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Giampieri R, Baleani MG, Bittoni A, Rastelli F, Catalano V, Del Prete M, Chiorrini S, Pinterpe G, Graziano F, Giorgi FC, Bisonni R, Silva R, Alessandroni P, Mencarini L, Berardi R. Impact of Signet-Ring Cell Histology in the Management of Patients with Non-Metastatic Gastric Cancer: Results from a Retrospective Multicenter Analysis Comparing FLOT Perioperative Chemotherapy vs. Surgery Followed by Adjuvant Chemotherapy. Cancers (Basel) 2023; 15:3342. [PMID: 37444451 PMCID: PMC10340225 DOI: 10.3390/cancers15133342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/14/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND FLOT perioperative chemotherapy represents the standard of care in non-metastatic gastric cancer patients. Signet-ring cell positivity is associated with a worse prognosis in patients with gastric cancer treated with chemotherapy. Comparison between FLOT perioperative chemotherapy vs. surgery followed by adjuvant chemotherapy based on signet-ring cell positivity is lacking. The aim of the analysis was to compare perioperative FLOT with adjuvant chemotherapy in gastric cancer patients stratified by signet-ring cell positivity. METHODS We conducted a retrospective multicenter analysis based on disease-free survival (DFS) and overall survival (OS) in patients with gastric cancer who received perioperative chemotherapy with a FLOT regimen and compared their survival with a historical cohort of patients treated with adjuvant chemotherapy, matched by cT and cN stage and by tumor histological features. RESULTS Seventy-six patients were enrolled and 24 (32%) were signet-ring cell positive. At a median follow-up time of 39 months, the median DFS was 26.3 months and the median OS was 37.3 months. Signet-ring cell positivity was associated with a shorter OS (median OS: 20.4 vs. 46.9 months, HR: 3.30, 95%CI: 1.56-6.99, p = 0.0018) and DFS (mDFS: 15.2 vs. 38.6 months, HR: 3.18, 95%CI: 1.55-6.54, p = 0.0016). This was confirmed by multivariate analysis for DFS (Exp(B): 2.55) and OS (Exp(B): 2.68). After propensity score matching, statistically significant shorter DFS (HR: 3.30, 95%CI: 1.50-7.35, p = 0.003) and OS (HR: 5.25, 95%CI: 2.18-12-68, p = 0.0002) were observed for patients with signet-ring cell positivity who received perioperative treatment vs. those who received surgery followed by adjuvant chemotherapy. CONCLUSIONS Signet-ring positivity was associated with shorter DFS and OS in patients who received perioperative treatment with FLOT compared with surgery followed by adjuvant therapy. These data suggest that for patients with signet-ring cell histology, FLOT perioperative treatment might not always be the best choice of treatment, and further research should be focused on this group of patients.
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Affiliation(s)
- Riccardo Giampieri
- Medical Oncology Unit, Dipartimento Scienze Cliniche e Molecolari, Università Politecnica delle Marche and Azienda Ospedaliero-Universitaria Ospedali Riuniti delle Marche, 60126 Ancona, Italy (R.B.)
| | | | - Alessandro Bittoni
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Francesca Rastelli
- Department of Oncology, Ospedale “C.e G. Mazzoni” Ascoli Piceno, 63100 Ascoli Piceno, Italy
| | - Vincenzo Catalano
- Department of Oncology, Ospedale Santa Maria della Misericordia, AV1, 61029 Urbino, Italy
| | - Michela Del Prete
- Department of Oncology, Ospedale Augusto Murri di Fermo, 63900 Fermo, Italy
| | - Silvia Chiorrini
- Department of Oncology, Ospedale E. Profili, 60044 Fabriano, Italy
| | - Giada Pinterpe
- Medical Oncology Unit, Dipartimento Scienze Cliniche e Molecolari, Università Politecnica delle Marche and Azienda Ospedaliero-Universitaria Ospedali Riuniti delle Marche, 60126 Ancona, Italy (R.B.)
| | - Francesco Graziano
- Department of Oncology, Azienda Ospedaliera Marche Nord, AV1, 61121 Pesaro, Italy
| | - Francesca Chiara Giorgi
- Department of Oncology, Ospedale Madonna del Soccorso, 63074 San Benedetto del Tronto, Italy
| | - Renato Bisonni
- Department of Oncology, Ospedale Augusto Murri di Fermo, 63900 Fermo, Italy
| | - Rosarita Silva
- Department of Oncology, Ospedale E. Profili, 60044 Fabriano, Italy
| | - Paolo Alessandroni
- Department of Oncology, Azienda Ospedaliera Marche Nord, AV1, 61121 Pesaro, Italy
| | - Lara Mencarini
- Medical Oncology Unit, Dipartimento Scienze Cliniche e Molecolari, Università Politecnica delle Marche and Azienda Ospedaliero-Universitaria Ospedali Riuniti delle Marche, 60126 Ancona, Italy (R.B.)
| | - Rossana Berardi
- Medical Oncology Unit, Dipartimento Scienze Cliniche e Molecolari, Università Politecnica delle Marche and Azienda Ospedaliero-Universitaria Ospedali Riuniti delle Marche, 60126 Ancona, Italy (R.B.)
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Poniewierska-Baran A, Warias P, Zgutka K. Sirtuins (SIRTs) As a Novel Target in Gastric Cancer. Int J Mol Sci 2022; 23:ijms232315119. [PMID: 36499440 PMCID: PMC9737976 DOI: 10.3390/ijms232315119] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/25/2022] [Accepted: 11/26/2022] [Indexed: 12/03/2022] Open
Abstract
Gastric cancer is a major health burden worldwide. Among all neoplasms, gastric cancer is the fifth most common and the third most deadly type of cancer. It is known that sirtuins (SIRTs), are NAD+-dependent histone deacetylases regulating important metabolic pathways. High expression of SIRTs in the human body can regulate metabolic processes; they prevent inflammation but also resist cell death and aging processes. The seven members of this family enzymes can also play a fundamental role in process of carcinogenesis by influencing cell viability, apoptosis and metastasis. This review collects and discusses the role of all seven sirtuins (SIRT1-SIRT7) in the pathogenesis of gastric cancer (GC).
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Affiliation(s)
- Agata Poniewierska-Baran
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland
- Correspondence:
| | - Paulina Warias
- Department of Physiology, Pomeranian Medical University in Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland
| | - Katarzyna Zgutka
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University, Szczecin, Żołnierska 54, 70-210 Szczecin, Poland
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Niu P, Huang H, Zhao L, Wang T, Zhang X, Wang W, Zhang Y, Guo C, Zhao D, Chen Y. Clinicopathological characteristics, survival outcomes, and genetic alterations of younger patients with gastric cancer: Results from the China National Cancer Center and
cBioPortal
datasets. Cancer Med 2022; 11:3057-3073. [PMID: 35486034 PMCID: PMC9385592 DOI: 10.1002/cam4.4669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/28/2022] [Accepted: 03/02/2022] [Indexed: 11/30/2022] Open
Abstract
Background The survival outcomes of younger patients with gastric cancer (GC) have remained controversial. This study explores the clinicopathological characteristics, survival outcomes, and genetic alterations of younger and older patients with GC. Methods Patients with GC were identified from the China National Cancer Center Gastric Cancer Database (NCCGCDB) during 1998–2018. Survival analysis was conducted using Kaplan–Meier estimates and Cox proportional hazards models. Sequencing datasets were enrolled from The Cancer Genome Atlas (TCGA) and Memorial Sloan–Kettering Cancer Center (MSKCC) databases. Results A total of 1146 younger (<40 years of age) and 16,988 older (≥40 years of age) cases were included in the study. Younger patients had more poorly differentiated lesions than older patients (53.7% vs. 33.8%, respectively; p < 0.0001), and were more often pTNM stage IV (19.5% vs. 11.8%, respectively; p < 0.001). The 5‐year overall survival (OS) of patients from the NCCGCDB increased from 1998 to 2018. Younger patients with pTNM stage III had a lower survival rate than older patients (p = 0.014), while no differences by age were observed at other stages. The mutation frequency of the LRP1B, GNAS, APC, and KMT2D genes was higher for older than younger patients (p < 0.05 for all genes). While not significantly different, younger patients from the TCGA and MSKCC databases were more likely to have CDH1, RHOA, and CTNNB1 gene mutations. Conclusions A stable proportion and improved survival of younger patients were reported using NCCGCDB data. Younger patients with pTNM stage III had lower rates of survival than older patients. Distinct molecular characteristics were identified in younger GC patients which may partly explain the histopathology and prognosis specific to this subpopulation.
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Affiliation(s)
- Penghui Niu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Huang Huang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Lulu Zhao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Tongbo Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Xiaojie Zhang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Wanqing Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Yawei Zhang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Chunguang Guo
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Dongbing Zhao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Yingtai Chen
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
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Bidar N, Rezaei T, Amini M, Jebelli A, Mokhtarzadeh A, Baradaran B. ZNF677 downregulation by promoter hypermethylation as a driver event through gastric tumorigenesis. Exp Mol Pathol 2021; 121:104663. [PMID: 34171355 DOI: 10.1016/j.yexmp.2021.104663] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 05/26/2021] [Accepted: 06/18/2021] [Indexed: 12/24/2022]
Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide, due to poor prognosis and treatment failure; demanding new diagnostic and therapeutic targets. Therefore, in the present study, the methylation and expression status of ZNF677, as a promising tumor suppressor, were investigated in GC. Gene Expression Omnibus (GEO) datasets were used to initially evaluate ZNF677 expression and methylation in GC samples. Confirmation was performed on fifty internal samples, including gastric tumors and adjacent normal specimens, using q-MSP and q-PCR methods. Further validations were done using The Cancer Genome Atlas (TCGA) data on human cancers. The obtained results in silico and experimentally illustrated that ZNF677 is significantly hypermethylated and downregulated through gastric tumorigenesis. ZNF677 methylation levels were also correlated with perineural invasion (p = 0.0382) in internal samples. Furthermore, Spearman's correlation analysis showed that ZNF677 methylation is negatively (r = -0.4614, p < 0.0001) correlated with its mRNA expression levels. ROC curve analysis also illustrated the high diagnostic value of ZNF677 methylation for early detection of GC (AUC = 0.8592). Gene set enrichment analysis further revealed that ZNF677 participates in the regulation of cellular processes such as cell proliferation in GC. Moreover, in addition to hypermethylation in other malignancies, including breast, lung, and colorectal cancers, ZNF677 was hypermethylated in precancerous gastric tissues with intestinal metaplasia, indicating its methylation as a driver event through tumorigenesis. Taken together, our results suggest ZNF677 as a potential tumor suppressor gene, which could be considered as a diagnostic and therapeutic target for GC.
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Affiliation(s)
- Negar Bidar
- Department of Biology, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Tayebeh Rezaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Asiyeh Jebelli
- Department of Biology, Higher Education Institute of Rab-Rashid, Tabriz, Iran; Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Zhou R, Sun J, He C, Huang C, Yu H. CCL19 suppresses gastric cancer cell proliferation, migration, and invasion through the CCL19/CCR7/AIM2 pathway. Hum Cell 2020; 33:1120-1132. [PMID: 32564199 DOI: 10.1007/s13577-020-00375-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 05/12/2020] [Indexed: 02/07/2023]
Abstract
Absent in melanoma 2 (AIM2) has been reported to be an important inflammasome component that exerts tumor suppression in several tumors. However, whether CCL19/CCR7/AIM2 is involved in the progression of GC still remains unclear. Quantitative real-time and ELISA assay were used to determine the expressions of AIM2, CCL19 and CCR7 in GC tissues and cell lines. CCK-8, Edu staining, flow cytometry, Transwell assay, and tumorigenesis in nude mice were used to explore the function of AIM2 and CCL19 in vitro and in vivo. Apoptosis and inflammation-related biomarkers were detected by Western blot and ELISA assay. H&E staining was used to assess the histological changes in the subcutaneous tumor model. Immunohistochemistry (IHC) was used to evaluate the expression of Ki-67. We found that expression levels of AIM2, CCL19 and CCR7 were obviously lower in early GC tissues than those in progressive GC tissues. In vitro assays revealed that CCL19 treatment could enhance the suppressive effects of AIM2 overexpression on cell proliferation, migration, and invasion through CCR7. An in vivo assay also demonstrated that silencing of AIM2 reversed the suppressive effects of CCL19 on tumor growth. Collectively, CCL19 overexpression significantly inhibited GC cell proliferation and tumor growth in vitro and in vivo by up-regulating the CCR7/AIM2 pathway. Thus, CCL19 activated CCR7/AIM2 signaling pathway and it may be a potential therapeutic approach for GC therapy.
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Affiliation(s)
- Rui Zhou
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Jun Sun
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Chunping He
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Chao Huang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuhan, 430060, Hubei, People's Republic of China
| | - Honggang Yu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuhan, 430060, Hubei, People's Republic of China.
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Andreollo NA, Drizlionoks E, Tercioti-Junior V, Coelho-Neto JDS, Ferrer JAP, Carvalheira JBC, Lopes LR. ADJUVANT CHEMORADIOTHERAPY AFTER SUBTOTAL OR TOTAL GASTRECTOMY AND D2 LIMPHADENECTOMY INCREASES SURVIVAL IN ADVANCED GASTRIC CANCER? ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA : ABCD = BRAZILIAN ARCHIVES OF DIGESTIVE SURGERY 2019; 32:e1464. [PMID: 31859917 PMCID: PMC6918727 DOI: 10.1590/0102-672020190001e1464] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 09/17/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND The treatment of advanced gastric cancer with curative intent is essentially surgical and chemoradiotherapy is indicated as neo or adjuvant to control the disease and prolong survival. AIM To assess the survival of patients undergoing subtotal or total gastrectomy with D2 lymphadenectomy followed by adjuvant chemoradiotherapy. METHODS Were retrospectively analyzed 87 gastrectomized patients with advanced gastric adenocarcinoma, considered stages IB to IIIC and submitted to adjuvant chemoradiotherapy (protocol INT 0116). Tumors of the esophagogastric junction, with peritoneal implants, distant metastases, and those that had a compromised surgical margin or early death after surgery were excluded. They were separated according to the extention of the gastrectomy and analyzed for tumor site and histopathology, lymph node invasion, staging, morbidity and survival. RESULTS The total number of patients who successfully completed the adjuvant treatment was 45 (51.7%). Those who started treatment and discontinued due to toxicity, tumor-related worsening, or loss of follow-up were 10 (11.5%) and reported as incomplete adjuvant. The number of patients who refused or did not start adjuvant treatment was 33 (48.3%). Subtotal gastrectomy was indicated in 60 (68.9%) and total in 27 (31.1%) and this had a shorter survival. The mean resected lymph nodes was 30.8. Staging and number of lymph nodes affected were predictors of worse survival and the more advanced the tumor. Patients undergoing adjuvant therapy with complete chemoradiotherapy showed a longer survival when compared to those who did it incompletely or underwent exclusive surgery. On the other hand, comparing the T4b (IIIB + IIIC) staging patients who had complete adjuvance with those who underwent the exclusive operation or who did not complete the adjuvant, there was a significant difference in survival. CONCLUSION Adjuvant chemoradiotherapy presents survival gain for T4b patients undergoing surgical treatment with curative intent.
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Affiliation(s)
| | - Eric Drizlionoks
- Digestive Diseases Surgical Unit and Gastrocenter, Campinas, SP, Brazil
| | | | | | | | - José Barreto Campello Carvalheira
- Division of Oncology, Department of Surgery and Internal Medicine, School of Medical Sciences, State University of Campinas - UNICAMP, Campinas, SP, Brazil
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Akbas A, Bakir H, Dasiran MF, Dagmura H, Ozmen Z, Yildiz Celtek N, Daldal E, Demir O, Kefeli A, Okan I. Significance of Gastric Wall Thickening Detected in Abdominal CT Scan to Predict Gastric Malignancy. JOURNAL OF ONCOLOGY 2019; 2019:8581547. [PMID: 31827513 PMCID: PMC6886315 DOI: 10.1155/2019/8581547] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 09/16/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Early diagnosis of gastric cancer is one of the most important parameters affecting the survival of the disease. In this study, we aimed to stress the importance of antrum wall thickness in CT examination. METHOD The study included 111 patients between ages of 18 and 95 who had antral wall thickening in computed tomography and also had endoscopic evaluation performed in the same clinic. The patients were divided into two groups as benign and malignant according to the pathology results. The thickness of the antrum wall in computed tomography, hemoglobin and albumin levels, and age was compared among these two groups. Parameters with significant differences were further analyzed by multivariate analysis using logistic regression analysis. RESULTS Of the 111 patients included in the study, 57 were male and 54 were female. Mean age was 65 years. Fifty-one patients were classified as benign and 60 patients as malignant. Mean age of the malignant patients was 70, while that of benign patients was 59 (p < 0.05). Antrum wall thickness was 13.68 ± 3.27 mm in malignant patients and 9.22 ± 2.17 mm in benign patients (p < 0.05). Similarly, hemoglobin level was significantly different in malignant and benign patients (10.78 ± 1.57 g/dl and 12.64 ± 1.43 g/dl, respectively; p < 0.05). Albumin levels were 3.36 ± 0.57 mg/dl in malignant patients and 3.97 ± 0.57 mg/dl in benign patients (p < 0.05). CONCLUSION Evaluation of antrum wall thickness, age, hemoglobin, and albumin values together may contribute to distinguishing the benign and malignant pathologies involving this region in patients with suspected stomach wall thickening in abdominal CT scan.
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Affiliation(s)
- A. Akbas
- Department of General Surgery, Tokat Gaziosmanpasa University, Tokat 60100, Turkey
| | - H. Bakir
- Department of General Surgery, Tokat Gaziosmanpasa University, Tokat 60100, Turkey
| | - M. F. Dasiran
- Department of General Surgery, Tokat Gaziosmanpasa University, Tokat 60100, Turkey
| | - H. Dagmura
- Department of General Surgery, Tokat Gaziosmanpasa University, Tokat 60100, Turkey
| | - Z. Ozmen
- Department of Radiology, Tokat Gaziosmanpasa University, Tokat 60100, Turkey
| | - N. Yildiz Celtek
- Department of Family Medicine, Tokat Gaziosmanpasa University, Tokat 60100, Turkey
| | - E. Daldal
- Department of General Surgery, Tokat Gaziosmanpasa University, Tokat 60100, Turkey
| | - O. Demir
- Department of Biostatics, Tokat Gaziosmanpasa University, Tokat 60100, Turkey
| | - A. Kefeli
- Department of Gastroenterology, Tokat Gaziosmanpasa University, Tokat 60100, Turkey
| | - I. Okan
- Department of General Surgery, Tokat Gaziosmanpasa University, Tokat 60100, Turkey
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Is pathologic tumor regression grade after neo-adjuvant chemotherapy a promising prognostic indicator for patients with locally advanced gastric cancer? A cohort study evaluating tumor regression response. Cancer Chemother Pharmacol 2019; 84:635-646. [DOI: 10.1007/s00280-019-03893-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 06/14/2019] [Indexed: 12/12/2022]
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Zhao L, Huang H, Zhao D, Wang C, Tian Y, Yuan X, Ma F, Ren H, Zhao Y, Aimaiti S, Zhang S, Zhou H, Wang T, Wang N, Sun Y, Bai X, Chen Y. Clinicopathological Characteristics and Prognosis of Proximal and Distal Gastric Cancer during 1997-2017 in China National Cancer Center. JOURNAL OF ONCOLOGY 2019; 2019:9784039. [PMID: 31312217 PMCID: PMC6595386 DOI: 10.1155/2019/9784039] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 05/08/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND The prognostic relevance of gastric tumor location has been reported and debated. Our study was conducted to examine the differences in clinicopathological features, prognostic factors, and overall survival (OS) between patients with proximal gastric cancer (PGC) and distal gastric cancer (DGC). PATIENTS AND METHODS Patients with PGC or DGC were identified from the China National Cancer Center Gastric Cancer Database (NCCGCDB) during 1997-2017. Survival analysis was performed via Kaplan-Meier estimates and Cox proportional hazards models. RESULTS We reviewed 16,119 cases of gastric cancer patients, including 6,479 of PGC and 9,640 of DGC. PGC patients presented as older patients (61.5 versus 56.4 years, P<0.001) and more males (82.9% versus 68.2%, P<0.001). Compared with DGC, PGC was more likely to be in later pT stage (pT3 and pT4, 65.0% versus 52.8%, P<0.001) and lymph node metastasis (54.8% versus 50.9%, P<0.001). In univariate analysis, PGC patients had a worse survival outcome in stage I (Hazard ratio [HR] = 2.04, 95% CI: 1.42-2.94) but a better prognosis in stage IV (HR = 0.85, 95% CI: 0.73-0.98) when compared to DGC patients. However, multivariate analysis demonstrated that PGC was not an independent predictor for poor survival (HR = 1.07, 95% CI: 1.00-1.14). Results from multivariate analysis also revealed that pT4, lymph node metastasis, distant metastasis, no gastrectomy, and Borrmann IV were independent predictors associated with poor survival for both PGC and DGC patients. Additional prognostic factors for PGC patients included underweight (BMI < 18.5) (HR = 1.29, 95% CI: 1.06-1.58), linitis plastica (HR = 2.13, 95% CI: 1.25-3.65), and overweight (23 ≤ BMI <27.5) (HR = 0.80, 95% CI: 0.71-0.90). During the 20-year study period, the 5-year OS increased significantly for both PGC and DGC, with the increase rate of 91.7% and 67.7%, respectively. CONCLUSION In China, PGC significantly differed from DGC in clinicopathological characteristics and prognostic factors. However, there was no significant relationship between survival outcome and gastric tumor location.
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Affiliation(s)
- Lulu Zhao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Huang Huang
- Department of Environmental Health Sciences, Yale University School of Public Health, New Haven, CT 06520, USA
| | - Dongbin Zhao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Chengfeng Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yantao Tian
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xinghua Yuan
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Fuhai Ma
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hu Ren
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yajie Zhao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Saderbiek Aimaiti
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Shuisheng Zhang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hong Zhou
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Tongbo Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Nianchang Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yuemin Sun
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xiaofeng Bai
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yingtai Chen
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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Wu J, Long Z, Cai H, Yu S, Liu X. Homeobox B7 accelerates the cancer progression of gastric carcinoma cells by promoting epithelial-mesenchymal transition (EMT) and activating Src-FAK pathway. Onco Targets Ther 2019; 12:3743-3751. [PMID: 31190875 PMCID: PMC6529037 DOI: 10.2147/ott.s198115] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 04/05/2019] [Indexed: 12/31/2022] Open
Abstract
Aim: To study the carcinogenetic mechanism of HOXB7 in gastric cancer (GC) remains. Methods: Two human GC cell lines — SGC7901 and SNU1 — were used for this study. SGC7901 cells were transfected with siRNA-HOXB7 (siHOXB7) to knock down HOXB7 expression, whereas, SNU1 cells were transduced with pCDNA3.1-HOXB7 to overexpress HOXB7. After transfection, cancer progression was assessed by determining cell proliferation, wound-healing process, cell cycle, apoptosis, invasion, and migration. The effect of HOXB7 on epithelial–mesenchymal transition (EMT) was measured by observing changes in F-actin cytoskeleton and evaluating the expression of EMT markers. p-Scr and p-FAK were evaluated to assess the mechanism. Results: Knockdown of HOXB7 suppressed cell proliferation, alleviated the wound-healing process, inhibited cell migration and invasion, and arrested the cell cycle while promoting cell apoptosis, suggesting the tumor-suppressive effect of siHOXB7 in human GC cells. On the contrary, HOXB7 overexpression showed a tumor-promoting effect on human GC cells. Moreover, we confirmed an inhibitory effect of siHOXB7 on the EMT process by preventing epithelial cells from acquiring a mesenchymal phenotype and downregulating mesenchymal markers (vimentin, β-catenin, N-cadherin, Twist) while upregulating epithelial markers (E-cadherin). Our data revealed that HOXB7 was associated with Src/FAK and favored the activation of the Src–FAK pathway in human GC cells. Conclusion: HOXB7 accelerated the malignancy of GC, by facilitating EMT and regulating the Scr–FAK pathway.
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Affiliation(s)
- Jianghong Wu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College of Fudan University, Shanghai 200032, People's Republic of China
| | - Ziwen Long
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College of Fudan University, Shanghai 200032, People's Republic of China
| | - Hong Cai
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College of Fudan University, Shanghai 200032, People's Republic of China
| | - Shengjia Yu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College of Fudan University, Shanghai 200032, People's Republic of China
| | - Xiaowen Liu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College of Fudan University, Shanghai 200032, People's Republic of China
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11
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KIF23 Promotes Gastric Cancer by Stimulating Cell Proliferation. DISEASE MARKERS 2019; 2019:9751923. [PMID: 31007778 PMCID: PMC6441499 DOI: 10.1155/2019/9751923] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 12/21/2018] [Accepted: 02/07/2019] [Indexed: 12/26/2022]
Abstract
Gastric cancer (GC) is one of the most aggressive malignant tumors with low early diagnosis and high metastasis. Despite progress in treatment, to combat this disease, a better understanding of the underlying mechanisms and novel therapeutic targets is needed. KIF23, which belongs to the KIF family, plays a vital role in various cell processes, such as cytoplasm separation and axon elongation. Nowadays, KIF23 has been found to be highly expressed in multiple tumor tissues and cells, suggesting a potential link between KIF23 and tumorigenesis. Herein, we reported that KIF23 expression was correlated with poor prognosis of gastric cancer and found an association between KIF23 and pTNM stage. An in vitro assay proved that the proliferation of gastric cancer cells was significantly inhibited, which is caused by KIF23 depletion. Additionally, knockdown of KIF23 resulted in a marked inhibition of cell proliferation of gastric cancer in mice, with significant downregulation of Ki67 and PCNA expression. In conclusion, these data indicate that KIF23 is a potential therapeutic target for gastric cancer treatment.
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12
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Yao S, Yan W. Overexpression of Mst1 reduces gastric cancer cell viability by repressing the AMPK-Sirt3 pathway and activating mitochondrial fission. Onco Targets Ther 2018; 11:8465-8479. [PMID: 30555239 PMCID: PMC6278716 DOI: 10.2147/ott.s180851] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Mammalian sterile 20-like kinase 1 (Mst1) plays a critical role in regulating cell survival and apoptosis. However, its influence on gastric cancer cell viability is not understood. Our study aims to explore the specific role of Mst1 in gastric cancer. MATERIALS AND METHODS Cellular viability was measured via TUNEL staining, MTT assays, and Western blotting. Immunofluorescence was performed to observe mitochondrial fission. Mst1 overexpression assays were conducted to observe the regulatory mechanisms of Mst1 in mitochondrial fission and cell apoptosis. RESULTS The results demonstrated that Mst1 was downregulated in AGS cells when compared with GES-1 cells. However, overexpression of Mst1 reduced cell viability and increased apoptosis in AGS cells. Molecular experiments showed that Mst1 overexpression mediated mitochondrial damage, as evidenced by decreased ATP production, increased ROS generation, more cyt-c translocation from the mitochondria into the cytoplasm and nucleus, and activated the caspase-9-related apoptotic pathway. Furthermore, we found that mitochondrial fission was required for Mst1-induced mitochondrial dysfunction; inhibition of mitochondrial fission sustained mitochondrial homeostasis in response to Mst1 overexpression. In addition, our data revealed that Mst1 controlled mitochondrial fission via repressing the AMPK-Sirt3 pathway. Activation of the AMPK-Sirt3 pathway negated the promoting effect of Mst1 overexpression on mitochondrial fission. CONCLUSION Altogether, our data identified Mst1 as a novel tumor-suppressive factor in promoting cell death in gastric cancer cells by triggering mitochondrial fission and blocking the AMPK-Sirt3 axis.
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Affiliation(s)
- Shiwei Yao
- Department of Gastroenterology, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing, China,
| | - Wei Yan
- Department of Gastroenterology, The First Hospital of Tsinghua University, Beijing, China
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13
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Liu X, Meng X, Li Y, Chai W, Qian J, Tang H. Role of CA19-9 in the prognostic evaluation of SOX neoadjuvant chemotherapy for gastric cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:5387-5393. [PMID: 31949620 PMCID: PMC6963008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 09/22/2018] [Indexed: 06/10/2023]
Abstract
OBJECTIVE Neoadjuvant chemotherapy refers to systemic chemotherapy applied before local surgery or radiotherapy for malignant tumors. The level of certain tumor markers is an important indicator for assessing the efficacy of neoadjuvant chemotherapy. This study aimed to investigate the effect of serum CA19-9 levels on subsequent neoadjuvant chemotherapy in the treatment of gastric adenocarcinoma. METHODS We collected 86 advanced gastric adenocarcinoma patients from January 2016 to May 2018. Patients received at least 2 cycles neoadjuvant chemotherapy with SOX (Oxaliplatin, S-1) before surgery. Effective chemotherapy was defined as producing CR or PR andineffective was defined as SD or PD. We analyze the role of serum CA19-9 level in predicting the effectiveness of neoadjuvant chemotherapy in patients with advanced gastric cancer. RESULTS In total 86 patients, 28 patients had abnormal and 58 patients had normal serum CA19-9 levels. The positivity rate of pretreatment serum CA19-9 was higher when PR or CR was achieved (P=0.0005***). The area under the ROC curve (AUC) for CA19-9 levels was 0.720 (95% CI 0.610-0.829) (P=0.001**). CONCLUSIONS Measurements of CA19-9 may be helpful in monitoring the efficacy of neoadjuvant chemotherapy in the treatment of patients with advanced gastric cancer and also may be able to effectively predict this effect, thereby reducing unnecessary chemotherapy.
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Affiliation(s)
- Xiaozhen Liu
- Clinical Sample Bank, Zhejiang Cancer HospitalHangzhou 310022, China
| | - Xuli Meng
- Department of General Surgery, Tongde Hospital of ZhejiangHangzhou 310012, China
| | - Yongfeng Li
- Department of Breast Surgery, Zhejiang Cancer HospitalHangzhou 310022, China
| | - Wubin Chai
- Department of The Second Surgery, Daishan First People’s HospitalZhoushan 316200, China
| | - Jiacheng Qian
- Zhejiang Chinese Medical UniversityHangzhou 310053, China
| | - Hongchao Tang
- Department of General Surgery, Zhejiang HospitalHangzhou 310013, China
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14
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Feng F, Liu J, Wang F, Zheng G, Wang Q, Liu S, Xu G, Guo M, Lian X, Zhang H. Prognostic value of differentiation status in gastric cancer. BMC Cancer 2018; 18:865. [PMID: 30176846 PMCID: PMC6122741 DOI: 10.1186/s12885-018-4780-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 08/28/2018] [Indexed: 02/07/2023] Open
Abstract
Background Up to date, investigation of the prognostic value of differentiation status mainly focused on signet ring cell and mucinous gastric cancer. Thus, the present study aims to investigate the clinicopathological features and prognosis of gastric cancer patients with well, moderately and poorly differentiation status. Methods From September 2008 to March 2015, a total of 3090 gastric cancer patients treated with radical D2 gastrectomy were enrolled in the present study. Clinicopathological characteristics and prognosis of gastric cancer patients with well, moderately and poorly differentiation status were analyzed. Results There were 2422 male (78.4%) and 668 female (21.6%). The median age was 58 (20–90) years. There were 370 (12.0%) well differentiated tumors, 836 (27.0%) moderately differentiated tumors and 1884 (61.0%) poorly differentiated tumors. Well and moderately differentiation status were associated with older age, male gender, smaller tumor, shallower invasion, less lymph node involvement and earlier tumor stage (all p < 0.001). Inversely, poorly differentiation status was associated with younger age, female gender, larger tumor, deeper invasion, more lymph node involvement and later tumor stage (all p < 0.001). With respect to prognosis, well differentiation status was associated with favorable overall survival and poorly differentiation status was associated with unfavorable overall survival (p < 0.001). However, after matching with age, tumor size, T and N stage, there was no significant difference among the overall survival of the three groups (p = 0.415). Conclusions Well, moderately and poorly differentiation status was significantly associated with clinicopathological features of gastric cancer patients. However, it was not associated with the prognosis of gastric cancer patients.
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Affiliation(s)
- Fan Feng
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Jinqiang Liu
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi, China.,Cadre' s sanitarium, 62101 Army of PLA, 67 Nahu Road, Xinyang, 464000, Henan, China
| | - Fei Wang
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi, China.,Department of General Surgery, No. 534 Hospital of PLA, Yingzhou Road, Luoyang, 471000, Henan, China
| | - Gaozan Zheng
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Qiao Wang
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi, China.,Department of General Surgery, No. 91 Hospital of PLA, 239Gongye Road, Jiaozuo, 454000, Henan, China
| | - Shushang Liu
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Guanghui Xu
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Man Guo
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Xiao Lian
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Hongwei Zhang
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi, China.
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