tumors with differentiated histology were significantly higher. The proportion of HER2-positive gastric tumors of Borrmann classification III or IV was significantly higher than tumors classified as I or II. CONCLUSIONS HER2-positive gastric cancer tends to be associated with male gender, differentiated histology, and Borrmann tumor classification of III or IV.
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Affiliation(s)
- Xiaomin Dai
- Department of Pathology, Zhejiang Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Xijiong Zhang
- Department of Pathology, The No.1 People’s Hospital of Pinghu, Jiaxing, Zhejiang, People’s Republic of China
| | - Jin Yu
- Department of Pathology, Zhejiang Hospital, Hangzhou, Zhejiang, People’s Republic of China
- Department of Pathology, The No.1 People’s Hospital of Pinghu, Jiaxing, Zhejiang, People’s Republic of China
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Cho J, Ahn S, Son DS, Kim NK, Lee KW, Kim S, Lee J, Park SH, Park JO, Kang WK, An JY, Choi MG, Lee JH, Sohn TS, Bae JM, Kim S, Kim KM. Bridging genomics and phenomics of gastric carcinoma. Int J Cancer 2019; 145:2407-2417. [PMID: 30801717 DOI: 10.1002/ijc.32228] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 12/26/2018] [Accepted: 01/28/2019] [Indexed: 12/25/2022]
Abstract
Genetic alterations are the starting point leading to numerous changes in clinical and pathologic features (phenotypes) of individual cancers; however, their inter-relationships in gastric cancers (GC) are unclear. We performed massive parallel sequencing of 381 cancer-related genes and compared the results with clinical and pathologic findings in 330 GC. High tumor mutation burden (TMB) accounted for 11% of GC (n = 37) and all 19 MSI-H GCs were high TMB. High TMB was significantly more frequent in intestinal-type by Lauren, tumor with higher host cellular immune response, earlier AJCC stage and favorable prognosis. The most significantly mutated genes were TP53 (54%), ARID1A (23%), CDH1 (22%), PIK3CA (12%), RNF43 (10%) and KRAS (9%). For receptor tyrosine kinases, amplifications detected by immunohistochemistry were higher than sequencing (HER2, 9.1% vs. 5.8%; EGFR, 11.2% vs. 6.1%; FGFR2, 4.6% vs. 3.9%, c-MET, 3.4% vs. 0.9%). PTEN protein loss (22%) correlated well with underlying PTEN alterations while ATM loss (27%) was not significantly correlated with genetic alterations of ATM. p53 protein expression predicted alterations of TP53 with high sensitivity (97.8%) and low (15.9%) specificity. The poorly cohesive histology/CDH1-mutant GC subgroup showed the worst survival (p < 0.001). PD-L1 expression was significantly associated with MSI-H, MLH1 loss, ATM loss, MET positivity, higher host immune response, and genetic alterations of ARID1A, BRD3, PIK3CA, KRAS, MAP3K13, CDH2, PTEN and ESR1. The merged clinical, pathology and genomics of GC provide a better understanding of GC and new insights into the treatment of GC.
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Affiliation(s)
- Junhun Cho
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Bundang Hospital, Seongnam City, Korea
| | - Dae-Soon Son
- Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
| | - Nayoung Kd Kim
- Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
| | - Ki-Wook Lee
- Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
| | - Seungtae Kim
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeeyun Lee
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se Hoon Park
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Oh Park
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Ki Kang
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Yeong An
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min Gew Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jun-Ho Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Sung Sohn
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Moon Bae
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Sanguedolce F, Russo D, Mancini V, Selvaggio O, Calo B, Carrieri G, Cormio L. Prognostic and therapeutic role of HER2 expression in micropapillary carcinoma of the bladder. Mol Clin Oncol 2019; 10:205-213. [PMID: 30680196 PMCID: PMC6327213 DOI: 10.3892/mco.2018.1786] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 11/22/2018] [Indexed: 12/18/2022] Open
Abstract
Micropapillary carcinoma of the bladder (MPBC) is a variant type of infiltrating urothelial carcinoma, which portends a poor biological behavior in terms of disease stage at first diagnosis and clinical outcome; its peculiar morphology raises issues concerning the ability of tumor detection by imaging techniques and proper biopsy procedure, and the appropriate treatment for non-muscle infiltrating and muscle-infiltrating MPBC remains a matter of debate. On the basis of its established prognostic and therapeutic role in breast and gastro-esophageal cancer in the first instance, the human epidermal growth factor receptor-2 (HER2) has been investigated in selected case series of MPBC over the last 10 years. The aim of the present review was to summarize the existing evidence on HER2 status in MPBC, and to discuss its present and future utility in risk assessment and treatment choice of this uncommon, yet aggressive, disease.
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Affiliation(s)
| | - Davide Russo
- Department of Pathology, University Hospital, I-71121 Foggia, Italy
| | - Vito Mancini
- Department of Urology and Renal Transplantation, University Hospital, I-71121 Foggia, Italy
| | - Oscar Selvaggio
- Department of Urology and Renal Transplantation, University Hospital, I-71121 Foggia, Italy
| | - Beppe Calo
- Department of Urology and Renal Transplantation, University Hospital, I-71121 Foggia, Italy
| | - Giuseppe Carrieri
- Department of Urology and Renal Transplantation, University Hospital, I-71121 Foggia, Italy
| | - Luigi Cormio
- Department of Urology and Renal Transplantation, University Hospital, I-71121 Foggia, Italy
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Bai XY, Liu YG, Song W, Li YY, Hou DS, Luo HM, Liu P. Anticancer activity of tetrandrine by inducing pro-death apoptosis and autophagy in human gastric cancer cells. J Pharm Pharmacol 2018; 70:1048-1058. [PMID: 29770446 DOI: 10.1111/jphp.12935] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 04/16/2018] [Indexed: 12/11/2022]
Abstract
OBJECTIVES To investigate the antitumour property of tetrandrine by inducing autophagy and apoptosis in human gastric cancer cells, and to explore the potential molecular mechanisms. METHODS The antitumour activity of tetrandrine was assessed through MTT assay. Apoptosis was measured by flow cytometry and microscopic examination of cellular morphology. The mitochondrial membrane potential was detected by staining with Rh-123. Induction of autophagy was monitored by transmission electron microscopy observation, using GFP-LC3 transfection. KEY FINDINGS The results revealed that tetrandrine exhibits significant antitumour activity against gastric human cancer cell and the antigastric tumour activity was depended on inducing autophagy and apoptosis through upregulating the apoptosis-related protein (cleaved PARP, cleaved caspase-3 and cleaved caspase-9) and autophagy-related protein (Beclin-1, LC3-II and p62), and decreasing the phosphorylation of AKT/mTOR, PS6K and P-4EBP1. Adding the inhibitor of autophagy, 3-MA or Baf-A1, increased the viability of tetrandrine-exposed gastric cancer cells, which confirmed the role of autophagy played in the gastric cancer cell death induced by tetrandrine. CONCLUSIONS These results demonstrated that the antitumour effects of tetrandrine by inducing autophagy and apoptosis involving Akt/mTOR pathway. Thus, tetrandrine may be a promising lead compound to be further developed in future for cancer therapy.
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Affiliation(s)
- Xin-Yu Bai
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yuan-Gui Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Wu Song
- College of Basic Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Ying-Ying Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Dong-Shun Hou
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Hao-Ming Luo
- College of Basic Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Ping Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
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Behzatoğlu K, Yörükoğlu K, Demir H, Bal N. Human Epidermal Growth Factor Receptor 2 Overexpression in Micropapillary and Other Variants of Urothelial Carcinoma. Eur Urol Focus 2018; 4:399-404. [DOI: 10.1016/j.euf.2016.06.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/29/2016] [Accepted: 06/11/2016] [Indexed: 01/06/2023]
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11
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Chuang YC, Wu HY, Lin YL, Tzou SC, Chuang CH, Jian TY, Chen PR, Chang YC, Lin CH, Huang TH, Wang CC, Chan YL, Liao KW. Blockade of ITGA2 Induces Apoptosis and Inhibits Cell Migration in Gastric Cancer. Biol Proced Online 2018; 20:10. [PMID: 29743821 PMCID: PMC5928594 DOI: 10.1186/s12575-018-0073-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 02/28/2018] [Indexed: 12/19/2022] Open
Abstract
Background Gastric cancer is currently the fourth leading cause of cancer-related death worldwide. Gastric cancer is often diagnosed at advanced stages and the outcome of the treatment is often poor. Therefore, identifying new therapeutic targets for this cancer is urgently needed. Integrin alpha 2 (ITGA2) subunit and the beta 1 subunit form a heterodimer for a transmembrane receptor for extracellular matrix, is an important molecule involved in tumor cell proliferation, survival and migration. Integrin α2β1 is over-expressed on a variety of cancer cells, but is low or absent in most normal organs and resting endothelial cells. Results In this report, we assessed the ITGA2 as the potential therapeutic target with the bioinformatics tools from the TCGA dataset in which composed of 375 gastric cancer tissues and 32 gastric normal tissues. According to the information from the Cancer Cell Line Encyclopedia (CCLE) database, the AGS cell line with ITGA2 high expression and the SUN-1 cell line with low expression were chosen for the further investigation. Interestingly, the anti-ITGA2 antibody (at 3 μg/ml) inhibited approximately 50% survival of the AGS cells (over-expressed ITGA2), but had no effect in SNU-1 cells (ITGA2 negative). The extents of antibody-mediated cancer inhibition positively correlated with the expression levels of the ITGA2. We further showed that the anti-ITGA2 antibody induced apoptosis by up-regulating the RhoA-p38 MAPK signaling to promote the expressions of Bim, Apaf-1 and Caspase-9, whereas the expressions of Ras and Bax/Bcl-2 were not affected. Moreover, blocking ITGA2 by the specific antibody at lower doses also inhibited cell migration of gastric cancer cells. Blockade of ITGA2 by a specific antibody down-regulated the expression of N-WASP, PAK and LIMK to impede actin organization and cell migration of gastric cancer cells. Conclusions Here, we showed that the mRNA expression levels of ITGA2 comparing to normal tissues significantly increased. In addition, the results revealed that targeting integrin alpha 2 subunit by antibodies did not only inhibit cell migration, but also induce apoptosis effect on gastric cancer cells. Interestingly, higher expression level of ITGA2 led to significant effects on apoptosis progression during anti-ITGA2 antibody treatment, which indicated that ITGA2 expression levels directly correlate with their functionality. Our findings suggest that ITGA2 is a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Yu-Chang Chuang
- 1Departmet of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Hsin-Yi Wu
- 2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Yu-Ling Lin
- 1Departmet of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China.,3Center for Bioinformatics Research, National Chiao Tung University, Hsinchu, Taiwan, Republic of China
| | - Shey-Cherng Tzou
- 1Departmet of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China.,2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Cheng-Hsun Chuang
- 2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Ting-Yan Jian
- 2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Pin-Rong Chen
- 2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China
| | - Yuan-Ching Chang
- 4Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China
| | - Chi-Hsin Lin
- 5Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan, Republic of China
| | - Tse-Hung Huang
- 6Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China.,7School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China.,8School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan, Republic of China
| | - Chao-Ching Wang
- 6Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China
| | - Yi-Lin Chan
- 9Department of Life Science, Chinese Culture University, 55, Hwa-Kang Rd., Yang-Ming-Shan, Taipei, 11114 Taiwan, Republic of China
| | - Kuang-Wen Liao
- 1Departmet of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China.,2Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300 Taiwan, Republic of China.,10College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, Republic of China.,11Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China.,12Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan, Republic of China
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12
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Wang Y, Wang JH, Zhang XL, Wang XL, Yang L. Endoplasmic reticulum chaperone glucose-regulated protein 78 in gastric cancer: An emerging biomarker. Oncol Lett 2018; 15:6087-6093. [PMID: 29616092 DOI: 10.3892/ol.2018.8114] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 06/15/2017] [Indexed: 12/17/2022] Open
Abstract
The endoplasmic reticulum (ER) is the principal organelle responsible for the synthesis, initial post-translational modification, folding, export and secretion of proteins. It is also responsible for the maintenance of cellular homeostasis. In response to cellular stress conditions including glucose deprivation, hypoxia and changes in calcium homeostasis, ER stress machinery is activated and triggers the unfolded protein response, resulting in the restoration of homeostasis or activation of cell death. Glucose-regulated protein 78 (GRP78), a molecular chaperone, may be induced by ER stress at the transcriptional and translational level. A number of studies have demonstrated that GRP78 serves an important role in tumor cell proliferation, metastasis, angiogenesis and drug-resistance. The present review systematically describes the association between GRP78 expression and gastric cancer pathogenesis, and emphasizes that GRP78 is a novel diagnostic and therapeutic biomarker of gastric cancer.
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Affiliation(s)
- Yan Wang
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Jian-Hong Wang
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Xun-Lei Zhang
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Xiao-Li Wang
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Lei Yang
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
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13
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Nika L, Wallner J, Palmberger D, Koczka K, Vorauer-Uhl K, Grabherr R. Expression of full-length HER2 protein in Sf 9 insect cells and its presentation on the surface of budded virus-like particles. Protein Expr Purif 2017; 136:27-38. [DOI: 10.1016/j.pep.2017.06.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 05/19/2017] [Accepted: 06/11/2017] [Indexed: 12/11/2022]
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14
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Wang H, Lu J, Tang J, Chen S, He K, Jiang X, Jiang W, Teng L. Establishment of patient-derived gastric cancer xenografts: a useful tool for preclinical evaluation of targeted therapies involving alterations in HER-2, MET and FGFR2 signaling pathways. BMC Cancer 2017; 17:191. [PMID: 28292264 PMCID: PMC5348902 DOI: 10.1186/s12885-017-3177-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 03/08/2017] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Targeted therapies are emerging treatment options for gastric cancer (GC). Patient-derived tumor xenograft(PDX) models of GC closely retain the features of the original clinical cancer, offering a powerful tool for preclinical drug efficacy testing. This study aimed to establish PDX GC models, and explore therapeutics targeting Her2, MET(cMet), and FGFR2, which may assist doctor to select the proper target therapy for selected patients. METHODS GC tissues from 32 patients were collected and implanted into immuno-deficient mice. Using immunohistochemistry(IHC) and fluorescent in-situ hybridization (FISH), protein levels and/or gene amplification of Her2, cMet and FGFR2 in those tissues were assessed. Finally, anti-tumor efficacy was tested in the PDX models using targeted inhibitors. RESULTS A total of 9 passable PDX models were successfully established from 32 gastric cancer xenograft donors, consisting of HER2,cMet and FGFR2 alterations with percentages of 4(12.5%), 8(25.0%) and 1(3.1%) respectively. Crizotinib and AZD4547 exerted marked antitumor effects exclusively in PDX models with cMet (G30,G31) and FGFR2(G03) amplification. Interestingly, synergistic antitumor activity was observed in G03 (FGFR2-amplifed and cMet non-amplified but IHC [2+]) with simultaneous treatment with Crizotinib and ADZ4547 at day 30 post-treatment. Further in vitro biochemistry study showed a synergistic inhibition of the MAPK/ERK pathway. HER2,cMet and FGFR2 alterations were found in 17 (10.4%), 32(19.6%) and 6(3.7%) in a group of 163 GC patients, and cMet gene amplification or protein overexpression(IHC 3+) was associated with poor prognosis. CONCLUSIONS These PDX GC models provide an ideal platform for drug screening and evaluation. GC patients with positive cMet or FGFR2 gene amplification may potentially benefit from cMet or FGFR2 targeted therapies or combined targeted therapy.
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Affiliation(s)
- Haiyong Wang
- Department of surgical oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, China
| | - Jun Lu
- Department of surgical oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, China
| | - Jian Tang
- Department of oncology, Jiaxing First Hospital, Jiaxing, 314000, Zhejiang Province, China
| | - Shitu Chen
- Department of surgical oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, China
| | - Kuifeng He
- Department of surgical oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, China
| | - Xiaoxia Jiang
- Department of surgical oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, China
| | - Weiqin Jiang
- Department of surgical oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, China
| | - Lisong Teng
- Department of surgical oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, China.
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15
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Ying S, Du X, Fu W, Yun D, Chen L, Cai Y, Xu Q, Wu J, Li W, Liang G. Synthesis, biological evaluation, QSAR and molecular dynamics simulation studies of potential fibroblast growth factor receptor 1 inhibitors for the treatment of gastric cancer. Eur J Med Chem 2017; 127:885-899. [DOI: 10.1016/j.ejmech.2016.10.066] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 10/12/2016] [Accepted: 10/31/2016] [Indexed: 01/06/2023]
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16
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Syu LJ, Zhao X, Zhang Y, Grachtchouk M, Demitrack E, Ermilov A, Wilbert DM, Zheng X, Kaatz A, Greenson JK, Gumucio DL, Merchant JL, di Magliano MP, Samuelson LC, Dlugosz AA. Invasive mouse gastric adenocarcinomas arising from Lgr5+ stem cells are dependent on crosstalk between the Hedgehog/GLI2 and mTOR pathways. Oncotarget 2016; 7:10255-70. [PMID: 26859571 PMCID: PMC4891118 DOI: 10.18632/oncotarget.7182] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Accepted: 01/24/2016] [Indexed: 02/07/2023] Open
Abstract
Gastric adenocarcinoma is the third most common cause of cancer-related death worldwide. Here we report a novel, highly-penetrant mouse model of invasive gastric cancer arising from deregulated Hedgehog/Gli2 signaling targeted to Lgr5-expressing stem cells in adult stomach. Tumor development progressed rapidly: three weeks after inducing the Hh pathway oncogene GLI2A, 65% of mice harbored in situ gastric cancer, and an additional 23% of mice had locally invasive tumors. Advanced mouse gastric tumors had multiple features in common with human gastric adenocarcinomas, including characteristic histological changes, expression of RNA and protein markers, and the presence of major inflammatory and stromal cell populations. A subset of tumor cells underwent epithelial-mesenchymal transition, likely mediated by focal activation of canonical Wnt signaling and Snail1 induction. Strikingly, mTOR pathway activation, based on pS6 expression, was robustly activated in mouse gastric adenocarcinomas from the earliest stages of tumor development, and treatment with rapamycin impaired tumor growth. GLI2A-expressing epithelial cells were detected transiently in intestine, which also contains Lgr5+ stem cells, but they did not give rise to epithelial tumors in this organ. These findings establish that deregulated activation of Hedgehog/Gli2 signaling in Lgr5-expressing stem cells is sufficient to drive gastric adenocarcinoma development in mice, identify a critical requirement for mTOR signaling in the pathogenesis of these tumors, and underscore the importance of tissue context in defining stem cell responsiveness to oncogenic stimuli.
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Affiliation(s)
- Li-Jyun Syu
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Xinyi Zhao
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Yaqing Zhang
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | | | - Elise Demitrack
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Alexandre Ermilov
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Dawn M Wilbert
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Xinlei Zheng
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Ashley Kaatz
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Joel K Greenson
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Deborah L Gumucio
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Juanita L Merchant
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.,Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | | | - Linda C Samuelson
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.,Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - Andrzej A Dlugosz
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.,Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
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17
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Cordts Filho RDM, Kassab P, Claro LCL, Fracassi MTDM, Colombo-Souza P, Fukuhara DK, Thuler FR, de Freitas Junior WR, Ilias EJ, Malheiros CA. Evaluation of the Expression of the Human Epithelial Receptor 2 (HER2) in Gastric Carcinoma. ScientificWorldJournal 2016; 2016:7951365. [PMID: 28105465 PMCID: PMC5220523 DOI: 10.1155/2016/7951365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 12/06/2016] [Indexed: 01/06/2023] Open
Abstract
Objective. To evaluate the HER2 expression on gastric adenocarcinoma from a Brazilian population and also to analyze the relations between the receptor and clinical characteristics, as well as the survival status. Materials and Methods. A retrospective analysis was conducted from January of 2008 to July of 2012, considering only gastrectomies with curative intent. Tumors were tested for HER2 status using immunohistochemistry. The relation between HER2 status and clinical aspects, surgical findings, and survival were also analyzed. Results. 222 patients with gastric carcinoma were submitted to surgery during that period, but only 121 (54,5%) were with curative intention. The immunohistochemistry revealed that 4 patients (3,3%) were HER2-positive, 6 patients (4,9%) HER2-undetermined, and 111 patients (91,7%) HER2-negative. There was no statistical concordance between HER2 status and survival or the clinical aspects. Conclusion. The HER2 overexpression rate was very low in this Brazilian population sample and cannot be considered as a prognostic factor.
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Affiliation(s)
| | - Paulo Kassab
- Gastric and Obesity Surgery Division, Surgery Department, Santa Casa of São Paulo Medical School, São Paulo, SP, Brazil
| | - Laura Carolina Lopez Claro
- Gastric and Obesity Surgery Division, Surgery Department, Santa Casa of São Paulo Medical School, São Paulo, SP, Brazil
| | | | - Patrícia Colombo-Souza
- Gastric and Obesity Surgery Division, Surgery Department, Santa Casa of São Paulo Medical School, São Paulo, SP, Brazil
| | - Daniel Kenji Fukuhara
- Gastric and Obesity Surgery Division, Surgery Department, Santa Casa of São Paulo Medical School, São Paulo, SP, Brazil
| | - Fábio Rodrigues Thuler
- Gastric and Obesity Surgery Division, Surgery Department, Santa Casa of São Paulo Medical School, São Paulo, SP, Brazil
| | | | - Elias Jirjoss Ilias
- Gastric and Obesity Surgery Division, Surgery Department, Santa Casa of São Paulo Medical School, São Paulo, SP, Brazil
| | - Carlos Alberto Malheiros
- Gastric and Obesity Surgery Division, Surgery Department, Santa Casa of São Paulo Medical School, São Paulo, SP, Brazil
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18
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Kim G, Chung YR, Kim B, Song B, Moon KC. Comparison of the FDA and ASCO/CAP Criteria for HER2 Immunohistochemistry in Upper Urinary Tract Urothelial Carcinoma. J Pathol Transl Med 2016; 50:436-441. [PMID: 27725621 PMCID: PMC5122728 DOI: 10.4132/jptm.2016.07.12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 07/11/2016] [Accepted: 07/12/2016] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) is one of the known oncogenes in urothelial carcinoma. However, the association between HER2 and the prognosis of upper urinary tract urothelial carcinoma (UUTUC) has not yet been fully clarified. The aim of this study was to evaluate HER2 expression using the United States Food and Drug Administration (FDA) criteria and American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria and compare their prognostic significance in UUTUC. METHODS HER2 expression was evaluated in 144 cases of UUTUC by immunohistochemistry (IHC) using tissue microarrays. We separately analyzed HER2 expression using the FDA and ASCO/CAP criteria. The IHC results were categorized into low (0, 1+) and high (2+, 3+) groups. RESULTS Using the FDA criteria, 94 cases were negative, 38 cases were 1+, nine cases were 2+, and three cases were 3+. Using the ASCO/CAP criteria, 94 cases were negative, 34 cases were 1+, 13 cases were 2+, and three cases were 3+. Four cases showing 2+ according to the ASCO/CAP criteria were reclassified as 1+ by the FDA criteria. High HER2 expression by both the FDA criteria and ASCO/CAP criteria was significantly associated with International Society of Urological Pathology high grade (p = .001 and p < .001). The high HER2 expression group classified with the FDA criteria showed significantly shorter cancer-specific survival (p = .004), but the HER2 high and low expression groups classified with the ASCO/CAP criteria did not show significant differences (p = .161) in cancer-specific survival. CONCLUSIONS HER2 high expression groups were significantly associated with shorter cancer-specific survival, and our study revealed that the FDA criteria are more suitable for determining HER2 expression in UUTUC.
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Affiliation(s)
- Gilhyang Kim
- Department of Pathology, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Yul Ri Chung
- Department of Pathology, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Bohyun Kim
- Department of Pathology, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Boram Song
- Department of Pathology, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung Chul Moon
- Department of Pathology, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.,Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
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19
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AT13148, a first-in-class multi-AGC kinase inhibitor, potently inhibits gastric cancer cells both in vitro and in vivo. Biochem Biophys Res Commun 2016; 478:330-336. [DOI: 10.1016/j.bbrc.2016.01.167] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 01/27/2016] [Indexed: 12/18/2022]
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20
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Riquelme I, Saavedra K, Espinoza JA, Weber H, García P, Nervi B, Garrido M, Corvalán AH, Roa JC, Bizama C. Molecular classification of gastric cancer: Towards a pathway-driven targeted therapy. Oncotarget 2016; 6:24750-79. [PMID: 26267324 PMCID: PMC4694793 DOI: 10.18632/oncotarget.4990] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 07/17/2015] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer mortality worldwide. Although surgical resection is a potentially curative approach for localized cases of GC, most cases of GC are diagnosed in an advanced, non-curable stage and the response to traditional chemotherapy is limited. Fortunately, recent advances in our understanding of the molecular mechanisms that mediate GC hold great promise for the development of more effective treatment strategies. In this review, an overview of the morphological classification, current treatment approaches, and molecular alterations that have been characterized for GC are provided. In particular, the most recent molecular classification of GC and alterations identified in relevant signaling pathways, including ErbB, VEGF, PI3K/AKT/mTOR, and HGF/MET signaling pathways, are described, as well as inhibitors of these pathways. An overview of the completed and active clinical trials related to these signaling pathways are also summarized. Finally, insights regarding emerging stem cell pathways are described, and may provide additional novel markers for the development of therapeutic agents against GC. The development of more effective agents and the identification of biomarkers that can be used for the diagnosis, prognosis, and individualized therapy for GC patients, have the potential to improve the efficacy, safety, and cost-effectiveness for GC treatments.
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Affiliation(s)
- Ismael Riquelme
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Kathleen Saavedra
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Jaime A Espinoza
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Helga Weber
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | - Patricia García
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Bruno Nervi
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marcelo Garrido
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alejandro H Corvalán
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, Santiago, Chile
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21
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Liang B, Zheng W, Fang L, Wu L, Zhou F, Yin X, Yu X, Zou Z. Overexpressed targeting protein for Xklp2 (TPX2) serves as a promising prognostic marker and therapeutic target for gastric cancer. Cancer Biol Ther 2016; 17:824-32. [PMID: 27314162 DOI: 10.1080/15384047.2016.1195046] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a putative oncogene in different human cancers. This study assessed TPX2 expression in gastric cancer tissue samples and then determined the effects of TPX2 knockdown on the regulation of gastric cancer cell malignant behaviors in vitro. Tissue samples from 115 gastric cancer patients were analyzed for TPX2 expression. The effects of TPX2 siRNA on gastric cancer cells were assessed in vitro, including cell viability, cell cycle distribution, apoptosis, migration, and invasion. The data showed that TPX2 was overexpressed in gastric cancer tissues compared to that in the adjacent normal epithelia. Moreover, TPX2 overexpression was associated with a poor overall survival and was an independent prognostic predictor of gastric cancer. In addition, the in vitro study further confirmed the ex vivo data, i.e., knockdown of TPX2 expression reduced gastric cancer cell viability but induced apoptosis and arrested cells at the G2/M phase of the cell cycle. Knockdown of TPX2 expression also inhibited the tumor cell migration and invasion capacity in vitro. At the gene level, knockdown of TPX2 expression upregulated the levels of cyclin B1, cdk4, p53, Bax, caspase-3, and E-cadherin, but downregulated the levels of cyclin D1, cdk2, N-cadherin, slug, matrix metalloprotease (MMP)-2, and MMP-9, suggesting that knockdown of TPX2 expression suppressed tumor cell epithelial-mesenchymal transition (EMT). This study demonstrated that detection of TPX2 overexpression could serve as a prognostic marker and therapeutic target for gastric cancer.
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Affiliation(s)
- Bo Liang
- a Department of General Surgery , The Second Affiliated Hospital of Nanchang University , Nanchang , Jiangxi , China
| | - Wenjuan Zheng
- b Jiangxi Provincial Center for Disease Control and Prevention , Nanchang , Jiangxi , China
| | - Lu Fang
- a Department of General Surgery , The Second Affiliated Hospital of Nanchang University , Nanchang , Jiangxi , China
| | - Linquan Wu
- a Department of General Surgery , The Second Affiliated Hospital of Nanchang University , Nanchang , Jiangxi , China
| | - Fan Zhou
- a Department of General Surgery , The Second Affiliated Hospital of Nanchang University , Nanchang , Jiangxi , China
| | - Xiangbao Yin
- a Department of General Surgery , The Second Affiliated Hospital of Nanchang University , Nanchang , Jiangxi , China
| | - Xin Yu
- a Department of General Surgery , The Second Affiliated Hospital of Nanchang University , Nanchang , Jiangxi , China
| | - Zhenhong Zou
- a Department of General Surgery , The Second Affiliated Hospital of Nanchang University , Nanchang , Jiangxi , China
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Li Y, Liu X, Jiang D, Lin Y, Wang Y, Li Q, Liu L, Jin YH. Betulin induces reactive oxygen species-dependent apoptosis in human gastric cancer SGC7901 cells. Arch Pharm Res 2016; 39:1257-65. [DOI: 10.1007/s12272-016-0761-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 05/16/2016] [Indexed: 12/26/2022]
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Ma Z, Bao X, Gu J. Effects of laparoscopic radical gastrectomy and the influence on immune function and inflammatory factors. Exp Ther Med 2016; 12:983-986. [PMID: 27446308 DOI: 10.3892/etm.2016.3404] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 05/23/2016] [Indexed: 12/19/2022] Open
Abstract
The effects of laparoscopic radical gastrectomy were observed, and changes in immune function and inflammatory factors of gastric cancer patients were examined. In total, 236 cases of laparoscopic radical gastrectomy were selected between March 2014 and October 2015 and divided into the control and experimental groups. The control group was treated using open radical gastrectomy, while laparoscopic radical gastrectomy was used in the experimental group. Treatment effects, immune function and inflammatory factor in the two groups were compared. Compared to the open radical gastrectomy group, surgery time in the laparoscopic radical gastrectomy group was longer, while blood loss during operation, time of exsufflation through anus after operation, duration of acesodyne use, length of stay and incidence of complications were lower, and the differences were statistically significant (P<0.05). As for the amount of lymph node dissection, differences between the two groups were of no statistical significance (P>0.05). CD3+, CD4+ and CD4+/CD8+ cell ratios in the two groups 1 and 7 days after surgery were obviously lower than those before surgery (P<0.05) while CD8+ was higher. In addition, compared with the open radical gastrectomy group, CD3+, CD4+, CD4+/CD8+ cell ratios in the laparoscopic radical gastrectomy group increased while CD8 was lower, and differences were statistically significant (P<0.05). Differences of interleukin (IL)-6, tumor necrosis factor (TNF) and CRP between the two groups 1 day before surgery were of no statistical significance (P>0.05). One day after surgery, IL-6, TNF and CRP in the two groups increased (P<0.05) and the values in the open radical gastrectomy group were higher (P<0.05). Differences in IL-6 between the two groups 7 days after surgery were of no statistical significance (P>0.05). However, for CRP and TNF, the two values gradually decreased and the differences between the groups were of statistical significance (P<0.05). In conclusion, laparoscopic radical gastrectomy has better treatment effects, lower inflammatory response, less impact on the immune system and fewer complications, which is worth clinical consideration.
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Affiliation(s)
- Zhao Ma
- Department of Gastrointestinal Surgery, The People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Xuebin Bao
- Department of Gastrointestinal Surgery, The People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Junbao Gu
- Department of Gastrointestinal Surgery, The People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
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Efficient isolation and proteomic analysis of cell plasma membrane proteins in gastric cancer reveal a novel differentiation and progression related cell surface marker, R-cadherin. Tumour Biol 2016; 37:11775-11787. [PMID: 27029387 PMCID: PMC5080335 DOI: 10.1007/s13277-016-5032-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 03/18/2016] [Indexed: 12/28/2022] Open
Abstract
Cell plasma membrane proteins, playing a crucial role in cell malignant transformation and development, were the main targets of tumor detection and therapy. In this study, CyDye/biotin double-labeling proteomic approach was adopted to profile the membrane proteome of gastric cancer cell line BGC-823 and paired immortalized gastric epithelial cell GES-1. Real-time PCR, Western blotting, and immunohistochemical staining were used to validate the differential expression of a novel identified cell surface marker R-cadherin in gastric cancer cells and tissues. Clinicopathological study and survival analysis were performed to estimate its roles in tumor progression and outcome prediction. Real-time PCR and Western blotting showed that the expression level of R-cadherin in gastric cancer were significantly lower than non-cancerous epithelial cell and tissues. Clinicopathological study indicated that R-cadherin was dominantly expressed on cell surface of normal gastric epithelium, and its expression deletion in gastric cancer tissues was associated with tumor site, differentiation, lymph node metastasis, and pTNM (chi-square test, P < 0.05). Those patients with R-cadherin positive expression displayed better overall survivals than negative expression group (log-rank test, P = 0.000). Cox multivariate survival analysis revealed lacking the expression of R-cadherin was a main independent predictor for poor clinical outcome in gastric cancer (RR = 5.680, 95 % CI 2.250–14.341, P < 0.01). We have established a fundamental membrane proteome database for gastric cancer and identified R-cadherin as a tumor differentiation and progression-related cell surface marker of gastric cancer. Lacking the expression of R-cadherin indicates poor prognosis in patients with gastric cancer.
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HER2 Protein Overexpression and Gene Amplification in Plasmacytoid Urothelial Carcinoma of the Urinary Bladder. DISEASE MARKERS 2016; 2016:8463731. [PMID: 27034533 PMCID: PMC4806278 DOI: 10.1155/2016/8463731] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 02/18/2016] [Indexed: 01/06/2023]
Abstract
Aim. HER2 overexpression has been reported in a minority of urothelial carcinomas, but little is known about HER2 protein expression and gene alterations in plasmacytoid urothelial carcinoma, a rare and aggressive variant. The aim of this study was to clarify the HER2 status in plasmacytoid urothelial carcinomas. Methods. Six cases of plasmacytoid urothelial carcinoma were included, in which we evaluated HER2 protein expression by immunohistochemistry (IHC) and HER2 gene amplification by fluorescence in situ hybridization (FISH). Results. The patients' ages ranged from 57 to 83 years (mean age, 71 years). Five patients were male and one was female. The ratio of the plasmacytoid component ranged from 30% to 100% (mean, 77%). HER2 expression score was 3+ in 4 cases, 2+ in one case, and negative in one case. HER2 gene amplification was positive in 3 cases, of which 2 cases showed a 3+ HER2 IHC score but one case was negative for HER2 IHC. Another 2 cases showed equivocal HER2 FISH results, and one remaining case was negative for HER2 FISH. Conclusion. Our observation that plasmacytoid urothelial carcinomas frequently demonstrated HER2 protein overexpression provides supporting evidence that HER2 may be a potential therapeutic target for plasmacytoid urothelial carcinoma.
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26
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Kanat O, O’Neil B, Shahda S. Targeted therapy for advanced gastric cancer: A review of current status and future prospects. World J Gastrointest Oncol 2015; 7:401-10. [PMID: 26690491 PMCID: PMC4678387 DOI: 10.4251/wjgo.v7.i12.401] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 09/18/2015] [Accepted: 10/23/2015] [Indexed: 02/05/2023] Open
Abstract
In the West in particular, the vast majority of gastric cancer (GC) patients present with advanced-stage disease. Although combination chemotherapy is still the most important component of treatment for these patients, it confers a modest survival advantage. Recently, increased knowledge of the key molecular signaling pathways involved in gastric carcinogenesis has led to the discovery of specific molecular-targeted therapeutic agents. Some of these agents such as trastuzumab and ramucirumab have changed the treatment paradigm for this disease. In this paper, we will summarize the current clinical status of targeted drug therapy in the management of GC.
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Pecqueux M, Fritzmann J, Adamu M, Thorlund K, Kahlert C, ReiΔfelder C, Weitz J, Rahbari NN. Free intraperitoneal tumor cells and outcome in gastric cancer patients: a systematic review and meta-analysis. Oncotarget 2015; 6:35564-78. [PMID: 26384352 PMCID: PMC4742125 DOI: 10.18632/oncotarget.5595] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 08/22/2015] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Despite continuously improving therapies, gastric cancer still shows poor survival in locally advanced stages with local recurrence rates of up to 50% and peritoneal recurrence rates of 17% after curative surgery. We performed a systematic review with meta-analyses to clarify whether positive intraperitoneal cytology (IPC) indicates a high risk of disease recurrence and poor overall survival in gastric cancer. METHODS Multiple databases were searched in December 2014 to identify studies on the prognostic significance of positive intraperitoneal cytology in gastric cancer, including: Medline, Biosis, Science Citation Index, Embase, CCMed and publisher databases. Hazard ratios (HR) and associated 95% confidence intervals (CI) were extracted from the identified studies. A meta-analysis was performed using a random-effects model on overall survival, disease-free survival and peritoneal recurrence free survival. RESULTS A total of 64 studies with a cumulative sample size of 12,883 patients were included. Cytology, quantitative real time polymerase chain reaction (PCR) or both were performed in 35; 21 and 8 studies, respectively. Meta analyses revealed free intraperitoneal tumor cells (FITC) to be associated with poor overall survival in univariate (HR 3.27; 95% CI 2.82 - 3.78]) and multivariate (HR 2.45; 95% CI 2.04 - 2.94) analysis and poor peritoneal recurrence free survival in univariate (4.15; 95% CI 3.10 - 5.57) and multivariate (3.09; 95% CI 2.02 - 4.71) analysis. Subgroup analysis showed this effect to be independent of the detection method, Western or Asian origin or the time of publication. CONCLUSIONS FITC oder positive peritoneal cytology is associated with poor survival and increased peritoneal recurrence in gastric cancer.
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Affiliation(s)
- Mathieu Pecqueux
- Department for Visceral, Thoracic and Vascular Surgery, University of Dresden, Dresden, Germany
| | - Johannes Fritzmann
- Department for Visceral, Thoracic and Vascular Surgery, University of Dresden, Dresden, Germany
| | - Mariam Adamu
- Department for Visceral, Thoracic and Vascular Surgery, University of Dresden, Dresden, Germany
| | - Kristian Thorlund
- Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada
| | - Christoph Kahlert
- Department for Visceral, Thoracic and Vascular Surgery, University of Dresden, Dresden, Germany
| | - Christoph ReiΔfelder
- Department for Visceral, Thoracic and Vascular Surgery, University of Dresden, Dresden, Germany
| | - Jürgen Weitz
- Department for Visceral, Thoracic and Vascular Surgery, University of Dresden, Dresden, Germany
| | - Nuh N. Rahbari
- Department for Visceral, Thoracic and Vascular Surgery, University of Dresden, Dresden, Germany
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28
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Böger C, Warneke VS, Behrens HM, Kalthoff H, Goodman SL, Becker T, Röcken C. Integrins αvβ3 and αvβ5 as prognostic, diagnostic, and therapeutic targets in gastric cancer. Gastric Cancer 2015; 18:784-95. [PMID: 25315085 PMCID: PMC4572058 DOI: 10.1007/s10120-014-0435-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Accepted: 09/23/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND We investigated the expression of two αv integrins, αvβ3 and αvβ5, in gastric cancer (GC) by testing the following hypotheses: that these molecules are expressed in GC; that they are implicated in GC biology; that they help to distinguish between the two major histological subtypes of GC, according to Laurén; and that they are prognostically relevant. METHODS Formalin-fixed and paraffin-embedded tissue samples from 482 GC samples were stained immunohistochemically using rabbit monoclonal antibodies directed against αvβ3 (EM22703) and αvβ5 (EM09902). Immunostaining of tumor, stroma, and endothelial cells was evaluated separately by the quantity and intensity, generating an immunoreactivity score. The immunoreactivity score of both antibodies was correlated with clinicopathology data and patient survival. RESULTS Each integrin was expressed in at least one tumor component in all GCs. Both were expressed significantly more often in the intestinal phenotype according to Laurén. Moreover, patients who grouped as "positive" for expression of αvβ3 on endothelial cells, and patients with an intestinal type GC, grouped as "negative" for expression of αvβ5 on stroma cells, had significantly longer survival. The expression of αvβ5 on stroma cells was confirmed to be an independent prognostic factor of intestinal-type GC. CONCLUSION The expression of αvβ3 and αvβ5 in at least one tumor component in all GC samples is an interesting new result that should form a basis for further investigations; for example, regarding selective integrin antagonists and the value of αvβ3 and αvβ5 as putative prognostic biomarkers. Moreover, both markers might be helpful in the routine classification of GC subtypes.
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Affiliation(s)
- Christine Böger
- Department of Pathology, Christian Albrechts University, Arnold-Heller-Str. 3, Haus 14, 24105, Kiel, Germany
| | - Viktoria S Warneke
- Department of Pathology, Christian Albrechts University, Arnold-Heller-Str. 3, Haus 14, 24105, Kiel, Germany
| | - Hans-Michael Behrens
- Department of Pathology, Christian Albrechts University, Arnold-Heller-Str. 3, Haus 14, 24105, Kiel, Germany
| | - Holger Kalthoff
- Department of Experimental Cancer Research, Christian Albrechts University, Kiel, Germany
| | - Simon L Goodman
- Oncology Platform, Department of Translational and Biomarkers Research, Merck KGaA, Darmstadt, Germany
| | - Thomas Becker
- Department of General Surgery and Thoracic Surgery, Christian Albrechts University, Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, Christian Albrechts University, Arnold-Heller-Str. 3, Haus 14, 24105, Kiel, Germany.
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Chen DH, Yu JW, Jiang BJ. Contactin 1: A potential therapeutic target and biomarker in gastric cancer. World J Gastroenterol 2015; 21:9707-9716. [PMID: 26361417 PMCID: PMC4562954 DOI: 10.3748/wjg.v21.i33.9707] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Revised: 06/02/2015] [Accepted: 07/15/2015] [Indexed: 02/06/2023] Open
Abstract
Despite advances in diagnosis and treatment, gastric cancer remains one of the most common malignant tumors worldwide, and early diagnosis remains a challenge. The lack of effective methods to detect these tumors early is a major factor contributing to the high mortality in patients with gastric cancer, who are typically diagnosed at an advanced stage. Additionally, the early detection of metastases and the curative treatment of gastric cancer are difficult to achieve, and the detailed mechanisms remain to be fully elucidated. Thus, the identification of valuable predictive biomarkers and therapeutic targets to improve the prognosis of patients with gastric cancer is becoming increasingly important. Contactin 1 (CNTN1), a cell adhesion molecule, is a glycosylphosphatidylinositol-anchored neuronal membrane protein that plays an important role in cancer progression. The expression of CNTN1 is upregulated in primary lesions, and its expression level correlates with tumor metastasis in cancer patients. The current evidence reveals that the functions of CNTN1 in the development and progression of cancer likely promote the invasion and metastasis of cancer cells via the VEGFC/FLT4 axis, the RHOA-dependent pathway, the Notch signaling pathway and the epithelial-mesenchymal transition progression. Therefore, CNTN1 may be a novel biomarker and a possible therapeutic target in cancer treatment in the near future.
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Single nucleotide polymorphisms in AREG and EREG are prognostic biomarkers in locally advanced gastric cancer patients after surgery with curative intent. Pharmacogenet Genomics 2015; 24:539-47. [PMID: 25203737 DOI: 10.1097/fpc.0000000000000087] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Amphiregulin (AREG) and epiregulin (EREG) are important ligands to the epithelial growth factor receptor, which is involved in the regulation of progression and stemness in gastric cancer (GC). This study investigated whether frequent single nucleotide polymorphisms (SNPs) in genes of AREG and EREG are associated with recurrence-free survival and overall survival in patients with locally advanced GC. METHODS SNPs with a minor allele frequency of at least 10% were analyzed using direct DNA sequencing in two independent study populations. RESULTS The minor allele of AREG rs1615111 was associated with a significantly higher 3-year recurrence rate and lower 3-year survival rate [hazard ratio (HR)=2.21 and 2.35, respectively] compared with patients homozygous for the dominant allele G. The value for overall survival could be validated with a HR of 2.54 (P=0.018) in an independent cohort. Patients homozygous for the minor allele A of EREG rs12641042 had a significantly higher 3-year survival rate than patients with allele C (HR 0.48; P=0.034), but significance was lost in multivariable analysis (P=0.066). The value of rs12641042 could not be validated (P=0.98). Exploratory multivariable subgroup analysis showed the strongest prognostic value for rs1615111 in tumors with a diffuse histology (Pfor interaction=0.004). CONCLUSION AREG rs1615111, located in the AREG genomic region, can significantly define different prognostic cohorts in locally advanced GC. This value is most evident in GC patients with diffuse histology, which might be relevant as none of the trials testing epithelial growth factor receptor inhibitors has been enriched for diffuse histology or a molecularly defined population.
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Yan HC, Wang HB. Significance of expression of ECT2 in gastric cancer. Shijie Huaren Xiaohua Zazhi 2015; 23:2215-2220. [DOI: 10.11569/wcjd.v23.i14.2215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of epithelial cell transforming sequence 2 (ECT2) in gastric cancer (GC) and to analyze its correlation with clinicopathological characteristics.
METHODS: Immunohistochemistry (IHC) and RT-PCR were used to examine the expression of ECT2 protein and mRNA in GC tissues and paired adjacent normal tissues. The correlation between ECT2 expression and clinicopathological characteristics was then analyzed.
RESULTS: In comparison with adjacent normal tissues (36.0%), the expression of ECT2 protein in GC tissues (76.0%) was significantly higher (P < 0.01), and the expression of ECT2 mRNA in GC tissues was also significantly higher in GC tissues than in adjacent normal tissues. The expression of ECT2 protein and mRNA was related to histologic differentiation, TNM stage and lymph node metastasis in GC (P < 0.05), but not to gender, age or tumor size (P > 0.05).
CONCLUSION: Both ECT2 protein and mRNA are overexpressed in GC, and ECT2 expression correlates with the histologic differentiation, TNM stage and lymph node metastasis in GC. ECT2 may play an important role during GC progression, and may serve as a good factor to indicate biologic behavior of GC.
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Morphological and molecular characteristics of HER2 amplified urothelial bladder cancer. Virchows Arch 2015; 466:703-10. [PMID: 25809292 PMCID: PMC4460277 DOI: 10.1007/s00428-015-1729-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 12/18/2014] [Accepted: 01/26/2015] [Indexed: 02/06/2023]
Abstract
Several (pre-) clinical trials are currently investigating the benefit of HER2-targeted therapy in urothelial bladder cancer (UBC). Patients with HER2 amplified UBC could potentially profit from these therapies. However, little is known about histomorphology, HER2 protein expression patterns and occurrence of alterations in the HER2 gene in their tumors. Among 150 metastasizing primary UBC, 13 HER2 amplified tumors were identified. Their histopathological features were compared with 13 matched, non-amplified UBC. HER2 protein expression was determined by immunohistochemistry. The 26 tumors were screened for mutations in exons 19 and 20 of the HER2 gene. UBC with HER2 amplification presented with a broad variety of histological variants (median 2 vs. 1), frequently featured micropapillary tumor components (77 % vs. 8 %) and demonstrated a high amount of tumor associated inflammation. Immunohistochemically, 10 of 13 (77 %) HER2 amplified tumors were strongly HER2 protein positive. Three tumors (23 %) were scored as HER2 negative. One of the HER2 amplified tumors harbored a D769N mutation in exon 19 of the HER2 gene; all other tested tumors were wild type. In conclusion, HER2 amplified UBC feature specific morphological characteristics. They frequently express the HER2 protein diffusely and are, therefore, promising candidates for HER2 targeted therapies. The detection of mutations at the HER2 locus might add new aspects to molecular testing of UBC.
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Deng J, Liang H, Dong Q, Hou Y, Xie X, Yu J, Fan D, Hao X. The survival decrease in gastric cancer is associated with the methylation of B-cell CLL/lymphoma 6 member B promoter. Open Biol 2015; 4:rsob.140067. [PMID: 25008234 PMCID: PMC4118602 DOI: 10.1098/rsob.140067] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The methylation of B-cell CLL/lymphoma 6 member B (BCL6B) DNA promoter was detected in several malignancies. Here, we quantitatively detect the methylated status of CpG sites of BCL6B DNA promoter of 459 patients with gastric cancer (GC) by using bisulfite gene sequencing. We show that patients with three or more methylated CpG sites in the BCL6B promoter were significantly associated with poor survival. Furthermore, by using the Akaike information criterion value calculation, we show that the methylated count of BCL6B promoter was identified to be the optimal prognostic predictor of GC patients.
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Affiliation(s)
- Jingyu Deng
- Department of Gastroenterology, Tianjin Medical University Cancer Hospital, City Key Laboratory of Tianjin Cancer Center and National Clinical Research Center for Cancer, Tianjin, People's Republic of China
| | - Han Liang
- Department of Gastroenterology, Tianjin Medical University Cancer Hospital, City Key Laboratory of Tianjin Cancer Center and National Clinical Research Center for Cancer, Tianjin, People's Republic of China
| | - Qiuping Dong
- Central Laboratory, Tianjin Medical University Cancer Hospital, City Key Laboratory of Tianjin Cancer Center and National Clinical Research Center for Cancer, Tianjin, People's Republic of China
| | - Yachao Hou
- Department of Gastroenterology, Tianjin Medical University Cancer Hospital, City Key Laboratory of Tianjin Cancer Center and National Clinical Research Center for Cancer, Tianjin, People's Republic of China
| | - Xingming Xie
- Department of Gastroenterology, Tianjin Medical University Cancer Hospital, City Key Laboratory of Tianjin Cancer Center and National Clinical Research Center for Cancer, Tianjin, People's Republic of China
| | - Jun Yu
- Institute of Digestive Disease, Li Ka Shing Institute of Health Science, Chinese University of HongKong, Shatin, Hong Kong
| | - Daiming Fan
- State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China
| | - Xishan Hao
- Department of Gastroenterology, Tianjin Medical University Cancer Hospital, City Key Laboratory of Tianjin Cancer Center and National Clinical Research Center for Cancer, Tianjin, People's Republic of China
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Hack SP, Bruey JM, Koeppen H. HGF/MET-directed therapeutics in gastroesophageal cancer: a review of clinical and biomarker development. Oncotarget 2015; 5:2866-80. [PMID: 24930887 PMCID: PMC4102777 DOI: 10.18632/oncotarget.2003] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Aberrant activation of the HGF/MET signaling axis has been strongly implicated in the malignant transformation and progression of gastroesophageal cancer (GEC). MET receptor overexpression in tumor samples from GEC patients has been consistently correlated with an aggressive metastatic phenotype and poor prognosis. In preclinical GEC models, abrogation of HGF/MET signaling has been shown to induce tumor regression as well as inhibition of metastatic dissemination. Promising clinical results in patient subsets in which MET is overexpressed have spurned several randomized studies of HGF/MET-directed agents, including two pivotal global Phase III trials. Available data highlight the need for predictive biomarkers in order to select patients most likely to benefit from HGF/MET inhibition. In this review, we discuss the current knowledge of mechanisms of MET activation in GEC, the current status of the clinical evaluation of MET-targeted therapies in GEC, characteristics of ongoing randomized GEC trials and the associated efforts to identify and validate biomarkers. We also discuss the considerations and challenges for HGF/MET inhibitor drug development in the GEC setting.
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Affiliation(s)
- Stephen P Hack
- Product Development, Genentech Inc., South San Francisco, CA, USA
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35
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Tanriverdi O, Ogunc H. A case report of three patients with metastatic gastric cancer on hemodialysis who were treated with cisplatin-fluorouracil regimen. J Oncol Pharm Pract 2015; 22:345-9. [PMID: 25567516 DOI: 10.1177/1078155214567160] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Gastric carcinoma is the first cause of death worldwide. In previous studies that included best supportive care and chemotherapy comparison, chemotherapy survival time was four to five months more than best supportive care. This time was reported as seven to nine months in cisplatin and fluorouracil therapy. We aimed to call attention to non-progression survival time which was being longer with cisplatin and fluorouracil therapy in three metastatic gastric carcinoma patients who were on hemodialysis due to chronic renal impairment related to diabetic nephropathy. We determined that this regimen was well tolerated with hemodialysis, and the median time to progression was eight months (range 7-10). This time was similar to the time results of previous studies. In our hypothesis, hemodialysis may increase the time to progression significantly and we aimed to discuss the hypothetical relation between dialysis membrane and circulating tumor cells.
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Affiliation(s)
- Ozgur Tanriverdi
- Faculty of Medicine, Department of Medical Oncology, Mugla Sitki Kocman University, Mugla, Turkey
| | - Handan Ogunc
- Nephrology Unit, Ordu Governmental Hospital, Ordu, Turkey
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Zhou W, Cao A, Wang L, Wu D. Kurarinone Synergizes TRAIL-Induced Apoptosis in Gastric Cancer Cells. Cell Biochem Biophys 2014; 72:241-9. [DOI: 10.1007/s12013-014-0444-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Kim S, Lee J, Hong ME, Do IG, Kang SY, Ha SY, Kim ST, Park SH, Kang WK, Choi MG, Lee JH, Sohn TS, Bae JM, Kim S, Kim DH, Kim KM. High-throughput sequencing and copy number variation detection using formalin fixed embedded tissue in metastatic gastric cancer. PLoS One 2014; 9:e111693. [PMID: 25372287 PMCID: PMC4221102 DOI: 10.1371/journal.pone.0111693] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 09/29/2014] [Indexed: 01/29/2023] Open
Abstract
In the era of targeted therapy, mutation profiling of cancer is a crucial aspect of making therapeutic decisions. To characterize cancer at a molecular level, the use of formalin-fixed paraffin-embedded tissue is important. We tested the Ion AmpliSeq Cancer Hotspot Panel v2 and nCounter Copy Number Variation Assay in 89 formalin-fixed paraffin-embedded gastric cancer samples to determine whether they are applicable in archival clinical samples for personalized targeted therapies. We validated the results with Sanger sequencing, real-time quantitative PCR, fluorescence in situ hybridization and immunohistochemistry. Frequently detected somatic mutations included TP53 (28.17%), APC (10.1%), PIK3CA (5.6%), KRAS (4.5%), SMO (3.4%), STK11 (3.4%), CDKN2A (3.4%) and SMAD4 (3.4%). Amplifications of HER2, CCNE1, MYC, KRAS and EGFR genes were observed in 8 (8.9%), 4 (4.5%), 2 (2.2%), 1 (1.1%) and 1 (1.1%) cases, respectively. In the cases with amplification, fluorescence in situ hybridization for HER2 verified gene amplification and immunohistochemistry for HER2, EGFR and CCNE1 verified the overexpression of proteins in tumor cells. In conclusion, we successfully performed semiconductor-based sequencing and nCounter copy number variation analyses in formalin-fixed paraffin-embedded gastric cancer samples. High-throughput screening in archival clinical samples enables faster, more accurate and cost-effective detection of hotspot mutations or amplification in genes.
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Affiliation(s)
- Seokhwi Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeeyun Lee
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min Eui Hong
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Cancer Companion Diagnostics Center, Samsung Medical Center, Seoul, Korea
| | - In-Gu Do
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Cancer Companion Diagnostics Center, Samsung Medical Center, Seoul, Korea
| | - So Young Kang
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang Yun Ha
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Tae Kim
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se Hoon Park
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Ki Kang
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min-Gew Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jun Ho Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Sung Sohn
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Moon Bae
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Duk-Hwan Kim
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Kyoung-Mee Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Cancer Companion Diagnostics Center, Samsung Medical Center, Seoul, Korea
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Matsuoka T, Yashiro M. Rho/ROCK signaling in motility and metastasis of gastric cancer. World J Gastroenterol 2014; 20:13756-13766. [PMID: 25320513 PMCID: PMC4194559 DOI: 10.3748/wjg.v20.i38.13756] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 04/21/2014] [Accepted: 06/13/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is one of the most frequent and lethal malignancies worldwide because of high frequency of metastasis. Tumor cell motility and invasion play fundamental roles in cancer metastasis. Recent studies have revealed that the Rho/Rho-associated protein kinases (ROCK) pathway plays a critical role in the regulation of cancer cell motility and invasion. In addition, the Rho/ROCK pathway plays important roles in invasion and metastasis on the basis of its predominant function of cell cytoskeletal regulation in gastric cancer. According to the current understanding of tumor motility, there are two modes of tumor cell movement: mesenchymal and amoeboid. In addition, cancer cell movement can be interchangeable between the mesenchymal and amoeboid movements under certain conditions. Control of cell motility through the actin cytoskeleton creates the potential for regulating tumor cell metastasis. In this review we discuss Rho GTPases and ROCK signaling and describe the mechanisms of Rho/ROCK activity with regard to motility and metastasis in gastric cancer. In addition, we provide an insight of the therapeutic potential of targeting the Rho/ROCK pathway.
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Schildberg CW, Weidinger T, Hohenberger W, Wein A, Langheinrich M, Neurath M, Boxberger F. Metastatic adenocarcinomas of the stomach or esophagogastric junction (UICC stage IV) are not always a palliative situation: a retrospective analysis. World J Surg 2014; 38:419-25. [PMID: 24146196 DOI: 10.1007/s00268-013-2293-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Gastric cancer is one of the most common cancers. Unfortunately, it is often diagnosed at the advanced stage International Union Against Cancer stage IV. This induced us to carry out an interdisciplinary analysis of this patient group with the Department of Internal Medicine 1. Our aim was to discuss cancers classified initially as unresectable in a meeting of the interdisciplinary tumor board after palliative chemotherapy, and to refer selected patients for surgery after establishing resectability. The outcome of the chemotherapy, operation method, complication rate, and long-term survival were analyzed. METHODS From 1999 to 2008, 76 patients with metastatic gastric cancer or carcinoma of the esophagogastric junction were discussed by the interdisciplinary tumor board of the University of Erlangen and classified initially as unresectable. The patients then received palliative chemotherapy according to the AIO regimen (weekly high-dose 5-fluorouracil/folinic acid [FU/FA] in a 24 h infusion), plus irinotecan. If the tumor was subsequently classified as resectable, the patient underwent either gastric resection or gastrectomy with DII-III dissection. Metastases were resected depending on their location (liver). Peritoneal carcinomatosis was treated additionally by HIPEC. Statistical analysis was with SPSSS version 20. RESULTS Surgical and general complications and hospital mortality were acceptable. There were no cases of anastomotic leak, but one patient died of fulminant pneumonia. The R0 resection rate was 69 %, and four patients had long-term survival of more than 60 months. There were significant survival advantages. CONCLUSIONS Metastatic gastric cancer or carcinoma of the esophagogastric junction can become resectable after downsizing the tumor with palliative chemotherapy. Long-term survival is achieved in some cases. Therefore, every patient with this type of cancer should be discussed by the interdisciplinary tumour board after palliative chemotherapy to provide him with a chance of cure after re-evaluation.
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Affiliation(s)
- Claus W Schildberg
- Department of Surgery, University of Erlangen/Nürnberg, Krankenhausstrasse 12, 91054, Erlangen, Germany,
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Pinheiro DDR, Ferreira WAS, Barros MBL, Araújo MD, Rodrigues-Antunes S, Borges BDN. Perspectives on new biomarkers in gastric cancer: Diagnostic and prognostic applications. World J Gastroenterol 2014; 20:11574-11585. [PMID: 25206265 PMCID: PMC4155351 DOI: 10.3748/wjg.v20.i33.11574] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 03/14/2014] [Accepted: 05/05/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is considered one of the most deadly tumors worldwide. Even with the decline in its incidence, the mortality rate of this disease has remained high, mainly due to its late diagnosis and to the lack of precise prognostic markers. The main purpose of this review is to present genetic, epigenetic and proteomic molecular markers that may be used in a diagnostic and prognostic manner and to discuss the pros and cons of each type of marker for improving clinical practice. In this sense, we observed that the use of genetic markers, especially mutations and polymorphisms, should be carefully considered, as they are strongly affected by ethnicity. Proteomic-based markers show promise, but the higher costs of the associated techniques continue to make this approach expensive for routine use. Alternatively, epigenetic markers appear to be very promising, as they can be detected in bodily fluids as well as tissues. However, such markers must be used carefully because epigenetic changes may occur due to environmental factors and aging. Despite the advances in technology and its access, to date, there are few defined biomarkers of prognostic and diagnostic use for gastric tumors. Therefore, the use of a panel of several approaches (genetic, epigenetic and proteomic) should be considered the best alternative for clinical practice.
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41
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Wolfrom CM, Laurent M, Deschatrette J. Can we negotiate with a tumor? PLoS One 2014; 9:e103834. [PMID: 25084359 PMCID: PMC4118912 DOI: 10.1371/journal.pone.0103834] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 07/08/2014] [Indexed: 12/18/2022] Open
Abstract
Recent progress in deciphering the molecular portraits of tumors promises an era of more personalized drug choices. However, current protocols still follow standard fixed-time schedules, which is not entirely coherent with the common observation that most tumors do not grow continuously. This unpredictability of the increases in tumor mass is not necessarily an obstacle to therapeutic efficiency, particularly if tumor dynamics could be exploited. We propose a model of tumor mass evolution as the integrated result of the dynamics of two linked complex systems, tumor cell population and tumor microenvironment, and show the practical relevance of this nonlinear approach.
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Affiliation(s)
- Claire M. Wolfrom
- Equipe « Dynamiques cellulaires et modélisation », Inserm Unité 757, Université Paris-Sud, Orsay, France
| | - Michel Laurent
- Equipe « Dynamiques cellulaires et modélisation », Inserm Unité 757, Université Paris-Sud, Orsay, France
| | - Jean Deschatrette
- Equipe « Dynamiques cellulaires et modélisation », Inserm Unité 757, Université Paris-Sud, Orsay, France
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42
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Duffy MJ, Lamerz R, Haglund C, Nicolini A, Kalousová M, Holubec L, Sturgeon C. Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update. Int J Cancer 2014; 134:2513-22. [PMID: 23852704 PMCID: PMC4217376 DOI: 10.1002/ijc.28384] [Citation(s) in RCA: 245] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 06/25/2013] [Indexed: 02/06/2023]
Abstract
Biomarkers currently play an important role in the detection and management of patients with several different types of gastrointestinal cancer, especially colorectal, gastric, gastro-oesophageal junction (GOJ) adenocarcinomas and gastrointestinal stromal tumors (GISTs). The aim of this article is to provide updated and evidence-based guidelines for the use of biomarkers in the different gastrointestinal malignancies. Recommended biomarkers for colorectal cancer include an immunochemical-based fecal occult blood test in screening asymptomatic subjects ≥50 years of age for neoplasia, serial CEA levels in postoperative surveillance of stage II and III patients who may be candidates for surgical resection or systemic therapy in the event of distant metastasis occurring, K-RAS mutation status for identifying patients with advanced disease likely to benefit from anti-EGFR therapeutic antibodies and microsatellite instability testing as a first-line screen for subjects with Lynch syndrome. In advanced gastric or GOJ cancers, measurement of HER2 is recommended in selecting patients for treatment with trastuzumab. For patients with suspected GIST, determination of KIT protein should be used as a diagnostic aid, while KIT mutational analysis may be used for treatment planning in patients with diagnosed GISTs.
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Affiliation(s)
- MJ Duffy
- Clinical Research Center, St Vincent’s University Hospital, Dublin 4 and UCD School of Medicine and Medical Science, Conway Institute, University College DublinDublin, Ireland
| | - R Lamerz
- Medical Department II, Klinikum Grosshadern, Med. Klinik IIMunich, Germany
| | - C Haglund
- Department of Surgery, Helsinki University Central HospitalHelsinki, Finland
| | - A Nicolini
- Department of Oncology, University of PisaPisa, Italy
| | - M Kalousová
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University in Prague and General University Hospital in PraguePrague, Czech Republic
| | - L Holubec
- Department of Oncology and Radiotherapy, University Hospital of PilsenPilsen, Czech Republic
| | - C Sturgeon
- Department of Clinical Biochemistry, Royal Infirmary of EdinburghEdinburgh, United Kingdom
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Ji D, Zhang Z, Cheng L, Chang J, Wang S, Zheng B, Zheng R, Sun Z, Wang C, Zhang Z, Liu R, Zhang X, Liu X, Wang X, Li J. The combination of RAD001 and MK-2206 exerts synergistic cytotoxic effects against PTEN mutant gastric cancer cells: involvement of MAPK-dependent autophagic, but not apoptotic cell death pathway. PLoS One 2014; 9:e85116. [PMID: 24416349 PMCID: PMC3887024 DOI: 10.1371/journal.pone.0085116] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 11/30/2013] [Indexed: 12/18/2022] Open
Abstract
In the current study, we showed that the combination of mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and Akt inhibitor MK-2206 exerted synergistic cytotoxic effects against low-phosphatase and tensin homolog (PTEN) gastric cancer cells (HGC-27 and SNU-601 lines). In HGC-27 cells, RAD001 and MK-2206 synergistically induced G1/S cell cycle arrest, growth inhibition, cell death but not apoptosis. RAD001 and MK-2206 synergistically induced light chain 3B (LC3B) and beclin-1 expression, two important autophagy indicators. Meanwhile, the autophagy inhibitor 3-methyladenine (3-MA) and chloroquine inhibited the cytotoxic effects by RAD001 and MK-2206, suggesting that autophagic, but not apoptotic cell death was important for the cytotoxic effects by the co-administration. We observed that the combination of RAD001 and MK-2206 exerted enhanced effects on Akt/mTOR inhibition, cyclin D1 down-regulation and ERK/MAPK(extracellular signal-regulated kinase/mitogen-activated protein kinases) activation. Intriguingly, MEK/ERK inhibitors PD98059 and U0126 suppressed RAD001 plus MK-2206-induced beclin-1 expression, autophagy induction and cytotoxicity in HGC-27 cells. In conclusion, these results suggested that the synergistic anti-gastric cancer cells ability by RAD001 and MK-2206 involves ERK-dependent autophagic cell death pathway.
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Affiliation(s)
- Dongmei Ji
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhe Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lei Cheng
- Department of Interventional Radiology, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, Jiangsu, China
| | - Jinjia Chang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shanshan Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Biqiang Zheng
- Department of Gastric Cancer and Soft Tissue Sarcomas, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Rongliang Zheng
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zuojun Sun
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chenchen Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhiqing Zhang
- Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China
| | - Rujiao Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaowei Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xin Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaofeng Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jin Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China
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Hong L, Han Y, Brain L. The role of epidermal growth factor receptor in prognosis and treatment of gastric cancer. Expert Rev Gastroenterol Hepatol 2014; 8:111-7. [PMID: 24410474 DOI: 10.1586/17474124.2014.844648] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Despite tremendous efforts to reduce deaths due to gastric cancer, it represents the second leading cause of cancer-related deaths worldwide. EGF receptor (EGFR) plays important roles in gastric carcinogenesis by regulation of cell cycle, angiogenesis and apoptosis. This review evaluates the functions, mechanisms and clinical uses of EGFR in gastric cancer. Although EGFR targeted single therapy shows limited effect, the combination of EGFR targeted agents with traditional chemotherapy regimens may bring about important progress in cancer therapy. More clinical trials should be performed to clarify both the prognostic and therapeutic value of EGFR in gastric cancer.
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Affiliation(s)
- Liu Hong
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
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45
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Hong L, Han Y, Liu J, Brain L. Fibroblast growth factor receptor 2: a therapeutic target in gastric cancer. Expert Rev Gastroenterol Hepatol 2013; 7:759-65. [PMID: 24134151 DOI: 10.1586/17474124.2013.837804] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gastric cancer remains a leading cause of cancer-related death in the world. FGF receptor 2 (FGFR2) is preferentially amplified and overexpressed in the diffuse type of gastric cancer. This review evaluates the expression and function of FGFR2 in gastric cancer, and analyzes the use of its inhibitors for gastric cancer therapy. This review also discusses the limitations of FGFR2-based therapy, and envisages future developments toward the clinical applications of FGFR2.
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Affiliation(s)
- Liu Hong
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China
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46
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Qian C, Yao J, Wang J, Wang L, Xue M, Zhou T, Liu W, Si J. ERK1/2 inhibition enhances apoptosis induced by JAK2 silencing in human gastric cancer SGC7901 cells. Mol Cell Biochem 2013; 387:159-70. [PMID: 24178240 DOI: 10.1007/s11010-013-1881-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2013] [Accepted: 10/18/2013] [Indexed: 12/11/2022]
Abstract
Recent studies suggest JAK2 signaling may be a therapeutic target for treatment of gastric cancer (GC). However, the exact roles of JAK2 in gastric carcinogenesis are not very clear. Here, we have targeted JAK2 to be silenced by shRNA and investigated the biological functions and related mechanisms of JAK2 in GC cell SGC7901. In this study, JAK2 is commonly highly expressed in GC tissues as compared to their adjacent normal tissues (n = 75, p < 0.01). Specific down-regulation of JAK2 suppressed cell proliferation and colony-forming units, induced G2/M arrest in SGC7901 cells, but had no significant effect on cell apoptosis in vitro or tumor growth inhibition in vivo. Interestingly, JAK2 silencing-induced activation of ERK1/2, and inactivation of ERK1/2 using the specific ERK inhibitor PD98059 markedly enhanced JAK2 shRNA-induced cell proliferation inhibition, cell cycle arrest and apoptosis. Ultimately, combination of PD98059 and JAK2 shRNA significantly inhibited tumor growth in nude mice. Our results implicate JAK2 silencing-induced cell proliferation inhibition, cell cycle arrest, and ERK1/2 inhibition could enhance apoptosis induced by JAK2 silencing in SGC7901 cells.
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Affiliation(s)
- Cuijuan Qian
- Institute of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, Zhejiang, People's Republic of China
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Luis M, Tavares A, Carvalho LS, Lara-Santos L, Araújo A, Mello RAD. Personalizing therapies for gastric cancer: molecular mechanisms and novel targeted therapies. World J Gastroenterol 2013; 19:6383-97. [PMID: 24151357 PMCID: PMC3801309 DOI: 10.3748/wjg.v19.i38.6383] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 07/24/2013] [Accepted: 08/05/2013] [Indexed: 02/06/2023] Open
Abstract
Globally, gastric cancer is the 4(th) most frequently diagnosed cancer and the 2(nd) leading cause of death from cancer, with an estimated 990000 new cases and 738000 deaths registered in 2008. In the advanced setting, standard chemotherapies protocols acquired an important role since last decades in prolong survival. Moreover, recent advances in molecular therapies provided a new interesting weapon to treat advanced gastric cancer through anti-human epidermal growth factor receptor 2 (HER2) therapies. Trastuzumab, an anti-HER2 monoclonal antibody, was the first target drug in the metastatic setting that showed benefit in overall survival when in association with platinum-5-fluorouracil based chemotherapy. Further, HER2 overexpression analysis acquired a main role in predict response for trastuzumab in this field. Thus, we conducted a review that will discuss the main points concerning trastuzumab and HER2 in gastric cancer, providing a comprehensive overview of molecular mechanisms and novel trials involved.
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48
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Zhang CΗ, Awasthi N, Schwarz MA, Schwarz RE. The dual PI3K/mTOR inhibitor NVP-BEZ235 enhances nab-paclitaxel antitumor response in experimental gastric cancer. Int J Oncol 2013; 43:1627-35. [PMID: 24042258 PMCID: PMC4144025 DOI: 10.3892/ijo.2013.2099] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Accepted: 08/05/2013] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer is the second most common cause of cancer-related deaths worldwide. Taxanes have shown therapeutic effects against gastric cancer while also activating the PI3K/mTOR signaling pathway. We investigated the effects of NVP-BEZ235 (BEZ235), a novel dual PI3K/mTOR inhibitor, alone and in combination with nanoparticle albumin-bound (nab)-paclitaxel in experimental gastric cancer. Cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and survival studies were performed in murine xenografts. Phosphorylated mTOR and 4E-BP1 levels were elevated in gastric cancer cells and tumor tissues by nab-paclitaxel. BEZ235 effectively inhibited cell proliferation in vitro and provided additive effects in combination with nab-paclitaxel. Furthermore, BEZ235 blocked the activated PI3K/mTOR pathway either alone or in combination with nab-paclitaxel in gastric cancer cells. BEZ235 and nab-paclitaxel caused an increase in PARP-1 and caspase-3 cleavage. Net local tumor growth inhibition for the BEZ235, nab-paclitaxel and BEZ235+nab-paclitaxel groups was 45.1, 77.9 and 97% compared to controls. The effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. BEZ235 also caused a decrease in phospho-mTOR and phospho-Akt in tumor tissue lysates. Median animal survival (controls, 23 days) was 26.5 days after BEZ235 (p=0.227), 90.5 days after nab-paclitaxel (p=0.001) and 97 days in the BEZ235+nab-paclitaxel combination treatment group (p=0.001). Our findings suggest that BEZ235 exerts some antitumor effects against gastric cancer and enhances effects of nab-paclitaxel through inhibition of cell proliferation and modulation of the PI3K/mTOR pathway. This approach may represent a promising combination targeted therapy for gastric cancer.
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Affiliation(s)
- Chang-Ηua Zhang
- Division of Surgical Oncology, Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, USA
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Chaudhury A, Kulhari A, Sheorayan A. Targeted Chemotherapeutics: An Overview of the Recent Progress in Effectual Cancer Treatment. PHARMACOLOGIA 2013; 4:535-552. [DOI: 10.5567/pharmacologia.2013.535.552] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/19/2023]
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50
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Falahi F, Huisman C, Kazemier HG, van der Vlies P, Kok K, Hospers GAP, Rots MG. Towards sustained silencing of HER2/neu in cancer by epigenetic editing. Mol Cancer Res 2013; 11:1029-39. [PMID: 23814024 DOI: 10.1158/1541-7786.mcr-12-0567] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
UNLABELLED The human epidermal growth factor receptor-2 (HER2/neu/ERBB2) is overexpressed in several cancer types. Although therapies targeting the HER2/neu protein result in inhibition of cell proliferation, the anticancer effect might be further optimized by limiting HER2/neu expression at the DNA level. Towards this aim, epigenetic editing was performed to suppress HER2/neu expression by inducing epigenetic silencing marks on the HER2/neu promoter.HER2/neu expression and HER2/neu promoter epigenetic modification status were determined in a panel of ovarian and breast cancer cell lines. HER2/neu-overexpressing cancer cells were transduced to express a zinc finger protein (ZFP), targeting the HER2/neugene, fused to histone methyltransferases (G9a, SUV39-H1)/super KRAB domain (SKD). Epigenetic assessment of the HER2/neu promoter showed that HER2/neu-ZFP fused to G9a efficiently induced the intended silencing histone methylation mark (H3K9me2). Importantly, H3K9me2 induction was associated with a dramatic downregulation of HER2/neu expression in HER2/neu- overexpressing cells. Downregulation by SKD, traditionally considered transient in nature, was associated with removal of the histone acetylation mark (H3ac). The downregulation of HER2/neu by induced H3K9 methylation and/or reduced H3 acetylation was sufficient to effectively inhibit cellular metabolic activity and clonogenicity. Furthermore, genome-wide analysis indicated preferential binding of the ZFP to its target sequence. These results not only show that H3K9 methylation can be induced but also that this epigenetic mark was instructive in promoting downregulation of HER2/neu expression. IMPLICATIONS Epigenetic editing provides a novel (synergistic) approach to modulate expression of oncogenes.
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Affiliation(s)
- Fahimeh Falahi
- University Medical Center Groningen, Groningen, 9713 GZ, the Netherlands.
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