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1
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Jiang W, Zhang B, Xu J, Xue L, Wang L. Current status and perspectives of esophageal cancer: a comprehensive review. Cancer Commun (Lond) 2025; 45:281-331. [PMID: 39723635 PMCID: PMC11947622 DOI: 10.1002/cac2.12645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 12/08/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024] Open
Abstract
Esophageal cancer (EC) continues to be a significant global health concern, with two main subtypes: esophageal squamous cell carcinoma and esophageal adenocarcinoma. Prevention and changes in etiology, improvements in early detection, and refinements in the treatment have led to remarkable progress in the outcomes of EC patients in the past two decades. This seminar provides an in-depth analysis of advances in the epidemiology, disease biology, screening, diagnosis, and treatment landscape of esophageal cancer, focusing on the ongoing debate surrounding multimodality therapy. Despite significant advancements, EC remains a deadly disease, underscoring the need for continued research into early detection methods, understanding the molecular mechanisms, and developing effective treatments.
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Affiliation(s)
- Wei Jiang
- Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenGuangdongP. R. China
| | - Bo Zhang
- Department of Medical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Jiaqi Xu
- Department of PathologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Liyan Xue
- Department of PathologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Luhua Wang
- Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenGuangdongP. R. China
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2
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Grabill N, Louis M, Adams R, Gherasim C, So S, Stevens T. Leptomeningeal carcinomatosis in advanced esophageal adenocarcinoma: A case report on presentation and diagnosis. Int J Surg Case Rep 2025; 126:110708. [PMID: 39642415 PMCID: PMC11667075 DOI: 10.1016/j.ijscr.2024.110708] [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: 09/26/2024] [Revised: 11/29/2024] [Accepted: 11/29/2024] [Indexed: 12/08/2024] Open
Abstract
INTRODUCTION AND IMPORTANCE Leptomeningeal carcinomatosis (LC) is an uncommon but severe complication of advanced esophageal adenocarcinoma. Typically diagnosed through MRI and cerebrospinal fluid analysis, LC carries a poor prognosis despite aggressive management. CASE PRESENTATION A 64-year-old male with a history of coronary artery disease, diabetes, and other comorbidities presented with progressive dysphagia. Diagnostic imaging and biopsy confirmed esophageal adenocarcinoma with local invasion and distant metastases, including mediastinal lymphadenopathy. Despite treatment with chemotherapy, radiation, and surgical interventions such as jejunostomy tube placement, the patient developed neurological symptoms suggestive of LC. MRI confirmed leptomeningeal involvement, and cerebrospinal fluid analysis revealed malignant cells. CLINICAL DISCUSSION Management focused on palliative care, including chemotherapy and radiation. The patient's condition deteriorated rapidly, consistent with the poor prognosis associated with LC in esophageal cancer. CONCLUSION This case discusses the importance of early detection and intervention in managing esophageal adenocarcinoma, particularly when neurological symptoms suggest central nervous system involvement. Despite advances in cancer treatment, LC remains a difficult condition to manage, with limited effective therapeutic options.
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Affiliation(s)
- Nathaniel Grabill
- Northeast Georgia Health System Inc, General Surgery Department, 743 Spring Street NE, Gainesville, GA 30501, United States of America.
| | - Mena Louis
- Northeast Georgia Health System Inc, General Surgery Department, 743 Spring Street NE, Gainesville, GA 30501, United States of America
| | - Richard Adams
- Northeast Georgia Health System Inc, General Surgery Department, 743 Spring Street NE, Gainesville, GA 30501, United States of America.
| | - Claudia Gherasim
- Northeast Georgia Health System Inc, Pathology Department, 743 Spring Street NE, Gainesville, GA 30501, United States of America.
| | - Sumi So
- Northeast Georgia Health System Inc, Pathology Department, 743 Spring Street NE, Gainesville, GA 30501, United States of America.
| | - Timothy Stevens
- Northeast Georgia Health System Inc, Trauma and Acute Care Surgery Department, 743 Spring Street NE, Gainesville, GA 30501, United States of America.
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Yu Z, Chen T, Peng H, Li A, Wei Y, Xiao S. Trends in incidence, treatment modalities and prognosis of esophageal adenocarcinoma in the US population. Cancer Epidemiol 2024; 93:102683. [PMID: 39366329 DOI: 10.1016/j.canep.2024.102683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 10/01/2024] [Accepted: 10/01/2024] [Indexed: 10/06/2024]
Abstract
BACKGROUND Esophageal adenocarcinoma (EAC) was the predominant subtype of esophageal cancer in the Western population. However, an updated and comprehensive analysis of epidemiologic, clinical, and prognostic characteristics of esophageal adenocarcinoma is lacking. MATERIALS AND METHODS This was a population-based cohort study using the Surveillance Epidemiology and End-Results (SEER) Database. Patients diagnosed with EAC between 1988 and 2020 were included. Incidence trends, clinical characteristics, treatment patterns, and relative survival were systematically analyzed. RESULTS The overall age-standardized incidence rate of EAC significantly increased from 1.7 per 100000 persons in 1988 to 3.6 per 100000 persons in 2020. There were no significant changes in the distribution of age group, sex, and primary site of EAC over time. However, the proportion of EAC clinically staged as I or II decreased from 35.1 % to 27.9 %. Over time, palliative chemotherapy in metastatic EAC increased from 26.7 % to 41.3 %, combination therapy was still the main treatment strategy for nonmetastatic EAC. Despite the 5-year survival rate was less than 20 %, 1-year survival has experienced a moderate increase from 46.7 % to 53.7 %. Specifically, 1-year survival rate for nonmetastatic EAC undergoing surgery only experienced a significant increase from 80.2 % in 2004-2006 to 94.7 % in 2019-2020. For metastatic EAC, obvious improvement in 1-year survival rate was observed in those treated with systematic therapy (from 26.6 % in 2004-2006 to 41.2 % in 2019-2020). In the multivariable analysis, older age, male sex, lower household income, living without a partner, advanced TNM stage, and receiving no cancer treatment were significantly associated with poor survival. CONCLUSION In summary, this population-based study of EAC patients in the US showed an increase in incidence, a shift in treatment modalities for metastatic EAC, and moderately improved 1-year survival. The search for more effective surveillance and treatment strategies should be continued in the future.
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Affiliation(s)
- Zhuoyang Yu
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Tong Chen
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Haoyu Peng
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Anyuan Li
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yutong Wei
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Shiyu Xiao
- Department of Gastroenterology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
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4
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Ray P, Jaiswal S, Ferrer-Torres D, Wang Z, Nancarrow D, Curtin M, Martinho MS, Lacy SM, Kasturirangan S, Thomas D, Spence JR, Truttmann MC, Lagisetty KH, Lawrence TS, Wang TD, Beer DG, Ray D. GRAIL1 Stabilizes Misfolded Mutant p53 through a Ubiquitin Ligase-Independent, Chaperone Regulatory Function. Mol Cancer Res 2024; 22:996-1010. [PMID: 39018356 PMCID: PMC11530312 DOI: 10.1158/1541-7786.mcr-24-0361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 06/25/2024] [Accepted: 07/11/2024] [Indexed: 07/19/2024]
Abstract
Frequent (>70%) TP53 mutations often promote its protein stabilization, driving esophageal adenocarcinoma (EAC) development linked to poor survival and therapy resistance. We previously reported that during Barrett's esophagus progression to EAC, an isoform switch occurs in the E3 ubiquitin ligase RNF128 (aka GRAIL-gene related to anergy in lymphocytes), enriching isoform 1 (hereby GRAIL1) and stabilizing the mutant p53 protein. Consequently, GRAIL1 knockdown degrades mutant p53. But, how GRAIL1 stabilizes the mutant p53 protein remains unclear. In search for a mechanism, here, we performed biochemical and cell biology studies to identify that GRAIL has a binding domain (315-PMCKCDILKA-325) for heat shock protein 40/DNAJ. This interaction can influence DNAJ chaperone activity to modulate misfolded mutant p53 stability. As predicted, either the overexpression of a GRAIL fragment (Frag-J) encompassing the DNAJ binding domain or a cell-permeable peptide (Pep-J) encoding the above 10 amino acids can bind and inhibit DNAJ-Hsp70 co-chaperone activity, thus degrading misfolded mutant p53. Consequently, either Frag-J or Pep-J can reduce the survival of mutant p53 containing dysplastic Barrett's esophagus and EAC cells and inhibit the growth of patient-derived organoids of dysplastic Barrett's esophagus in 3D cultures. The misfolded mutant p53 targeting and growth inhibitory effects of Pep-J are comparable with simvastatin, a cholesterol-lowering drug that can degrade misfolded mutant p53 also via inhibiting DNAJA1, although by a distinct mechanism. Implications: We identified a novel ubiquitin ligase-independent, chaperone-regulating domain in GRAIL and further synthesized a first-in-class novel misfolded mutant p53 degrading peptide having future translational potential.
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Affiliation(s)
- Paramita Ray
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109
| | - Sangeeta Jaiswal
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
| | | | - Zhuwen Wang
- Department of Thoracic Surgery, University of Michigan, Ann Arbor, MI 48109
| | - Derek Nancarrow
- Department of Thoracic Surgery, University of Michigan, Ann Arbor, MI 48109
| | - Meghan Curtin
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109
| | - May San Martinho
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109
| | - Shannon M. Lacy
- Department of Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109
| | | | - Dafydd Thomas
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109
| | - Jason R. Spence
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109
| | - Matthias C. Truttmann
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109
| | - Kiran H. Lagisetty
- Department of Thoracic Surgery, University of Michigan, Ann Arbor, MI 48109
| | | | - Thomas D. Wang
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
| | - David G. Beer
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
| | - Dipankar Ray
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109
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5
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David J, Woo M, Congly S, Andrews CN, Jeyalingam T, Belletrutti PJ, Gupta M. Quality of life, clinical outcomes and cost utilization of endoscopic therapy in patients with Barrett's esophagus and early esophageal cancer-an 8-year Canadian experience. J Can Assoc Gastroenterol 2024; 7:368-375. [PMID: 39416720 PMCID: PMC11477975 DOI: 10.1093/jcag/gwae018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2024] Open
Abstract
Background and Aims Endoscopic treatment is a definitive and cost-effective management strategy for early neoplasia in Barrett's oesophagus (BE). However, little is known of its impact on quality of life (QoL). This study reports outcomes of endoscopic eradication treatment (EET), focusing on QoL and costs in a Canadian tertiary referral centre. Methods A retrospective cohort study using a prospectively maintained clinical database captured validated QoL metrics during and at the end of EET, risk factors for BE, treatment response, complications, costs, and follow-up response of all treated Barrett patients in Calgary and Southern Alberta, Canada. Results A total of 147 BE patients were treated from 2013 to 2021. All patients showed significant improvement in almost all QoL parameters except depression. There was significant improvement in 7 of the 8 QoL metrics in those who achieved complete eradication of intestinal metaplasia (CEIM). EET was successful in achieving complete eradication of dysplasia (CED) and CEIM in 93.4% and 74.3% of patients, respectively, with a median of 3 radio frequency ablation treatments. Longer circumferential segments of BE (Cx) predicted a lower likelihood of achieving CEIM. The average total cost to achieve CED and CEIM were $10 414.58 and $9347.93CAD, respectively (compared to oesophagectomy estimated at $58 332.30 CAD). Conclusion This Canadian cohort reports significant post-treatment improvement in QoL parameters in patients treated to CEIM or CED over an 8-year period. EET for BE eradication is cost-effective compared to oesophagectomy. There was a low rate of complications and recurrence post-CEIM.
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Affiliation(s)
- Joel David
- Division of Gastroenterology and Hepatology, University of Calgary, Cumming School of Medicine, 3330 Hospital Dr NW. Calgary, AB T2N 4N1, Canada
| | - Matthew Woo
- Division of Gastroenterology and Hepatology, University of Calgary, Cumming School of Medicine, 3330 Hospital Dr NW. Calgary, AB T2N 4N1, Canada
| | - Stephen Congly
- Division of Gastroenterology and Hepatology, University of Calgary, Cumming School of Medicine, 3330 Hospital Dr NW. Calgary, AB T2N 4N1, Canada
| | - Christopher N Andrews
- Division of Gastroenterology and Hepatology, University of Calgary, Cumming School of Medicine, 3330 Hospital Dr NW. Calgary, AB T2N 4N1, Canada
| | - Thurarshen Jeyalingam
- Division of Gastroenterology and Hepatology, University of Toronto, 27 King’s College Cir, Toronto, ON M5S 1A1, Canada
| | - Paul J Belletrutti
- Division of Gastroenterology and Hepatology, University of Calgary, Cumming School of Medicine, 3330 Hospital Dr NW. Calgary, AB T2N 4N1, Canada
| | - Milli Gupta
- Division of Gastroenterology and Hepatology, University of Calgary, Cumming School of Medicine, 3330 Hospital Dr NW. Calgary, AB T2N 4N1, Canada
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McNamee N, Rajagopalan P, Tal-Mason A, Roytburd S, Sachdeva UM. AMPK Activation Serves as a Common Pro-Survival Pathway in Esophageal Adenocarcinoma Cells. Biomolecules 2024; 14:1115. [PMID: 39334882 PMCID: PMC11429576 DOI: 10.3390/biom14091115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/26/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
Esophageal adenocarcinoma (EAC) is a subtype of esophageal cancer that is difficult to treat, with overall poor survival and frequent recurrence despite curative-intent treatment strategies. There is limited understanding of EAC resistance mechanisms to chemotherapy or radiation. We have found that the AMP-activated protein kinase (AMPK) can serve a pro-survival function in EAC cells in response to cytotoxic treatments. Treatment with the IL-6 inhibitor tocilizumab, which previously has been shown to inhibit EAC organoid growth, resulted in the activation of AMPK in the OE33 EAC cell line, which was accompanied by a decrease in MTORC1 signaling and an increase in oxidative mitochondrial metabolism, both known downstream effects of AMPK activation to promote cell survival under conditions of metabolic stress. This increase in oxidative metabolism was abrogated in cells with a genetic knockdown of AMPK expression. Furthermore, we found that AMPK was activated in OE33 cells following treatment with cisplatin or ionizing radiation. Treatment with the AMPK inhibitor Compound C or genetic knockdown of AMPK expression enhanced cell death in a synergistic manner with chemotherapeutics or ionizing radiation. These findings were recapitulated in human patient-derived EAC organoids, suggesting that AMPK may be a common pro-survival mechanism to confer treatment resistance in EAC and may serve as a novel target to enhance the efficacy of current and future treatment strategies.
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Affiliation(s)
- Niamh McNamee
- Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Pavithra Rajagopalan
- Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Aya Tal-Mason
- Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Samuel Roytburd
- Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Uma M Sachdeva
- Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA 02114, USA
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7
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Hara Y, Baba Y, Oda E, Harada K, Yamashita K, Toihata T, Kosumi K, Iwatsuki M, Miyamoto Y, Tsutsuki H, Gan Q, Waters RE, Komohara Y, Sawa T, Ajani JA, Baba H. Presence of Fusobacterium nucleatum in relation to patient survival and an acidic environment in oesophagogastric junction and gastric cancers. Br J Cancer 2024; 131:797-807. [PMID: 38992099 PMCID: PMC11368944 DOI: 10.1038/s41416-024-02753-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 05/24/2024] [Accepted: 06/05/2024] [Indexed: 07/13/2024] Open
Abstract
BACKGROUND Fusobacterium nucleatum inhabits the oral cavity and affects the progression of gastrointestinal cancer. Our prior findings link F. nucleatum to poor prognosis in oesophageal squamous cell carcinoma via NF-κB pathway. However, its role in oesophagogastric junction and gastric adenocarcinoma remains unexplored. We investigated whether F. nucleatum influences these cancers, highlighting its potential impact. METHODS Two cohorts of EGJ and gastric adenocarcinoma patients (438 from Japan, 380 from the USA) were studied. F. nucleatum presence was confirmed by qPCR, FISH, and staining. Patient overall survival (OS) was assessed based on F. nucleatum positivity. EGJ and gastric adenocarcinoma cell lines were exposed to F. nucleatum to study molecular and phenotypic effects, validated in xenograft mouse model. RESULTS In both cohorts, F. nucleatum-positive EGJ or gastric adenocarcinoma patients had notably shorter OS. F. nucleatum positivity decreased in more acidic tumour environments. Cancer cell lines with F. nucleatum showed enhanced proliferation and NF-κB activation. The xenograft model indicated increased tumour growth and NF-κB activation in F. nucleatum-treated cells. Interestingly, co-occurrence of F. nucleatum and Helicobacter pylori, a known risk factor, was rare. CONCLUSIONS F. nucleatum can induce the NF-κB pathway in EGJ and gastric adenocarcinomas, leading to tumour progression and poor prognosis.
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Affiliation(s)
- Yoshihiro Hara
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Yoshifumi Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
- Division of Translational Research and Advanced Treatment Against Gastrointestinal Cancer, Kumamoto University, 1-1-1 Honjo, Chuoku, Kumamoto, 860-8556, Japan.
| | - Eri Oda
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Kazuto Harada
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Kohei Yamashita
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tasuku Toihata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Keisuke Kosumi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Masaaki Iwatsuki
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Hiroyasu Tsutsuki
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Qiong Gan
- Department of Pathology, UT M. D. Anderson Cancer Center, Houston, USA
| | - Rebecca E Waters
- Department of Pathology, UT M. D. Anderson Cancer Center, Houston, USA
| | - Yoshihiro Komohara
- Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Tomohiro Sawa
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
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Baumeister T, Proaño-Vasco A, Metwaly A, Kleigrewe K, Kuznetsov A, Schömig L, Borgmann M, Khiat M, Anand A, Böttcher K, Haller D, Dunkel A, Somoza V, Reiter S, Meng C, Thimme R, Schmid RM, Patil DT, Burgermeister E, Huang Y, Sun Y, Wang HH, Wang TC, Abrams JA, Quante M. Microbiota metabolized Bile Acids accelerate Gastroesophageal Adenocarcinoma via FXR inhibition. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.11.598405. [PMID: 38915718 PMCID: PMC11195123 DOI: 10.1101/2024.06.11.598405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Background The incidence of Barrett esophagus (BE) and Gastroesophageal Adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BA) support fat digestion and undergo microbial metabolization in the gut. The farnesoid X receptor (FXR) is an important modulator of the BA homeostasis. The capacity of inhibiting cancer-related processes when activated, make FXR an appealing therapeutic target. In this work, we assess the role of diet on the microbiota-BA axis and evaluate the role of FXR in disease progression. Results Here we show that high fat diet (HFD) accelerated tumorigenesis in L2-IL1B mice (BE- and GEAC- mouse model) while increasing BA levels and enriching gut microbiota that convert primary to secondary BA. While upregulated in BE, expression of FXR was downregulated in GEAC in mice and humans. In L2-IL1B mice, FXR knockout enhanced the dysplastic phenotype and increased Lgr5 progenitor cell numbers. Treatment of murine organoids and L2-IL1B mice with the FXR agonist obeticholic acid (OCA) deacelerated GEAC progression. Conclusion We provide a novel concept of GEAC carcinogenesis being accelerated via the diet-microbiome-metabolome axis and FXR inhibition on progenitor cells. Further, FXR activation protected with OCA ameliorated the phenotype in vitro and in vivo, suggesting that FXR agonists have potential as differentiation therapy in GEAC prevention.
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Affiliation(s)
- Theresa Baumeister
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg; Germany
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich; Germany
| | - Andrea Proaño-Vasco
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg; Germany
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg; Germany
- Faculty of Biology, University of Freiburg; Germany
| | - Amira Metwaly
- Chair of Nutrition and Immunology; Technical University of Munich; Germany
| | - Karin Kleigrewe
- Bavarian Center for Biomolecular Mass Spectrometry, TUM School of Life Sciences, Technical University of Munich; Germany
| | - Alexander Kuznetsov
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg; Germany
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg; Germany
- Faculty of Biology, University of Freiburg; Germany
| | - Linus Schömig
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg; Germany
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg; Germany
- Faculty of Biology, University of Freiburg; Germany
| | - Martin Borgmann
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg; Germany
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg; Germany
- Faculty of Biology, University of Freiburg; Germany
| | - Mohammed Khiat
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg; Germany
| | - Akanksha Anand
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich; Germany
| | - Katrin Böttcher
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich; Germany
| | - Dirk Haller
- Chair of Nutrition and Immunology; Technical University of Munich; Germany
| | - Andreas Dunkel
- Leibniz-Institute for Food Systems Biology, Technical University of Munich; Germany
- Chair of Food Chemistry and Molecular Sensory Science, TUM School of Life Sciences, Technical University of Munich; Germany
| | - Veronika Somoza
- Leibniz-Institute for Food Systems Biology, Technical University of Munich; Germany
| | - Sinah Reiter
- Chair of Food Chemistry and Molecular Sensory Science, TUM School of Life Sciences, Technical University of Munich; Germany
| | - Chen Meng
- Bavarian Center for Biomolecular Mass Spectrometry, TUM School of Life Sciences, Technical University of Munich; Germany
| | - Robert Thimme
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg; Germany
| | - Roland M. Schmid
- Klinik und Poliklinik für Innere Medizin II, Technical University of Munich; Germany
| | - Deepa T. Patil
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School; Boston, USA
| | - Elke Burgermeister
- Dept. of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University; Germany
| | - Yiming Huang
- Systems & Synthetic Biology, Columbia University Medical Center; New York, NY, USA
| | - Yiwei Sun
- Systems & Synthetic Biology, Columbia University Medical Center; New York, NY, USA
| | - Harris H. Wang
- Systems & Synthetic Biology, Columbia University Medical Center; New York, NY, USA
| | - Timothy C. Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Julian A. Abrams
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Michael Quante
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg; Germany
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg; Germany
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9
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Mascaretti F, Haider S, Amoroso C, Caprioli F, Ramai D, Ghidini M. Role of the Microbiome in the Diagnosis and Management of Gastroesophageal Cancers. J Gastrointest Cancer 2024; 55:662-678. [PMID: 38411876 DOI: 10.1007/s12029-024-01021-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2024] [Indexed: 02/28/2024]
Abstract
PURPOSE Stomach and esophageal cancers are among the highest mortality from cancers worldwide. Microbiota has an interplaying role within the human gastrointestinal (GI) tract. Dysbiosis occurs when a disruption of the balance between the microbiota and the host happens. With this narrative review, we discuss the main alterations in the microbiome of gastroesophageal cancer, revealing its potential role in the pathogenesis, early detection, and treatment. RESULTS Helicobacter pylori plays a major role the development of a cascade of preneoplastic conditions ranging from atrophic gastritis to metaplasia and dysplasia, ultimately culminating in gastric cancer, while other pathogenic agents are Fusobacterium nucleatum, Bacteroides fragilis, Escherichia coli, and Lactobacillus. Campylobacter species (spp.)'s role in the progression of esophageal adenocarcinoma may parallel that of Helicobacter pylori in the context of gastric cancer, with other esophageal carcinogenic agents being Escherichia coli, Bacteroides fragilis, and Fusobacterium nucleatum. Moreover, gut microbiome could significantly alter the outcomes of chemotherapy and immunotherapy. The gut microbiome can be modulated through interventions such as antibiotics, probiotics, or prebiotics intake. Fecal microbiota transplantation has emerged as a therapeutic strategy as well. CONCLUSIONS Nowadays, it is widely accepted that changes in the normal gut microbiome causing dysbiosis and immune dysregulation play a role gastroesophageal cancer. Different interventions, including probiotics and prebiotics intake are being developed to improve therapeutic outcomes and mitigate toxicities associated with anticancer treatment. Further studies are required in order to introduce the microbiome among the available tools of precision medicine in the field of anticancer treatment.
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Affiliation(s)
- Federica Mascaretti
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Salman Haider
- Department of Internal Medicine, Brooklyn Hospital Center, Brooklyn, New York, NY, USA
| | - Chiara Amoroso
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Daryl Ramai
- Division of Gastroenterology and Hepatology, University of Utah Health, Salt Lake City, UT, USA
| | - Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Via Sforza 28, Milan, Italy.
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10
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Li S, Hoefnagel SJM, Krishnadath KK. Molecular Biology and Clinical Management of Esophageal Adenocarcinoma. Cancers (Basel) 2023; 15:5410. [PMID: 38001670 PMCID: PMC10670638 DOI: 10.3390/cancers15225410] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/10/2023] [Accepted: 11/12/2023] [Indexed: 11/26/2023] Open
Abstract
Esophageal adenocarcinoma (EAC) is a highly lethal malignancy. Due to its rising incidence, EAC has become a severe health challenge in Western countries. Current treatment strategies are mainly chosen based on disease stage and clinical features, whereas the biological background is hardly considered. In this study, we performed a comprehensive review of existing studies and discussed how etiology, genetics and epigenetic characteristics, together with the tumor microenvironment, contribute to the malignant behavior and dismal prognosis of EAC. During the development of EAC, several intestinal-type proteins and signaling cascades are induced. The anti-inflammatory and immunosuppressive microenvironment is associated with poor survival. The accumulation of somatic mutations at the early phase and chromosomal structural rearrangements at relatively later time points contribute to the dynamic and heterogeneous genetic landscape of EAC. EAC is also characterized by frequent DNA methylation and dysregulation of microRNAs. We summarize the findings of dysregulations of specific cytokines, chemokines and immune cells in the tumor microenvironment and conclude that DNA methylation and microRNAs vary with each different phase of BE, LGD, HGD, early EAC and invasive EAC. Furthermore, we discuss the suitability of the currently employed therapies in the clinic and possible new therapies in the future. The development of targeted and immune therapies has been hampered by the heterogeneous genetic characteristics of EAC. In view of this, the up-to-date knowledge revealed by this work is absolutely important for future EAC studies and the discovery of new therapeutics.
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Affiliation(s)
- Shulin Li
- Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
- Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands
| | | | - Kausilia Krishnawatie Krishnadath
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, 2650 Edegem, Belgium
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, 2000 Antwerpen, Belgium
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11
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Peleg N, Ringel Y, Shamah S, Schmilovitz-Weiss H, Leshno M, Benjaminov F, Shinhar N, Gingold-Belfer R, Dotan I, Sapoznikov B. Development and validation of a prediction model for histologic progression in patients with nondysplastic Barrett's esophagus. Dig Endosc 2023; 35:718-725. [PMID: 36567638 DOI: 10.1111/den.14505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 12/22/2022] [Indexed: 12/27/2022]
Abstract
OBJECTIVES Patients with Barrett's esophagus (BE) are at risk of progression to esophageal adenocarcinoma (EAC). We developed a model to predict histologic progression in patients with nondysplastic BE (NDBE). METHODS A longitudinal study in three referral centers was performed between January 2010 and December 2019. As progression to low-grade dysplasia (LGD) can be considered an indication for ablative therapy, the study end-point was histopathologic progression to LGD, high-grade dysplasia, or EAC at 3 years after diagnosis. We used logistic regression to create the model. Seventy percent of the cohort were used to stem the model and the remaining 30% for internal validation. RESULTS A total of 542 patients were included, 69.4% of whom were male, mean age 62.2 years. Long-segment BE at index endoscopy was diagnosed in 20.8% of the patients. After a mean follow-up of 6.7 years, 133 patients (24.5%) had histologic progression. Our model identified a neutrophil-to-lymphocyte ratio (odds ratio [OR] 2.08, 95% confidence interval [CI] 1.77-2.32, P < 0.001), BE length (OR 1.22, 95% CI 1.09-1.36, P < 0.001), age (OR 1.03, 95% CI 1.02-1.05, P = 0.02), smoking (OR 1.66, 95% CI 1.09-2.75, P = 0.04), and renal failure (OR 1.51, 95% CI 0.93-2.43, P = 0.07) as predictors of histologic progression at 3 years. The areas under the receiver operating characteristic curves of this model were 0.88 and 0.76 in the training and validation cohorts, respectively. CONCLUSION This novel, internally validated model may predict histologic progression, even in patients with NDBE who generally have low rates of progression over time, and may contribute to enhanced patient selection for more intense surveillance programs.
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Affiliation(s)
- Noam Peleg
- Division of Gastroenterology, Rabin Medical Center, Beilinson and Hasharon Hospitals, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yehuda Ringel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Division of Gastroenterology and Hepatology, Meir Medical Center, Kefar Sava, Israel
| | - Steven Shamah
- Division of Gastroenterology, Rabin Medical Center, Beilinson and Hasharon Hospitals, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Hemda Schmilovitz-Weiss
- Division of Gastroenterology, Rabin Medical Center, Beilinson and Hasharon Hospitals, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Moshe Leshno
- Coller School of Management, Tel Aviv University, Tel Aviv, Israel
| | - Fabiana Benjaminov
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Division of Gastroenterology and Hepatology, Meir Medical Center, Kefar Sava, Israel
| | - Nadav Shinhar
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Division of Gastroenterology and Hepatology, Meir Medical Center, Kefar Sava, Israel
| | - Rachel Gingold-Belfer
- Division of Gastroenterology, Rabin Medical Center, Beilinson and Hasharon Hospitals, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Iris Dotan
- Division of Gastroenterology, Rabin Medical Center, Beilinson and Hasharon Hospitals, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Boris Sapoznikov
- Division of Gastroenterology, Rabin Medical Center, Beilinson and Hasharon Hospitals, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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12
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Proaño-Vasco A, Quante M. Esophageal dysbiosis and neoplasia: Moving from Barrett's esophagus to adenocarcinoma. ESOPHAGEAL DISEASE AND THE ROLE OF THE MICROBIOME 2023:77-90. [DOI: 10.1016/b978-0-323-95070-1.00013-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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13
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Zhang Q, Lin X, Jiang K, Deng J, Ke L, Wu Z, Xia P, Li Q, Yu L, Ni P, Lv W, Hu J. PD0166285 sensitizes esophageal squamous cell carcinoma to radiotherapy by dual inhibition of WEE1 and PKMYT1. Front Oncol 2022. [DOI: 10.3389/fonc.2022.1061988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
BackgroundEsophageal squamous cell carcinoma (ESCC) is an aggressive tumor with a 5-year survival rate of only 20%. More than 80% of ESCC patients possess TP53 mutation, which abolishes the G1/S checkpoint and accelerates the cell cycle. Thus, WEE1 and PKMYT1, regulators of G2/M phase in cell cycle, play essential roles in TP53-mutated cancer cells. PD0166285(PD) is a pyridopyrimidine compound that can inhibit WEE1 and PKMYT1 simultaneously, however, the effects of PD on ESCC, either as monotherapy or in combination therapy with radiotherapy, remain unclear.MethodsTo measure the anti-tumor efficacy of PD in ESCC cells, cell viability, cell cycle and cell apoptosis assays were examined in KYSE150 and TE1 cells with PD treatment. The combination therapy of PD and irradiation was also performed in ESCC cells to find whether PD can sensitize ESCC cells to irradiation. Vivo assays were also performed to investigate the efficacy of PD.ResultsWe found that the IC50 values of PD among ESCC cells ranged from 234 to 694 nM, PD can regulate cell cycle and induce cell apoptosis in ESCC cells in a dose-dependent manner. When combined with irradiation, PD sensitized ESCC cells to irradiation by abolishing G2/M phase arrest, inducing a high ratio of mitosis catastrophe, eventually leading to cell death. We also demonstrated that PD can attenuate DNA damage repair by inhibiting Rad51, further research also found the interaction of WEE1 and Rad51. In vivo assays, PD inhibited the tumor growth in mice, combination therapy showed better therapeutic efficacy.ConclusionPD0166285 can exert antitumor effect by inhibiting the function of WEE1 and PKMYT1 in ESCC cells, and also sensitize ESCC cells to irradiation not only by abolishing G2/M arrest but also attenuating DNA repair directly. We believe PD0166285 can be a potent treatment option for ESCC in the future.
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14
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Zaidi AH, Pratama MY, Omstead AN, Gorbonova A, Mansoor R, Melton-Kreft R, Jobe BA, Wagner PL, Kelly RJ, Goel A. A blood-based circulating microbial metagenomic panel for early diagnosis and prognosis of oesophageal adenocarcinoma. Br J Cancer 2022; 127:2016-2024. [PMID: 36097175 PMCID: PMC9681745 DOI: 10.1038/s41416-022-01974-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 08/23/2022] [Accepted: 08/25/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Emerging evidence indicates the potential clinical significance of specific microbial signatures as diagnostic and prognostic biomarkers, in multiple cancers. However, to date, no studies have systematically interrogated circulating metagenome profiling in oesophageal adenocarcinoma (EAC) patients, particularly as novel non-invasive, early detection, surveillance and prognostic classifiers. METHODS Metagenome sequencing was performed on 81 serum specimens collected across EAC spectrum, with sequencing reads classified using Bracken and MetaPhlAn3. Followed by the Linear Discriminant Analysis effect size (LEfSe) method to identify microbial profiles between groups. Logistic regression and Kaplan-Meier analyses were used to build classifiers. RESULTS A significant loss of alpha and beta diversity was identified in serum specimens from EAC patients. We observed a shift in microbial taxa between each group-at the phylum, genus, and species level-with Lactobacillus sakei as the most prominent species in gastroesophageal reflux (GERD) vs other patient groups. Interestingly, LEfSe analysis identified a complete loss of Lactobacillus (L. Sakei and L. Curvatus), Collinsella stercoris and Bacteroides stercoris but conversely a significant increase in Escherichia coli in patients with EAC. Finally, we developed a metagenome panel that discriminated EAC from GERD patients with an AUC value of 0.89 (95% CI: 0.78-0.95; P < 0.001) and this panel in conjunction with the TNM stage was a robust predictor of overall survival (≥24 months; AUC = 0.84 (95% CI: 0.66-0.92; P = 0.006)). CONCLUSION This study firstly describes unique blood-based microbial profiles in patients across EAC carcinogenesis, that are further utilised to establish a novel circulating diagnostic and prognostic metagenomic signature for EAC. TRANSLATIONAL RELEVANCE Accumulating data indicates the clinical relevance of specific microbial signatures as diagnostic and prognostic biomarkers, in multiple cancers. However, to date, no studies have systematically interrogated circulating metagenome profiling in patients with oesophageal adenocarcinoma (EAC). Herein, we performed metagenome sequencing in serum specimens from EAC patients 81 collected across EAC spectrum and observed a significant loss of alpha and beta diversity, with a shift in microbial taxa between each group-at the phylum, genus, and species level-with Lactobacillus sakei as the most prominent species in gastroesophageal reflux (GERD) vs other patient groups. Interestingly, LEfSe analysis identified a complete loss of Lactobacillus (L. Sakei and L. Curvatus), Collinsella stercoris and Bacteroides stercoris but conversely a significant increase in Escherichia coli in patients with EAC. Finally, we developed a metagenome panel that discriminated EAC from GERD patients with an AUC value of 0.89 and this panel, in conjunction with the TNM stage, was a robust predictor of overall survival. This study for the first time describes unique blood-based microbial profiles in patients across EAC carcinogenesis, that are further utilised to establish a novel circulating diagnostic and prognostic metagenomic signature for EAC.
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Affiliation(s)
- Ali H Zaidi
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA
| | - Muhammad Yogi Pratama
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA
| | - Ashten N Omstead
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA
| | - Anastasia Gorbonova
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA
| | - Rubab Mansoor
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA
| | - Rachael Melton-Kreft
- The Allegheny Health Network, Center of Excellence in Biofilm Research, Pittsburgh, PA, USA
| | - Blair A Jobe
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA
| | - Patrick L Wagner
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA
| | - Ronan J Kelly
- The Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA.
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
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15
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Liu J, Liu L, Su Y, Wang Y, Zhu Y, Sun X, Guo Y, Shan J. IL-33 Participates in the Development of Esophageal Adenocarcinoma. Pathol Oncol Res 2022; 28:1610474. [PMID: 36110250 PMCID: PMC9469785 DOI: 10.3389/pore.2022.1610474] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/17/2022] [Indexed: 11/13/2022]
Abstract
Background: The progression from chronic gastroesophageal reflux disease (GERD) to Barrett esophagus (BE) and esophageal adenocarcinoma (EAC) is an inflammatory-driven neoplastic change. Interleukin-33 (IL-33) has identified as a crucial factor in several inflammatory disorders and malignancies.Methods: The high-density tissue microarray of the human EAC was analyzed with IL-33 immunohistochemistry staining (IHC). By anastomosing the jejunum with the esophagus, the rat model of EAC with mixed gastroduodenal reflux was established. The expression of IL-33 was determined using quantitative real-time polymerase chain reaction (RT-qPCR), western blot (WB), IHC and enzyme-linked immunosorbent assay (ELISA). Esophageal adenocarcinoma cells (OE19 and OE33) and human esophageal epithelial cells (HEECs) were used.Results: In the cytoplasm of human EAC tissue, IL-33 expression was substantially greater than in adjacent normal tissue. In rat model, the expression of IL-33 in the EAC group was considerably greater than in the control group, and this expression increased with the upgrade of pathological stage. In in vitro experiment, the mRNA and protein levels of IL-33 were considerably greater in OE19 and OE33 than in HEECs. The stimulation of IL-33 enhanced the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of OE19 and OE33, but soluble ST2 (sST2) inhibited these effects. IL-33 stimulated the release of IL-6 by OE19 and OE33 cells.Conclusion: This study demonstrated the overexpression of IL-33 in the transition from GERD to EAC and that IL-33 promoted carcinogenesis in EAC cells through ST2. IL-33 might be a possible preventive target for EAC.
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Affiliation(s)
- Jia Liu
- School of Medicine, Southwest Jiaotong University, Chengdu, China
- The Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, China
| | - Lei Liu
- Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, China
| | - Yang Su
- School of Medicine, Southwest Jiaotong University, Chengdu, China
- The Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, China
| | - Yi Wang
- North Sichuan Medical College, Nanchong, China
| | - Yuchun Zhu
- North Sichuan Medical College, Nanchong, China
| | - Xiaobin Sun
- Department of Gastroenterology, The Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, China
| | - Yuanbiao Guo
- Medical Research Center, The Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, China
| | - Jing Shan
- Department of Gastroenterology, The Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, China
- *Correspondence: Jing Shan,
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16
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Jiangang S, Nayoung K, Hongfang W, Junda L, Li C, Xuefeng B, Mingsong L. COX-2 strengthens the effects of acid and bile salts on human esophageal cells and Barrett esophageal cells. BMC Mol Cell Biol 2022; 23:19. [PMID: 35413817 PMCID: PMC9004192 DOI: 10.1186/s12860-022-00418-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 04/07/2022] [Indexed: 11/23/2022] Open
Abstract
Aims Investigate the effect and mechanism of COX-2 on viability, intestinal metaplasia, and atypia in human esophageal squamous and Barrett esophageal cell lines. Methods Human esophageal squamous and Barrett esophageal cell lines were transfected with a COX-2 expression vector and a COX-2 siRNA, and then were treated with acid, bile salts, and a mixture of both. Cell viability, the expression of COX-2, NF-κB(p65), CDX-2, MUC2, c-myb, and BMP-4, and the morphology and microstructure of cells were then observed. Results The viability of COX-2 overexpressed cells was significantly higher than that of control cells, while the viability of COX-2 siRNA-treated cells was significantly lower than that of control cells. Intestinal metaplasia and atypia were observed in cells overexpressing COX-2. Acid, bile salts, and their mixture inhibited the viability of these two cell lines, but the inhibitory effect of the mixture was stronger than a single treatment in either. SiRNA mediated knockdown of COX-2 strengthened the antiproliferative effects of the mixture on HET-1A and BAR-T cells. The expression of p-p65, CDX-2, and BMP-4 was positively correlated with COX-2 expression, while the expression levels of p65, MUC2, and c-myb remained unchanged. Conclusion COX-2 may influence the viability, atypia, and intestinal metaplasia of human esophageal cells and Barrett esophageal cells. Activation of the p-p65, CDX-2, and BMP-4 signaling pathways by COX-2 may be part of this mechanism. Supplementary Information The online version contains supplementary material available at 10.1186/s12860-022-00418-5.
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Affiliation(s)
- Shen Jiangang
- Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.,Department of Gastroenterology, Shenzhen Longhua District People' Hospital, Shenzhen, 518109, China
| | - Kang Nayoung
- Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Wang Hongfang
- Department of Gastroenterology, Shenzhen Luohu People' Hospital, Shenzhen, 518003, China
| | - Li Junda
- Department of Gastroenterology, Shenzhen Longhua District People' Hospital, Shenzhen, 518109, China
| | - Chen Li
- Department of Gastroenterology, Shenzhen Longhua District People' Hospital, Shenzhen, 518109, China
| | - Bai Xuefeng
- Department of Pathology and Comprehensive Cancer Center, Ohio State University Medical Centre, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH, 43210, USA
| | - Li Mingsong
- Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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Evans JA, Carlotti E, Lin ML, Hackett RJ, Haughey MJ, Passman AM, Dunn L, Elia G, Porter RJ, McLean MH, Hughes F, ChinAleong J, Woodland P, Preston SL, Griffin SM, Lovat L, Rodriguez-Justo M, Huang W, Wright NA, Jansen M, McDonald SAC. Clonal Transitions and Phenotypic Evolution in Barrett's Esophagus. Gastroenterology 2022; 162:1197-1209.e13. [PMID: 34973296 PMCID: PMC8972067 DOI: 10.1053/j.gastro.2021.12.271] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 12/21/2021] [Accepted: 12/22/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS Barrett's esophagus (BE) is a risk factor for esophageal adenocarcinoma but our understanding of how it evolves is poorly understood. We investigated BE gland phenotype distribution, the clonal nature of phenotypic change, and how phenotypic diversity plays a role in progression. METHODS Using immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsy specimens from patients with nondysplastic BE and those who had progressed to dysplasia or had developed postesophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome. RESULTS We identified 5 different gland phenotypes in a cohort of 51 nondysplastic patients where biopsy specimens were taken at the same anatomic site (1.0-2.0 cm superior to the gastroesophageal junction. Here, we observed the same number of glands with 1 and 2 phenotypes, but 3 phenotypes were rare. We showed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have shown a clonal relationship between cardiac-type glands and specialized and mature intestinal glands. Using the Shannon diversity index as a marker of gland diversity, we observed significantly increased phenotypic diversity in patients with BE adjacent to dysplasia and predysplasia compared to nondysplastic BE and postesophagectomy BE, suggesting that diversity develops over time. CONCLUSIONS We showed that the range of BE phenotypes represents an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we showed a common ancestry between gastric and intestinal-type glands in BE.
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Affiliation(s)
- James A Evans
- Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom
| | - Emanuela Carlotti
- Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom
| | - Meng-Lay Lin
- Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom
| | - Richard J Hackett
- Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom
| | - Magnus J Haughey
- School of Mathematical Sciences, Queen Mary University of London, London, United Kingdom
| | - Adam M Passman
- Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom
| | - Lorna Dunn
- Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom
| | - George Elia
- Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom
| | - Ross J Porter
- Department of Gastroenterology, University of Aberdeen, Aberdeen, United Kingdom
| | - Mairi H McLean
- Department of Gastroenterology, University of Aberdeen, Aberdeen, United Kingdom
| | - Frances Hughes
- Department of Surgery, Barts Health NHS Trust, Royal London Hospital, London, United Kingdom
| | - Joanne ChinAleong
- Department of Histopathology, Barts Health NHS Trust, Royal London Hospital, London, United Kingdom
| | - Philip Woodland
- Endoscopy Unit, Barts Health NHS Trust, Royal London Hospital, London, United Kingdom
| | - Sean L Preston
- Endoscopy Unit, Barts Health NHS Trust, Royal London Hospital, London, United Kingdom
| | - S Michael Griffin
- School of Mathematical Sciences, Queen Mary University of London, London, United Kingdom; Royal College of Surgeons of Edinburgh, Edinburgh, United Kingdom
| | - Laurence Lovat
- Oeosophagogastric Disorders Centre, Department of Gastroenterology, University College London Hospitals, London, United Kingdom; Research Department of Tissue and Energy, University College London Division of Surgical and Interventional Science, University College London, London, United Kingdom
| | - Manuel Rodriguez-Justo
- Department of Cellular Pathology, University College London Hospitals, London, United Kingdom
| | - Weini Huang
- School of Mathematical Sciences, Queen Mary University of London, London, United Kingdom
| | - Nicholas A Wright
- Epithelial Stem Cell Laboratory, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Marnix Jansen
- Department of Cellular Pathology, University College London Hospitals, London, United Kingdom; UCL Cancer Institute, University College London, London, United Kingdom
| | - Stuart A C McDonald
- Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom.
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18
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Wu C, Wang M, Zhou Q, Shi H. Associations of Changes in Intestinal Flora and Inflammatory Factors with Prognosis of Patients with Esophageal Cancer. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:2426301. [PMID: 35388334 PMCID: PMC8977330 DOI: 10.1155/2022/2426301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/03/2022] [Accepted: 03/08/2022] [Indexed: 11/29/2022]
Abstract
This study aims to explore the associations of changes in intestinal flora and inflammatory factors with the prognosis of patients with esophageal cancer (EC). A total of 40 EC patients treated and 40 normal people who underwent gastroscopy and CT examination for gastrointestinal discomfort during the same period were selected as the participants of the study. The endotoxin level, colonization ability of intestinal flora, and distribution of intestinal flora (Bifidobacterium, Lactobacillus, Escherichia coli, and Enterococcus) were compared between the two groups. The levels of inflammatory factors interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and tumor necrosis factor-α (TNF-α) were also compared between the two groups. All participants were followed up for 3 years, and the associations of survival time with colonization ability of intestinal flora and changes in hs-CRP were analyzed. Finally, the univariate and multivariate logistic regression analyses were performed for related factors affecting the survival time of EC patients. In the observation group, the endotoxin level was significantly higher (P < 0.05), the colonization ability of intestinal flora was significantly weaker (P < 0.05), the levels of Bifidobacterium and Lactobacillus were obviously lower (P < 0.05), and the levels of Escherichia coli and Enterococcus were obviously higher than those in the normal group (P < 0.05). Besides, the observation group had abnormal and evidently higher levels of IL-6, hs-CRP, and TNF-α than the normal group (P < 0.05). The survival time was positively correlated with the colonization ability of intestinal flora (P < 0.05), but negatively correlated with the changes in hs-CRP (P < 0.05). Moreover, the increased level of endotoxin, weakened colonization ability of intestinal flora, abnormal distribution of intestinal flora, and elevated levels of inflammatory factors were all related and independent risk factors affecting the survival time of EC patients. In EC patients, the endotoxin level markedly rises, the colonization ability of intestinal flora declines, and there are intestinal flora disorders and enhanced inflammatory response. With the decline in colonization ability of intestinal flora and the increase of inflammatory response, the survival time of EC patients will be shortened.
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Affiliation(s)
- Cheng Wu
- Department of Gastroenterology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China
| | - Ming Wang
- Department of Gastroenterology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China
| | - Qing Zhou
- Department of Gastroenterology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China
| | - Hui Shi
- Department of Gastroenterology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China
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19
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Sahm V, Maurer C, Baumeister T, Anand A, Strangmann J, Schmid RM, Wang TC, Quante M. Telomere shortening accelerates tumor initiation in the L2-IL1B mouse model of Barrett esophagus and emerges as a possible biomarker. Oncotarget 2022; 13:347-359. [PMID: 35178191 PMCID: PMC8842791 DOI: 10.18632/oncotarget.28198] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 02/07/2022] [Indexed: 11/30/2022] Open
Abstract
Barrett’s esophagus (BE) is a precursor of the esophageal adenocarcinoma (EAC). BE- development and its progression to cancer is associated with gastroesophageal reflux disease. However, there is currently no molecular risk prediction model that accurately identifies patients at high risk for EAC. Here, we investigated the impact of shortened telomeres in a mouse model for Barrett esophagus (L2-IL1B). The L2-IL1B mouse model is characterized by IL-1β-mediated inflammation, which leads to a Barrett-like metaplasia in the transition zone between the squamous forestomach and glandular cardia/stomach. Telomere shortening was achieved by mTERC knockout. In the second generation (G2) of mTERC knockout L2-IL1B.mTERC−/− G2 mice exhibited telomere dysfunction with significantly shorter telomeres as measured by qFISH compared to L2-IL1B mice, correlating with stronger DNA damage in the form of phosphorylation of H2AX (γH2AX). Macroscopically, tumor area along the squamocolumnar junction (SCJ) was increased in L2-IL1B.mTERC−/− G2 mice, along with increased histopathological dysplasia. In vitro studies indicated increased organoid formation capacity in BE tissue from L2-IL1B.mTERC−/− G2 mice. In addition, pilot studies of human BE-, dysplasia- and EAC tissue samples confirmed that BE epithelial cells with or without dysplasia (LGD) had shorter telomeres compared to gastric cardia tissue. Of note, differentiated goblet cells retained longer telomeres than columnar lined BE epithelium. In conclusion, our studies suggest that shortened telomeres are functionally important for tumor development in a mouse model of BE and are associated with proliferating columnar epithelium in human BE. We propose that shortened telomeres should be evaluated further as a possible biomarker of cancer risk in BE patients.
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Affiliation(s)
- Vincenz Sahm
- II Medizinische Klinik, Technische Universität München, Munich, Germany
| | - Carlo Maurer
- II Medizinische Klinik, Technische Universität München, Munich, Germany
| | - Theresa Baumeister
- II Medizinische Klinik, Technische Universität München, Munich, Germany
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg, Freiburg, Germany
| | - Akanksha Anand
- II Medizinische Klinik, Technische Universität München, Munich, Germany
| | - Julia Strangmann
- II Medizinische Klinik, Technische Universität München, Munich, Germany
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg, Freiburg, Germany
| | - Roland M. Schmid
- II Medizinische Klinik, Technische Universität München, Munich, Germany
| | - Timothy C. Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Michael Quante
- II Medizinische Klinik, Technische Universität München, Munich, Germany
- Klinik für Innere Medizin II, Universitätsklinikum Freiburg, Freiburg, Germany
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20
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Schmidt M, Hackett RJ, Baker AM, McDonald SAC, Quante M, Graham TA. Evolutionary dynamics in Barrett oesophagus: implications for surveillance, risk stratification and therapy. Nat Rev Gastroenterol Hepatol 2022; 19:95-111. [PMID: 34728819 DOI: 10.1038/s41575-021-00531-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/24/2021] [Indexed: 12/13/2022]
Abstract
Cancer development is a dynamic evolutionary process characterized by marked intratumoural heterogeneity at the genetic, epigenetic and phenotypic levels. Barrett oesophagus, the pre-malignant condition to oesophageal adenocarcinoma (EAC), is an exemplary system to longitudinally study the evolution of malignancy. Evidence has emerged of Barrett oesophagus lesions pre-programmed for progression to EAC many years before clinical detection, indicating a considerable window for therapeutic intervention. In this Review, we explore the mechanisms underlying clonal expansion and contraction that establish the Barrett oesophagus clonal mosaicism over time and space and discuss intrinsic genotypic and extrinsic environmental drivers that direct the evolutionary trajectory of Barrett oesophagus towards a malignant phenotype. We propose that understanding and exploiting the evolutionary dynamics of Barrett oesophagus will identify novel therapeutic targets, improve prognostic tools and offer the opportunity for personalized surveillance programmes geared to prevent progression to EAC.
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Affiliation(s)
- Melissa Schmidt
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany
| | - Richard J Hackett
- Clonal Dynamics in Epithelia Group; Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Ann-Marie Baker
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Stuart A C McDonald
- Clonal Dynamics in Epithelia Group; Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Michael Quante
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany
- Department of Medicine II, Universitaetsklinikum Freiburg, Freiburg, Germany
| | - Trevor A Graham
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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21
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Krause J, Brokmann F, Rosenbaum C, Weitschies W. The challenges of drug delivery to the esophagus and how to overcome them. Expert Opin Drug Deliv 2022; 19:119-131. [DOI: 10.1080/17425247.2022.2033206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Julius Krause
- University of Greifswald, Institute of Pharmacy, Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, Felix-Hausdorff-Str. 3, 17489 Greifswald, Germany
| | - Friederike Brokmann
- University of Greifswald, Institute of Pharmacy, Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, Felix-Hausdorff-Str. 3, 17489 Greifswald, Germany
| | - Christoph Rosenbaum
- University of Greifswald, Institute of Pharmacy, Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, Felix-Hausdorff-Str. 3, 17489 Greifswald, Germany
| | - Werner Weitschies
- University of Greifswald, Institute of Pharmacy, Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, Felix-Hausdorff-Str. 3, 17489 Greifswald, Germany
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22
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Dan W, Peng L, Yan B, Li Z, Pan F. Human Microbiota in Esophageal Adenocarcinoma: Pathogenesis, Diagnosis, Prognosis and Therapeutic Implications. Front Microbiol 2022; 12:791274. [PMID: 35126331 PMCID: PMC8815000 DOI: 10.3389/fmicb.2021.791274] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/23/2021] [Indexed: 11/29/2022] Open
Abstract
Esophageal adenocarcinoma (EAC) is one of the main subtypes of esophageal cancer. The incidence rate of EAC increased progressively while the 5-year relative survival rates were poor in the past two decades. The mechanism of EAC has been studied extensively in relation to genetic factors, but less so with respect to human microbiota. Currently, researches about the relationship between EAC and the human microbiota is a newly emerging field of study. Herein, we present the current state of knowledge linking human microbiota to esophageal adenocarcinoma and its precursor lesion—gastroesophageal reflux disease and Barrett’s esophagus. There are specific human bacterial alternations in the process of esophageal carcinogenesis. And bacterial dysbiosis plays an important role in the process of esophageal carcinogenesis via inflammation, microbial metabolism and genotoxicity. Based on the human microbiota alternation in the EAC cascade, it provides potential microbiome-based clinical application. This review is focused on novel targets in prevention, diagnosis, prognosis, and therapy for esophageal adenocarcinoma.
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Affiliation(s)
- Wanyue Dan
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Nankai University, Tianjin, China
| | - Lihua Peng
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Bin Yan
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zhengpeng Li
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Fei Pan
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
- *Correspondence: Fei Pan,
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23
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Maslyonkina KS, Konyukova AK, Alexeeva DY, Sinelnikov MY, Mikhaleva LM. Barrett's esophagus: The pathomorphological and molecular genetic keystones of neoplastic progression. Cancer Med 2022; 11:447-478. [PMID: 34870375 PMCID: PMC8729054 DOI: 10.1002/cam4.4447] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/07/2021] [Accepted: 11/09/2021] [Indexed: 02/06/2023] Open
Abstract
Barrett's esophagus is a widespread chronically progressing disease of heterogeneous nature. A life threatening complication of this condition is neoplastic transformation, which is often overlooked due to lack of standardized approaches in diagnosis, preventative measures and treatment. In this essay, we aim to stratify existing data to show specific associations between neoplastic transformation and the underlying processes which predate cancerous transition. We discuss pathomorphological, genetic, epigenetic, molecular and immunohistochemical methods related to neoplasia detection on the basis of Barrett's esophagus. Our review sheds light on pathways of such neoplastic progression in the distal esophagus, providing valuable insight into progression assessment, preventative targets and treatment modalities. Our results suggest that molecular, genetic and epigenetic alterations in the esophagus arise earlier than cancerous transformation, meaning the discussed targets can help form preventative strategies in at-risk patient groups.
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24
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Fang HY, Stangl S, Marcazzan S, Carvalho MJB, Baumeister T, Anand A, Strangmann J, Huspenina JS, Wang TC, Schmid RM, Feith M, Friess H, Ntziachristos V, Multhoff G, Gorpas D, Quante M. Targeted Hsp70 fluorescence molecular endoscopy detects dysplasia in Barrett's esophagus. Eur J Nucl Med Mol Imaging 2022; 49:2049-2063. [PMID: 34882260 PMCID: PMC9016004 DOI: 10.1007/s00259-021-05582-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 10/03/2021] [Indexed: 01/21/2023]
Abstract
PURPOSE The incidence of esophageal adenocarcinoma (EAC) has been increasing for decades without significant improvements in treatment. Barrett's esophagus (BE) is best established risk factor for EAC, but current surveillance with random biopsies cannot predict progression to cancer in most BE patients due to the low sensitivity and specificity of high-definition white light endoscopy. METHODS Here, we evaluated the membrane-bound highly specific Hsp70-specific contrast agent Tumor-Penetrating Peptide (Hsp70-TPP) in guided fluorescence molecular endoscopy biopsy. RESULTS Hsp70 was significantly overexpressed as determined by IHC in dysplasia and EAC compared with non-dysplastic BE in patient samples (n = 12) and in high-grade dysplastic lesions in a transgenic (L2-IL1b) mouse model of BE. In time-lapse microscopy, Hsp70-TPP was rapidly taken up and internalized by human BE dysplastic patient-derived organoids. Flexible fluorescence endoscopy of the BE mouse model allowed a specific detection of Hsp70-TPP-Cy5.5 that corresponded closely with the degree of dysplasia but not BE. Ex vivo application of Hsp70-TPP-Cy5.5 to freshly resected whole human EAC specimens revealed a high (> 4) tumor-to-background ratio and a specific detection of previously undetected tumor infiltrations. CONCLUSION In summary, these findings suggest that Hsp70-targeted imaging using fluorescently labeled TPP peptide may improve tumor surveillance in BE patients.
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Affiliation(s)
- Hsin-Yu Fang
- II Medizinische Klinik, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany
| | - Stefan Stangl
- Department of Radiation Oncology and Central Institute for Translational Cancer Research, (TranslaTUM), Technische Universität München, Munich, Germany
| | - Sabrina Marcazzan
- II Medizinische Klinik, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany ,Chair of Biological Imaging, School of Medicine, Technische Universität München, Munich, Germany; Helmholtz Zentrum München, Institute of Biological and Medical Imaging, Neuherberg, Germany
| | - Marcos J. Braz Carvalho
- II Medizinische Klinik, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany
| | - Theresa Baumeister
- II Medizinische Klinik, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany
| | - Akanksha Anand
- II Medizinische Klinik, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany
| | - Julia Strangmann
- II Medizinische Klinik, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany ,Innere Medizin II, Universitätsklinik Freiburg, Universität Freiburg, Freiburg im Breisgau, Germany
| | | | - Timothy C. Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, NY USA
| | - Roland M. Schmid
- II Medizinische Klinik, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany
| | - Marcus Feith
- Chirurgische Klinik, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany
| | - Helmut Friess
- Chirurgische Klinik, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany
| | - Vasilis Ntziachristos
- Chair of Biological Imaging, School of Medicine, Technische Universität München, Munich, Germany; Helmholtz Zentrum München, Institute of Biological and Medical Imaging, Neuherberg, Germany
| | - Gabriele Multhoff
- Department of Radiation Oncology and Central Institute for Translational Cancer Research, (TranslaTUM), Technische Universität München, Munich, Germany
| | - Dimitris Gorpas
- Chair of Biological Imaging, School of Medicine, Technische Universität München, Munich, Germany; Helmholtz Zentrum München, Institute of Biological and Medical Imaging, Neuherberg, Germany
| | - Michael Quante
- II Medizinische Klinik, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany ,Innere Medizin II, Universitätsklinik Freiburg, Universität Freiburg, Freiburg im Breisgau, Germany
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25
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Zhu L, Yang F, Li X, Li Q, Zhong C. Glycolysis Changes the Microenvironment and Therapeutic Response Under the Driver of Gene Mutation in Esophageal Adenocarcinoma. Front Genet 2021; 12:743133. [PMID: 34956314 PMCID: PMC8693172 DOI: 10.3389/fgene.2021.743133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 10/25/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Esophageal cancer is one of the most leading and lethal malignancies. Glycolysis and the tumor microenvironment (TME) are responsible for cancer progressions. We aimed to study the relationships between glycolysis, TME, and therapeutic response in esophageal adenocarcinoma (EAC). Materials and Methods: We used the ESTIMATE algorithm to divide EAC patients into ESTIMATE high and ESTIMATE low groups based on the gene expression data downloaded from TCGA. Weighted gene co-expression network analysis (WGCNA) and Gene Set Enrichment Analysis (GSEA) were performed to identify different glycolytic genes in the TME between the two groups. The prognostic gene signature for overall survival (OS) was established through Cox regression analysis. Impacts of glycolytic genes on immune cells were assessed and validated. Next, we conducted the glycolytic gene mutation analysis and drug therapeutic response analysis between the two groups. Finally, the GEO database was employed to validate the impact of glycolysis on TME in patients with EAC. Results: A total of 78 EAC patients with gene expression profiles and clinical information were included for analysis. Functional enrichment results showed that the genes between ESTIMATE high and ESTIMATE low groups (N = 39, respectively) were strongly related with glycolytic and ATP/ADP metabolic pathways. Patients in the low-risk group had probabilities to survive longer than those in the high-risk group (p < 0.001). Glycolytic genes had significant impacts on the components of immune cells in TME, especially on the T-cells and dendritic cells. In the high-risk group, the most common mutant genes were TP53 and TTN, and the most frequent mutation type was missense mutation. Glycolysis significantly influenced drug sensitivity, and high tumor mutation burden (TMB) was associated with better immunotherapeutic response. GEO results confirmed that glycolysis had significant impacts on immune cell contents in TME. Conclusion: We performed a comprehensive study of glycolysis and TME and demonstrated that glycolysis could influence the microenvironment and drug therapeutic response in EAC. Evaluation of the glycolysis pattern could help identify the individualized therapeutic regime.
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Affiliation(s)
- Lei Zhu
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.,Department of Thoracic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Fugui Yang
- Department of Thoracic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xinrui Li
- Department of Neurology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qinchuan Li
- Department of Thoracic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Chunlong Zhong
- Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
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26
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Dong X, Chen X, Lu D, Diao D, Liu X, Mai S, Feng S, Xiong G. LncRNA miR205HG hinders HNRNPA0 translation: anti-oncogenic effects in esophageal carcinoma. Mol Oncol 2021; 16:795-812. [PMID: 34821009 PMCID: PMC8807358 DOI: 10.1002/1878-0261.13142] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 09/23/2021] [Accepted: 11/23/2021] [Indexed: 12/14/2022] Open
Abstract
Esophageal carcinoma (ESCA) affects 4 450 000 people and causes approximately 400 000 deaths annually worldwide, making it the sixth most lethal and eighth most common cancer. Patients with ESCA are often diagnosed at the later stages in which cancer cell metastasis is the main factor contributing to the low 5‐year survival rate (< 20%) of this disease. Long noncoding RNAs (lncRNAs) are a group of regulatory RNAs with a length of > 200 nucleotides but which fail to encode proteins. In this study, by using real‐time quantitative PCR, we found that the expression of the miR205 host gene (miR205HG; a lncRNA) was downregulated in ESCA tumors when compared with normal esophageal tissues or adjacent normal tissues of tumors. Furthermore, we demonstrated that miR205HG modulates the expression of extracellular matrix‐related genes in ESCA cells. In the transwell assay, downregulation of miR205HG contributes to migration and invasion of ESCA cells. In relation to the mechanism, our data show that miR205HG interacts with heterogeneous nuclear ribonucleoprotein A0 (HNRNPA0) mRNA and then hamper its translation by interacting with lin‐28 homolog A (LIN28A). Altogether, we highlight that the miR205HG‐HNRNPA0 axis is implicated in the migration and invasion of ESCA cells and that these members of this pathway may serve as therapeutic targets to inhibit metastasis of ESCA.
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Affiliation(s)
- Xiaoying Dong
- Department of Thoracic SurgerySouthern Medical University Nanfang HospitalGuangzhouChina
| | - Xuyuan Chen
- Department of Thoracic SurgerySouthern Medical University Nanfang HospitalGuangzhouChina
| | - Di Lu
- Department of Thoracic SurgerySouthern Medical University Nanfang HospitalGuangzhouChina
| | - Dingwei Diao
- Department of Thoracic SurgerySouthern Medical University Nanfang HospitalGuangzhouChina
| | - Xiguang Liu
- Department of Thoracic SurgerySouthern Medical University Nanfang HospitalGuangzhouChina
| | - Shijie Mai
- Department of Thoracic SurgerySouthern Medical University Nanfang HospitalGuangzhouChina
| | - Siyang Feng
- Department of Thoracic SurgerySouthern Medical University Nanfang HospitalGuangzhouChina
| | - Gang Xiong
- Department of Thoracic SurgerySouthern Medical University Nanfang HospitalGuangzhouChina
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27
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Yao C, Li Y, Luo L, Xiong Q, Zhong X, Xie F, Feng P. Identification of miRNAs and genes for predicting Barrett's esophagus progressing to esophageal adenocarcinoma using miRNA-mRNA integrated analysis. PLoS One 2021; 16:e0260353. [PMID: 34818353 PMCID: PMC8612537 DOI: 10.1371/journal.pone.0260353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 11/08/2021] [Indexed: 11/29/2022] Open
Abstract
Barrett's esophagus (BE) is defined as any metaplastic columnar epithelium in the distal esophagus, which predisposes to esophageal adenocarcinoma (EAC). Yet, the mechanism through which BE develops to EAC still remain unclear. Moreover, the miRNA-mRNA regulatory network in distinguishing BE from EAC still remains poorly understood. To identify differentially expressed miRNAs (DEMs) and genes (DEGs) between EAC and BE from tissue samples, gene expression microarray datasets GSE13898, GSE26886, GSE1420 and miRNA microarray datasets GSE16456, GSE20099 were downloaded from Gene Expression Omnibus (GEO) database. GEO2R was used to screen the DEMs and DEGs. Pathway and functional enrichment analysis were performed by DAVID database. The protein-protein interaction (PPI) network was constructed by STRING and been visualized by Cytoscape software. Finnal, survival analysis was performed basing TCGA database. A total of 21 DEMs were identified. The enriched functions and pathways analysis inclued Epstein-Barr virus infection, herpesvirus infection and TRP channels. GART, TNFSF11, GTSE1, NEK2, ICAM1, PSMD12, CTNNB1, CDH1, PSEN1, IL1B, CTNND1, JAG1, CDH17, ITCH, CALM1 and ITGA6 were considered as the hub-genes. Hsa-miR-143 and hsa-miR-133b were the highest connectivity target gene. JAG1 was predicted as the largest number of target miRNAs. The expression of hsa-miR-181d, hsa-miR-185, hsa-miR-15b, hsa-miR-214 and hsa-miR-496 was significantly different between normal tissue and EAC. CDH1, GART, GTSE1, NEK2 and hsa-miR-496, hsa-miR-214, hsa-miR-15b were found to be correlated with survival.
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Affiliation(s)
- Chengjiao Yao
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Geriatrics of the Affiliated Hospital, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Yilin Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Lihong Luo
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Qin Xiong
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xiaowu Zhong
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- * E-mail: (PF); (XZ)
| | - Fengjiao Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Peimin Feng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- * E-mail: (PF); (XZ)
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28
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He S, Xu J, Liu X, Zhen Y. Advances and challenges in the treatment of esophageal cancer. Acta Pharm Sin B 2021; 11:3379-3392. [PMID: 34900524 PMCID: PMC8642427 DOI: 10.1016/j.apsb.2021.03.008] [Citation(s) in RCA: 152] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 01/24/2021] [Accepted: 02/06/2021] [Indexed: 12/18/2022] Open
Abstract
Esophageal cancer (EC) is one of the most common cancers with high morbidity and mortality rates. EC includes two histological subtypes, namely esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC primarily occurs in East Asia, whereas EAC occurs in Western countries. The currently available treatment strategies for EC include surgery, chemotherapy, radiation therapy, molecular targeted therapy, and combinations thereof. However, the prognosis remains poor, and the overall five-year survival rate is very low. Therefore, achieving the goal of effective treatment remains challenging. In this review, we discuss the latest developments in chemotherapy and molecular targeted therapy for EC, and comprehensively analyze the application prospects and existing problems of immunotherapy. Collectively, this review aims to provide a better understanding of the currently available drugs through in-depth analysis, promote the development of new therapeutic agents, and eventually improve the treatment outcomes of patients with EC.
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Affiliation(s)
- Shiming He
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
| | - Jian Xu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
| | - Xiujun Liu
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
| | - Yongsu Zhen
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
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Ray P, Nancarrow DJ, Ferrer-Torres D, Wang Z, San Martinho M, Hinton T, Wu JH, Wu A, Turgeon DK, Hammer MA, Dame MK, Lawrence TS, O'Brien PJ, Spence JR, Beer DG, Ray D. UBCH5 Family Members Differentially Impact Stabilization of Mutant p53 via RNF128 Iso1 During Barrett's Progression to Esophageal Adenocarcinoma. Cell Mol Gastroenterol Hepatol 2021; 13:129-149. [PMID: 34416429 PMCID: PMC8593620 DOI: 10.1016/j.jcmgh.2021.08.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 08/05/2021] [Accepted: 08/10/2021] [Indexed: 12/10/2022]
Abstract
BACKGROUND & AIMS TP53 mutations underlie Barrett's esophagus (BE) progression to dysplasia and cancer. During BE progression, the ubiquitin ligase (E3) RNF128/GRAIL switches expression from isoform 2 (Iso2) to Iso1, stabilizing mutant p53. However, the ubiquitin-conjugating enzyme (E2) that partners with Iso1 to stabilize mutant p53 is unknown. METHODS Single-cell RNA sequencing of paired normal esophagus and BE tissues identified candidate E2s, further investigated in expression data from BE to esophageal adenocarcinoma (EAC) progression samples. Biochemical and cellular studies helped clarify the role of RNF128-E2 on mutant p53 stability. RESULTS The UBE2D family member 2D3 (UBCH5C) is the most abundant E2 in normal esophagus. However, during BE to EAC progression, loss of UBE2D3 copy number and reduced expression of RNF128 Iso2 were noted, 2 known p53 degraders. In contrast, expression of UBE2D1 (UBCH5A) and RNF128 Iso1 in dysplastic BE and EAC forms an inactive E2-E3 complex, stabilizing mutant p53. To destabilize mutant p53, we targeted RNF128 Iso1 either by mutating asparagine (N48, 59, and 101) residues to block glycosylation to facilitate β-TrCP1-mediated degradation or by mutating proline (P54 and 105) residues to restore p53 polyubiquitinating ability. In addition, either loss of UBCH5A catalytic activity, or disruption of the Iso1-UBCH5A interaction promoted Iso1 loss. Consequently, overexpression of either catalytically dead or Iso1-binding-deficient UBCH5A mutants destabilized Iso1 to degrade mutant p53, thus compromising the clonogenic survival of mutant p53-dependent BE cells. CONCLUSIONS Loss of RNF128 Iso2-UBCH5C and persistence of the Iso1-UBCH5A complex favors mutant p53 stability to promote BE cell survival. Therefore, targeting of Iso1-UBCH5A may provide a novel therapeutic strategy to prevent BE progression.
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Affiliation(s)
- Paramita Ray
- Department of Radiation Oncology, Ann Arbor, Michigan
| | | | | | | | | | - Tonaye Hinton
- Department of Radiation Oncology, Ann Arbor, Michigan
| | - Joshua H Wu
- Department of Internal Medicine, Ann Arbor, Michigan
| | - Angeline Wu
- Department of Internal Medicine, Ann Arbor, Michigan
| | | | - Max A Hammer
- Department of Internal Medicine, Ann Arbor, Michigan
| | | | | | | | - Jason R Spence
- Department of Internal Medicine, Ann Arbor, Michigan; Department of Cell and Developmental Biology, Ann Arbor, Michigan; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - David G Beer
- Department of Radiation Oncology, Ann Arbor, Michigan; Department of Surgery, Ann Arbor, Michigan
| | - Dipankar Ray
- Department of Radiation Oncology, Ann Arbor, Michigan.
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Peleg N, Schmilovitz-Weiss H, Shamah S, Schwartz A, Dotan I, Sapoznikov B. Neutrophil to lymphocyte ratio and risk of neoplastic progression in patients with Barrett's esophagus. Endoscopy 2021; 53:774-781. [PMID: 33075822 DOI: 10.1055/a-1292-8747] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Patient's with Barrett's esophagus (BE) are at risk of progression to esophageal adenocarcinoma (EAC). Neutrophil to lymphocyte ratio (NLR) was found to be a predictor of poor prognosis in patients with EAC; however, its performance in premalignant esophageal lesions is vague. We aimed to evaluate the utility of NLR as a predictor of histologic progression in patients with BE. METHODS : A prospective cohort of patients with proven BE in a tertiary referral center was retrospectively analyzed. All biopsies were reviewed by an expert gastrointestinal pathologist. The discriminatory capacity of NLR was evaluated by area under the receiver operating characteristic (AUC) curve analysis and Cox regression analysis. RESULTS 324 patients (mean age 62.3 years, 241 [74.4 %] males) were included in the final analysis. Overall, 13 patients demonstrated histologic progression to neoplasia over a mean follow-up of 3.7 years (progression risk 1.0 % per year). The AUC of NLR for progression to high grade dysplasia (HGD) or EAC was 0.88 (95 % confidence interval [CI] 0.83 - 0.96), and baseline NLR was associated with a 3-fold increase of progression to HGD and EAC during follow-up (hazard ratio [HR] 3.2, 95 %CI 1.5 - 5.8; P < 0.001). Notably, in a subgroup analysis of patients with nondysplastic BE (NDBE) at presentation, NLR was also a risk factor for histologic progression (HR 2.4, 95 %CI 1.7 - 3.4; P < 0.001). CONCLUSION NLR predicted histologic progression in patients with BE. Patients with NDBE and NLR above 2.4 can be considered for specific surveillance programs with shorter intervals between sessions.
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Affiliation(s)
- Noam Peleg
- Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Hemda Schmilovitz-Weiss
- Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Steven Shamah
- Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ariel Schwartz
- Department of Pathology, Rabin Medical Center, Petah-Tikva, Israel
| | - Iris Dotan
- Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Boris Sapoznikov
- Division of Gastroenterology, Rabin Medical Center, Petah-Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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31
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Mucosa-Associated Microbiota in Barrett's Esophagus, Dysplasia, and Esophageal Adenocarcinoma Differ Similarly Compared With Healthy Controls. Clin Transl Gastroenterol 2021; 11:e00199. [PMID: 32955191 PMCID: PMC7473866 DOI: 10.14309/ctg.0000000000000199] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Alterations in the composition of the human gut microbiome and its metabolites have been linked to gut epithelial neoplasia. We hypothesized that differences in mucosa-adherent Barrett's microbiota could link to risk factors, providing risk of progression to neoplasia.
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Gil-Gómez G, Fassan M, Nonell L, Garrido M, Climent M, Anglada R, Iglesias M, Guzzardo V, Borga C, Grande L, de Bolós C, Pera M. miR-24-3p regulates CDX2 during intestinalization of cardiac-type epithelium in a human model of Barrett's esophagus. Dis Esophagus 2021; 34:6131383. [PMID: 33558874 DOI: 10.1093/dote/doab005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 12/15/2020] [Accepted: 01/07/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Cardiac-type epithelium has been proposed as the precursor of intestinal metaplasia in the development of Barrett's esophagus. Dysregulation of microRNAs (miRNAs) and their effects on CDX2 expression may contribute to intestinalization of cardiac-type epithelium. The aim of this study was to examine the possible effect of specific miRNAs on the regulation of CDX2 in a human model of Barrett's esophagus. METHODS Microdissection of cardiac-type glands was performed in biopsy samples from patients who underwent esophagectomy and developed cardiac-type epithelium in the remnant esophagus. OpenArray™ analysis was used to compare the miRNAs profiling of cardiac-type glands with negative or fully positive CDX2 expression. CDX2 was validated as a miR-24 messenger RNA target by the study of CDX2 expression upon transfection of miRNA mimics and inhibitors in esophageal adenocarcinoma cell lines. The CDX2/miR-24 regulation was finally validated by in situ miRNA/CDX2/MUC2 co-expression analysis in cardiac-type mucosa samples of Barrett's esophagus. RESULTS CDX2 positive glands were characterized by a unique miRNA profile with a significant downregulation of miR-24-3p, miR-30a-5p, miR-133a-3p, miR-520e-3p, miR-548a-1, miR-597-5p, miR-625-3p, miR-638, miR-1255b-1, and miR-1260a, as well as upregulation of miR-590-5p. miRNA-24-3p was identified as potential regulator of CDX2 gene expression in three databases and confirmed in esophageal adenocarcinoma cell lines. Furthermore, miR-24-3p expression showed a negative correlation with the expression of CDX2 in cardiac-type mucosa samples with different stages of mucosal intestinalization. CONCLUSION These results showed that miRNA-24-3p regulates CDX2 expression, and the downregulation of miRNA-24-3p was associated with the acquisition of the intestinal phenotype in esophageal cardiac-type epithelium.
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Affiliation(s)
- Gabriel Gil-Gómez
- Gastroesophageal Carcinogenesis Research Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padua, Padua, Italy
| | - Lara Nonell
- MARGenomics, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Marta Garrido
- Gastroesophageal Carcinogenesis Research Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Marta Climent
- Gastroesophageal Carcinogenesis Research Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.,Section of Gastrointestinal Surgery, Hospital Universitario del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Roger Anglada
- Genomics Core Facility, Universitat Pompeu Fabra, Barcelona, Spain
| | - Mar Iglesias
- Gastroesophageal Carcinogenesis Research Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.,Department of Pathology, Hospital Universitario del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Vicenza Guzzardo
- Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padua, Padua, Italy
| | - Chiara Borga
- Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padua, Padua, Italy
| | - Luis Grande
- Section of Gastrointestinal Surgery, Hospital Universitario del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Carme de Bolós
- Gastroesophageal Carcinogenesis Research Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Manuel Pera
- Gastroesophageal Carcinogenesis Research Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.,Section of Gastrointestinal Surgery, Hospital Universitario del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain
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Anand A, Fang HY, Mohammad-Shahi D, Ingermann J, Baumeister T, Strangmann J, Schmid RM, Wang TC, Quante M. Elimination of NF-κB signaling in Vimentin+ stromal cells attenuates tumorigenesis in a mouse model of Barrett's Esophagus. Carcinogenesis 2021; 42:405-413. [PMID: 33068426 DOI: 10.1093/carcin/bgaa109] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 09/29/2020] [Accepted: 10/13/2020] [Indexed: 12/16/2022] Open
Abstract
Chronic inflammation induces Barrett's Esophagus (BE) which can advance to esophageal adenocarcinoma. Elevated levels of interleukin (IL)-1b, IL-6 and IL-8 together with activated nuclear factor-kappaB (NF-κB), have been identified as important mediators of tumorigenesis. The inflammatory milieu apart from cancer cells and infiltrating immune cells contains myofibroblasts (MFs) that express aSMA and Vimentin. As we observed that increased NF-κB activation and inflammation correlates with increased MF recruitment and an accelerated phenotype we here analyze the role of NF-κB in MF during esophageal carcinogenesis in our L2-IL-1B mouse model. To analyze the effect of NF-κB signaling in MFs, we crossed L2-IL-1B mice to tamoxifen inducible Vim-Cre (Vim-CreTm) mice and floxed RelA (p65fl/fl) mice to specifically eliminate NF-κB signaling in MF (IL-1b.Vim-CreTm.p65fl/fl). The interaction of epithelial cells and stromal cells was further analyzed in mouse BE organoids and patient-derived human organoids. Histological scoring of IL-1b.Vim-CreTm.p65fl/fl mice showed a significantly attenuated phenotype compared with L2-IL-1B mice, with mild inflammation, decreased metaplasia and no dysplasia. This correlated with decreased proliferation and increased differentiation in cardia tissue of IL-1b.Vim-CreTm.p65fl/fl compared with L2-IL-1B mice. Distinct changes of cytokines and chemokines within the local microenvironment in IL-1b.Vim-CreTm.p65fl/fl mice reflected the histopathological abrogated phenotype. Co-cultured NF-κB inhibitor treated MF with mouse BE organoids demonstrated NF-κB-dependent growth and migration. MFs are essential to form an inflammatory and procarcinogenic microenvironment and NF-κB signaling in stromal cells emerges as an important driver of esophageal carcinogenesis. Our data suggest anti-inflammatory approaches as preventive strategies during surveillance of BE patients.
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Affiliation(s)
- Akanksha Anand
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany
| | - Hsin-Yu Fang
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany
| | - Donja Mohammad-Shahi
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany
| | - Jonas Ingermann
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany
| | - Theresa Baumeister
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany
| | - Julia Strangmann
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany
| | - Roland M Schmid
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany
| | - Timothy C Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Michael Quante
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany.,Universitätsklinikum Freiburg, Klinik für Innere Medizin II, Hugstetter Straße 55, Freiburg, Germany
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Manning MA, Shafa S, Mehrotra AK, Grenier RE, Levy AD. Role of Multimodality Imaging in Gastroesophageal Reflux Disease and Its Complications, with Clinical and Pathologic Correlation. Radiographics 2021; 40:44-71. [PMID: 31917657 DOI: 10.1148/rg.2020190029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Gastroesophageal reflux disease (GERD) is a common condition and impairs the quality of life for millions of patients, accounts for considerable health care spending, and is a primary risk factor for esophageal adenocarcinoma. There have been substantial advances in understanding the pathogenesis of GERD and its complications and much progress in diagnosis and management of GERD; however, these have not been comprehensively discussed in the recent radiology literature. Understanding the role of imaging in GERD and its complications is important to aid in multidisciplinary treatment of GERD. GERD results from prolonged or recurrent reflux of gastric contents into the esophagus. Common symptoms include heartburn or regurgitation. Prolonged reflux of gastric contents into the esophagus can cause erosive esophagitis. Over time, the inflammatory response related to esophagitis can lead to deposition of fibrous tissue and development of strictures. Alternatively, the esophageal mucosa can undergo metaplasia (Barrett esophagus), a precursor to dysplasia (which can lead to adenocarcinoma). Conventional barium esophagography has long been considered the primary imaging modality for the esophagus, and the fluoroscopic findings for diagnosis of GERD have been well established. Multimodality imaging has a clear role in detection and assessment of the complications of GERD, specifically reflux esophagitis and Barrett esophagus; differentiation of benign and malignant strictures; and detection, staging, and posttreatment surveillance of esophageal adenocarcinoma. Given the dramatic changes in utilization of abdominal imaging during the past 2 decades, with significantly declining volume of fluoroscopic procedures and concomitant increase in CT and MRI studies, it is crucial that modern radiologists appreciate the value of barium esophagography in the workup of GERD and recognize the key imaging features of GERD and its complications at CT and MRI.
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Affiliation(s)
- Maria A Manning
- From the American Institute for Radiologic Pathology, 1100 Wayne Ave, Suite 1020, Silver Spring, MD 20910 (M.A.M.); Department of Radiology (M.A.M., A.D.L.) and Division of Gastroenterology and Hepatology (S.S.), MedStar Georgetown University Hospital, Washington, DC; the Joint Pathology Center, Silver Spring, Md (A.K.M.); and Georgetown University School of Medicine, Washington, DC (R.E.G.)
| | - Shervin Shafa
- From the American Institute for Radiologic Pathology, 1100 Wayne Ave, Suite 1020, Silver Spring, MD 20910 (M.A.M.); Department of Radiology (M.A.M., A.D.L.) and Division of Gastroenterology and Hepatology (S.S.), MedStar Georgetown University Hospital, Washington, DC; the Joint Pathology Center, Silver Spring, Md (A.K.M.); and Georgetown University School of Medicine, Washington, DC (R.E.G.)
| | - Anupamjit K Mehrotra
- From the American Institute for Radiologic Pathology, 1100 Wayne Ave, Suite 1020, Silver Spring, MD 20910 (M.A.M.); Department of Radiology (M.A.M., A.D.L.) and Division of Gastroenterology and Hepatology (S.S.), MedStar Georgetown University Hospital, Washington, DC; the Joint Pathology Center, Silver Spring, Md (A.K.M.); and Georgetown University School of Medicine, Washington, DC (R.E.G.)
| | - Rachel E Grenier
- From the American Institute for Radiologic Pathology, 1100 Wayne Ave, Suite 1020, Silver Spring, MD 20910 (M.A.M.); Department of Radiology (M.A.M., A.D.L.) and Division of Gastroenterology and Hepatology (S.S.), MedStar Georgetown University Hospital, Washington, DC; the Joint Pathology Center, Silver Spring, Md (A.K.M.); and Georgetown University School of Medicine, Washington, DC (R.E.G.)
| | - Angela D Levy
- From the American Institute for Radiologic Pathology, 1100 Wayne Ave, Suite 1020, Silver Spring, MD 20910 (M.A.M.); Department of Radiology (M.A.M., A.D.L.) and Division of Gastroenterology and Hepatology (S.S.), MedStar Georgetown University Hospital, Washington, DC; the Joint Pathology Center, Silver Spring, Md (A.K.M.); and Georgetown University School of Medicine, Washington, DC (R.E.G.)
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Kunze B, Wein F, Fang HY, Anand A, Baumeister T, Strangmann J, Gerland S, Ingermann J, Münch NS, Wiethaler M, Sahm V, Hidalgo-Sastre A, Lange S, Lightdale CJ, Bokhari A, Falk GW, Friedman RA, Ginsberg GG, Iyer PG, Jin Z, Nakagawa H, Shawber CJ, Nguyen T, Raab WJ, Dalerba P, Rustgi AK, Sepulveda AR, Wang KK, Schmid RM, Wang TC, Abrams JA, Quante M. Notch Signaling Mediates Differentiation in Barrett's Esophagus and Promotes Progression to Adenocarcinoma. Gastroenterology 2020; 159:575-590. [PMID: 32325086 PMCID: PMC7484392 DOI: 10.1053/j.gastro.2020.04.033] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 03/19/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Studies are needed to determine the mechanism by which Barrett's esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis. METHODS We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5+ (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB. RESULTS Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5+ cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5+ cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5+ cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation. CONCLUSIONS Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.
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Affiliation(s)
- Bettina Kunze
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Frederik Wein
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Hsin-Yu Fang
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Akanksha Anand
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Theresa Baumeister
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Julia Strangmann
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Sophie Gerland
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Jonas Ingermann
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | | | - Maria Wiethaler
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Vincenz Sahm
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Ana Hidalgo-Sastre
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Sebastian Lange
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Charles J Lightdale
- Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Aqiba Bokhari
- Yosemite Pathology Medical Group, Modesto, California
| | - Gary W Falk
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Richard A Friedman
- Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
| | - Gregory G Ginsberg
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Prasad G Iyer
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Zhezhen Jin
- Department of Biostatistics, Columbia University Mailman School of Public Health, New York, New York
| | - Hiroshi Nakagawa
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
| | - Carrie J Shawber
- Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York
| | - TheAnh Nguyen
- Oregon Health and Science University, Portland, Oregon
| | - William J Raab
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Piero Dalerba
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York; Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, New York
| | - Anil K Rustgi
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
| | - Antonia R Sepulveda
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Kenneth K Wang
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Roland M Schmid
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany
| | - Timothy C Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
| | - Julian A Abrams
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
| | - Michael Quante
- II. Medizinische Klinik, Technische Universitat München, Munich, Germany.
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Han P, Cao P, Hu S, Kong K, Deng Y, Zhao B, Li F. Esophageal Microenvironment: From Precursor Microenvironment to Premetastatic Niche. Cancer Manag Res 2020; 12:5857-5879. [PMID: 32765088 PMCID: PMC7371556 DOI: 10.2147/cmar.s258215] [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: 04/24/2020] [Accepted: 06/29/2020] [Indexed: 12/15/2022] Open
Abstract
Esophageal cancer (EC) is the sixth most deadly cancer, and its incidence is still increasing year by year. Although the researches on the molecular mechanisms of EC have been widely carried out and incremental progress has been made, its overall survival rate is still low. There is cumulative evidence showing that the esophageal microenvironment plays a vital role in the development of EC. In precancerous lesions of the esophagus, high-risk environmental factors can promote the development of precancerous lesions by inducing the production of inflammatory factors and the recruitment of immune cells. In the tumor microenvironment, tumor-promoting cells can inhibit anti-tumor immunity and promote tumor progression through a variety of pathways, such as bone marrow-derived suppressor cells (MDSCs), tumor-associated fibroblasts (CAFs), and regulatory T cells (Tregs). The formation of extracellular hypoxia and acidic microenvironment and the change of extracellular matrix stiffness are also important factors affecting tumor progression and metastasis. Simultaneously, primary tumor-derived cytokines and bone marrow-derived immune cells can also promote the formation of pre-metastasis niche of EC lymph nodes, which are beneficial to EC lymph node metastasis. Further research on the specific mechanism of these processes in the occurrence, development, and metastasis of each EC subtype will support us to grasp the overall pre-cancerous prevention, targeted treatment, and metastatic assessment of EC.
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Affiliation(s)
- Peng Han
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Peng Cao
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Shan Hu
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Kangle Kong
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Yu Deng
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Bo Zhao
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Fan Li
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
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37
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Barber G, Anand A, Katarzyna Oficjalska, Phelan JJ, Heeran AB, Flis E, Clarke NE, Watson JA, Strangmann J, Flood B, O'Neill H, O'Toole D, MacCarthy F, Ravi N, Reynolds JV, Kay EW, Quante M, O'Sullivan J, Creagh EM. Characterizing caspase-1 involvement during esophageal disease progression. Cancer Immunol Immunother 2020; 69:2635-2649. [PMID: 32613271 DOI: 10.1007/s00262-020-02650-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 06/19/2020] [Indexed: 12/16/2022]
Abstract
Barrett's esophagus (BE) is an inflammatory condition and a neoplastic precursor to esophageal adenocarcinoma (EAC). Inflammasome signaling, which contributes to acute and chronic inflammation, results in caspase-1 activation leading to the secretion of IL-1β and IL-18, and inflammatory cell death (pyroptosis). This study aimed to characterize caspase-1 expression, and its functional importance, during disease progression to BE and EAC. Three models of disease progression (Normal-BE-EAC) were employed to profile caspase-1 expression: (1) a human esophageal cell line model; (2) a murine model of BE; and (3) resected tissue from BE-associated EAC patients. BE patient biopsies and murine BE organoids were cultured ex vivo in the presence of a caspase-1 inhibitor, to determine the importance of caspase-1 for inflammatory cytokine and chemokine secretion.Epithelial caspase-1 expression levels were significantly enhanced in BE (p < 0.01). In contrast, stromal caspase-1 levels correlated with histological inflammation scores during disease progression (p < 0.05). Elevated secretion of IL-1β from BE explanted tissue, compared to adjacent normal tissue (p < 0.01), confirmed enhanced activity of caspase-1 in BE tissue. Caspase-1 inhibition in LPS-stimulated murine BE organoids caused a significant reduction in IL-1β (p < 0.01) and CXCL1 (p < 0.05) secretion, confirming the importance of caspase-1 in the production of cytokines and chemokines associated with disease progression from BE to EAC. Targeting caspase-1 activity in BE patients should therefore be tested as a novel strategy to prevent inflammatory complications associated with disease progression.
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Affiliation(s)
- Gillian Barber
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.,Department of Surgery, Trinity Translational Medicine Institute, Trinity College and St. James's Hospital Dublin, Dublin 8, Ireland
| | - Akanksha Anand
- Department of Internal Medicine, Technical University of Munich, Munich, Germany
| | - Katarzyna Oficjalska
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - James J Phelan
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College and St. James's Hospital Dublin, Dublin 8, Ireland
| | - Aisling B Heeran
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College and St. James's Hospital Dublin, Dublin 8, Ireland
| | - Ewelina Flis
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Niamh E Clarke
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College and St. James's Hospital Dublin, Dublin 8, Ireland
| | - Jenny A Watson
- Royal College of Surgeons in Ireland and Beaumont Hospital, Dublin 9, Ireland
| | - Julia Strangmann
- Department of Internal Medicine, Technical University of Munich, Munich, Germany
| | - Brian Flood
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Hazel O'Neill
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College and St. James's Hospital Dublin, Dublin 8, Ireland
| | - Dermot O'Toole
- National Oesophageal and Gastric Centre, St. James's Hospital, Dublin 8, Ireland
| | - Finbar MacCarthy
- National Oesophageal and Gastric Centre, St. James's Hospital, Dublin 8, Ireland
| | - Narayanasamy Ravi
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College and St. James's Hospital Dublin, Dublin 8, Ireland.,National Oesophageal and Gastric Centre, St. James's Hospital, Dublin 8, Ireland
| | - John V Reynolds
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College and St. James's Hospital Dublin, Dublin 8, Ireland.,National Oesophageal and Gastric Centre, St. James's Hospital, Dublin 8, Ireland
| | - Elaine W Kay
- Royal College of Surgeons in Ireland and Beaumont Hospital, Dublin 9, Ireland
| | - Michael Quante
- Department of Internal Medicine, Technical University of Munich, Munich, Germany
| | - Jacintha O'Sullivan
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College and St. James's Hospital Dublin, Dublin 8, Ireland.
| | - Emma M Creagh
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
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38
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Lv J, Zhao HP, Dai K, Cheng Y, Zhang J, Guo L. Circulating exosomal miRNAs as potential biomarkers for Barrett's esophagus and esophageal adenocarcinoma. World J Gastroenterol 2020; 26:2889-2901. [PMID: 32587437 PMCID: PMC7304109 DOI: 10.3748/wjg.v26.i22.2889] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 03/26/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023] Open
Abstract
Exosomes, a class of extracellular vesicles, are small membrane-bound vesicles derived from almost all cell types that can play important roles in intercellular communication. Exosomes contain proteins, lipids, and nucleic acids that are obtained from the parental cells and participate in various pathophysiological processes, including cell growth, migration, inflammation, immune regulation, and tumor pathogenesis. Moreover, exosomes might be applied in clinical settings, such as diagnosis, treatment, and outcome prediction of diseases, including various cancers. The incidence rates of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) have increased in recent decades, and studies have proposed specific factors that may contribute to the development and progression of these diseases. However, how exosomes play a role in this pathological process needs to be clarified. Studies have identified candidate microRNAs (miRNAs) that might be related to BE/EAC. Further studies are needed to ascertain whether circulating exosomal miRNAs are altered before or after disease onset, which could also help understand the pathophysiology of and find potential targets for prevention, diagnosis, and therapy in BE/EAC. This review summarizes recent findings on the features of circulating exosomal miRNAs in BE/EAC, which could be valuable for the early diagnosis, therapeutic approaches, and outcome prediction of BE/EAC.
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Affiliation(s)
- Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
| | - He-Ping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
| | - Kun Dai
- Department of Clinical Laboratory, Yanliang Railway Hospital of Xi’an, Xi'an 710089, Shaanxi Province, China
| | - Yan Cheng
- Department of Gastroenterology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Jun Zhang
- Department of Gastroenterology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Lei Guo
- Department of Spinal Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
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Holleczek B, Schöttker B, Brenner H. Helicobacter pylori
infection, chronic atrophic gastritis and risk of stomach and esophagus cancer: Results from the prospective population‐based ESTHER cohort study. Int J Cancer 2020; 146:2773-2783. [DOI: 10.1002/ijc.32610] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 07/14/2019] [Accepted: 07/19/2019] [Indexed: 12/24/2022]
Affiliation(s)
- Bernd Holleczek
- Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research Center (DKFZ) Heidelberg Germany
- Saarland Cancer Registry Saarbrücken Germany
| | - Ben Schöttker
- Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research Center (DKFZ) Heidelberg Germany
- Network Aging Research, University of Heidelberg Heidelberg Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research Center (DKFZ) Heidelberg Germany
- Division of Preventive OncologyGerman Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg Germany
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40
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Bhatia SJ, Makharia GK, Abraham P, Bhat N, Kumar A, Reddy DN, Ghoshal UC, Ahuja V, Rao GV, Devadas K, Dutta AK, Jain A, Kedia S, Dama R, Kalapala R, Alvares JF, Dadhich S, Dixit VK, Goenka MK, Goswami BD, Issar SK, Leelakrishnan V, Mallath MK, Mathew P, Mathew P, Nandwani S, Pai CG, Peter L, Prasad AVS, Singh D, Sodhi JS, Sud R, Venkataraman J, Midha V, Bapaye A, Dutta U, Jain AK, Kochhar R, Puri AS, Singh SP, Shimpi L, Sood A, Wadhwa RT. Indian consensus on gastroesophageal reflux disease in adults: A position statement of the Indian Society of Gastroenterology. Indian J Gastroenterol 2019; 38:411-440. [PMID: 31802441 DOI: 10.1007/s12664-019-00979-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 07/17/2019] [Indexed: 02/06/2023]
Abstract
The Indian Society of Gastroenterology developed this evidence-based practice guideline for management of gastroesophageal reflux disease (GERD) in adults. A modified Delphi process was used to develop this consensus containing 58 statements, which were generated by electronic voting iteration as well as face-to-face meeting and review of the supporting literature primarily from India. These statements include 10 on epidemiology, 8 on clinical presentation, 10 on investigations, 23 on treatment (including medical, endoscopic, and surgical modalities), and 7 on complications of GERD. When the proportion of those who voted either to accept completely or with minor reservation was 80% or higher, the statement was regarded as accepted. The prevalence of GERD in India ranges from 7.6% to 30%, being < 10% in most population studies, and higher in cohort studies. The dietary factors associated with GERD include use of spices and non-vegetarian food. Helicobacter pylori is thought to have a negative relation with GERD; H. pylori negative patients have higher grade of symptoms of GERD and esophagitis. Less than 10% of GERD patients in India have erosive esophagitis. In patients with occasional or mild symptoms, antacids and histamine H2 receptor blockers (H2RAs) may be used, and proton pump inhibitors (PPI) should be used in patients with frequent or severe symptoms. Prokinetics have limited proven role in management of GERD.
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Affiliation(s)
- Shobna J Bhatia
- Seth GS Medical College and KEM Hospital, Mumbai, 400 012, India.
| | | | - Philip Abraham
- P D Hinduja Hospital and MRC, and Hinduja Heathcare Surgical, Mumbai, 400 016, India
| | - Naresh Bhat
- Aster CMI Hospital, Bengaluru, 560 092, India
| | - Ajay Kumar
- Fortis Escorts Liver and Digestive Diseases Institute, Delhi, 110 025, India
| | | | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India
| | - Vineet Ahuja
- All India Institute of Medical Sciences, New Delhi, 110 029, India
| | - G Venkat Rao
- Asian Institute of Gastroenterology, Hyderabad, 500 082, India
| | | | - Amit K Dutta
- Christian Medical College, Vellore, 632 004, India
| | - Abhinav Jain
- Seth GS Medical College and KEM Hospital, Mumbai, 400 012, India
| | - Saurabh Kedia
- All India Institute of Medical Sciences, New Delhi, 110 029, India
| | - Rohit Dama
- Asian Institute of Gastroenterology, Hyderabad, 500 082, India
| | - Rakesh Kalapala
- Asian Institute of Gastroenterology, Hyderabad, 500 082, India
| | | | | | - Vinod Kumar Dixit
- Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India
| | | | - B D Goswami
- Gauhati Medical College, Dispur Hospitals, Guwahati, 781 032, India
| | - Sanjeev K Issar
- JLN Hospital and Research Center, Bhilai Steel Plant, Bhilai, 490 009, India
| | | | | | | | - Praveen Mathew
- Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, 560 066, India
| | | | - Cannanore Ganesh Pai
- Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576 104, India
| | | | - A V Siva Prasad
- Institute of Gastroenterology, Visakhapatnam, 530 002, India
| | | | | | - Randhir Sud
- Medanta - The Medicity, Gurugram, 122 001, India
| | | | - Vandana Midha
- Dayanand Medical College and Hospital, Ludhiana, 141 001, India
| | - Amol Bapaye
- Deenanath Mangeshkar Hospital and Research Center, Pune, 411 004, India
| | - Usha Dutta
- Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Ajay K Jain
- Choithram Hospital and Research Centre, Indore, 452 014, India
| | - Rakesh Kochhar
- Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | | | | | | | - Ajit Sood
- Dayanand Medical College and Hospital, Ludhiana, 141 001, India
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41
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Münch NS, Fang HY, Ingermann J, Maurer HC, Anand A, Kellner V, Sahm V, Wiethaler M, Baumeister T, Wein F, Einwächter H, Bolze F, Klingenspor M, Haller D, Kavanagh M, Lysaght J, Friedman R, Dannenberg AJ, Pollak M, Holt PR, Muthupalani S, Fox JG, Whary MT, Lee Y, Ren TY, Elliot R, Fitzgerald R, Steiger K, Schmid RM, Wang TC, Quante M. High-Fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett's Esophagus via Interleukin 8 and Alterations to the Gut Microbiome. Gastroenterology 2019; 157:492-506.e2. [PMID: 30998992 PMCID: PMC6662596 DOI: 10.1053/j.gastro.2019.04.013] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 04/03/2019] [Accepted: 04/06/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice. METHODS Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions. RESULTS L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development. CONCLUSIONS In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.
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Affiliation(s)
- Natasha Stephens Münch
- Department of Internal Medicine, Technical University of Munich, Germany,Chair of Molecular Nutritional Medicine, Technical University of Munich, Germany
| | - Hsin-Yu Fang
- Department of Internal Medicine, Technical University of Munich, Germany
| | - Jonas Ingermann
- Department of Internal Medicine, Technical University of Munich, Germany,Chair of Molecular Nutritional Medicine, Technical University of Munich, Germany
| | - H. Carlo Maurer
- Department of Internal Medicine, Technical University of Munich, Germany,Irvine Cancer Research Center, Columbia University, New York, USA
| | - Akanksha Anand
- Department of Internal Medicine, Technical University of Munich, Germany
| | - Victoria Kellner
- Department of Internal Medicine, Technical University of Munich, Germany
| | - Vincenz Sahm
- Department of Internal Medicine, Technical University of Munich, Germany
| | - Maria Wiethaler
- Department of Internal Medicine, Technical University of Munich, Germany
| | - Theresa Baumeister
- Department of Internal Medicine, Technical University of Munich, Germany
| | - Frederik Wein
- Department of Internal Medicine, Technical University of Munich, Germany
| | - Henrik Einwächter
- Department of Internal Medicine, Technical University of Munich, Germany
| | - Florian Bolze
- Chair of Molecular Nutritional Medicine, Technical University of Munich, Germany,EKFZ – Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Germany,ZIEL – Institute of Food & Health, Technical University of Munich, Germany
| | - Martin Klingenspor
- Chair of Molecular Nutritional Medicine, Technical University of Munich, Germany,EKFZ – Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Germany,ZIEL – Institute of Food & Health, Technical University of Munich, Germany
| | - Dirk Haller
- Chair of Nutrition and Immunology; Technical University of Munich, Germany
| | - Maria Kavanagh
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, Ireland
| | - Joanne Lysaght
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, Ireland
| | - Richard Friedman
- Irvine Cancer Research Center, Columbia University, New York, USA
| | | | | | | | | | - James G. Fox
- Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Mark T. Whary
- Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Yoomi Lee
- Irvine Cancer Research Center, Columbia University, New York, USA
| | - Tony Y. Ren
- Irvine Cancer Research Center, Columbia University, New York, USA
| | | | | | - Katja Steiger
- Institute of Pathology, Technical University of Munich, Germany
| | - Roland M. Schmid
- Department of Internal Medicine, Technical University of Munich, Germany
| | - Timothy C. Wang
- Irvine Cancer Research Center, Columbia University, New York, USA
| | - Michael Quante
- Department of Internal Medicine, Technical University of Munich, Germany.
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42
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Lv J, Guo L, Liu JJ, Zhao HP, Zhang J, Wang JH. Alteration of the esophageal microbiota in Barrett's esophagus and esophageal adenocarcinoma. World J Gastroenterol 2019; 25:2149-2161. [PMID: 31143067 PMCID: PMC6526156 DOI: 10.3748/wjg.v25.i18.2149] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 03/27/2019] [Accepted: 04/11/2019] [Indexed: 02/06/2023] Open
Abstract
The incidence of esophageal adenocarcinoma (EAC) has increased in recent decades, and its 5-year survival rate is less than 20%. As a well-established precursor, patients with Barrett's esophagus (BE) have a persistent risk of progression to EAC. Many researchers have already identified some factors that may contribute to the development of BE and EAC, and the identified risks include gastroesophageal reflux (GER), male sex, older age, central obesity, tobacco smoking, Helicobacter pylori (H. pylori) eradication, and the administration of proton pump inhibitors (PPIs) and antibiotics. The human gut harbors trillions of microorganisms, the majority of which are bacteria. These microorganisms benefit the human host in many ways, such as helping in digestion, assisting in the synthesis of certain vitamins, promoting the development of the gastrointestinal immune system, regulating metabolism and preventing invasion by specific pathogens. In contrast, microbial dysbiosis may play important roles in various diseases, such as inflammation and cancers. The composition of the microbiota located in the normal esophagus is relatively conserved without distinct microbial preferences in the upper, middle and lower esophagus. Six major phyla constitute the esophageal microbiota, including Firmicutes, Bacteroides, Actinobacteria, Proteobacteria, Fusobacteria and TM7, similar to the oral microbiota. Streptococcus dominates the esophageal microbiota. However, the microbiota varies in different esophageal diseases compared to that in the healthy esophagus. The type I microbiota, which is primarily composed of gram-positive bacteria, is closely associated with the normal esophagus, while type II microbiota has enriched gram-negative bacteria and is mainly associated with the abnormal esophagus. These increased gram-negative anaerobes/microaerophiles include Veillonella, Prevotella, Haemophilus, Neisseria, Granulicatella and Fusobacterium, many of which are associated with BE. The microbial diversity in the esophagus is decreased in EAC patients, and Lactobacillus fermentum is enriched compared to that in controls and BE patients. Furthermore, the microbiota may be associated with BE and EAC by interacting with their risk factors, including central obesity, GER, H. pylori, administration of PPIs and antibiotics. Therefore, a large gap in research must be bridged to elucidate the associations among these factors. Some studies have already proposed several potential mechanisms by which the microbiota participates in human carcinogenesis by complicated interactions with the human host immune system and signaling pathways. The activation of the LPS-TLR4-NF-κB pathway may contribute to inflammation and malignant transformation. This exciting field of gastrointestinal microbiota allows us to unravel the mystery of carcinogenesis from another perspective. Further studies are needed to explore whether the microbiota changes before or after disease onset, to improve our understanding of the pathogenesis, and to find novel targets for prevention, diagnosis and therapy, which could offer more cost-effective and relatively safe choices.
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Affiliation(s)
- Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
| | - Lei Guo
- Department of Spinal Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
| | - Ji-Jun Liu
- Department of Spinal Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
| | - He-Ping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
| | - Jun Zhang
- Department of Gastroenterology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Ji-Han Wang
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China
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43
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Abstract
Oesophageal adenocarcinoma (OAC) has increased dramatically in Western countries, including the UK, over the past 30 years. It usually presents de novo, but is often preceded by Barrett's oesophagus (BO), a premalignant condition whereby the normal squamous epithelium is replaced by columnar lined epithelium with intestinal metaplasia. The main risk factors for BO include male sex, obesity and chronic gastro-oesophageal reflux of acid and bile. The estimated annual risk of BO progression is 0.3%, increasing substantially, up to 30%, when dysplasia is present. Endoscopic surveillance is recommended to detect neoplastic changes at an early stage and considerable evidence supports endoscopic treatment for confirmed low- and high-grade dysplasia, and intramucosal adenocarcinoma. Most OACs are diagnosed at a more advanced stage requiring CT-PET assessment and multi-modal treatment. Surgical treatment is performed in specialist centres, increasingly combined with cytotoxic chemotherapy and radiotherapy, involving close liaison between members of the multidisciplinary team. Molecular targeted therapies, such as HER2 and VEGFR-inhibitors, are beginning to penetrate clinical practice, but high molecular heterogeneity has impeded progress. In view of the overall dismal survival (<20%) for advanced OAC, there is renewed interest in screening techniques for early detection and intervention of dysplastic BO.
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Affiliation(s)
- Wladyslaw Januszewicz
- MRC Cancer Unit Hutchinson/MRC Research Centre, University of Cambridge and an Endoscopy Honorary Clinical Fellow in the Gastroenterology Department, Cambridge University Hospitals NHSFT, UK
| | - Rebecca C Fitzgerald
- MRC Cancer Unit, Hutchinson/MRC Research Centre, University of Cambridge, and Honorary Consultant in Gastroenterology, Cambridge University Hospitals NHSFT, UK
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44
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Siddiki HA, Lam-Himlin DM, Kahn A, Bandres MV, Burdick GE, Crowell MD, Pannala R, Ramirez FC, Vela MF, Fleischer DE. Intestinal metaplasia of the gastric cardia: findings in patients with versus without Barrett's esophagus. Gastrointest Endosc 2019; 89:759-768. [PMID: 30447215 DOI: 10.1016/j.gie.2018.10.048] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 10/31/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS There is controversy about finding intestinal metaplasia (IM) of the gastric cardia on biopsy. The most recent American College of Gastroenterology guideline comments that IM cardia is not more common in patients with Barrett's esophagus (BE). It provides limited guidance on whether the cardia should be treated when patients with BE undergo endoscopic eradication therapy (EET) and whether the cardia should undergo biopsy after ablation. The aims of our study were to determine the frequency in the proximal stomach of (1) histologic gastric cardia mucosa and (2) IM cardia. A third aim was to explore the frequency of advanced pathology (dysplasia and adenocarcinoma) in the cardia after patients with BE have undergone EET. METHODS Consecutive patients undergoing esophagogastroduodenoscopy between January 2008 and December 2014 who had proximal stomach biopsies were included. Patients who had histologically confirmed BE were compared with those without BE. RESULTS Four hundred sixty-two patients, 289 with BE and 173 without BE, were included. Histologically confirmed cardiac mucosa was found in 81.6% of all patients. This was more frequent in those with versus without BE (86% vs 75%; odds ratio [OR], 2.06; 95% confidence interval [CI], 1.28-3.32; P = .003). IM cardia was more common in the BE group (17% vs 7%; OR, 2.67; 95% CI, 1.38-5.19; P = .004). Advanced pathology was more likely in the patients with BE who had undergone EET. CONCLUSIONS Cardiac mucosa is present in most patients who undergo endoscopy for upper GI symptoms. IM cardia is more common in patients with BE than those without. Advanced histologic changes in the cardia were seen only in the subgroup of patients with BE who had undergone EET.
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Affiliation(s)
- Hassan A Siddiki
- Division of Gastroenterology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Dora M Lam-Himlin
- Department of Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Allon Kahn
- Division of Gastroenterology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - M Veronica Bandres
- Department of Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA
| | - George E Burdick
- Division of Gastroenterology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Michael D Crowell
- Division of Gastroenterology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Rahul Pannala
- Division of Gastroenterology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | | | - Marcelo F Vela
- Division of Gastroenterology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - David E Fleischer
- Division of Gastroenterology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
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Developing a blood-based gene mutation assay as a novel biomarker for oesophageal adenocarcinoma. Sci Rep 2019; 9:5168. [PMID: 30914682 PMCID: PMC6435702 DOI: 10.1038/s41598-019-41490-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 03/06/2019] [Indexed: 12/20/2022] Open
Abstract
The Phosphatidylinositol glycan class A (PIG-A) gene mutation assay phenotypically measures erythrocyte mutations, assessed here for their correlation to neoplastic progression in the gastro-oesophageal reflux disease (GORD)-Barrett’s metaplasia (BM)-oesophageal adenocarcinoma (OAC) model. Endoscopy patients underwent venipuncture and erythrocytes fluorescently stained for glycosyl phosphatidylinositol (GPI)–anchored proteins; CD55 and CD59. Using flow cytometry, GPI–anchor negative erythrocytes (mutants) were scored and compared amongst groups. The study enlisted 200 patients and 137 healthy volunteers. OAC patients had a three–fold increase in erythrocyte mutant frequency (EMF) compared to GORD patients (p < 0.001) and healthy volunteers (p < 0.001). In OAC patients, higher EMF was associated with worsening tumour staging (p = 0.014), nodal involvement (p = 0.019) and metastatic disease (p = 0.008). Chemotherapy patients demonstrated EMF’s over 19–times higher than GORD patients. Patients were further classified into groups containing those with non-neoplastic disease and those with high-grade dysplasia/cancer with 72.1% of cases correctly classified by high EMF. Within the non-neoplastic group, aspirin users had lower EMF (p = 0.001) and there was a positive correlation between body mass index (p = 0.03) and age (p < 0.001) and EMF. Smokers had EMF’s over double that of non-smokers (p = 0.011). Results suggest this test could help detect OAC and may be a useful predictor of disease progression.
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Chwiesko A, Kowal-Bielecka O, Sierakowski S. Perspectives on the interlinked nature of systemic sclerosis and reflux disease. Expert Rev Gastroenterol Hepatol 2019; 13:213-227. [PMID: 30791766 DOI: 10.1080/17474124.2019.1561274] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Systemic sclerosis (SSc) is a multisystem connective tissue disease, characterized by chronic inflammation and vascular changes that result in esophageal smooth muscle atrophy and fibrosis. Subsequent progressive loss of peristalsis in the distal esophagus and loss of lower esophageal sphincter function lead to problems with the protective barrier and exposure of sensitive tissues to the gastroduodenal contents, a disorder called reflux disease. Areas covered: Depending on the range, nature and symptoms of the disease, the term 'reflux disease' may refer to gastroesophageal reflux, laryngopharyngeal reflux, microaspiration into the airways and silent reflux. Despite the links between these visceral complications, this connection remains controversial. This is due to a lack of complete understanding, the asymptomatic nature of the disease and the limited diagnostic accuracy of tests, which can delay diagnosis. Such delays are problematic, given that the early detection of GERD in SSc patients, the timing of assessment, the treatment of the organs involved are critical aspects of patient prognosis and disease outcome. Expert commentary: This review summarizes the most recent knowledge about the pathophysiology, diagnosis and prospective treatment of GERD in SSc patients and highlights how innovative technologies applied through an integrative, interdisciplinary approach may soon lead to effective treatment strategies.
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Affiliation(s)
- Adam Chwiesko
- a Department of Gastroenterology and Internal Medicine , Medical University of Bialystok , Bialystok , Poland
| | - Otylia Kowal-Bielecka
- b Department of Rheumatology and Internal Medicine , Medical University of Bialystok , Bialystok , Poland
| | - Stanislaw Sierakowski
- b Department of Rheumatology and Internal Medicine , Medical University of Bialystok , Bialystok , Poland
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Lv J, Guo L, Wang JH, Yan YZ, Zhang J, Wang YY, Yu Y, Huang YF, Zhao HP. Biomarker identification and trans-regulatory network analyses in esophageal adenocarcinoma and Barrett’s esophagus. World J Gastroenterol 2019; 25:233-244. [PMID: 30670912 PMCID: PMC6337015 DOI: 10.3748/wjg.v25.i2.233] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 12/10/2018] [Accepted: 12/15/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Esophageal adenocarcinoma (EAC) is an aggressive disease with high mortality and an overall 5-year survival rate of less than 20%. Barrett’s esophagus (BE) is the only known precursor of EAC, and patients with BE have a persistent and excessive risk of EAC over time. Individuals with BE are up to 30-125 times more likely to develop EAC than the general population. Thus, early detection of EAC and BE could significantly improve the 5-year survival rate of EAC. Due to the limitations of endoscopic surveillance and the lack of clinical risk stratification strategies, molecular biomarkers should be considered and thoroughly investigated.
AIM To explore the transcriptome changes in the progression from normal esophagus (NE) to BE and EAC.
METHODS Two datasets from the Gene Expression Omnibus (GEO) in NCBI Database (https://www.ncbi.nlm.nih.gov/geo/) were retrieved and used as a training and a test dataset separately, since NE, BE, and EAC samples were included and the sample sizes were adequate. This study identified differentially expressed genes (DEGs) using the R/Bioconductor project and constructed trans-regulatory networks based on the Transcriptional Regulatory Element Database and Cytoscape software. Enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) terms was identified using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources. The diagnostic potential of certain DEGs was assessed in both datasets.
RESULTS In the GSE1420 dataset, the number of up-regulated DEGs was larger than that of down-regulated DEGs when comparing EAC vs NE and BE vs NE. Among these DEGs, five differentially expressed transcription factors (DETFs) displayed the same trend in expression across all the comparison groups. Of these five DETFs, E2F3, FOXA2, and HOXB7 were up-regulated, while PAX9 and TFAP2C were down-regulated. Additionally, the majority of the DEGs in trans-regulatory networks were up-regulated. The intersection of these potential DEGs displayed the same direction of changes in expression when comparing the DEGs in the GSE26886 dataset to the DEGs in trans-regulatory networks above. The receiver operating characteristic curve analysis was performed for both datasets and found that TIMP1 and COL1A1 could discriminate EAC from NE tissue, while REG1A, MMP1, and CA2 could distinguish BE from NE tissue. DAVID annotation indicated that COL1A1 and MMP1 could be potent biomarkers for EAC and BE, respectively, since they participate in the majority of the enriched KEGG and GO terms that are important for inflammation and cancer.
CONCLUSION After the construction and analyses of the trans-regulatory networks in EAC and BE, the results indicate that COL1A1 and MMP1 could be potential biomarkers for EAC and BE, respectively.
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Affiliation(s)
- Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Lei Guo
- Department of Spinal Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Ji-Han Wang
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Yu-Zhu Yan
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Jun Zhang
- Department of Gastroenterology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Yang-Yang Wang
- The Tenth Research Institute of Telecommunications Technology, Xi’an 710000, Shaanxi Province, China
| | - Yan Yu
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Yun-Fei Huang
- Department of Spinal Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - He-Ping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
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Yin F, Hernandez Gonzalo D, Lai J, Liu X. Histopathology of Barrett’s Esophagus and Early-Stage Esophageal Adenocarcinoma: An Updated Review. GASTROINTESTINAL DISORDERS 2018; 1:147-163. [DOI: 10.3390/gidisord1010011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Esophageal adenocarcinoma carries a very poor prognosis. For this reason, it is critical to have cost-effective surveillance and prevention strategies and early and accurate diagnosis, as well as evidence-based treatment guidelines. Barrett’s esophagus is the most important precursor lesion for esophageal adenocarcinoma, which follows a defined metaplasia–dysplasia–carcinoma sequence. Accurate recognition of dysplasia in Barrett’s esophagus is crucial due to its pivotal prognostic value. For early-stage esophageal adenocarcinoma, depth of submucosal invasion is a key prognostic factor. Our systematic review of all published data demonstrates a “rule of doubling” for the frequency of lymph node metastases: tumor invasion into each progressively deeper third of submucosal layer corresponds with a twofold increase in the risk of nodal metastases (9.9% in the superficial third of submucosa (sm1) group, 22.0% in the middle third of submucosa (sm2) group, and 40.7% in deep third of submucosa (sm3) group). Other important risk factors include lymphovascular invasion, tumor differentiation, and the recently reported tumor budding. In this review, we provide a concise update on the histopathological features, ancillary studies, molecular signatures, and surveillance/management guidelines along the natural history from Barrett’s esophagus to early stage invasive adenocarcinoma for practicing pathologists.
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Affiliation(s)
- Feng Yin
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - David Hernandez Gonzalo
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Jinping Lai
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Xiuli Liu
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA
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Kinoshita H, Hayakawa Y, Konishi M, Hata M, Tsuboi M, Hayata Y, Hikiba Y, Ihara S, Nakagawa H, Ikenoue T, Ushiku T, Fukayama M, Hirata Y, Koike K. Three types of metaplasia model through Kras activation, Pten deletion, or Cdh1 deletion in the gastric epithelium. J Pathol 2018; 247:35-47. [PMID: 30168144 DOI: 10.1002/path.5163] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Revised: 08/22/2018] [Accepted: 08/24/2018] [Indexed: 12/14/2022]
Abstract
Chronic inflammation and intestinal metaplasia are strongly associated with gastric carcinogenesis. Kras activation and Pten deletion are observed in intestinal-type gastric cancer, and Cdh1 mutation is associated with diffuse-type gastric cancer. Although various mouse models of gastric carcinogenesis have been reported, few mouse lines enable gene manipulation selectively in the stomach. Here we established a Tff1-Cre bacterial artificial chromosome transgenic mouse line in an attempt to induce gene modification specifically in the gastric pit lineage. In the stomach, Tff1-Cre-mediated recombination was most evident in the pit lineage in the corpus and in entire antral glands; recombination was also observed in a few gastric chief and parietal cells. Outside the stomach, recombination was patchy throughout the intestines, and particularly frequently in the duodenum (Brunner glands), cecum, and proximal colon. In the stomachs of Tff1-Cre;LSL-KrasG12D mice, proliferating cell clusters expanded throughout the corpus glands, with foveolar cell expansion with ectopic Alcian blue-positive mucins, oxyntic atrophy, and pseudopyloric changes with spasmolytic polypeptide-expressing metaplasia; however, gastric cancer was not observed even at 12 months of age. Corpus-derived organoids from Tff1-Cre;LSL-KrasG12D mice exhibited accelerated growth and abnormal differentiation with a loss of chief and parietal cell markers. Tff1-Cre;Ptenflox/flox mice displayed similar changes to those seen in Tff1-Cre;LSL-KrasG12D mice, both with aberrant ERK activation within 3 months. In contrast, Tff1-Cre;Cdh1flox/flox mice initially showed signet ring-like cells that were rapidly lost with disruption of the mucosal surface, and later developed gastric epithelial shedding with hyperproliferation and loss of normal gastric lineages. Eventually, the glandular epithelium in Tff1-Cre;Cdh1flox/flox mice was completely replaced by squamous epithelium which expanded from the forestomach. Tff1-Cre mice offer an additional useful tool for studying gastric carcinogenesis both in vivo and in vitro. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Hiroto Kinoshita
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mitsuru Konishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masahiro Hata
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mayo Tsuboi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yuki Hayata
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yohko Hikiba
- Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Sozaburo Ihara
- Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tsuneo Ikenoue
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masashi Fukayama
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshihiro Hirata
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Division of Advanced Genome Medicine, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Wright NA. Is Barrett's-Associated Esophageal Adenocarcinoma a Clonal Disease? Dig Dis Sci 2018; 63:2022-2027. [PMID: 29951796 DOI: 10.1007/s10620-018-5164-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In this study, we argue that the basic clonal unit that makes up the Barrett's segment is at the level of the gland. There is expansion of this clonal unit, the gland, by fission, and there is evidence that the Barrett's segment is itself a clonal proliferation. Barrett's esophagus arises from both goblet cell-containing metaplasia and non-goblet cell-containing metaplasia and may arise from a stable clone, but the genomic changes occurring are subject to selection, usually with little or no evolution, appearing indolent from the evolutionary perspective. Genomic changes leading to dysplastic phenotypes are selected, but without any single clone predominating within the segment.
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Affiliation(s)
- Nicholas A Wright
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
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