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Sica E, Shore KT, Yang L, Phelps KC, Hammer STG, Gopal P, Karamchandani DM, Mitchell JM. Utility of IMP3, p53, and S100P immunohistochemical stains in distinguishing reactive atypia from dysplasia in cholecystectomy specimens. Diagn Pathol 2024; 19:129. [PMID: 39334193 PMCID: PMC11429068 DOI: 10.1186/s13000-024-01550-w] [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: 07/26/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Distinguishing reactive atypia from dysplasia in cholecystectomy specimens can be histologically challenging. The aim of this study was to evaluate the utility of IMP3, p53, and S100P immunostains in differentiating reactive atypia from dysplasia in cholecystectomies. METHODS Fifty-four cholecystectomies were reviewed and characterized into 5 groups: 2 normal, 29 reactive atypia, 16 low-grade dysplasia, 2 high-grade dysplasia, and 5 adenocarcinoma. IMP3, p53, and S100P immunostains were performed and evaluated. IMP3 (nuclear) and S100P (nuclear or nuclear/cytoplasmic) were categorized into negative or positive expression, and p53 was categorized into wild-type and aberrant/mutant expression. Chi-square test was used for statistical analysis. RESULTS The patients were mostly middle-aged women (mean 44, range 19-87 years, 81% female), with predominantly Hispanic White ethnicity (80%). The majority of the normal and reactive atypia cases showed negative IMP3 (100% and 75.9%, respectively) and wild-type p53 (100% and 89.7%, respectively) staining. Over half (56.3%) of the low-grade dysplasia and all the high-grade dysplasia cases showed IMP3 positivity. Aberrant p53 staining pattern was seen in half of both low and high-grade dysplasia cases. Adenocarcinoma showed IMP3 positivity in 80% and p53 aberrancy in all cases. S100P showed no statistical significance among the diagnostic categories. Significant differences in staining patterns were found between reactive atypia vs. low-grade dysplasia, and reactive atypia vs. low-grade + high-grade dysplasia using a combination of IMP3 and p53 stains (all p < 0.05). CONCLUSIONS In challenging cholecystectomies, IMP3 positivity or aberrant p53 expression may serve as a useful adjunct to support a diagnosis of dysplasia over reactive atypia.
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Affiliation(s)
- Evan Sica
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9072, USA
| | - Karen T Shore
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9072, USA
| | - Limin Yang
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9072, USA
| | | | - Suntrea T G Hammer
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9072, USA
| | - Purva Gopal
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9072, USA
| | - Dipti M Karamchandani
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9072, USA
| | - James Michael Mitchell
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9072, USA.
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Kumar A, Sarangi Y, Gupta A, Sharma A. Gallbladder cancer: Progress in the Indian subcontinent. World J Clin Oncol 2024; 15:695-716. [PMID: 38946839 PMCID: PMC11212610 DOI: 10.5306/wjco.v15.i6.695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/25/2024] [Accepted: 05/15/2024] [Indexed: 06/24/2024] Open
Abstract
Gallbladder cancer (GBC) is one of the commonest biliary malignancies seen in India, Argentina, and Japan. The disease has dismal outcome as it is detected quite late due to nonspecific symptoms and signs. Early detection is the only way to improve the outcome. There have been several advances in basic as well as clinical research in the hepatobiliary and pancreatic diseases in the West and other developed countries but not enough has been done in GBC. Therefore, it is important and the responsibility of the countries with high burden of GBC to find solutions to the many unanswered questions like etiopathogenesis, early diagnosis, treatment, and prognostication. As India being one of the largest hubs for GBC in the world, it is important to know how the country has progressed on GBC. In this review, we will discuss the outcome of the publications from India highlighting the work and the developments taken place in past several decades both in basic and clinical research.
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Affiliation(s)
- Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Yajnadatta Sarangi
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Annapurna Gupta
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Aarti Sharma
- Division of Haematology, Mayo Clinic Arizona, Phoenix, AZ 85054, United States
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3
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Bojan A, Pricop C, Ciocoiu M, Vladeanu MC, Bararu Bojan I, Badulescu OV, Badescu MC, Plesoianu CE, Halitchi DI, Foia LG. Environmental and Metabolic Risk Factors Linked to Gallbladder Dysplasia. Metabolites 2024; 14:273. [PMID: 38786750 PMCID: PMC11123122 DOI: 10.3390/metabo14050273] [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: 03/28/2024] [Revised: 04/25/2024] [Accepted: 04/28/2024] [Indexed: 05/25/2024] Open
Abstract
Gallbladder disorders encompass a spectrum from congenital anomalies to inflammatory and neoplastic conditions, frequently requiring surgical intervention. Epithelial abnormalities like adenoma and metaplasia have the potential to progress to carcinoma, emphasizing the importance of histopathological assessment for early detection of malignancy. Gallbladder cancer (GBC) may be incidentally discovered during cholecystectomy for presumed benign conditions, underscoring the need for a thorough examination. However, the lack of clarity regarding the molecular mechanisms of GBC has impeded diagnostic and therapeutic advancements. Timely detection is crucial due to GBC's aggressive nature and poor prognosis. Chronic inflammation plays a central role in carcinogenesis, causing DNA damage and oncogenic alterations due to persistent insults. Inflammatory cytokines and microRNAs are among the various mediators contributing to this process. Gallbladder calcifications, particularly stippled ones, may signal malignancy and warrant preemptive removal. Molecular pathways involving mutations in oncogenes and tumor suppressor genes drive GBC pathogenesis, with proposed sequences such as gallstone-induced inflammation leading to carcinoma formation. Understanding these mechanisms, alongside evaluating mucin characteristics and gene mutations, can deepen comprehension of GBC's pathophysiology. This, in turn, facilitates the identification of high-risk individuals and the development of improved treatment strategies, ultimately enhancing patient outcomes. Thus, in this review, our aim has been to underscore the primary mechanisms underlying the development of gallbladder dysplasia and neoplasia.
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Affiliation(s)
- Andrei Bojan
- Department of Surgical Sciences, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania (C.P.)
| | - Catalin Pricop
- Department of Surgical Sciences, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania (C.P.)
| | - Manuela Ciocoiu
- Department of Pathophysiology, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.V.)
| | - Maria Cristina Vladeanu
- Department of Pathophysiology, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.V.)
| | - Iris Bararu Bojan
- Department of Pathophysiology, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.V.)
| | - Oana Viola Badulescu
- Department of Pathophysiology, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.V.)
| | - Minerva Codruta Badescu
- Department of Internal Medicine, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.B.)
| | - Carmen Elena Plesoianu
- Department of Internal Medicine, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.B.)
| | - Dan Iliescu Halitchi
- Department of Internal Medicine, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania; (M.C.B.)
| | - Liliana Georgeta Foia
- Department of Biochemistry, University of Medicine and Pharmacy Grigore T. Popa, 700115 Iasi, Romania;
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Saxena R, Chakrapani B, Sarath Krishnan MP, Gupta A, Gupta S, Das J, Gupta SC, Mirza AA, Rao S, Goyal B. Next generation sequencing uncovers multiple miRNAs associated molecular targets in gallbladder cancer patients. Sci Rep 2023; 13:19101. [PMID: 37925508 PMCID: PMC10625549 DOI: 10.1038/s41598-023-44767-3] [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: 05/13/2023] [Accepted: 10/12/2023] [Indexed: 11/06/2023] Open
Abstract
Gallbladder cancer (GBC) is a lethal disease with surgical resection as the only curative treatment. However, many patients are ineligible for surgery, and current adjuvant treatments exhibit limited effectiveness. Next-generation sequencing has improved our understanding of molecular pathways in cancer, sparking interest in microRNA-based gene regulation. The aim of the study is to identify dysregulated miRNAs in GBC and investigate their potential as therapeutic tools for effective and targeted treatment strategies. GBC and control tissue samples were sequenced for miRNA expression using the Illumina HiSeq platform. Biological processes and related pathways were determined using the Panther and Gene Ontology databases. 439 significantly differentially expressed miRNAs were identified; 19 of them were upregulated and 29 were downregulated. Key enriched biological processes included immune cell apoptosis, endoplasmic reticulum (ER) overload response, and negative regulation of the androgen receptor (AR) signaling pathway. Panther analysis revealed the insulin-like growth factor (IGF)-mitogen activated protein kinases (MAPK) cascade, p38 MAPK pathway, p53 pathway, and FAS (a subgroup of the tumor necrosis factor receptor) signaling pathway as highly enriched among dysregulated miRNAs. Kirsten rat sarcoma virus (KRAS), AR, and interferon gamma (IFN-γ) pathways were identified among the key pathways potentially amenable to targeted therapy. We concluded that a combination approach involving miRNA-based interventions could enhance therapeutic outcomes. Our research emphasizes the importance of precision medicine, targeting pathways using sense and anti-sense miRNAs as potential therapies in GBC.
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Affiliation(s)
- Rahul Saxena
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India
| | - Baskar Chakrapani
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India
| | - M P Sarath Krishnan
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India
| | - Amit Gupta
- Department of General Surgery, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Sweety Gupta
- Department of Radiation Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Jayanta Das
- Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, Assam, India
| | - Subash C Gupta
- Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, Assam, India
| | - Anissa A Mirza
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India
| | - Shalinee Rao
- Department of Pathology and Laboratory Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Bela Goyal
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, 249203, India.
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Rawal N, Awasthi S, Dash NR, Kumar S, Das P, Ranjan A, Chopra A, Khan MA, Saluja S, Hussain S, Tanwar P. Prognostic Relevance of PDL1 and CA19-9 Expression in Gallbladder Cancer vs. Inflammatory Lesions. Curr Oncol 2023; 30:1571-1584. [PMID: 36826082 PMCID: PMC9954833 DOI: 10.3390/curroncol30020121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/13/2023] [Accepted: 01/13/2023] [Indexed: 01/26/2023] Open
Abstract
Chronic inflammation in the gallbladder leading to persistent epithelium damage promotes invasive cancer. The study aimed to assess the prognostic value of PDL1 and CA19-9 markers in cancer/inflammatory lesions of the gallbladder. A total of 29 cases (19 cancer and 10 inflammatory) were included. The PDL1 protein concentration level and mRNA expression were assessed in the tissues' lysates by ELISA and real-time PCR, respectively. PDL1 and CA19-9 concentration levels were compared and statistically related with clinico-pathological variables. The PDL1 protein level and its relative mRNA expression were correlated. Kaplan-Meir survival and Cox regression analyses were conducted for predicting prognosis. This study investigated the PDL1 and CA19-9 marker expression in both cancer and inflammatory cases of the gallbladder (p = 0.48 and p = 0.17 respectively). PDL1 protein expression was significantly associated with the hormonal profile of the cases (p = 0.04) at an optimum cut-off value of 13 pg/mL, while the CA19-9 marker expression was correlated with the status of liver metastasis (p = 0.0043) and size of the tumor (p = 0.004). A low PDL1 concentration was found when compared to the CA19-9 level among cancer cases (p = 0.12) and proportional in the inflammatory lesions (p = 0.63). A significant positive correlation was found between the PDL1 protein and its relative mRNA expressions in the inflammatory lesions (p = 0.029) when compared to cancer cases (p = 0.069). Our results showed that a protein-based assay for PDL1 expression would be more sensitive compared to RNA based assays for GBC risk stratifications. Overall survival was predicted with CA19-9 and PDL1 levels (p = 0.0074, p = 0.23, respectively). PDL1 and CA19-9 may act as a probable predictor of a poor prognosis in gallbladder cancer (GBC) cases.
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Affiliation(s)
- Neetu Rawal
- Laboratory Oncology Unit, Dr. B.R.A. Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Supriya Awasthi
- Laboratory Oncology Unit, Dr. B.R.A. Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Nihar Ranjan Dash
- Department of GI Surgery, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Sunil Kumar
- Department of Surgical Oncology, Dr. B.R.A. Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Amar Ranjan
- Laboratory Oncology Unit, Dr. B.R.A. Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Anita Chopra
- Laboratory Oncology Unit, Dr. B.R.A. Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Maroof Ahmad Khan
- Department of Biostatistics, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Sundeep Saluja
- Department of GI Surgery, GB Pant Hospital, New Delhi 110002, India
| | - Showket Hussain
- Divison of Molecular Oncology, National Institute of Cancer Prevention & Research, NICPR-ICMR, Noida 201301, India
| | - Pranay Tanwar
- Laboratory Oncology Unit, Dr. B.R.A. Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
- Correspondence:
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Saklani N, Chauhan V, Akhtar J, Upadhyay SK, Sirdeshmukh R, Gautam P. In silico analysis to identify novel ceRNA regulatory axes associated with gallbladder cancer. Front Genet 2023; 14:1107614. [PMID: 36873948 PMCID: PMC9978489 DOI: 10.3389/fgene.2023.1107614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 02/03/2023] [Indexed: 02/18/2023] Open
Abstract
Competitive endogenous RNA (ceRNA) networks are reported to play a crucial role in regulating cancer-associated genes. Identification of novel ceRNA networks in gallbladder cancer (GBC) may improve the understanding of its pathogenesis and might yield useful leads on potential therapeutic targets for GBC. For this, a literature survey was done to identify differentially expressed lncRNAs (DELs), miRNAs (DEMs), mRNAs (DEGs) and proteins (DEPs) in GBC. Ingenuity pathway analysis (IPA) using DEMs, DEGs and DEPs in GBC identified 242 experimentally observed miRNA-mRNA interactions with 183 miRNA targets, of these 9 (CDX2, MTDH, TAGLN, TOP2A, TSPAN8, EZH2, TAGLN2, LMNB1, and PTMA) were reported at both mRNA and protein levels. Pathway analysis of 183 targets revealed p53 signaling among the top pathway. Protein-protein interaction (PPI) analysis of 183 targets using the STRING database and cytoHubba plug-in of Cytoscape software revealed 5 hub molecules, of which 3 of them (TP53, CCND1 and CTNNB1) were associated with the p53 signaling pathway. Further, using Diana tools and Cytoscape software, novel lncRNA-miRNA-mRNA networks regulating the expression of TP53, CCND1, CTNNB1, CDX2, MTDH, TOP2A, TSPAN8, EZH2, TAGLN2, LMNB1, and PTMA were constructed. These regulatory networks may be experimentally validated in GBC and explored for therapeutic applications.
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Affiliation(s)
- Neeraj Saklani
- Laboratory of Molecular Oncology, ICMR- National Institute of Pathology, New Delhi, India
| | - Varnit Chauhan
- Department of Biotechnology, Gautam Buddha University, Greater Noida, Uttar Pradesh, India
| | - Javed Akhtar
- Laboratory of Molecular Oncology, ICMR- National Institute of Pathology, New Delhi, India
| | - Santosh Kumar Upadhyay
- Department of Biotechnology, Sir J. C. Bose Technical Campus, Bhimtal, Kumaun University, Nainital, Uttarakhand, India
| | - Ravi Sirdeshmukh
- Manipal Academy of Higher Education (MAHE), Manipal, India.,Institute of Bioinformatics, International Tech Park, Bangalore, India
| | - Poonam Gautam
- Laboratory of Molecular Oncology, ICMR- National Institute of Pathology, New Delhi, India
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Sinha SR, Prakash P, Singh RK, Sinha DK. Assessment of tumor markers CA 19-9, CEA, CA 125, and CA 242 for the early diagnosis and prognosis prediction of gallbladder cancer. World J Gastrointest Surg 2022; 14:1272-1284. [PMID: 36504513 PMCID: PMC9727569 DOI: 10.4240/wjgs.v14.i11.1272] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/20/2022] [Accepted: 10/12/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Gallbladder cancer (GBC) is one of the leading and aggressive cancers in this region of India. It is very difficult to diagnose in the early stage, as it lacks typical early signs and symptoms; thus, the diagnosis is often in the advanced stage, which ultimately leads to a poor 5-year survival outcome. Tumor markers including carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), CA 125, CA 242, and alpha fetoprotein are used as indicators in the diagnosis and prognosis of GBC.
AIM To compare tumor marker levels between GBC and benign GB diseases (GBDs) and to assess the combined use of tumor markers to increase the diagnostic accuracy for GBC.
METHODS Patients of either sex aged ≥ 18 years, with suspected GBC (GB polyp, irregular thick GB wall, GB mass, porcelain GB) on the basis of radiological imaging were included in this study. GB wall thickness using ultrasonography and tumor markers CEA, CA 125, CA 19-9, and CA 242 in all patients were recorded. All cases after surgical intervention were divided into two groups, GBC and benign GBD, according to histopathological examination findings. The cases were followed up and clinical findings, radiological findings, and levels of tumor markers were assessed.
RESULTS A total of 200 patients were included in this study, of whom 80 patients had GBC and 120 patients had benign GBD. The median (interquartile range) age was 52.0 (41.0-60.0) years and the majority of patients (132, 66.0%) were women. Tumor markers including CA 19-9, CA 125, CEA, and CA 242 were significantly elevated in patients with GBC (P < 0.001). There was a significant reduction in tumor markers at 3 and 6 mo from baseline (P < 0.001). The mean survival of patients with normal and elevated levels of tumor markers CA 125, CA 19-9, and CEA was comparable; however lymph node metastasis and CA 242 expression level were independent prognostic factors.
CONCLUSION Serum levels of tumor markers including CA 19-9, CA 125, CEA, and CA 242 were significantly associated with GBC. However, no significant association was observed between the presence of elevated levels of any tumor marker with respect to survival. Tumor marker assessment during follow-up may represent a treatment response.
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Affiliation(s)
- Seema Rani Sinha
- Biochemistry, Indira Gandhi Institute of Medical Sciences, Patna 800014, India
| | - Prem Prakash
- General Surgery, Indira Gandhi Institute of Medical Sciences, Patna 800014, India
| | - Rakesh Kumar Singh
- Surgical Gastroenterology, Indira Gandhi Institute of Medical Sciences, Patna 800014, India
| | - Dinesh Kumar Sinha
- Radiation Oncology, State Cancer Institute, Indira Gandhi Institute of Medical Sciences, Patna 800014, Bihar, India
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Neogi K, Murumkar PR, Sharma P, Yadav P, Tewari M, Karunagaran D, Nayak PK, Yadav MR. Design, synthesis and evaluation of 4,7-disubstituted 8-methoxyquinazoline derivatives as potential cytotoxic agents targeting β-catenin/TCF4 signaling pathway. Transl Oncol 2022; 19:101395. [PMID: 35325837 PMCID: PMC8938628 DOI: 10.1016/j.tranon.2022.101395] [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: 11/07/2021] [Revised: 02/15/2022] [Accepted: 03/09/2022] [Indexed: 11/18/2022] Open
Abstract
Overactivation of Wnt/β-catenin signaling by accumulated β-catenin in the nucleus has been shown to play a crucial role in the etiology of cancer. Interaction of β-catenin with Transcription factor 4 (TCF4) is a key step for the activation of Wnt genes in response to upstream signals of the Wnt/β-catenin pathway. Hence, down regulation of Wnt/β-catenin signaling or targeting downstream events by selective β-catenin/TCF4 protein-protein interaction inhibitors could be a potential therapeutic strategy against such cancers. In this study structure-based drug design approach was followed to design novel 4,7-disubstituted 8-methoxyquinazoline-based derivatives which could act as potential cytotoxic agents inhibiting the β-catenin/TCF4 protein-protein interactions. Fifteen compounds possessing 4,7-disubstituted 8-methoxyquinazoline scaffold were synthesized. Cytotoxic potential of the synthesised derivatives were determined against constitutively activated β-catenin/TCF4 signaling pathway cancer cells (HCT116 and HepG2) using the sulforhodamine B assay. The most potent compound (18B) was selected for detailed biological evaluation. Cell morphology, Hoechst 33342 and Annexin V/PI staining were used to detect apoptosis, while inhibition of cell migration was assessed by in vitro wound healing assay against HCT116 and HepG2 cells. Effect on β-catenin/TCF mediated transcriptional activity was assessed by TOPFlash/FOPFlash assay, TCF4 and β-catenin protein expression by immunocytofluorescence, and Wnt target genes (like c-MYC and Cyclin D1) mRNA levels by RT-PCR against HCT116 cells. Cytotoxic potency of the most potential compound (18B) against primary human gallbladder cancer cells was also evaluated. The derivatives showed interactions with active site residues of β-catenin and were capable of hindering the TCF4 binding, thereby disrupting β-catenin/TCF4 interactions. Cytotoxic potencies (IC50) of these derivatives ranged from 5.64 ± 0.68 to 23.18 ± 0.45 μM against HCT116 and HepG2 cells respectively. Compound (18B), the most potent compound among the series, induced apoptosis and inhibited cell migration against HCT116 and HepG2 cells. Mechanistic studies indicated that compound (18B) downregulated β-catenin/TCF4 signaling pathway, β-catenin and TCF4 protein expression, and mRNA levels of c-MYC andCyclin D1 in HCT116 cells and showed cytotoxicity against primary human gallbladder cancer cells with IC50 value of 8.50 ± 1.44 μM. Thus, novel 4,7-disubstituted 8-methoxyquinazoline derivatives were identified as potential cytotoxic agents with potencies comparable to that of imatinib mesylate. Compound (18B) represents a promising lead molecule as anticancer agent against colon, hepatocellular and gallbladder cancers targeting β-catenin/TCF4 signaling pathway.
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Affiliation(s)
- Kaushik Neogi
- Department of Pharmaceutical Engineering and Technorlogy, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, India
| | - Prashant R Murumkar
- Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India
| | - Priyanshu Sharma
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Poonam Yadav
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Mallika Tewari
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Devarajan Karunagaran
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Prasanta Kumar Nayak
- Department of Pharmaceutical Engineering and Technorlogy, Indian Institute of Technology (Banaras Hindu University), Varanasi, Uttar Pradesh, India.
| | - Mange Ram Yadav
- Centre of Research for Development, Parul University, Vadodara, Gujarat, India.
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Fujisawa M, Matsushima M, Carreras J, Hirabayashi K, Y Kikuti Y, Ueda T, Kaneko M, Fujimoto R, Sano M, Teramura E, Monma M, Nakae H, Suzuki T, Suzuki H, Nakamura N. Whole-genome copy number and immunohistochemical analyses on surgically resected intracholecystic papillary neoplasms. Pathol Int 2021; 71:823-830. [PMID: 34643317 DOI: 10.1111/pin.13177] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 09/18/2021] [Indexed: 01/10/2023]
Abstract
Intracholecystic papillary neoplasms are newly defined precancerous lesions. According to Classification of the World Health Organization, they have four histological morphologies, which are biliary, gastric, intestinal, and oncocytic. This study evaluated 17 patients with resected intracholecystic papillary neoplasms in terms of histological, immunohistochemical, and copy number variation (CNV). The histological subtypes included 5 cases of low-grade (5 gastric) and 12 cases of high-grade (6 gastric and 6 biliary) neoplasms. Most cases showed high expression of MUC1, MUC5AC, and CK7, moderate expression of MUC6 and Ki-67, and low expression of CK20, MUC2, and CDX2. The CNV profile identified gain of 7q in 12%, and loss of 1p (18%), 5q (29%), 9p (35%), 12p (17%), 17p (24%), and 19p (18%). No CNVs were observed in low-grade neoplasms, whereas high-grade ones had increasing abnormalities. β-catenin was often expressed in the nucleus of neoplasms with gastric morphology, suggesting the involvement of the Wnt/β-catenin pathway. However, it was not expressed among those with biliary morphology, which instead exhibited high p53 expression. Neoplasms with biliary morphology showed more CNV changes (9p, 17p, 19p losses). Distinct immunological and CNV patterns were seen in both morphologies, suggesting differences in their pathogenesis. More CNVs accumulated with tumor progression.
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Affiliation(s)
- Mia Fujisawa
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Masashi Matsushima
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Joaquim Carreras
- Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Kenichi Hirabayashi
- Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Yara Y Kikuti
- Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Takashi Ueda
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Motoki Kaneko
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Ryutaro Fujimoto
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Masaya Sano
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Erika Teramura
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Makiko Monma
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Hirohiko Nakae
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Takayoshi Suzuki
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Hidekazu Suzuki
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Naoya Nakamura
- Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
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Song X, Hu Y, Li Y, Shao R, Liu F, Liu Y. Overview of current targeted therapy in gallbladder cancer. Signal Transduct Target Ther 2020; 5:230. [PMID: 33028805 PMCID: PMC7542154 DOI: 10.1038/s41392-020-00324-2] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/08/2020] [Accepted: 09/10/2020] [Indexed: 02/08/2023] Open
Abstract
Gallbladder cancer (GBC) is rare, but is the most malignant type of biliary tract tumor. Unfortunately, only a small population of cancer patients is acceptable for the surgical resection, the current effective regimen; thus, the high mortality rate has been static for decades. To substantially circumvent the stagnant scenario, a number of therapeutic approaches owing to the creation of advanced technologic measures (e.g., next-generation sequencing, transcriptomics, proteomics) have been intensively innovated, which include targeted therapy, immunotherapy, and nanoparticle-based delivery systems. In the current review, we primarily focus on the targeted therapy capable of specifically inhibiting individual key molecules that govern aberrant signaling cascades in GBC. Global clinical trials of targeted therapy in GBC are updated and may offer great value for novel pathologic and therapeutic insights of this deadly disease, ultimately improving the efficacy of treatment.
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Affiliation(s)
- Xiaoling Song
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Yunping Hu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Yongsheng Li
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Rong Shao
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
- Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| | - Fatao Liu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China.
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
| | - Yingbin Liu
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
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11
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Dixit R, Pandey M, Tripathi SK, Dwivedi AND, Shukla VK. Genetic mutational analysis of β-catenin gene affecting GSK-3β phosphorylation plays a role in gallbladder carcinogenesis: Results from a case control study. Cancer Treat Res Commun 2020; 23:100173. [PMID: 32344182 DOI: 10.1016/j.ctarc.2020.100173] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/21/2020] [Accepted: 03/24/2020] [Indexed: 02/06/2023]
Abstract
UNLABELLED This manuscript has reported different mutations of β-catenin gene in gallbladder cancer patients which affect GSK-3β phosphorylation site. PURPOSE Gallbladder carcinoma (GBC) is a relatively rare and fatal cancer with poor prognosis. The molecular mechanism of gallbladder carcinogenesis is still not clear. Wnt signaling pathway is a highly conserved pathway that regulates proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. β-catenin plays major role in Wnt signaling and aberrations in β-catenin has found to be involved in several cancers pathogenesis. This study was carried out to document the mutations of β-catenin gene in gallbladder cancer and to evaluate its possible role in gallbladder carcinogenesis. METHODS PCR-SSCP (Single Stranded Conformation Polymorphism) for ctnnb1 was performed in 50 patients each of gallbladder cancer, cholelithiasis and 50 healthy controls. Samples that showed variation in banding pattern were sequenced. RESULTS Variation in banding pattern was observed in 9 (18%) samples of GBC, 4 (8%) of cholelithiasis and 2 (4%) of control. Sequencing analysis showed 9 novel mutations of ctnnb1 in exon 3 in 18% of gallbladder cancer (χ2 = 5.778; p < 0.05). Six point mutations, 1 deletion and 1 insertion mutation were found in 9 cases of gallbladder cancer. All point mutations were mis-sense mutation that affected highly conserved serine or threonine region that is important for GSK-3β phosphorylation. CONCLUSION Findings of the study suggests that high frequency of non synonymous mutations of β-catenin gene (ctnnb1) occurs in patients with gallbladder cancer. As these mutations mainly effect GSK 3β phosphorylation, it may be concluded that this might be an important step in gallbladder carcinogenesis. These β-catenin mutations lead to Wnt pathway activation and appear to have a role in progression from inflammation to cancer in gallbladder.
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Affiliation(s)
- Ruhi Dixit
- Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India
| | - Manoj Pandey
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India
| | - Sunil Kumar Tripathi
- Department of Forensic Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India
| | - Amit Nandan Dhar Dwivedi
- Department of Radio Diagnosis, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India
| | - Vijay Kumar Shukla
- Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India.
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12
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García P, Bizama C, Rosa L, Espinoza JA, Weber H, Cerda-Infante J, Sánchez M, Montecinos VP, Lorenzo-Bermejo J, Boekstegers F, Dávila-López M, Alfaro F, Leiva-Acevedo C, Parra Z, Romero D, Kato S, Leal P, Lagos M, Roa JC. Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor. Biol Res 2020; 53:13. [PMID: 32293552 PMCID: PMC7158131 DOI: 10.1186/s40659-020-00282-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 04/06/2020] [Indexed: 12/19/2022] Open
Abstract
Background Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry. Results After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. Conclusions The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.
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Affiliation(s)
- Patricia García
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Lorena Rosa
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.,Applied Molecular and Cellular Biology PhD Program, Universidad de La Frontera, Temuco, Chile
| | - Jaime A Espinoza
- Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Helga Weber
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Javier Cerda-Infante
- Department of Hematology Oncology; Cellular and Molecular Biology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marianela Sánchez
- Department of Hematology Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Viviana P Montecinos
- Department of Hematology Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Justo Lorenzo-Bermejo
- Statistical Genetics Research Group, Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Felix Boekstegers
- Statistical Genetics Research Group, Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Marcela Dávila-López
- Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Francisca Alfaro
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Claudia Leiva-Acevedo
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Zasha Parra
- Cytogenetics Laboratory, Complejo Asistencial Dr. Sótero del Río, Santiago, Chile
| | - Diego Romero
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Sumie Kato
- Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pamela Leal
- Center of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Marcela Lagos
- Department of Clinical Laboratory, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Carlos Roa
- Department of Pathology, Faculty of Medicine, Millennium Institute of Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.
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13
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Serum Expression of β-Catenin Is a Potential Detection Marker in Patients with Colorectal Cancer. DISEASE MARKERS 2019; 2019:5070524. [PMID: 31781302 PMCID: PMC6855041 DOI: 10.1155/2019/5070524] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 08/20/2019] [Accepted: 09/05/2019] [Indexed: 02/07/2023]
Abstract
Object To investigate the correlation between the level of serum β-catenin and the disease progression of colorectal polyp (CRP) and colorectal cancer (CRC) and find its potential diagnostic value. Methods A total of 327 clinical serum samples and their electronic medical records were collected. Detecting by enzyme-linked immunosorbent assay (ELISA), the correlations of serum β-catenin with tumor marker carcinoembryonic antigen (CEA) and CRC clinicopathological parameters and the receiver operating characteristic (ROC) curve were analyzed. Results Serum β-catenin levels in the CRP and CRC patients were significantly higher than those in the healthy control (HC) group (P < 0.05 and P < 0.001). Compared with CRP, serum β-catenin level in CRC was also increased (P < 0.05). However, there was no significant difference in gender, age, location, tumor size, Dukes staging, or metastasis (P > 0.05) between serum β-catenin and clinical parameters of CRC. There was no correlation between serum β-catenin levels and CEA in CRC patients (P = 0.14). ROC curve analysis showed that serum β-catenin possessed the maximum diagnostic efficiency in CRP (AUC = 0.73, P < 0.05) with 86.41% sensitivity and 51.56% specificity. β-Catenin combined with CEA had the highest diagnostic efficiency (AUC = 0.88, P < 0.05) with 81.88% sensitivity and 73.44% specificity. With CRC patients from CRP patients, ROC analysis of the combining detection (AUC = 0.70, P < 0.05) had the 70% sensitivity and 84.5% specificity. Conclusion The serum β-catenin levels are gradually increased in CRP and CRC, while there is no correlation between its levels and CRC disease process. Single serum β-catenin or combined CEA would be one of the potential candidate biomarkers for colorectal disease diagnosis.
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Ushio N, Chambers JK, Watanabe KI, Kishimoto TE, Shiga T, Li JY, Nakayama H, Uchida K. Chronic Inflammatory and Proliferative Lesions of the Gallbladder in Aged Pigs. Vet Pathol 2019; 57:122-131. [PMID: 31551021 DOI: 10.1177/0300985819875749] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Primary epithelial tumors of the gallbladder are rarely reported in animals. In this study, 9 aged pigs (6-12 years old) were histopathologically examined for gallbladder proliferative lesions. At necropsy, a large gallstone occupied the lumen of the gallbladder of 3 pigs. Histopathological examination revealed chronic cholecystitis in all 9 pigs, mucosal hyperplasia in 2 pigs, adenoma in 1 pig, and adenocarcinoma in 2 pigs. Bacilli were detected in the gallbladder lumen of 6 pigs by Warthin-Starry stain. Mucosal hyperplasia, adenoma, and adenocarcinoma were characterized by papillary projections of the mucosa with occasional acinar structures. Tumor invasion of the surrounding tissue was observed in the cases of adenocarcinoma. On Alcian blue and periodic acid-Schiff double-stained sections, the acinar structure of gallbladder mucosa in chronic cholecystitis and mucosal hyperplasia was stained in a mosaic pattern, indicating pyloric gland metaplasia. The results of immunohistochemistry revealed a CD10-positive epithelial brush border and mucin (MUC) 2-positive goblet cells in chronic cholecystitis, adenoma, and adenocarcinomas, indicating intestinal metaplasia. Immunoreactivity of MUC5 AC and cytokeratin 19 was weaker in adenoma and adenocarcinomas compared with the normal and hyperplastic gallbladder mucosa. The number of p53-positive nuclei and the Ki-67 index were higher in adenocarcinomas compared with benign lesions. These results suggest that chronic cholecystitis associated with gallstones and/or bacterial infections may contribute to metaplastic changes and development of gallbladder tumors in aged pigs. Alteration of mucin, cytokeratin, and p53 profiles in gallbladder proliferative lesions in pigs were similar to that in humans, suggesting a common pathogenesis in tumor development.
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Affiliation(s)
- Nanako Ushio
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - James K Chambers
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Ken-Ichi Watanabe
- Department of Veterinary Medicine, Research Center for Global Agromedicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan
| | - Takuya E Kishimoto
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Takanori Shiga
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Jun-You Li
- Animal Resource Science Center, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Ibaraki, Japan
| | - Hiroyuki Nakayama
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Kazuyuki Uchida
- Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
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15
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Xu S, Zhan M, Wang J. Epithelial-to-mesenchymal transition in gallbladder cancer: from clinical evidence to cellular regulatory networks. Cell Death Discov 2017; 3:17069. [PMID: 29188076 PMCID: PMC5702855 DOI: 10.1038/cddiscovery.2017.69] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 08/19/2017] [Accepted: 08/23/2017] [Indexed: 02/08/2023] Open
Abstract
Gallbladder cancer (GBC), with late diagnosis, rapid disease progression and early metastasis, is a highly aggressive malignant tumor found worldwide. Patients with GBC have poor survival, low curative resection rates and early recurrence. For such a lethal tumor, uncovering the mechanisms and exploring new strategies to prevent tumor progression and metastasis are critically important. Epithelial-to-mesenchymal transition (EMT) has a prominent role in the early steps of tumor progression and metastasis by initiating polarized epithelial cell transition into motile mesenchymal cells. Accumulating evidence suggests that EMT can be modulated by the cooperation of multiple mechanisms affecting common targets. Signaling pathways, transcriptional and post-transcriptional regulation and epigenetic alterations are involved in the stepwise EMT regulatory network in GBC. Loss of epithelial markers, acquisition of mesenchymal markers and dysregulation of EMT-inducing transcription factors (EMT-TFs) have been observed and are associated with the clinicopathology and prognosis of GBC patients. Therefore, EMT may be a detectable and predictable event for predicting GBC progression and metastasis in the clinic. In this review, we will provide an overview of EMT from the clinical evidence to cellular regulatory networks that have been studied thus far in clinical and basic GBC studies.
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Affiliation(s)
- Sunwang Xu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ming Zhan
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jian Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol 2017; 23:3978-3998. [PMID: 28652652 PMCID: PMC5473118 DOI: 10.3748/wjg.v23.i22.3978] [Citation(s) in RCA: 259] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 02/01/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. Late diagnosis and deprived prognosis are major problems for treatment of gallbladder carcinoma. The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis. An understanding to the relationship between epidemiology, molecular genetics and pathogenesis of gallbladder cancer can add new insights to its undetermined pathophysiology. Present review article provides a recent update regarding epidemiology, pathogenesis, and molecular genetics of gallbladder cancer. We systematically reviewed published literature on gallbladder cancer from online search engine PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Various keywords used for retrieval of articles were Gallbladder, cancer Epidemiology, molecular genetics and bullion operators like AND, OR, NOT. Cross references were manually searched from various online search engines (http://www.ncbi.nlm.nih.gov/pubmed,https://scholar.google.co.in/, http://www.medline.com/home.jsp). Most of the articles published from 1982 to 2015 in peer reviewed journals have been included in this review.
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17
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Kumari S, Tewari S, Husain N, Agarwal A, Pandey A, Singhal A, Lohani M. Quantification of Circulating Free DNA as a Diagnostic Marker in Gall Bladder Cancer. Pathol Oncol Res 2016; 23:91-97. [PMID: 27475647 DOI: 10.1007/s12253-016-0087-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 07/05/2016] [Indexed: 01/01/2023]
Abstract
Gall bladder Carcinoma (GBC) is the fifth most common cancer of the digestive tract and frequently diagnosed in late stage of disease. Estimation of circulating free DNA (cfDNA) in serum has been applied as a "liquid biopsy" in several deep seated malignancies. Its value in diagnosis of gall bladder carcinoma has not been studied. The present study was designed to assess the role of cfDNA in the diagnosis of GBC and correlate levels with the TNM stage. Serum was collected from 34 patients with GBC and 39 age and sex matched controls including 22 cholecystitis and 17 healthy individuals. Serum cfDNA levels were measured through quantitative polymerase chain reaction (qPCR) by amplification of β-globin gene. Performance of the assay was calculated through the receiver operating characteristic (ROC) curve. The cfDNA level was significantly lower in healthy controls and cholecystitis (89.32 ± 59.76 ng/ml, 174.21 ± 99.93 ng/ml) compared to GBC (1245.91 ± 892.46 ng/ml, p = <0.001). The cfDNA level was significantly associated with TNM stage, lymph node involvement and jaundice (0.002, 0.027, and 0.041, respectively). Area under curve of ROC analysis for cancer group versus healthy and cholecystitis group was 1.00 and 0.983 with sensitivity of 100 %, 88.24 % and specificity of 100 % respectively. Quantitative analysis of cfDNA may distinguish cholecystitis and gall bladder carcinoma and may serve as new diagnostic, noninvasive marker adjunct to imaging for the diagnosis of GBC.
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Affiliation(s)
- Swati Kumari
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, U.P, Lucknow, 226010, India
| | - Shikha Tewari
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, U.P, Lucknow, 226010, India
| | - Nuzhat Husain
- Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, U.P, Lucknow, 226010, India.
| | - Akash Agarwal
- Department of Surgical Oncology, Dr. Ram Manohar Lohia Institute of Medical Sciences, U.P, Lucknow, 226010, India
| | - Anshuman Pandey
- Department of Gastrosurgery, Dr. Ram Manohar Lohia Institute of Medical Sciences, U.P, Lucknow, 226010, India
| | - Ashish Singhal
- Department of Surgical Oncology, Dr. Ram Manohar Lohia Institute of Medical Sciences, U.P, Lucknow, 226010, India
| | - Mohtashim Lohani
- Department of Biosciences, Integral University, U.P, Lucknow, 226026, India
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Zhang D, Wang Y, Dai Y, Wang J, Suo T, Pan H, Liu H, Shen S, Liu H. CIZ1 promoted the growth and migration of gallbladder cancer cells. Tumour Biol 2015; 36:2583-2591. [PMID: 25427641 DOI: 10.1007/s13277-014-2876-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 11/18/2014] [Indexed: 12/19/2022] Open
Abstract
Gallbladder cancer (GBC) is one of the most common and aggressive diseases among the gastrointestinal tract malignancies, and the molecular mechanism underlying this disease remains largely unknown. CIZ1 (Cip1 interacting zinc finger protein 1), a binding partner of p21(Cip1/Waf1), has been found to be involved in the tumorigenesis recently. However, the expression pattern and biological functions of CIZ1 in the progression of GBC are not fully understood. In this study, it was found that the expression of CIZ1 was significantly elevated in GBC samples compared to their adjacent normal tissues. Moreover, overexpression of CIZ1 promoted the growth and migration of GBC cells, while knocking down the expression of CIZ1 inhibited the growth, migration, and tumorigenesis of GBC cells in vitro and in vivo. Mechanistically, CIZ1 was found to interact with TCF4 (T-cell factor) and activate beta-catenin/TCF signaling. Our study demonstrated that CIZ1 played an oncogenic role in the progression of GBC and CIZ1 might be a promising target for the treatment of GBC.
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Affiliation(s)
- Dexiang Zhang
- General Surgery Department, Zhongshan Hospital, General Surgery Institute, Fudan University, 180 Fenglin Rd., 200032, Shanghai, China
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Dwivedi AND, Jain S, Dixit R. Gall bladder carcinoma: Aggressive malignancy with protean loco-regional and distant spread. World J Clin Cases 2015; 3:231-244. [PMID: 25789296 PMCID: PMC4360495 DOI: 10.12998/wjcc.v3.i3.231] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 11/21/2014] [Accepted: 12/16/2014] [Indexed: 02/05/2023] Open
Abstract
The most common malignancy of biliary tract is gallbladder cancer (GBC) which is the third most common cancer in gastrointestinal tract. It is a lethal disease for most patients in spite of growing awareness and improved diagnostic techniques. GBC has a very poor prognosis and the 5 year survival rate is < 10%. Although etiology of the carcinoma of the gallbladder is still obscure, various factors have been implicated, cholelithiasis being the most frequent. The incidence of GBC worldwide is based on the gender, geography and ethnicity which suggest that both genetic and environmental factors can cause GBC. The major route of spread of gallbladder cancer (GC) is loco-regional rather than distant. It spreads by lymphatic, vascular, neural, intraperitoneal, and intraductal routes. Sonography is usually the most common imaging test to evaluate symptoms of biliary tract disease including suspected GC. With recent advances in imaging modalities like multi-detector computed tomography (CT) scanners, magnetic resonance imaging-positron emission tomography/CT diagnosis of gallbladder cancer has improved. Studies have also targeted molecular and genetic pathways. Treatment options have included extended and radical surgeries and adjuvant chemotherapy. This review article deals in detail with important aspects of carcinoma gallbladder and its manifestations and challenges. Role of various imaging modalities in characterization and accurate staging has been discussed. The loco-regional spread of this aggressive malignancy is dealt explicitly.
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Wang YF, Feng FL, Zhao XH, Ye ZX, Zeng HP, Li Z, Jiang XQ, Peng ZH. Combined detection tumor markers for diagnosis and prognosis of gallbladder cancer. World J Gastroenterol 2014; 20:4085-4092. [PMID: 24744600 PMCID: PMC3983467 DOI: 10.3748/wjg.v20.i14.4085] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Revised: 01/23/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To clarify the value of combined use of markers for the diagnosis of gallbladder cancer and prediction of its prognosis.
METHODS: Serum cancer antigens (CA)199, CA242, carcinoembryonic antigen (CEA), and CA125 levels were measured in 78 patients with gallbladder cancer (GBC), 78 patients with benign gallbladder diseases, and 78 healthy controls using electrochemiluminescence. CA199, CA242, CEA, and CA125 levels and positive rates were analyzed and evaluated pre- and post-operatively. Receiver operator characteristic curves were used to determine diagnostic sensitivity and specificity of GBC. Survival time analysis, including survival curves, and multivariate survival analysis of a Cox proportional hazards model was performed to evaluate independent prognostic factors.
RESULTS: Serum CA242, CA125, and CA199 levels in the GBC group were significantly higher when compared with those in the benign gallbladder disease and healthy control groups (P < 0.01). With a single tumor marker for GBC diagnosis, the sensitivity of CA199 was the highest (71.7%), with the highest specificity being in CA242 (98.7%). Diagnostic accuracy was highest with a combination of CA199, CA242, and CA125 (69.2%). CA242 could be regarded as a tumor marker of GBC infiltration in the early stage. The sensitivity of CA199 and CA242 increased with progression of GBC and advanced lymph node metastasis (P < 0.05). The 78 GBC patients were followed up for 6-12 mo (mean: 8 mo), during which time serum CA199, CA125, and CA242 levels in the recurrence group were significantly higher than in patients without recurrence (P < 0.01). The post-operative serum CA199, CA125, and CA242 levels in the non-recurrence group were significantly lower than those in the GBC group (P < 0.01). Multivariate survival analysis using a Cox proportional hazards model showed that cancer of the gallbladder neck and CA199 expression level were independent prognostic factors.
CONCLUSION: CA242 is a marker of GBC infiltration in the early stage. CA199 and cancer of the gallbladder neck are therapeutic and prognostic markers.
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Rai R, Sharma KL, Sharma S, Misra S, Kumar A, Mittal B. Death receptor (DR4) haplotypes are associated with increased susceptibility of gallbladder carcinoma in north Indian population. PLoS One 2014; 9:e90264. [PMID: 24587306 PMCID: PMC3938657 DOI: 10.1371/journal.pone.0090264] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 01/27/2014] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND AND AIM Defective apoptosis is a hallmark of cancer development and progression. Death receptors (DR4, FAS) and their ligands (TRAIL, FASL) are thought to mediate the major extrinsic apoptotic pathway in the cell. SNPs in these genes may lead to defective apoptosis. Hence, the present study aimed to investigate the association of functional SNPs of DR4 (rs20575, rs20576 and rs6557634), FAS (rs2234767) and FASL (rs763110) with gallbladder cancer (GBC) risk. METHODS This case-control study included 400 GBC and 246 healthy controls (HC). Genotyping was carried out by Taqman genotyping assays. Statistical analysis was performed by using SPSS ver16. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2.0, BIOSTAT, Englewood, NJ) to systematically summarize the possible association of SNP with cancer risk. Functional prediction of these variants was carried out using Bioinformatics tools (FAST-SNP, F-SNP). False discovery rate (FDR test) was used in multiple comparisons. RESULTS The DR4 C rs20575 A rs20576 A rs6557634, G rs20575 A rs20576 G rs6557634 and G rs20575 C rs20576 G rs6557634 haplotypes conferred two-fold increased risk for GBC. Among these, the DR4 C rs20575 A rs20576 A rs6557634 haplotype emerged as main factor influencing GBC susceptibility as the risk was not modulated by gender or gallstone stratification. Our meta-analysis results showed significant association of DR4 rs6557634 with overall cancer risk, GI cancers as well as in Caucasians. We didn't find any association of FAS and FASL SNPs with GBC susceptibility. CONCLUSIONS The DR4 haplotype C rs20575 A rs20576 A rs6557634 represents an important factor accounting the patients susceptibility to GBC probably due to decreased apoptosis. However, additional well-designed studies with larger sample size focusing on different ethnicities are required to further validate the results.
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Affiliation(s)
- Rajani Rai
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, India
| | - Kiran L. Sharma
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, India
| | - Surbhi Sharma
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, India
| | - Sanjeev Misra
- Department of Surgical Oncology, KGMU, Lucknow, India
| | - Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, India
| | - Balraj Mittal
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, India
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