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1
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Gabellone S, Vanni S, Fausti V, Miserocchi G, Liverani C, Spadazzi C, Cocchi C, Calabrese C, Cavaliere D, Pacilio CA, Ercolani G, Pieri F, Gurrieri L, Riva N, Jones R, De Vita A. Exploring nanotechnology solutions for improved outcomes in gastrointestinal stromal tumors. Heliyon 2024; 10:e40596. [PMID: 39687122 PMCID: PMC11647801 DOI: 10.1016/j.heliyon.2024.e40596] [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: 11/21/2023] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
Objectives Gastrointestinal stromal tumors, the most prevalent mesenchymal tumors (80 %) of the gastrointestinal tract, comprise less than 1 % of all gastrointestinal neoplasms and about 5 % of all sarcomas. Despite their rarity, Gastrointestinal stromal tumors present diverse clinical manifestations, anatomic locations, histological subtypes, and prognostic outcomes. Methods This scoping review comprehensively explores the epidemiology, clinical characteristics, diagnostic and prognostic modalities, as well as new therapeutic options for Gastrointestinal stromal tumors. Results A particular focus is placed on the promising role of bio-nanomaterials as multifunctional agents for drug delivery and 3D tumor microenvironment modeling. Bio-nanomaterials offer promising opportunities for targeted drug delivery, overcoming treatment resistance, and improving therapeutic efficacy. Conclusion Despite significant advancements, Gastrointestinal stromal tumors remain a complex clinical entity with ongoing challenges. The integration of nanotechnology into Gastrointestinal stromal tumors management offers the potential to enhance patient outcomes. Future studies should prioritize the development and evaluation of nanomaterial-based therapies in clinical trials to facilitate the translation of laboratory discoveries into real-world clinical applications.
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Affiliation(s)
- Sofia Gabellone
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Silvia Vanni
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Valentina Fausti
- Clinical and Experimental Oncology, Immunotherapy, Rare Cancers and Biological Resource Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Giacomo Miserocchi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Chiara Liverani
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Chiara Spadazzi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Claudia Cocchi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Chiara Calabrese
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Davide Cavaliere
- General and Oncologic Surgery, “Morgagni-Pierantoni” Hospital, 47121, Forlì, Italy
| | | | - Giorgio Ercolani
- General and Oncologic Surgery, “Morgagni-Pierantoni” Hospital, 47121, Forlì, Italy
| | - Federica Pieri
- Pathology Unit, “Morgagni-Pierantoni” Hospital, 47121, Forlì, Italy
| | - Lorena Gurrieri
- Clinical and Experimental Oncology, Immunotherapy, Rare Cancers and Biological Resource Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Nada Riva
- Clinical and Experimental Oncology, Immunotherapy, Rare Cancers and Biological Resource Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Robin Jones
- Sarcoma Unit, The Royal Marsden NHS Foundation Trust, SW3 6JJ, London, UK
| | - Alessandro De Vita
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
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Pancsa T, Martínek P, Michal M. Malignant Esophageal Glomus Tumor With CARMN::NOTCH2 Fusion: An Additional Tumor Underscoring the Frequent Tendency of Esophageal Glomus Tumors for Aggressive Behavior. Int J Surg Pathol 2024:10668969241291887. [PMID: 39523591 DOI: 10.1177/10668969241291887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
Malignant glomus tumors are rare tumors of pericytic origin with a propensity to develop in the upper gastrointestinal tract. Hereby we demonstrate a tumor of a 20-year-old man, who presented with dysphagia and an exophytic esophageal mass. Histologic examination of the resected mass revealed a multinodular tumor in the esophageal wall composed of epithelioid cells showing nesting and monomorphic atypia, staghorn vessels and scanty stroma. Immunohistochemically, the neoplastic cells were positive for SMA, and H-caldesmon, while desmin was negative. Collagen IV and laminin decorated a dense intercellular basal membrane meshwork. RNA-sequencing using TruSight RNA Pan-Cancer Panel revealed a CARMN::NOTCH2 fusion, that is a recurrent, frequently described and so far specific genetic alteration in glomus tumors. In spite of the adjuvant chemotherapy regimens, the patient died of disseminated metastatic disease 2 years after the diagnosis. Our patient presentation and the previous reports in the literature highlight the frequently aggressive behavior of glomus tumors arising in the esophagus.
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Affiliation(s)
| | | | - Michael Michal
- Bioptical Laboratory Ltd, Pilsen, Czechia
- Department of Pathology, Faculty of Medicine in Plzen, Charles University, Plzen, Czechia
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3
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Renne SL, Cammelli M, Santori I, Tassan-Mangina M, Samà L, Ruspi L, Sicoli F, Colombo P, Terracciano LM, Quagliuolo V, Cananzi FCM. True Mitotic Count Prediction in Gastrointestinal Stromal Tumors: Bayesian Network Model and PROMETheus (Preoperative Mitosis Estimator Tool) Application Development. J Med Internet Res 2024; 26:e50023. [PMID: 39437385 PMCID: PMC11538881 DOI: 10.2196/50023] [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: 06/16/2023] [Revised: 05/14/2024] [Accepted: 07/21/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) present a complex clinical landscape, where precise preoperative risk assessment plays a pivotal role in guiding therapeutic decisions. Conventional methods for evaluating mitotic count, such as biopsy-based assessments, encounter challenges stemming from tumor heterogeneity and sampling biases, thereby underscoring the urgent need for innovative approaches to enhance prognostic accuracy. OBJECTIVE The primary objective of this study was to develop a robust and reliable computational tool, PROMETheus (Preoperative Mitosis Estimator Tool), aimed at refining patient stratification through the precise estimation of mitotic count in GISTs. METHODS Using advanced Bayesian network methodologies, we constructed a directed acyclic graph (DAG) integrating pertinent clinicopathological variables essential for accurate mitotic count prediction on the surgical specimen. Key parameters identified and incorporated into the model encompassed tumor size, location, mitotic count from biopsy specimens, surface area evaluated during biopsy, and tumor response to therapy, when applicable. Rigorous testing procedures, including prior predictive simulations, validation utilizing synthetic data sets were employed. Finally, the model was trained on a comprehensive cohort of real-world GIST cases (n=80), drawn from the repository of the Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, with a total of 160 cases analyzed. RESULTS Our computational model exhibited excellent diagnostic performance on synthetic data. Different model architecture were selected based on lower deviance and robust out-of-sample predictive capabilities. Posterior predictive checks (retrodiction) further corroborated the model's accuracy. Subsequently, PROMETheus was developed. This is an intuitive tool that dynamically computes predicted mitotic count and risk assessment on surgical specimens based on tumor-specific attributes, including size, location, surface area, and biopsy-derived mitotic count, using posterior probabilities derived from the model. CONCLUSIONS The deployment of PROMETheus represents a potential advancement in preoperative risk stratification for GISTs, offering clinicians a precise and reliable means to anticipate mitotic counts on surgical specimens and a solid base to stratify patients for clinical studies. By facilitating tailored therapeutic strategies, this innovative tool is poised to revolutionize clinical decision-making paradigms, ultimately translating into improved patient outcomes and enhanced prognostic precision in the management of GISTs.
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Affiliation(s)
- Salvatore Lorenzo Renne
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Pathology Department, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Manuela Cammelli
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Ilaria Santori
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Marta Tassan-Mangina
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Laura Samà
- Sarcoma, Melanoma and Rare Tumors Surgery Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Laura Ruspi
- Sarcoma, Melanoma and Rare Tumors Surgery Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Federico Sicoli
- Sarcoma, Melanoma and Rare Tumors Surgery Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Piergiuseppe Colombo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Pathology Department, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Luigi Maria Terracciano
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Pathology Department, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Vittorio Quagliuolo
- Sarcoma, Melanoma and Rare Tumors Surgery Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Ferdinando Carlo Maria Cananzi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Sarcoma, Melanoma and Rare Tumors Surgery Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Rozzano, Milan, Italy
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Mousavi S, Ono Y, VanderLaan PA, Guzmán-Arocho YD. Gastrointestinal stromal tumors in fine-needle aspiration biopsies. Diagn Cytopathol 2024; 52:575-581. [PMID: 38396207 DOI: 10.1002/dc.25285] [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: 01/15/2024] [Revised: 01/24/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024]
Abstract
Gastrointestinal stromal tumors (GISTs), although rare, are the most common mesenchymal neoplasms of the gastrointestinal tract. Their potential for malignancy underscores the significance of identifying them through cytomorphologic findings and pertinent immunohistochemical markers. GISTs can emerge anywhere along the gastrointestinal tract with a predilection for the stomach. The clinical manifestations vary from nonspecific abdominal symptoms to incidental discovery during diagnostic interventions for unrelated signs and symptoms. Cytologically, GIST aspirates contain spindle or epithelioid cells with immunoreactivity for CD117/c-KIT, DOG-1, and CD34. Molecularly, KIT or PDGFRA mutations are prevalent, guiding targeted therapy with tyrosine kinase inhibitors. Distinct subtypes like succinate dehydrogenase-deficient GISTs pose challenges, often affecting younger individuals and displaying unique features. Histologically, GISTs are graded by mitotic rates, aiding prognostication. Distinguishing GISTs from similar entities is pivotal, necessitating attention to their immunostaining patterns for making an accurate diagnosis and molecular alterations for effectively planning treatment. Common differential diagnoses include leiomyoma, schwannoma, and solitary fibrous tumor. This article presents a classic GIST case and showcases relatively simple diagnostic clues for identifying similar lesions that may occur in diverse locations.
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Affiliation(s)
- Seyedreza Mousavi
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Yuho Ono
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Paul A VanderLaan
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Yaileen D Guzmán-Arocho
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
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5
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Angın YS, Ceylan C, Sağlam K, Aydın C. The coexistence of gastrointestinal stromal tumors and malignancies: Our 10-year results. Turk J Surg 2024; 40:197-203. [PMID: 39917403 PMCID: PMC11792897 DOI: 10.47717/turkjsurg.2024.6389] [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: 03/22/2024] [Accepted: 08/29/2024] [Indexed: 02/09/2025]
Abstract
Objectives Gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal tumors in the gastrointestinal system, occurring frequently after epithelial tumors. Although rare, secondary epithelial malignancies can be associated with GISTs. It was planned to conduct a retrospective cohort study evaluating the coexistence of GISTs with malignancies and their long-term outcomes through clinical and pathological findings. Material and Methods Demographic and clinicopathological data of 69 patients who underwent surgery for GIST between January 2011 and November 2021 were retrieved from the patient database. Variables between the groups with only GIST and those with a secondary malignancy alongside GIST were analyzed using the Chi-square test and Mann-Whitney U test. Long-term survival analyses were conducted using the Kaplan-Meier test. A p-value of <0.05 was considered statistically significant. Results Out of the 69 patients in our population, 40 (58%) were male, and the median age was 65 years (interquartile range= 56-75). GIST was the most commonly located in the stomach (59.4%), and nine (13%) patients had a secondary malignancy. Tumor size, smooth muscle antibody (SMA), and S100 antibody expression showed significant differences between the groups (p <0.001, p= 0.015, p= 0.006). Shorter survival was observed in patients with GIST plus secondary malignancy (p= 0.005). Conclusion The incidence of other intraabdominal malignancies occurring alongside GISTs is more common than have been previously thought. While the presence of a secondary malignancy does not impact the overall survival (OS) in GISTs, it was observed that survival is dependent on the primary malignancy. Patients diagnosed with GISTs require thorough investigation and close monitoring for secondary malignancies.
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Affiliation(s)
- Yavuz Selim Angın
- Department of General Surgery, İnönü University Faculty of Medicine, Malatya, Türkiye
| | - Cengiz Ceylan
- Department of General Surgery, İnönü University Faculty of Medicine, Malatya, Türkiye
| | - Kutay Sağlam
- Department of General Surgery, İnönü University Faculty of Medicine, Malatya, Türkiye
| | - Cemalettin Aydın
- Department of General Surgery, İnönü University Faculty of Medicine, Malatya, Türkiye
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Lajara S, Jo VY. Soft Tissue Fine-Needle Aspiration: Current and Future Impact on Patient Care. Surg Pathol Clin 2024; 17:483-507. [PMID: 39129144 DOI: 10.1016/j.path.2024.04.009] [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] [Indexed: 08/13/2024]
Abstract
Soft tissue neoplasms pose many diagnostic challenges on fine-needle aspiration (FNA), owing largely to their rarity, large number of entities, and histologic diversity. Advances in ancillary testing now allow detection of the characteristic immunophenotypes and molecular alterations for many neoplasms and include reliable surrogate immunohistochemical markers for underlying molecular events that are highly efficient in small biopsies. A morphology-based framework is recommended to guide appropriate differentials and judicious selection of ancillary tests for small biopsies. The accurate diagnosis of soft tissue tumors is crucial for patient management and prognostication, with many potential implications in this era of precision medicine.
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Affiliation(s)
- Sigfred Lajara
- Department of Pathology, UPMC Shadyside Hospital, Cancer Pavilion, Suite 201, 5150 Centre Avenue, Pittsburgh, PA 15232, USA
| | - Vickie Y Jo
- Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
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7
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Boroojerdi S, Weidemann S, Menz A, Lennartz M, Dwertmann Rico S, Schlichter R, Kind S, Reiswich V, Viehweger F, Bawahab AA, Höflmeyer D, Fraune C, Gorbokon N, Luebke AM, Hube-Magg C, Büscheck F, Krech T, Hinsch A, Jacobsen F, Burandt E, Sauter G, Simon R, Kluth M, Steurer S, Minner S, Marx AH, Bernreuther C, Clauditz TS, Dum D, Lebok P. Staining pattern of specific and cross-reacting Melan-A antibodies: A comparative study on 15,840 samples from 133 human tumor types. APMIS 2024; 132:479-491. [PMID: 38757248 DOI: 10.1111/apm.13408] [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: 02/13/2023] [Accepted: 03/12/2024] [Indexed: 05/18/2024]
Abstract
The Melan-A (melanocyte antigen) protein, also termed 'melanoma antigen recognized by T cells 1' (MART-1) is a protein with unknown function whose expression is specific for the melanocyte lineage. Antibodies against Melan-A are thus used for identifying melanocytic tumors, but some Melan-A antibodies show an additional - diagnostically useful - cross-reactivity against an unspecified protein involved in corticosteroid hormone synthesis. To comprehensively compare the staining patterns of a specific and a cross-reactive Melan-A antibody in normal and neoplastic tissues, tissue microarrays containing 15,840 samples from 133 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry. For the Melan-A-specific antibody 'Melan-A specific' (MSVA-900M), Melan-A positivity was seen in 96.0% of 25 benign nevi, 93.0% of 40 primary and 86.7% of 75 metastatic melanomas, 82.4% of 85 renal angiomyolipomas as well as 96.4% of 84 neurofibromas, 2.2% of 46 granular cell tumors, 1.0% of 104 schwannomas, and 1.1% of 87 leiomyosarcomas. The cross-reactive antibody 'Melan-A+' (MSVA-901M+) stained 98.1% of the tumors stained by 'Melan-A specific'. In addition, high positivity rates were seen in sex-cord-stroma tumors of the ovary (35.3%-100%) and the testis (86.7%) as well as for adrenocortical neoplasms (76.3%-83.0%). Only nine further tumor groups showed Melan-A+ staining, including five different categories of urothelial carcinomas. Our data provide a comprehensive overview on the staining patterns of specific and cross-reactive Melan-A antibodies. The data demonstrate that both antibodies are highly useful for their specific purpose. It is important for pathologists to distinguish these two Melan-A antibody subtypes for their daily work.
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Affiliation(s)
- Shiva Boroojerdi
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anne Menz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Ria Schlichter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Simon Kind
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Viktor Reiswich
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florian Viehweger
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ahmed Abdulwahab Bawahab
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Pathology, Faculty of Medicine, University of Jeddah, Jeddah, Saudi Arabia
| | - Doris Höflmeyer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas M Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas H Marx
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David Dum
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
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Schreiber R, Ousingsawat J, Kunzelmann K. The anoctamins: Structure and function. Cell Calcium 2024; 120:102885. [PMID: 38642428 DOI: 10.1016/j.ceca.2024.102885] [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: 02/21/2024] [Revised: 04/03/2024] [Accepted: 04/04/2024] [Indexed: 04/22/2024]
Abstract
When activated by increase in intracellular Ca2+, anoctamins (TMEM16 proteins) operate as phospholipid scramblases and as ion channels. Anoctamin 1 (ANO1) is the Ca2+-activated epithelial anion-selective channel that is coexpressed together with the abundant scramblase ANO6 and additional intracellular anoctamins. In salivary and pancreatic glands, ANO1 is tightly packed in the apical membrane and secretes Cl-. Epithelia of airways and gut use cystic fibrosis transmembrane conductance regulator (CFTR) as an apical Cl- exit pathway while ANO1 supports Cl- secretion mainly by facilitating activation of luminal CFTR and basolateral K+ channels. Under healthy conditions ANO1 modulates intracellular Ca2+ signals by tethering the endoplasmic reticulum, and except of glands its direct secretory contribution as Cl- channel might be small, compared to CFTR. In the kidneys ANO1 supports proximal tubular acid secretion and protein reabsorption and probably helps to excrete HCO3-in the collecting duct epithelium. However, under pathological conditions as in polycystic kidney disease, ANO1 is strongly upregulated and may cause enhanced proliferation and cyst growth. Under pathological condition, ANO1 and ANO6 are upregulated and operate as secretory channel/phospholipid scramblases, partly by supporting Ca2+-dependent processes. Much less is known about the role of other epithelial anoctamins whose potential functions are discussed in this review.
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Affiliation(s)
- Rainer Schreiber
- Physiological Institute, University of Regensburg, University street 31, D-93053 Regensburg, Germany
| | - Jiraporn Ousingsawat
- Physiological Institute, University of Regensburg, University street 31, D-93053 Regensburg, Germany
| | - Karl Kunzelmann
- Physiological Institute, University of Regensburg, University street 31, D-93053 Regensburg, Germany.
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Park SH, Lee Y, Jeon H, Park J, Kim J, Kang M, Namkung W. Anticancer Effect of Hemin through ANO1 Inhibition in Human Prostate Cancer Cells. Int J Mol Sci 2024; 25:6032. [PMID: 38892219 PMCID: PMC11172662 DOI: 10.3390/ijms25116032] [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: 04/15/2024] [Revised: 05/25/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
Anoctamin1 (ANO1), a calcium-activated chloride channel, is overexpressed in a variety of cancer cells, including prostate cancer, and is involved in cancer cell proliferation, migration, and invasion. Inhibition of ANO1 in these cancer cells exhibits anticancer effects. In this study, we conducted a screening to identify novel ANO1 inhibitors with anticancer effects using PC-3 human prostate carcinoma cells. Screening of 2978 approved and investigational drugs revealed that hemin is a novel ANO1 inhibitor with an IC50 value of 0.45 μM. Notably, hemin had no significant effect on intracellular calcium signaling and cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic AMP (cAMP)-regulated chloride channel, and it showed a weak inhibitory effect on ANO2 at 3 μM, a concentration that completely inhibits ANO1. Interestingly, hemin also significantly decreased ANO1 protein levels and strongly inhibited the cell proliferation and migration of PC-3 cells in an ANO1-dependent manner. Furthermore, it strongly induced caspase-3 activation, PARP degradation, and apoptosis in PC-3 cells. These findings suggest that hemin possesses anticancer properties via ANO1 inhibition and could be considered for development as a novel treatment for prostate cancer.
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Affiliation(s)
- So-Hyeon Park
- College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea; (S.-H.P.); (Y.L.); (H.J.); (J.P.)
| | - Yechan Lee
- College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea; (S.-H.P.); (Y.L.); (H.J.); (J.P.)
| | - Hyejin Jeon
- College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea; (S.-H.P.); (Y.L.); (H.J.); (J.P.)
| | - Junghwan Park
- College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea; (S.-H.P.); (Y.L.); (H.J.); (J.P.)
| | - Jieun Kim
- Graduate Program of Industrial Pharmaceutical Science, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea; (J.K.); (M.K.)
| | - Mincheol Kang
- Graduate Program of Industrial Pharmaceutical Science, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea; (J.K.); (M.K.)
| | - Wan Namkung
- College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea; (S.-H.P.); (Y.L.); (H.J.); (J.P.)
- Graduate Program of Industrial Pharmaceutical Science, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea; (J.K.); (M.K.)
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10
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Jayant D, Goyal M, Thakur V, Sahu S, Babu B, Subbiah Nagaraj S, Tandup C, Behera A. Advanced and Metastatic Gastrointestinal Stromal Tumors Presenting With Surgical Emergencies Managed With Surgical Resection: A Case Series. Cureus 2024; 16:e53851. [PMID: 38465042 PMCID: PMC10924631 DOI: 10.7759/cureus.53851] [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] [Accepted: 02/03/2024] [Indexed: 03/12/2024] Open
Abstract
Advanced and metastatic gastrointestinal stromal tumors (GISTs) presenting with surgical emergencies are rare. Neoadjuvant imatinib being the treatment of choice for non-metastatic advanced disease with a proven role in downstaging the disease may not be feasible in patients presenting with bleeding and obstruction. We present a case series with retrospective analysis of a prospectively maintained database of patients with advanced and metastatic GISTs presenting with surgical emergencies. Clinical characteristics, imaging and endoscopic findings, surgical procedures, histological findings, and outcomes in these patients were studied. Four patients were included in this case series, with three males and one female (age range: 24-60 years). Two patients presented with melena; one with hemodynamic instability despite multiple blood transfusions underwent urgent exploratory laparotomy for bleeding gastric GIST, while the other underwent surgical exploration after careful evaluation given the recurrent, metastatic disease with a stable metabolic response on six months of imatinib. One patient with metastatic jejunal GIST who presented with an umbilical nodule and intestinal obstruction was given a trial of non-operative management for 72 hours, but due to non-resolution of obstruction, segmental jejunal en bloc resection with the dome of the urinary bladder with reconstruction and metastasectomy was needed. The patient with advanced gastric GIST who presented with gastric outlet obstruction was resuscitated, and an attempt of endoscopic naso-jejunal tube placement was tried, which failed, and exploration was needed. The mean length of hospital stay was 7.5 days. Histopathological examination confirmed GIST in all four patients with microscopic negative resection margins. All patients were started on imatinib with dose escalation to 800 mg in the patient with recurrent and metastatic disease; however, the patient with bleeding gastric GIST experienced severe adverse effects of imatinib and discontinued the drug shortly. All four patients are disease-free on follow-ups of 15 months, 48 months for the patient with advanced non-metastatic disease, and six and 24 months for the patients with metastatic disease. In the era of tyrosine kinase inhibitor (TKI) therapy for advanced and metastatic disease, upfront surgery is usually reserved for surgical emergencies only. Surgical resection, the cornerstone for the treatment of resectable GIST, may also be clinically relevant in metastatic settings, although it requires a careful and individualized approach.
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Affiliation(s)
- Divij Jayant
- General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, IND
| | - Mrinal Goyal
- General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, IND
| | - Vipul Thakur
- General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, IND
| | - Swapnesh Sahu
- General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, IND
| | - Basil Babu
- General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, IND
| | - Satish Subbiah Nagaraj
- General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, IND
| | - Cherring Tandup
- General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, IND
| | - Arunanshu Behera
- General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, IND
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11
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Schroder PM, Biesterveld BE, Al-Adra DP. Premalignant Lesions in the Kidney Transplant Candidate. Semin Nephrol 2024; 44:151495. [PMID: 38490902 DOI: 10.1016/j.semnephrol.2024.151495] [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] [Indexed: 03/17/2024]
Abstract
End-stage kidney disease patients who are referred for transplant undergo an extensive evaluation process to ensure their health prior to transplant due in part to the shortage of available organs. Although management and surveillance guidelines exist for malignancies identified in the transplant and waitlist populations, less is written about the management of premalignant lesions in this population. This review covers the less common premalignant lesions (intraductal papillary mucinous neoplasm, gastrointestinal stromal tumor, thymoma, and pancreatic neuroendocrine tumor) that can be found in the transplant candidate population. High-level evidence for the management of these rarer premalignant lesions in the transplant population is lacking, and this review extrapolates evidence from the general population and should not be a substitute for a multidisciplinary discussion with medical and surgical oncologists.
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Affiliation(s)
- Paul M Schroder
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Ben E Biesterveld
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - David P Al-Adra
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI.
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12
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Arreola J, Pérez-Cornejo P, Segura-Covarrubias G, Corral-Fernández N, León-Aparicio D, Guzmán-Hernández ML. Function and Regulation of the Calcium-Activated Chloride Channel Anoctamin 1 (TMEM16A). Handb Exp Pharmacol 2024; 283:101-151. [PMID: 35768554 DOI: 10.1007/164_2022_592] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Various human tissues express the calcium-activated chloride channel Anoctamin 1 (ANO1), also known as TMEM16A. ANO1 allows the passive chloride flux that controls different physiological functions ranging from muscle contraction, fluid and hormone secretion, gastrointestinal motility, and electrical excitability. Overexpression of ANO1 is associated with pathological conditions such as hypertension and cancer. The molecular cloning of ANO1 has led to a surge in structural, functional, and physiological studies of the channel in several tissues. ANO1 is a homodimer channel harboring two pores - one in each monomer - that work independently. Each pore is activated by voltage-dependent binding of two intracellular calcium ions to a high-affinity-binding site. In addition, the binding of phosphatidylinositol 4,5-bisphosphate to sites scattered throughout the cytosolic side of the protein aids the calcium activation process. Furthermore, many pharmacological studies have established ANO1 as a target of promising compounds that could treat several illnesses. This chapter describes our current understanding of the physiological roles of ANO1 and its regulation under physiological conditions as well as new pharmacological compounds with potential therapeutic applications.
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Affiliation(s)
- Jorge Arreola
- Physics Institute, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico.
| | - Patricia Pérez-Cornejo
- Department of Physiology and Biophysics, School of Medicine of Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | - Guadalupe Segura-Covarrubias
- Physics Institute, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
- Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA
| | - Nancy Corral-Fernández
- Department of Physiology and Biophysics, School of Medicine of Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | - Daniel León-Aparicio
- Physics Institute, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
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13
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Sanders KM, Drumm BT, Cobine CA, Baker SA. Ca 2+ dynamics in interstitial cells: foundational mechanisms for the motor patterns in the gastrointestinal tract. Physiol Rev 2024; 104:329-398. [PMID: 37561138 PMCID: PMC11281822 DOI: 10.1152/physrev.00036.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 06/29/2023] [Accepted: 08/06/2023] [Indexed: 08/11/2023] Open
Abstract
The gastrointestinal (GI) tract displays multiple motor patterns that move nutrients and wastes through the body. Smooth muscle cells (SMCs) provide the forces necessary for GI motility, but interstitial cells, electrically coupled to SMCs, tune SMC excitability, transduce inputs from enteric motor neurons, and generate pacemaker activity that underlies major motor patterns, such as peristalsis and segmentation. The interstitial cells regulating SMCs are interstitial cells of Cajal (ICC) and PDGF receptor (PDGFR)α+ cells. Together these cells form the SIP syncytium. ICC and PDGFRα+ cells express signature Ca2+-dependent conductances: ICC express Ca2+-activated Cl- channels, encoded by Ano1, that generate inward current, and PDGFRα+ cells express Ca2+-activated K+ channels, encoded by Kcnn3, that generate outward current. The open probabilities of interstitial cell conductances are controlled by Ca2+ release from the endoplasmic reticulum. The resulting Ca2+ transients occur spontaneously in a stochastic manner. Ca2+ transients in ICC induce spontaneous transient inward currents and spontaneous transient depolarizations (STDs). Neurotransmission increases or decreases Ca2+ transients, and the resulting depolarizing or hyperpolarizing responses conduct to other cells in the SIP syncytium. In pacemaker ICC, STDs activate voltage-dependent Ca2+ influx, which initiates a cluster of Ca2+ transients and sustains activation of ANO1 channels and depolarization during slow waves. Regulation of GI motility has traditionally been described as neurogenic and myogenic. Recent advances in understanding Ca2+ handling mechanisms in interstitial cells and how these mechanisms influence motor patterns of the GI tract suggest that the term "myogenic" should be replaced by the term "SIPgenic," as this review discusses.
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Affiliation(s)
- Kenton M Sanders
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada-Reno, Reno, Nevada, United States
| | - Bernard T Drumm
- Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Ireland
| | - Caroline A Cobine
- Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Ireland
| | - Salah A Baker
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada-Reno, Reno, Nevada, United States
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14
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Wang X, Hao A, Song G, Elena V, Sun Y, Zhang H, Zhan Y, An H, Chen Y. Inhibitory effect of daidzein on the calcium-activated chloride channel TMEM16A and its anti-lung adenocarcinoma activity. Int J Biol Macromol 2023; 253:127261. [PMID: 37802433 DOI: 10.1016/j.ijbiomac.2023.127261] [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: 07/19/2023] [Revised: 09/19/2023] [Accepted: 10/03/2023] [Indexed: 10/10/2023]
Abstract
TMEM16A is highly expressed in a variety of tumor cells and is involved in the growth and metastasis of malignancies. It has been established that down-regulation of TMEM16A expression or functional activity can inhibit tumor cells growth. However, there is a lack of targeted inhibitors with high efficiency and low toxicity. Here, we identified a novel inhibitor daidzein from dozens of natural product molecules. Whole-cell patch clamp data indicated that daidzein inhibits TMEM16A channel in a dose-dependent manner, with IC50 of 1.39 ± 0.59 μM. Western blot result showed that daidzein can also reduce the expression of TMEM16A protein in LA795 cells. These results indicated that the inhibitory effects of daidzein exert on TMEM16A in two ways, both inhibiting TMEM16A current and decreasing its protein expression. In addition, the putative binding sites of daidzein on TMEM16A are G608, G628, and K839 through molecular docking. Moreover, daidzein concentration-dependently reduced cell viability and cell migration, causing G1/S cell cycle arrest in vitro. It was also confirmed that daidzein can effectively inhibit the growth of LA795 lung adenocarcinoma cells implanted nude mice in vivo. In conclusion, daidzein can be used as a lead compound for the development of therapeutic drugs for lung adenocarcinoma.
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Affiliation(s)
- Xuzhao Wang
- Hebei Provincial Key Laboratory of Molecular Biophysics, Hebei University of Technology, Tianjin 300401, China; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China; State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300401, China; School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300401, China; School of Electrical Engineering, Hebei University of Technology, Tianjin 300401, China
| | - Anqi Hao
- Hebei Provincial Key Laboratory of Molecular Biophysics, Hebei University of Technology, Tianjin 300401, China; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China
| | - Guoqiang Song
- Hebei Provincial Key Laboratory of Molecular Biophysics, Hebei University of Technology, Tianjin 300401, China; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China
| | - Vorobeva Elena
- Hebei Provincial Key Laboratory of Molecular Biophysics, Hebei University of Technology, Tianjin 300401, China; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China
| | - Yiming Sun
- Hebei Provincial Key Laboratory of Molecular Biophysics, Hebei University of Technology, Tianjin 300401, China; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China
| | - Hailin Zhang
- College of Pharmacy, Hebei Medical University, Shijiazhuang 050017, Hebei, China
| | - Yong Zhan
- Hebei Provincial Key Laboratory of Molecular Biophysics, Hebei University of Technology, Tianjin 300401, China; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China; State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300401, China; School of Electrical Engineering, Hebei University of Technology, Tianjin 300401, China
| | - Hailong An
- Hebei Provincial Key Laboratory of Molecular Biophysics, Hebei University of Technology, Tianjin 300401, China; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China; State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300401, China; School of Electrical Engineering, Hebei University of Technology, Tianjin 300401, China
| | - Yafei Chen
- Hebei Provincial Key Laboratory of Molecular Biophysics, Hebei University of Technology, Tianjin 300401, China; Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China; State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin 300401, China; School of Electrical Engineering, Hebei University of Technology, Tianjin 300401, China.
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15
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Li S, Wang Z, Geng R, Zhang W, Wan H, Kang X, Guo S. TMEM16A ion channel: A novel target for cancer treatment. Life Sci 2023; 331:122034. [PMID: 37611692 DOI: 10.1016/j.lfs.2023.122034] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/13/2023] [Accepted: 08/18/2023] [Indexed: 08/25/2023]
Abstract
Cancer draws attention owing to the high morbidity and mortality. It is urgent to develop safe and effective cancer therapeutics. The calcium-activated chloride channel TMEM16A is widely distributed in various tissues and regulates physiological functions. TMEM16A is abnormally expressed in several cancers and associate with tumorigenesis, metastasis, and prognosis. Knockdown or inhibition of TMEM16A in cancer cells significantly inhibits cancer development. Therefore, TMEM16A is considered as a biomarker and therapeutic target for some cancers. This work reviews the cancers associated with TMEM16A. Then, the molecular mechanism of TMEM16A overexpression in cancer was analyzed, and the possible signal transduction mechanism of TMEM16A regulating cancer development was summarized. Finally, TMEM16A inhibitors with anticancer effect and their anticancer mechanism were concluded. We hope to provide new ideas for pharmacological studies on TMEM16A in cancer.
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Affiliation(s)
- Shuting Li
- School of Life Sciences, Hebei University, Baoding 071002, Hebei, China
| | - Zhichen Wang
- School of Life Sciences, Hebei University, Baoding 071002, Hebei, China
| | - Ruili Geng
- School of Life Sciences, Hebei University, Baoding 071002, Hebei, China
| | - Weiwei Zhang
- School of Basic Medical Sciences, Hebei University, Baoding 071002, Hebei, China
| | - Haifu Wan
- School of Life Sciences, Hebei University, Baoding 071002, Hebei, China; Institute of Life Sciences and Green Development, Hebei University, Baoding 071002, Hebei, China
| | - Xianjiang Kang
- School of Life Sciences, Hebei University, Baoding 071002, Hebei, China; Institute of Life Sciences and Green Development, Hebei University, Baoding 071002, Hebei, China.
| | - Shuai Guo
- School of Life Sciences, Hebei University, Baoding 071002, Hebei, China; Institute of Life Sciences and Green Development, Hebei University, Baoding 071002, Hebei, China.
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16
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Nagano H, Ohyama S, Sato A, Igarashi J, Yamamoto T, Kadoya M, Kobayashi M. Jejunal gastrointestinal stromal tumor that developed in a patient with neurofibromatosis type 1: a case report. Diagn Pathol 2023; 18:110. [PMID: 37789344 PMCID: PMC10546696 DOI: 10.1186/s13000-023-01398-6] [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: 08/14/2023] [Accepted: 09/28/2023] [Indexed: 10/05/2023] Open
Abstract
BACKGROUND Neurofibromatosis type 1 (NF1) is known to be associated with the frequent occurrence of unique gastrointestinal stromal tumors (GISTs), preferably occurring in the small intestine, with no mutations in the c-kit proto-oncogene or platelet-derived growth factor receptor-alpha (PDGFRA), with a high tendency for multifocal development, indolent nature, with low proliferation activity and favorable prognosis. CASE PRESENTATION A woman in her forties visited her local doctor complaining of menstrual pain; a large mass was detected in her lower abdomen, and she was referred to our hospital. The patient had hundreds of skin warts and café au lait spots. The patient's mother had been diagnosed with type 1 neurofibromatosis. The patient met the diagnostic criteria for NF1 and was diagnosed with NF1. Ultrasonography showed a large heterogeneous cystic mass with various echo patterns, solid compartments and multiple septations. Magnetic resonance imaging showed a multilocular cystic mass with liquid content exhibiting various intensities, including that of blood. A small round solid mass was also observed close to the cystic tumor. Contrast-enhanced computed tomography showed that the round solid mass showed strong enhancement in the early phase, unlike the cystic tumor component. Open laparotomy revealed a multicystic exophytic tumor measuring 11.5 cm originating from the jejunal wall, 20 cm distal to the duodenojejunal flexure. A solid tumor measuring 2.1 cm was also found on the anal side of the large tumor. We resected the short segment of the jejunum, including the two lesions. Microscopic findings revealed that the cystic and solid tumors consisted of spindle-shaped tumor cells showing little atypia with a fascicular or bundle arrangement. Nuclear mitosis was scarce. Immunostaining of the tumor cells showed positive staining for KIT and DOG1 and negative staining for S100 and desmin. The NF1 patient was diagnosed with multiple GISTs accompanied by intratumoral hemorrhagic denaturation arising from the jejunum. The TNM staging was pT4N0M0, stage IIIA. CONCLUSION We report a case of GISTs associated with NF1 that showed a jejunal origin, multifocal development and few mitotic figures. The recurrence risk, survival prognosis and need for adjuvant chemotherapy, particularly in cases where the initial GIST exhibits a very indolent pathology in NF1-related GISTs, remain to be elucidated.
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Affiliation(s)
- Hideki Nagano
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan.
| | - Shigekazu Ohyama
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Atsushi Sato
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Jun Igarashi
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Tomoko Yamamoto
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Masumi Kadoya
- Department of Radiology, Marunouchi Hospital, Matsumoto Nagano, Japan
| | - Mikiko Kobayashi
- Department of Pathology, Marunouchi Hospital, Matsumoto Nagano, Japan
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17
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Marando A, Di Blasi E, Tucci F, Aquilano MC, Bonoldi E. DOG1 expression in neuroendocrine neoplasms: Potential applications and diagnostic pitfalls. Pathol Res Pract 2023; 248:154623. [PMID: 37331184 DOI: 10.1016/j.prp.2023.154623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 06/20/2023]
Abstract
Neuroendocrine neoplasms represent a heterogeneous group of rare tumors, more frequently arising from gastroenteropancreatic tract and lungs. At the time of diagnosis, 20% of cases are metastatic, and 10% of cases are considered as cancer of unknown primary origin. Several immunohistochemical markers are routinely used to confirm the neuroendocrine differentiation, first among all Synaptophysin and Chromogranin-A; on the other hand, different immunohistochemical markers are used to establish primary anatomical site, as TTF1, CDX2, Islet-1 and Calcitonin, but no marker is available in order to distinguish among different sites of the digestive tract. DOG1 (discovered on GIST-1) is a gene normally expressed in interstitial cells of Cajal and, in routine practice, DOG1 immunostaining is used in diagnosis of GIST (gastrointestinal stromal tumor). DOG1 expression has been described in several neoplasms other than GIST, both in mesenchymal and epithelial neoplasms. In the present study, DOG1 immunostaining has been performed in a large cohort of neuroendocrine neoplasms, including neuroendocrine tumors and neuroendocrine carcinomas, in order to evaluate frequency, intensity and pattern of expression in different anatomical site and in different tumor grade. DOG1 expression was detected in a large percentage of neuroendocrine tumors, with statistically significant association between DOG1 expression and gastrointestinal tract neuroendocrine tumors. As a consequence, DOG1 could be included in marker panel for the identification of primary site in neuroendocrine metastases of unknown primary origin; moreover, these results recommend careful evaluation of DOG1 expression in gastrointestinal neoplasms, in particular in differential diagnosis between epithelioid GIST and neuroendocrine tumors.
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Affiliation(s)
- A Marando
- Department of Surgical Pathology, Niguarda Hospital, Milano, Italy.
| | - E Di Blasi
- School of Pathology, University of Milan, Milan, Italy
| | - F Tucci
- School of Pathology, University of Milan, Milan, Italy
| | - M C Aquilano
- Department of Surgical Pathology, Niguarda Hospital, Milano, Italy
| | - E Bonoldi
- Department of Surgical Pathology, Niguarda Hospital, Milano, Italy
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18
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Boșoteanu M, Cristian M, Așchie M, Baz RA, Zielonka AM, Cozaru GC, Boșoteanu LA. The Malignant Gastrointestinal Neuroectodermal Tumor (GNET): A Distinct Entity and the Challenging Differential Diagnosis with Mesenchymal, Lymphoid, and Melanic Tumors: A Case Report and Brief Review of the Literature. Diagnostics (Basel) 2023; 13:diagnostics13061131. [PMID: 36980439 PMCID: PMC10047330 DOI: 10.3390/diagnostics13061131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/12/2023] [Accepted: 03/13/2023] [Indexed: 03/19/2023] Open
Abstract
(1) Background: A malignant gastrointestinal neuroectodermal tumor (GNET) is an ultra-rare primary neoplasm with a distinctive histopathological, immunohistochemical, molecular, and ultramicroscopic profile, synonymous terminology with clear cell sarcoma-like tumor of the gastrointestinal tract. This case report aims to describe a case of GNET with challenging mesenchymal, lymphoid, and melanic tumor differential diagnosis. (2) Case presentation: We discuss the case of a 67-year-old male patient who presented with diffuse abdominal pain, intermittent lack of intestinal transit, and frequent episodes of nausea, followed by segmental resection of the jejunum and sigmoid colon. The patient had no relevant medical history. The surgical specimen underwent immunohistochemical staining and morphological evaluation. (3) Results: Histopathological analysis reveals a moderately homogeneous polyhedral-epithelioid and spindle cell neoplastic proliferation with a zonal discohesive pattern and extensive and focal fasciculated architecture. Twenty monoclonal antibodies were used for immunostaining, which allowed GNET to be diagnosed on the basis of the tumoral immune profile, characterized by positive reactivity of S100, SOX10, and CD 56. (4) Conclusions: The poor prognosis of GNET is highlighted in the present study, along with the vital importance of differential diagnosis issues with mesenchymal, lymphoid, and melanic tumors, which make the diagnosis difficult for both pathologists and clinicians.
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Affiliation(s)
- Mădălina Boșoteanu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania
- Department of Clinical Pathology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania
- Department of Pathology, “Ovidius” Clinical Hospital, 905900 Constanta, Romania
| | - Miruna Cristian
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania
- Department of Clinical Pathology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology—CEDMOG, “Ovidius” University of Constanta, 900591 Constanta, Romania
- Institute of Doctoral Studies, School of Medicine, “Ovidius” University of Constanta, 900573 Constanta, Romania
- Correspondence: (M.C.); (R.A.B.); Tel.: +40-735-868-090 (M.C.)
| | - Mariana Așchie
- Department of Clinical Pathology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology—CEDMOG, “Ovidius” University of Constanta, 900591 Constanta, Romania
- Academy of Medical Sciences, 030167 Bucharest, Romania
| | - Radu Andrei Baz
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania
- Department of Radiology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania
- Correspondence: (M.C.); (R.A.B.); Tel.: +40-735-868-090 (M.C.)
| | | | - Georgeta Camelia Cozaru
- Department of Clinical Pathology, “Sf. Apostol Andrei” Emergency County Hospital, 900591 Constanta, Romania
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology—CEDMOG, “Ovidius” University of Constanta, 900591 Constanta, Romania
| | - Luana Andreea Boșoteanu
- Institute of Doctoral Studies, School of Medicine, “Ovidius” University of Constanta, 900573 Constanta, Romania
- Dermatology Department, “Elias” Emergency University Hospital, 011461 Bucharest, Romania
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19
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Hamed H, Wahab MA, Elmahdy Y, El-Wahab RMA, El-Magd ESA. Gastrointestinal stromal tumors of the small intestine: the challenge of diagnosis and the outcome of management. World J Surg Oncol 2023; 21:85. [PMID: 36894972 PMCID: PMC9996990 DOI: 10.1186/s12957-023-02968-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
PURPOSES Gastrointestinal stromal tumor (GIST) is a rare small intestinal tumor. Most patients usually report long-period complaints due to difficult diagnoses. A high grade of suspicion is required for early diagnosis and initiation of the proper management. METHODS A retrospective study of all patients with small intestinal GIST who were operated in the period between January 2008 and May 2021 at Mansoura University Gastrointestinal Surgical Center (GIST). RESULTS Thirty-four patients were included in the study with a mean age of 58.15 years (± 12.65) with a male to female ratio of 1.3:1. The mean duration between onset of symptoms and diagnosis was 4.62 years (± 2.34). Diagnosis of a small intestinal lesion was accomplished through abdominal computed tomography (CT) in 19 patients (55.9%). The mean size of the tumor was 8.76 cm (± 7.76) ranging from 1.5 to 35 cm. The lesion was of ileal origin in 20 cases (58.8%) and jejunal in 14 cases (41.2%). During the scheduled follow-up period, tumor recurrence occurred in one patient (2.9%). No mortality was encountered. CONCLUSION Diagnosis of a small bowel GISTs requires a high grade of suspicion. Implementing new diagnostic techniques like angiography, capsule endoscopy, and enteroscopy should be encouraged when suspecting these lesions. Surgical resection is always associated with an excellent postoperative recovery profile and very low recurrence rates.
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Affiliation(s)
- Hosam Hamed
- Department of General Surgery, Faculty of Medicine, Gastrointestinal Surgical Center GISC, Mansoura University, Gehan Street, Al Dakahlia Governorate, 35511, Mansoura, Egypt
| | - Mohamed Abdel Wahab
- Department of General Surgery, Faculty of Medicine, Gastrointestinal Surgical Center GISC, Mansoura University, Gehan Street, Al Dakahlia Governorate, 35511, Mansoura, Egypt
| | - Youssif Elmahdy
- Department of General Surgery, Faculty of Medicine, Gastrointestinal Surgical Center GISC, Mansoura University, Gehan Street, Al Dakahlia Governorate, 35511, Mansoura, Egypt
| | - Rihame M Abd El-Wahab
- Department of General Surgery, Faculty of Medicine, Gastrointestinal Surgical Center GISC, Mansoura University, Gehan Street, Al Dakahlia Governorate, 35511, Mansoura, Egypt
| | - El-Sayed Abou El-Magd
- Department of General Surgery, Faculty of Medicine, Gastrointestinal Surgical Center GISC, Mansoura University, Gehan Street, Al Dakahlia Governorate, 35511, Mansoura, Egypt.
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20
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Pallio S, Crinò SF, Maida M, Sinagra E, Tripodi VF, Facciorusso A, Ofosu A, Conti Bellocchi MC, Shahini E, Melita G. Endoscopic Ultrasound Advanced Techniques for Diagnosis of Gastrointestinal Stromal Tumours. Cancers (Basel) 2023; 15:1285. [PMID: 36831627 PMCID: PMC9954263 DOI: 10.3390/cancers15041285] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/08/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023] Open
Abstract
Gastrointestinal Stromal Tumors (GISTs) are subepithelial lesions (SELs) that commonly develop in the gastrointestinal tract. GISTs, unlike other SELs, can exhibit malignant behavior, so differential diagnosis is critical to the decision-making process. Endoscopic ultrasound (EUS) is considered the most accurate imaging method for diagnosing and differentiating SELs in the gastrointestinal tract by assessing the lesions precisely and evaluating their malignant risk. Due to their overlapping imaging characteristics, endosonographers may have difficulty distinguishing GISTs from other SELs using conventional EUS alone, and the collection of tissue samples from these lesions may be technically challenging. Even though it appears to be less effective in the case of smaller lesions, histology is now the gold standard for achieving a final diagnosis and avoiding unnecessary and invasive treatment for benign SELs. The use of enhanced EUS modalities and elastography has improved the diagnostic ability of EUS. Furthermore, recent advancements in artificial intelligence systems that use EUS images have allowed them to distinguish GISTs from other SELs, thereby improving their diagnostic accuracy.
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Affiliation(s)
- Socrate Pallio
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy
| | | | - Marcello Maida
- Gastroenterology and Endoscopy Unit, S. Elia-Raimondi Hospital, 93100 Caltanissetta, Italy
| | - Emanuele Sinagra
- Gastroenterology and Endoscopy Unit, Fondazione Istituto San Raffaele Giglio, 90015 Cefalù, Italy
| | | | - Antonio Facciorusso
- Gastroenterology Unit, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy
| | - Andrew Ofosu
- Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH 45201, USA
| | | | - Endrit Shahini
- Gastroenterology Unit, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Castellana Grotte, 70013 Castellana Grotte, Italy
| | - Giuseppinella Melita
- Human Pathology of Adult and Child Department, University of Messina, 98100 Messina, Italy
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21
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Hornick JL, Webster F, Dei Tos AP, Hemmings C, Miettinen M, Oda Y, Raut CP, Rubin BP, Von Mehren M, Wardelmann E, Fletcher CDM. Dataset for reporting of gastrointestinal stromal tumours: recommendations from the International Collaboration on Cancer Reporting (ICCR). Histopathology 2023; 82:376-384. [PMID: 36073677 DOI: 10.1111/his.14791] [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: 07/17/2022] [Revised: 09/04/2022] [Accepted: 09/05/2022] [Indexed: 01/20/2023]
Abstract
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract and are among the most frequent sarcomas. Accurate diagnosis, classification, and reporting are critical for prognostication and patient management, including selection of appropriate targeted therapy. Here we report on international consensus-based datasets for the pathology reporting of biopsy and resection specimens of GIST. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major international pathology and cancer organizations. An international expert panel consisting of pathologists, a surgical oncologist, and a medical oncologist produced a set of core and noncore data items for biopsy and resection specimens based on a critical review and discussion of current evidence. All professionals involved were subspecialized soft tissue tumour experts and affiliated with tertiary referral centres. Commentary was provided for each data item to explain its clinical relevance and the rationale for selection as a core or noncore element. Following international public consultation, the datasets, which include synoptic reporting guides, were finalized and ratified, and published on the ICCR website. These first international datasets for GIST are intended to promote high-quality, standardised pathology reporting. Their widespread adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will ultimately help to improve the management of patients with GIST. All the ICCR datasets, including these on GIST, are freely available worldwide on the ICCR website (www.iccr-cancer.org/datasets).
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Affiliation(s)
- Jason L Hornick
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Fleur Webster
- International Collaboration on Cancer Reporting, Sydney, NSW, Australia
| | - Angelo Paolo Dei Tos
- Department of Pathology, Azienda Ospedaliera Universitaria di Padova, Padova, Italy.,Department of Medicine, University of Padua School of Medicine, Padua, Italy
| | - Chris Hemmings
- Department of Anatomic Pathology, Canterbury Health Laboratories, Christchurch, New Zealand.,Department of Pathology and Biomedical Science, Christchurch Clinical School, University of Otago School of Medicine, Christchurch, New Zealand
| | - Markku Miettinen
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, Bethesda, MD, USA
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Chandrajit P Raut
- Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.,Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Brian P Rubin
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Margaret Von Mehren
- Department of Hematology and Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Eva Wardelmann
- Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany
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22
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Bernareggi A, Zangari M, Constanti A, Zacchi P, Borelli V, Mangogna A, Lorenzon P, Zabucchi G. Asbestos Fibers Enhance the TMEM16A Channel Activity in Xenopus Oocytes. MEMBRANES 2023; 13:180. [PMID: 36837683 PMCID: PMC9960392 DOI: 10.3390/membranes13020180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/24/2023] [Accepted: 01/27/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND The interaction of asbestos fibers with target cell membranes is still poorly investigated. Here, we detected and characterized an enhancement of chloride conductance in Xenopus oocyte cell membranes induced by exposure to crocidolite (Croc) asbestos fibers. METHODS A two-microelectrode voltage clamp technique was used to test the effect of Croc fiber suspensions on outward chloride currents evoked by step membrane depolarization. Calcium imaging experiments were also performed to investigate the variation of 'resting' oocyte [Ca2+]i following asbestos exposure. RESULTS The increase in chloride current after asbestos treatment, was sensitive to [Ca2+]e, and to specific blockers of TMEM16A Ca2+-activated chloride channels, MONNA and Ani9. Furthermore, asbestos treatment elevated the 'resting' [Ca2+]i likelihood by increasing the cell membrane permeability to Ca2 in favor of a tonic activation of TMEME16A channels. Western blot analysis confirmed that TMEME16A protein was endogenously present in the oocyte cell membrane and absorbed by Croc. CONCLUSION the TMEM16A channels endogenously expressed by Xenopus oocytes are targets for asbestos fibers and represent a powerful tool for asbestos-membrane interaction studies. Interestingly, TMEM16A channels are highly expressed in many types of tumors, including some asbestos-related cancers, suggesting them, for the first time, as a possible early target of crocidolite-mediated tumorigenic effects on target cell membranes.
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Affiliation(s)
- Annalisa Bernareggi
- Department of Life Sciences, University of Trieste, Via Fleming 22, 34127 Trieste, Italy
| | - Martina Zangari
- Department of Life Sciences, University of Trieste, Via Fleming 22, 34127 Trieste, Italy
| | - Andrew Constanti
- Department of Pharmacology, UCL School of Pharmacy, 29/39 Brunswick Square, London WC1N 1AX, UK
| | - Paola Zacchi
- Department of Life Sciences, University of Trieste, Via Valerio 28/1, 34127 Trieste, Italy
| | - Violetta Borelli
- Department of Life Sciences, University of Trieste, Via Valerio 28/1, 34127 Trieste, Italy
| | - Alessandro Mangogna
- Institute for Maternal and Child Health—IRCCS Burlo Garofolo, Via Dell’Istria 65/1, 34137 Trieste, Italy
| | - Paola Lorenzon
- Department of Life Sciences, University of Trieste, Via Fleming 22, 34127 Trieste, Italy
| | - Giuliano Zabucchi
- Department of Life Sciences, University of Trieste, Via Valerio 28/1, 34127 Trieste, Italy
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23
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Wu Y, Li W, Chen X, Wang H, Su S, Xu Y, Deng X, Yang T, Wei M, Li L, Liu Y, Yang J, Li W. DOG1 as a novel antibody-drug conjugate target for the treatment of multiple gastrointestinal tumors and liver metastasis. Front Immunol 2023; 14:1051506. [PMID: 36776873 PMCID: PMC9909470 DOI: 10.3389/fimmu.2023.1051506] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 01/09/2023] [Indexed: 01/27/2023] Open
Abstract
Discovered On Gastrointestinal stromal tumors protein 1 (DOG1), a major calcium-activated chloride channel, has been used as a common diagnostic marker for gastrointestinal stromal tumors. However, the therapeutic application of DOG1 was not well defined. Here, we aim to investigate its potential as a therapeutic target for an antibody-drug conjugate (ADC) in various cancers of the alimentary tract and metastasis. The DOG1 expression profile was determined among TCGA samples and tissue microarrays. High levels of DOG1 expression were ubiquitously observed in multiple cancer samples from the alimentary tract determined by TCGA samples and tissue microarrays. Circulating tumor cells isolated from metastatic colon cancer patients were also positive for DOG1 expression. The mechanisms of anti-DOG1 antibody were investigated by dual-luciferase reporter assay. The anti-DOG1 antibody could inhibit proliferation and metastasis via p53 signaling in limited cancer cell lines. The anti-DOG1 antibody was conjugated with a microtubule inhibitor DM4, to construct a new anti-DOG1-DM4-ADC to strengthen its activity. The anti-DOG1-DM4-ADC showed cytotoxicity at the nanomolar level in vitro. In the murine xenograft tumor models, treatment of anti-DOG1-DM4-ADC achieved a significant tumor growth inhibition rate. Our study indicates that anti-DOG1-DM4-ADC may be promising therapeutic molecules for DOG1-positive alimentary tract tumors and may be effective in inhibiting recurrence after curative resection of liver metastases of colorectal origin.
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Affiliation(s)
- Yangping Wu
- Targeted Tracer Research and Development Laboratory, Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Wenting Li
- State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangzheng Chen
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Haichuan Wang
- Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Siyuan Su
- Department of Chemistry, University of Illinois Chicago, Chicago, IL, United States
| | - Ying Xu
- Targeted Tracer Research and Development Laboratory, Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangbing Deng
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Tinghan Yang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Mingtian Wei
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Li Li
- Institute of Clinical Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Yixin Liu
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jinliang Yang
- State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Weimin Li, ; Jinliang Yang,
| | - Weimin Li
- Targeted Tracer Research and Development Laboratory, Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Weimin Li, ; Jinliang Yang,
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24
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Jeon D, Jo M, Lee Y, Park SH, Phan HTL, Nam JH, Namkung W. Inhibition of ANO1 by Cis- and Trans-Resveratrol and Their Anticancer Activity in Human Prostate Cancer PC-3 Cells. Int J Mol Sci 2023; 24:ijms24021186. [PMID: 36674697 PMCID: PMC9862168 DOI: 10.3390/ijms24021186] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 12/26/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Anoctamin1 (ANO1), a calcium-activated chloride channel, is involved in the proliferation, migration, and invasion of various cancer cells including head and neck squamous cell carcinoma, lung cancer, and prostate cancer. Inhibition of ANO1 activity or downregulation of ANO1 expression in these cancer cells is known to exhibit anticancer effects. Resveratrol, a natural polyphenol abundant in wines, grapes, berries, soybeans, and peanuts, shows a wide variety of biological effects including anti-inflammatory, antioxidant, and anticancer activities. In this study, we investigated the effects of two stereoisomers of resveratrol on ANO1 activity and found that cis- and trans-resveratrol inhibited ANO1 activity with different potencies. Cis- and trans-resveratrol inhibited ANO1 channel activity with IC50 values of 10.6 and 102 μM, respectively, and had no significant effect on intracellular calcium signaling at 10 and 100 μM, respectively. In addition, cis-resveratrol downregulated mRNA and protein expression levels of ANO1 more potently than trans-resveratrol in PC-3 prostate cancer cells. Cis- and trans-resveratrol significantly reduced cell proliferation and cell migration in an ANO1-dependent manner, and both resveratrol isomers strongly increased caspase-3 activity, PARP cleavage, and apoptotic sub-G1 phase ratio in PC-3 cells. These results revealed that cis-resveratrol is a potent inhibitor of ANO1 and exhibits ANO1-dependent anticancer activity against human metastatic prostate cancer PC-3 cells.
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Affiliation(s)
- Dongkyu Jeon
- College of Pharmacy and Yonsei, Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Minjae Jo
- College of Pharmacy and Yonsei, Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Yechan Lee
- College of Pharmacy and Yonsei, Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - So-Hyeon Park
- College of Pharmacy and Yonsei, Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - Hong Thi Lam Phan
- Department of Physiology, College of Medicine, Dongguk University, 123 Dongdae-ro, Gyeongju 38066, Republic of Korea
- Channelopathy Research Center (CRC), College of Medicine, Dongguk University, 32 Dongguk-ro, Ilsan Dong-gu, Goyang 10326, Republic of Korea
| | - Joo Hyun Nam
- Department of Physiology, College of Medicine, Dongguk University, 123 Dongdae-ro, Gyeongju 38066, Republic of Korea
- Channelopathy Research Center (CRC), College of Medicine, Dongguk University, 32 Dongguk-ro, Ilsan Dong-gu, Goyang 10326, Republic of Korea
| | - Wan Namkung
- College of Pharmacy and Yonsei, Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
- Correspondence:
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25
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Muacevic A, Adler JR, Vagha SJ. KIT (CD117) Positive Huge Primary Malignant Extra Gastrointestinal Stromal Tumors (EGISTs) Arising From Jejunal Mesentery: A Rare Case Report. Cureus 2022; 14:e33168. [PMID: 36742272 PMCID: PMC9891314 DOI: 10.7759/cureus.33168] [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: 07/23/2022] [Accepted: 12/31/2022] [Indexed: 01/01/2023] Open
Abstract
Tumors arising outside gastrointestinal systems are known as extra gastrointestinal stromal tumors (EGISTs). Outside gastrointestinal sites include the mesentery, omentum, peritoneum, pancreas, and liver. Our case highlights a rare occurrence of an EGIST in jejunal mesentery in a 45-year-old male with an asymptomatic large abdominal growth and weight loss. A contrast-enhanced multi-dimensional computed tomography scan showed a large heterogeneous mass in the left hypochondrium. lumbar, and paraumbilical regions. Later, the patient underwent surgical resection of the tumor along with the involved jejunal segment and small tumor masses in the mesentery. Histopathological examination reported a malignant EGIST of mesentery and invasion into the jejunum, further confirmed by immunohistochemistry (IHC) markers like CD117 and smooth muscle actin with a high proliferative index (Ki67). One should be aware that these are different from other malignancies arising from the mesentery. Their cell of origin is different and needs a specific type of treatment. The clinical history, radiological findings, histopathology, and IHC help in diagnosing especially when they are arising from unusual areas like jejunal mesentery. Surgical intervention and chemotherapy are mainstay treatments.
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26
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Hu X, Zhang Q, Wang Z, Ren H, Su P, Kou Y. Retrospective study of the clinicopathological characteristics and prognostic factors of gastrointestinal stromal tumors in Chinese patients. Ann Diagn Pathol 2022; 61:152050. [DOI: 10.1016/j.anndiagpath.2022.152050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/17/2022] [Accepted: 10/03/2022] [Indexed: 11/01/2022]
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27
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Hu X, Wang Z, Su P, Zhang Q, Kou Y. Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors. Front Oncol 2022; 12:933248. [PMID: 36147927 PMCID: PMC9485670 DOI: 10.3389/fonc.2022.933248] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 08/18/2022] [Indexed: 11/15/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. At present, surgery is the first-line treatment for primary resectable GISTs; however, the recurrence rate is high. Imatinib mesylate (IM) is an effective first-line drug used for the treatment of unresectable or metastatic recurrent GISTs. More than 80% of patients with GISTs show significantly improved 5-year survival after treatment; however, approximately 50% of patients develop drug resistance after 2 years of IM treatment. Therefore, an in-depth research is urgently needed to reveal the mechanisms of secondary resistance to IM in patients with GISTs and to develop new therapeutic targets and regimens to improve their long-term prognoses. In this review, research on the mechanisms of secondary resistance to IM conducted in the last 5 years is discussed and summarized from the aspects of abnormal energy metabolism, gene mutations, non-coding RNA, and key proteins. Studies have shown that different drug-resistance mechanism networks are closely linked and interconnected. However, the influence of these drug-resistance mechanisms has not been compared. The combined inhibition of drug-resistance mechanisms with IM therapy and the combined inhibition of multiple drug-resistance mechanisms are expected to become new therapeutic options in the treatment of GISTs. In addition, implementing individualized therapies based on the identification of resistance mechanisms will provide new adjuvant treatment options for patients with IM-resistant GISTs, thereby delaying the progression of GISTs. Previous studies provide theoretical support for solving the problems of drug-resistance mechanisms. However, most studies on drug-resistance mechanisms are still in the research stage. Further clinical studies are needed to confirm the safety and efficacy of the inhibition of drug-resistance mechanisms as a potential therapeutic target.
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Affiliation(s)
- Xiangchen Hu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhe Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Peng Su
- Medical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qiqi Zhang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Youwei Kou
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Youwei Kou,
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28
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Jansen K, Kluth M, Blessin NC, Hube-Magg C, Neipp M, Mofid H, Lárusson H, Daniels T, Isbert C, Coerper S, Ditterich D, Rupprecht H, Goetz A, Bernreuther C, Sauter G, Uhlig R, Wilczak W, Simon R, Steurer S, Burandt E, Perez D, Izbicki JR, Jacobsen F, Clauditz TS, Marx AH, Krech T. DOG1 overexpression is associated with mismatch repair deficiency and BRAF mutations but unrelated to cancer progression in colorectal cancer. Histol Histopathol 2022; 37:739-748. [PMID: 35642329 DOI: 10.14670/hh-18-475] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
INTRODUCTION The transmembrane channel protein DOG1 (Discovered on GIST1) is normally expressed in the gastrointestinal interstitial cells of Cajal and also in gastrointestinal stroma tumors arising from these cells. However, there is also evidence for a relevant role of DOG1 expression in colorectal cancers. This study was undertaken to search for associations between DOG1 expression and colon cancer phenotype and key molecular alterations. METHODS A tissue microarray containing samples from more than 1,800 colorectal cancer patients was analyzed by immunohistochemistry. RESULTS DOG1 immunostaining was detected in 503 (30.2%) of 1,666 analyzable colorectal cancers and considered weak in 360 (21.6%), moderate in 78 (4.7%), and strong in 65 (3.9%). Strong DOG1 immunostaining was associated with advanced pT stage (p=0.0367) and nodal metastases (p=0.0145) but these associations were not retained in subgroups of 1,135 mismatch repair proficient and 86 mismatch repair deficient tumors. DOG1 positivity was significantly linked to several molecular tumor features including mismatch repair deficiency (p=0.0034), BRAF mutations (p<0.0001), nuclear p53 accumulation (p=0.0157), and PD-L1 expression (p=0.0199) but unrelated to KRAS mutations and the density of tumor infiltrating CD8 positive lymphocytes. CONCLUSION Elevated DOG1 expression is frequent in colorectal cancer and significantly linked to important molecular alterations. However, DOG1 overexpression is largely unrelated to histopathological parameters of cancer aggressiveness and may thus not serve as a prognostic parameter for this tumor entity.
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Affiliation(s)
- Kristina Jansen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Niclas C Blessin
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Neipp
- General, Vascular and Visceral Surgery Clinic, Itzehoe Medical Center, Itzehoe, Germany
| | - Hamid Mofid
- General, Visceral Thoracic and Vascular Surgery Clinic, Regio Clinic Pinneberg, Pinneberg, Germany
| | - Hannes Lárusson
- General, Visceral Thoracic and Vascular Surgery Clinic, Regio Clinic Pinneberg, Pinneberg, Germany
| | - Thies Daniels
- General, Visceral and Tumor Surgery Clinic, Albertinen Hospital, Hamburg, Germany
| | - Christoph Isbert
- Department of General, Gastrointestinal and Colorectal Surgery, Amalie Sieveking Hospital, Hamburg, Germany
| | - Stephan Coerper
- Department of Surgery, General Hospital Martha-Maria Hospital Nuernberg, Nuernberg, Germany
| | - Daniel Ditterich
- Department of Surgery, General Hospital Neustadt/Aisch, Neustadt an der Aisch, Germany
| | - Holger Rupprecht
- Department of Thoracic Surgery, Academic Hospital Neumarkt, Neumarkt/Oberpfalz, Germany
| | - Albert Goetz
- Department of Surgery, General Hospital Roth, Roth, Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ria Uhlig
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Waldemar Wilczak
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Daniel Perez
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R Izbicki
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas H Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
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29
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Barkley D, Moncada R, Pour M, Liberman DA, Dryg I, Werba G, Wang W, Baron M, Rao A, Xia B, França GS, Weil A, Delair DF, Hajdu C, Lund AW, Osman I, Yanai I. Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment. Nat Genet 2022; 54:1192-1201. [PMID: 35931863 PMCID: PMC9886402 DOI: 10.1038/s41588-022-01141-9] [Citation(s) in RCA: 210] [Impact Index Per Article: 70.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 06/22/2022] [Indexed: 02/01/2023]
Abstract
Transcriptional heterogeneity among malignant cells of a tumor has been studied in individual cancer types and shown to be organized into cancer cell states; however, it remains unclear to what extent these states span tumor types, constituting general features of cancer. Here, we perform a pan-cancer single-cell RNA-sequencing analysis across 15 cancer types and identify a catalog of gene modules whose expression defines recurrent cancer cell states including 'stress', 'interferon response', 'epithelial-mesenchymal transition', 'metal response', 'basal' and 'ciliated'. Spatial transcriptomic analysis linked the interferon response in cancer cells to T cells and macrophages in the tumor microenvironment. Using mouse models, we further found that induction of the interferon response module varies by tumor location and is diminished upon elimination of lymphocytes. Our work provides a framework for studying how cancer cell states interact with the tumor microenvironment to form organized systems capable of immune evasion, drug resistance and metastasis.
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Affiliation(s)
- Dalia Barkley
- Institute for Computational Medicine, New York, NY, USA
| | | | - Maayan Pour
- Institute for Computational Medicine, New York, NY, USA
| | | | - Ian Dryg
- Department of Dermatology, NYU School of Medicine, New York, NY, USA
| | - Gregor Werba
- Department of Surgery, NYU School of Medicine, New York, NY, USA,Department of Pathology, NYU School of Medicine, New York, NY, USA
| | - Wei Wang
- Department of Surgery, NYU School of Medicine, New York, NY, USA,Department of Pathology, NYU School of Medicine, New York, NY, USA
| | - Maayan Baron
- Institute for Computational Medicine, New York, NY, USA
| | - Anjali Rao
- Institute for Computational Medicine, New York, NY, USA
| | - Bo Xia
- Institute for Computational Medicine, New York, NY, USA
| | | | - Alejandro Weil
- Department of Pathology, NYU School of Medicine, New York, NY, USA
| | | | - Cristina Hajdu
- Department of Pathology, NYU School of Medicine, New York, NY, USA
| | - Amanda W. Lund
- Department of Dermatology, NYU School of Medicine, New York, NY, USA,Department of Surgery, NYU School of Medicine, New York, NY, USA,Perlmutter Cancer Center NYU School of Medicine, New York, NY, USA
| | - Iman Osman
- Department of Dermatology, NYU School of Medicine, New York, NY, USA,Department of Pathology, NYU School of Medicine, New York, NY, USA,Perlmutter Cancer Center NYU School of Medicine, New York, NY, USA
| | - Itai Yanai
- Institute for Computational Medicine, New York, NY, USA,Perlmutter Cancer Center NYU School of Medicine, New York, NY, USA,Corresponding author:
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30
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Koufopoulos N, Damaskou V, Siozopoulou V, Kokoropoulos P, Gouloumis AR, Arkadopoulos N, Panayiotides IG. DOG1-Positive Primary Mesenteric Leiomyosarcoma: Report of a Case and Review of the Literature. Cureus 2022; 14:e25263. [PMID: 35755504 PMCID: PMC9224980 DOI: 10.7759/cureus.25263] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2022] [Indexed: 11/20/2022] Open
Abstract
The mesentery constitutes a common location for the metastatic spread of malignant gastrointestinal tumors. Primary mesenteric tumors, on the other hand, are very rare; lymphomas are the most common, followed by benign and malignant mesenchymal tumors. We present a case of a 43-year-old patient operated on for a primary mesenteric leiomyosarcoma with a positive immunostain for DOG1, despite having no KIT or PDGFRa mutations on molecular analysis. Moreover, we review the pertinent literature.
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31
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Li H, Yu Z, Wang H, Wang N, Sun X, Yang S, Hua X, Liu Z. Role of ANO1 in tumors and tumor immunity. J Cancer Res Clin Oncol 2022; 148:2045-2068. [PMID: 35471604 DOI: 10.1007/s00432-022-04004-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 03/29/2022] [Indexed: 12/24/2022]
Abstract
Dysregulation of gene amplification, cell-signaling-pathway transduction, epigenetic and transcriptional regulation, and protein interactions drives tumor-cell proliferation and invasion, while ion channels also play an important role in the generation and development of tumor cells. Overexpression of Ca2+-activated Cl- channel anoctamin 1 (ANO1) is shown in numerous cancer types and correlates with poor prognosis. However, the mechanisms involved in ANO1-mediated malignant cellular transformation and the role of ANO1 in tumor immunity remain unknown. In this review, we discuss recent studies to determine the role of ANO1 in tumorigenesis and provide novel insights into the role of ANO1 in the context of tumor immunity. Furthermore, we analyze the roles and potential mechanisms of ANO1 in different types of cancers, and provide novel notions for the role of ANO1 in the tumor microenvironment and for potential use of ANO1 in clinical applications. Our review shows that ANO1 is involved in tumor immunity and microenvironment, and may, therefore, be an effective biomarker and therapeutic drug target.
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Affiliation(s)
- Haini Li
- Department of Gastroenterology, Qingdao Sixth People's Hospital, Qingdao, 266001, China
| | - Zongxue Yu
- Department of Endocrinology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266001, China
| | - Haiyan Wang
- Department of Clinical Laboratory, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266021, China
| | - Ning Wang
- Department of Clinical Laboratory, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266021, China
| | - Xueguo Sun
- Department of Gastroenterology, Qingdao University Affiliated Hospital, Qingdao, 266001, China
| | - Shengmei Yang
- Department of Gynecology, Qingdao University Affiliated Hospital, Qingdao, 266001, China
| | - Xu Hua
- Department of Clinical Laboratory, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266021, China
| | - Zongtao Liu
- Department of Clinical Laboratory, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, 266021, China.
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Kawanishi A, Umekawa M, Miyawaki S, Fujitani S, Ishizawa T, Ushiku T, Hongo H, Teranishi Y, Shojima M, Shin M, Hasegawa K, Saito N. Long-term progression-free survival achieved in the skull base metastasis of gastrointestinal stromal tumor with introduction of tyrosine kinase inhibitor: illustrative case. JOURNAL OF NEUROSURGERY: CASE LESSONS 2022; 3:CASE2257. [PMID: 36303489 PMCID: PMC9379722 DOI: 10.3171/case2257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 03/03/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are common subepithelial tumors that rarely metastasize to the intracranial space. Because the standard treatment for metastatic intracranial GISTs has not been established, multimodal therapies are needed, especially in the case of skull base metastasis. However, its outcome has not always been favorable. The authors report the longest known surviving case of skull base metastasis of GIST treated with imatinib only. OBSERVATIONS A 52-year-old male with a history of GIST presented with left facial swelling and numbness. Examinations revealed a 70-mm tumor occupying the left middle cranial fossa and the orbit. The authors performed transnasal endoscopic tumor biopsy for definitive diagnosis and reintroduced imatinib treatment. The tumor significantly decreased in size early after the introduction of imatinib, and symptoms completely disappeared within several weeks. The lesion has remained shrunk radiologically for 63 months, and the patient is continuously being followed up under imatinib treatment. LESSONS The authors reported a rare case of skull base metastasis of GIST successfully treated solely with systemic therapy with a tyrosine kinase inhibitor, achieving tumor control for over 5 years. This case suggests that tyrosine kinase inhibitors might play a key role in the multidisciplinary treatment for skull base metastases of GIST.
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Affiliation(s)
- Akiya Kawanishi
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Motoyuki Umekawa
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Satoru Miyawaki
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shigeta Fujitani
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takeaki Ishizawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and
| | - Hiroki Hongo
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yu Teranishi
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaaki Shojima
- Department of Neurosurgery, School of Medicine, Teikyo University, Tokyo, Japan
| | - Masahiro Shin
- Department of Neurosurgery, School of Medicine, Teikyo University, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nobuhito Saito
- Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
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33
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Ueda K, Takanosu M, Kagawa Y, Ueda A, Ano N, Nomura K, Ozaki K. Gastrointestinal stromal tumors with Kit gene mutation in 4 guinea pigs ( Cavia porcellus). Vet Pathol 2022; 59:740-746. [PMID: 35393902 DOI: 10.1177/03009858221087630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) have been rarely reported in guinea pigs. We aimed to characterize the clinical and pathological features of GISTs in 4 guinea pigs and investigate the presence of mutations in exon 11 of the KIT proto-oncogene receptor tyrosine kinase (Kit) gene. Two subjects were male and 2 were female; 2 were 6 years old, 1 was 7 years old, and 1 was of an unknown age. Three cases had primary gastric tumors, whereas 1 had a primary small intestinal tumor. All cases had tumors that extended from the submucosa to the serosa with extraluminal growth. A gastric tumor had gastric, pancreatic, and cecal metastases. Histologically, the tumors were sharply demarcated and composed of spindle cells arranged in bundles, intermixed with small amounts of collagenous stroma. The tumor cells had mild atypia with few mitotic figures (0-5/50 high power fields, 7.95 mm2) and were immunolabeled for KIT and Discovered-on-GIST 1 (DOG1). All cases had mutations in exon 11 of the Kit gene. These findings indicate that GISTs in guinea pigs are similar to those in humans and dogs. GISTs in guinea pigs are potentially malignant submucosal tumors with KIT- and DOG1-immunolabeling, exon 11 KIT mutations, and the possibility of metastasis.
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Affiliation(s)
- Kengo Ueda
- Vogel Animal Hospital, Kobe, Hyogo, Japan.,Setsunan University, Hirakata, Osaka, Japan
| | | | | | - Akiko Ueda
- Vogel Animal Hospital, Kobe, Hyogo, Japan
| | - Naoko Ano
- Marupi Lifetech Co., Ltd., Ikeda, Osaka, Japan
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The Diagnosis of Small Gastrointestinal Subepithelial Lesions by Endoscopic Ultrasound-Guided Fine Needle Aspiration and Biopsy. Diagnostics (Basel) 2022; 12:diagnostics12040810. [PMID: 35453857 PMCID: PMC9027519 DOI: 10.3390/diagnostics12040810] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/21/2022] [Accepted: 03/23/2022] [Indexed: 12/02/2022] Open
Abstract
Endoscopic ultrasonography (EUS) has been widely accepted in the diagnosis of all types of tumors, especially pancreatic tumors, lymph nodes, and subepithelial lesions (SELs). One reason is that the examination can provide a detailed observation, with tissue samples being immediately obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Many SELs are detected incidentally during endoscopic examinations without symptoms. Most SELs are mesenchymal tumors originating from the fourth layer, such as gastrointestinal stromal tumors (GISTs), leiomyomas, and schwannomas. GISTs are potentially malignant. Surgical treatment is recommended for localized GISTs of ≥20 mm. However, the indications for the diagnosis and follow-up of GISTs of <20 mm in size are controversial. There are several reports on the rapid progression or metastasis of small GISTs. Therefore, it is important to determine whether a SEL is a GIST or not. The main diagnostic method is EUS-FNA. Recently, endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) using a new biopsy needle has been reported to obtain larger tissue samples. Additionally, various biopsy methods have been reported to have a high diagnostic rate for small GISTs. In local gastric SELs, regardless of the tumor size, EUS can be performed first; then, EUS-FNA/B or various biopsy methods can be used to obtain tissue samples for decision-making in relation to therapy and the follow-up period.
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35
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Intraoperative Near-Infrared Fluorescence Imaging with Indocyanine Green for Identification of Gastrointestinal Stromal Tumors (GISTs), a Feasibility Study. Cancers (Basel) 2022; 14:cancers14061572. [PMID: 35326721 PMCID: PMC8946640 DOI: 10.3390/cancers14061572] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/14/2022] [Accepted: 03/14/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Surgical resection plays a pivotal role in the treatment of GIST patients. The current study aims to explore the use of near-infrared fluorescence imaging to optimize the intraoperative tumor identification of GISTs. For this purpose, the potential and limitations of the widely used, and non-specific, tracer indocyanine green were assessed in a multicenter study including 10 patients. Our results show that GISTs typically have similar fluorescence intensity to the surrounding tissue, within several minutes after the intravenous administration of indocyanine green. These findings justify future research into specific fluorescent tracers for GISTs, and set a reference for future intraoperative imaging trials. Abstract Background: Optimal intraoperative tumor identification of gastrointestinal stromal tumors (GISTs) is important for the quality of surgical resections. This study aims to assess the potential of near-infrared fluorescence (NIRF) imaging with indocyanine green (ICG) to improve intraoperative tumor identification. Methods: Ten GIST patients, planned to undergo resection, were included. During surgery, 10 mg of ICG was intravenously administered, and NIRF imaging was performed at 5, 10, and 15 min after the injection. The tumor fluorescence intensity was visually assessed, and tumor-to-background ratios (TBRs) were calculated for exophytic lesions. Results: Eleven GIST lesions were imaged. The fluorescence intensity of the tumor was visually synchronous and similar to the background in five lesions. In one lesion, the tumor fluorescence was more intense than in the surrounding tissue. Almost no fluorescence was observed in both the tumor and healthy peritoneal tissue in two patients with GIST lesions adjacent to the liver. In three GISTs without exophytic growth, no fluorescence of the tumor was observed. The median TBRs at 5, 10, and 15 min were 1.0 (0.4–1.2), 1.0 (0.5–1.9), and 0.9 (0.7–1.2), respectively. Conclusion: GISTs typically show similar fluorescence intensity to the surrounding tissue in NIRF imaging after intraoperative ICG administration. Therefore, intraoperatively administered ICG is currently not applicable for adequate tumor identification, and further research should focus on the development of tumor-specific fluorescent tracers for GISTs.
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36
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Gorunova L, Boye K, Panagopoulos I, Berner JM, Bjerkehagen B, Hompland I, Lobmaier I, Hølmebakk T, Hveem TS, Heim S, Micci F. Cytogenetic and molecular analyses of 291 gastrointestinal stromal tumors: site-specific cytogenetic evolution as evidence of pathogenetic heterogeneity. Oncotarget 2022; 13:508-517. [PMID: 35284037 PMCID: PMC8901076 DOI: 10.18632/oncotarget.28209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/17/2022] [Indexed: 12/02/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm with variable behavior. An increased understanding of the tumor pathogenesis may improve clinical decision-making. Our aim was to obtain more data about the overall chromosome aberrations and intratumor cytogenetic heterogeneity in GIST. We analyzed 306 GIST samples from 291 patients using G-banding, direct sequencing, and statistics. Clonal chromosome aberrations were found in 81% of samples, with 34% of 226 primary tumors demonstrating extensive cytogenetic heterogeneity. 135 tumors had simple (≤5 changes) and 91 had complex (>5 changes) karyotypes. The karyotypically complex tumors more often were non-gastric (P < 0.001), larger (P < 0.001), more mitotically active (P = 0.009) and had a higher risk of rupture (P < 0.001) and recurrence (P < 0.001). Significant differences between gastric and non-gastric tumors were found also in the frequency of main chromosome losses: of 14q (79% vs. 63%), 22q (38% vs. 67%), 1p (23% vs. 88%), and 15q (18% vs. 77%). Gastric PDGFRA-mutated tumors, compared with gastric KIT-mutated, had a lower incidence of 22q losses (18% vs. 43%) but a higher rate of 1p losses (42% vs. 22%). The present, largest by far karyotypic study of GISTs provides further evidence for the existence of variable pathogenetic pathways operating in these tumors’ development.
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Affiliation(s)
- Ludmila Gorunova
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Kjetil Boye
- Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ioannis Panagopoulos
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Jeanne-Marie Berner
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Bodil Bjerkehagen
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Institute of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
| | - Ivar Hompland
- Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ingvild Lobmaier
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Toto Hølmebakk
- Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Tarjei S. Hveem
- Section for Applied Informatics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Sverre Heim
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Francesca Micci
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
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Zhou Z, Zhang C, Ma Z, Wang H, Tuo B, Cheng X, Liu X, Li T. Pathophysiological role of ion channels and transporters in HER2-positive breast cancer. Cancer Gene Ther 2022; 29:1097-1104. [PMID: 34997219 DOI: 10.1038/s41417-021-00407-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/21/2021] [Accepted: 11/08/2021] [Indexed: 11/09/2022]
Abstract
The incidence of breast cancer (BC) has been increasing each year, and BC is now the most common malignant tumor in women. Among the numerous BC subtypes, HER2-positive BC can be treated with a variety of strategies based on targeting HER2. Although there has been great progress in the treatment of HER2-positive BC, recurrence, metastasis and drug resistance remain considerable challenges. The dysfunction of ion channels and transporters can affect the development and progression of HER2-positive BC, so these entities are expected to be new therapeutic targets. This review summarizes various ion channels and transporters associated with HER2-positive BC and suggests potential targets for the development of new and effective therapies.
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Affiliation(s)
- Zhengxing Zhou
- Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China
| | - Chengmin Zhang
- Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China
| | - Zhiyuan Ma
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China
| | - Hu Wang
- Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China
| | - Xiaoming Cheng
- Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China
| | - Xuemei Liu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China.
| | - Taolang Li
- Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou Province, China.
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38
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Pinto MC, Botelho HM, Silva IAL, Railean V, Neumann B, Pepperkok R, Schreiber R, Kunzelmann K, Amaral MD. Systems Approaches to Unravel Molecular Function: High-content siRNA Screen Identifies TMEM16A Traffic Regulators as Potential Drug Targets for Cystic Fibrosis. J Mol Biol 2022; 434:167436. [PMID: 34990652 DOI: 10.1016/j.jmb.2021.167436] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 11/25/2022]
Abstract
An attractive approach to treat people with Cystic Fibrosis (CF), a life-shortening disease caused by mutant CFTR, is to compensate for the absence of this chloride/bicarbonate channel by activating alternative (non-CFTR) chloride channels. One obvious target for such "mutation-agnostic" therapeutic approach is TMEM16A (anoctamin-1/ANO1), a calcium-activated chloride channel (CaCC) which is also expressed in the airways of people with CF, albeit at low levels. To find novel TMEM16A regulators of both traffic and function, with the main goal of identifying candidate CF drug targets, we performed a fluorescence cell-based high-throughput siRNA microscopy screen for TMEM16A trafficking using a double-tagged construct expressed in human airway cells. About 700 genes were screened (2 siRNAs per gene) of which 262 were identified as candidate TMEM16A modulators (179 siRNAs enhanced and 83 decreased TMEM16A traffic), being G-protein coupled receptors (GPCRs) enriched on the primary hit list. Among the 179 TMEM16A traffic enhancer siRNAs subjected to secondary screening 20 were functionally validated. Further hit validation revealed that siRNAs targeting two GPCRs - ADRA2C and CXCR3 - increased TMEM16A-mediated chloride secretion in human airway cells, while their overexpression strongly diminished calcium-activated chloride currents in the same cell model. The knockdown, and likely also the inhibition, of these two TMEM16A modulators is therefore an attractive potential therapeutic strategy to increase chloride secretion in CF.
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Affiliation(s)
- Madalena C Pinto
- BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal. https://twitter.com/madalenacfpinto
| | - Hugo M Botelho
- BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
| | - Iris A L Silva
- BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
| | - Violeta Railean
- BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal
| | - Beate Neumann
- Cell Biology/Biophysics Unit, and ALMF, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany
| | - Rainer Pepperkok
- Cell Biology/Biophysics Unit, and ALMF, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany
| | - Rainer Schreiber
- Institut für Physiologie, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany
| | - Karl Kunzelmann
- Institut für Physiologie, University of Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany
| | - Margarida D Amaral
- BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8, 1749-016 Lisboa, Portugal.
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Adhya A, Mishra P, Biswas D, Pattnaik S, Patra S, Muduly D, Balasubiramaniyan V. Malignant gastrointestinal neuroectodermal tumor: A case-based review of literature. J Cancer Res Ther 2022; 18:885-897. [DOI: 10.4103/jcrt.jcrt_829_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
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40
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Dittmer J. Biological effects and regulation of IGFBP5 in breast cancer. Front Endocrinol (Lausanne) 2022; 13:983793. [PMID: 36093095 PMCID: PMC9453429 DOI: 10.3389/fendo.2022.983793] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
The insulin-like growth factor receptor (IGF1R) pathway plays an important role in cancer progression. In breast cancer, the IGF1R pathway is linked to estrogen-dependent signaling. Regulation of IGF1R activity is complex and involves the actions of its ligands IGF1 and IGF2 and those of IGF-binding proteins (IGFBPs). Six IGFBPs are known that share the ability to form complexes with the IGFs, by which they control the bioavailability of these ligands. Besides, each of the IGFBPs have specific features. In this review, the focus lies on the biological effects and regulation of IGFBP5 in breast cancer. In breast cancer, estrogen is a critical regulator of IGFBP5 transcription. It exerts its effect through an intergenic enhancer loop that is part of the chromosomal breast cancer susceptibility region 2q35. The biological effects of IGFBP5 depend upon the cellular context. By inhibiting or promoting IGF1R signaling, IGFBP5 can either act as a tumor suppressor or promoter. Additionally, IGFBP5 possesses IGF-independent activities, which contribute to the complexity by which IGFBP5 interferes with cancer cell behavior.
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Upregulation of TTYH3 promotes epithelial-to-mesenchymal transition through Wnt/β-catenin signaling and inhibits apoptosis in cholangiocarcinoma. Cell Oncol (Dordr) 2021; 44:1351-1361. [PMID: 34796468 DOI: 10.1007/s13402-021-00642-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2021] [Indexed: 01/05/2023] Open
Abstract
PURPOSE Cholangiocarcinoma (CCA) is a highly invasive malignant tumor originating from the bile duct epithelium. Tweety homolog 3 (TTYH3) is a member of the family of calcium-activated chloride channels, which have several biological functions. Here, we aimed to investigate the expression and biological function of TTYH3 in CCA. METHODS The mRNA and protein expression levels of TTYH3 were investigated in primary human CCA tissues and normal tissues. The DNA methylation levels of three CpG sites in the TTYH3 promoter region were evaluated using pyrosequencing. The effect of TTYH3 expression on proliferation, apoptosis, migration and invasion were assessed in HUCCT1 and QBC939 cells. Xenograft models were developed to substantiate its role in the development of CCA. Western blot analysis was used to investigate the mechanistic role of TTYH3 in regulating CCA progression. RESULTS We found that TTYH3 was highly expressed both at the mRNA and protein levels in CCA (p = 0.0001) and that the expression levels were significantly related to a poor overall survival of the patients (p = 0.0019). The DNA methylation levels of three CpG sites in the TTYH3 promoter region were significantly lower in CCA tissues compared to normal tissues (p < 0.05). In vitro studies indicated that TTYH3 can promote the proliferation, migration and invasion of the CCA cells. TTYH3 overexpression significantly promoted tumor progression and cellular proliferation in vivo as indicated by Ki-67 expression. In addition, we found that exogenous TTYH3 overexpression induced epithelial-mesenchymal transition (EMT) in CCA as indicated by expression changes in E-cadherin, N-cadherin and vimentin. The EMT process was found to occur through the Wnt/β-catenin signaling pathway, with simultaneous changes in P-GSK3β and β-catenin levels. CONCLUSIONS Our data indicate that DNA hypomethylation-induced overexpression of TTYH3 regulates CCA development and metastasis through the Wnt/β-catenin pathway.
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Wang MX, Devine C, Segaran N, Ganeshan D. Current update on molecular cytogenetics, diagnosis and management of gastrointestinal stromal tumors. World J Gastroenterol 2021; 27:7125-7133. [PMID: 34887632 PMCID: PMC8613640 DOI: 10.3748/wjg.v27.i41.7125] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/28/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract and are thought to arise from precursors of the interstitial cells of Cajal. GISTs can arise anywhere in the GI tract, but most commonly originate from the stomach and small intestine. The majority of GISTs occur as a result of activating mutations in two receptor protein tyrosine kinases: KIT and/or platelet-derived growth factor receptor-α. Mutational analyses allow for predicting patient prognosis and treatment response. Clinical presentations can vary from no symptoms, typical in the case of small incidentally found tumors, to GI bleeding, abdominal discomfort, and ulcer-related symptoms when the tumor is enlarged. Imaging plays a critical role in the diagnosis and management of these tumors with multiphasic computed tomography serving as the imaging modality of choice. Magnetic resonance imaging and positron emission tomography-computed tomography can serve as imaging adjuncts in lesion characterization, especially with liver metastases, and subsequent staging and assessment for treatment response or recurrence. Surgical resection is the preferred management for small GISTs, while tyrosine kinase inhibitors − imatinib mesylate and sunitinib malate − serve as crucial molecular-targeted therapies for locally advanced and metastatic GISTs. This review article highlights the clinical presentation, pathology and molecular cytogenetics, imaging features, and current management of GISTs.
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Affiliation(s)
- Mindy X Wang
- Department of Diagnostic Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Catherine Devine
- Department of Diagnostic Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Nicole Segaran
- Department of Radiology, Mayo Clinic Arizona, Phoenix, AZ 85259, United States
| | - Dhakshinamoorthy Ganeshan
- Department of Diagnostic Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
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Dermawan JK, Rubin BP. Molecular Pathogenesis of Gastrointestinal Stromal Tumor: A Paradigm for Personalized Medicine. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2021; 17:323-344. [PMID: 34736340 DOI: 10.1146/annurev-pathol-042220-021510] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Over the past three to four decades, the molecular pathogenesis of gastrointestinal stromal tumors (GISTs) has been elucidated in great detail. In this review, we discuss the biological genesis of GISTs, identification of the various primary activating driver mutations (focusing on KIT and PDGFRA), oncogene addiction and targeted therapies with imatinib and other tyrosine kinase inhibitors, and the subsequent characterization of the various mechanisms of drug resistance. We illustrate how GIST has become a quintessential paradigm for personalized medicine. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Josephine K Dermawan
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; ,
| | - Brian P Rubin
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; ,
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Jansen K, Farahi N, Büscheck F, Lennartz M, Luebke AM, Burandt E, Menz A, Kluth M, Hube-Magg C, Hinsch A, Höflmayer D, Weidemann S, Fraune C, Möller K, Lebok P, Sauter G, Simon R, Uhlig R, Wilczak W, Jacobsen F, Minner S, Krech R, Clauditz T, Bernreuther C, Dum D, Krech T, Marx A, Steurer S. DOG1 expression is common in human tumors: A tissue microarray study on more than 15,000 tissue samples. Pathol Res Pract 2021; 228:153663. [PMID: 34717148 DOI: 10.1016/j.prp.2021.153663] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 10/17/2021] [Indexed: 02/03/2023]
Abstract
DOG1 (Discovered on GIST1) is a voltage-gated calcium-activated chloride and bicarbonate channel that is highly expressed in interstitial cells of Cajal and in gastrointestinal stromal tumors (GIST) derived from Cajal cells. To systematically determine in what tumor entities and normal tissue types DOG1 may be further expressed, a tissue microarray (TMA) containing 15,965 samples from 121 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. DOG1 immunostaining was found in 67 tumor types including GIST (95.7%), esophageal squamous cell carcinoma (31.9%), pancreatic ductal adenocarcinoma (33.6%), adenocarcinoma of the Papilla Vateri (20%), squamous cell carcinoma of the vulva (15.8%) and the oral cavity (15.3%), mucinous ovarian cancer (15.3%), esophageal adenocarcinoma (12.5%), endometrioid endometrial cancer (12.1%), neuroendocrine carcinoma of the colon (11.1%) and diffuse gastric adenocarcinoma (11%). Low level-DOG1 immunostaining was seen in 17 additional tumor entities. DOG1 expression was unrelated to histopathological parameters of tumor aggressiveness and/or patient prognosis in cancers of the breast (n = 1002), urinary bladder (975), ovary (469), endometrium (173), stomach (233), and thyroid gland (512). High DOG1 expression was linked to estrogen receptor expression in breast cancer (p < 0.0001) and absence of HPV infection in squamous cell carcinomas (p = 0.0008). In conclusion, our data identify several tumor entities that can show DOG1 expression levels at similar levels as in GIST. Although DOG1 is tightly linked to a diagnosis of GIST in spindle cell tumors, the differential diagnosis is much broader in DOG1 positive epithelioid neoplasms.
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Affiliation(s)
- Kristina Jansen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nagina Farahi
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas M Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anne Menz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Doris Höflmayer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Katharina Möller
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Ria Uhlig
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Waldemar Wilczak
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rainer Krech
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Till Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David Dum
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Andreas Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Torrence D, Xie Z, Zhang L, Chi P, Antonescu CR. Gastrointestinal stromal tumors with BRAF gene fusions. A report of two cases showing low or absent KIT expression resulting in diagnostic pitfalls. Genes Chromosomes Cancer 2021; 60:789-795. [PMID: 34398495 DOI: 10.1002/gcc.22991] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 01/02/2023] Open
Abstract
Although most gastrointestinal stromal tumors (GISTs) exhibit activating mutations in either KIT or PDGFRA, rare cases have shown to be driven by gene fusions involving kinases, mainly involving NTRK3, and rarely BRAF or FGFR1. BRAF gene rearrangements have been described in only two patients to date, as separate case reports. In addition, BRAF V600E mutation is an uncommon but established oncogenic pathway in GIST. In this report, we describe two new GIST cases harboring novel BRAF fusion genes, arising in two young-adult women (37 and 40 years of age) in the small bowel and distal esophagus, both with a spindle cell phenotype. The small bowel GIST measured 2.8 cm and showed a high cellularity and a mitotic rate of 20/50 HPFs, while the esophageal lesion measured 7 cm and 1/50 HPFs. Immunohistochemically, both tumors showed diffuse reactivity for DOG1, while KIT/CD117 was weakly positive in the small bowel GIST and completely negative in the esophageal tumor. Based on these findings, the latter case was misinterpreted as a low-grade myxoid leiomyosarcoma, as it showed a myxoid stroma, reactivity for SMA and focal positivity for desmin. Archer FusionPlex revealed a fusion between BRAF with either AGAP3 or MKRN1 gene partners. Moreover, MSK-IMPACT DNA targeted sequencing confirmed both fusions but did not identify additional mutations. In one case with available material, the BRAF gene rearrangement was also validated by FISH. The recognition of BRAF fusion-positive GISTs is critical as it may be associated with a low level of KIT expression and may result in diagnostic challenges with significant impact on therapeutic management. The clinical benefit with KIT inhibitors, such as imatinib, remains to be determined.
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Affiliation(s)
- Dianne Torrence
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Ziyu Xie
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Lei Zhang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Ping Chi
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Cristina R Antonescu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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Jansen K, Büscheck F, Moeller K, Kluth M, Hube-Magg C, Blessin NC, Perez D, Izbicki J, Neipp M, Mofid H, Daniels T, Nahrstedt U, Fraune C, Jacobsen F, Bernreuther C, Lebok P, Sauter G, Uhlig R, Wilczak W, Simon R, Steurer S, Burandt E, Marx A, Krech T, Clauditz T. DOG1 is commonly expressed in pancreatic adenocarcinoma but unrelated to cancer aggressiveness. PeerJ 2021; 9:e11905. [PMID: 34414034 PMCID: PMC8344676 DOI: 10.7717/peerj.11905] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 07/13/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND DOG1 (ANO1; TMEM16A) is a voltage-gated calcium-activated chloride and bicarbonate channel. DOG1 is physiologically expressed in Cajal cells, where it plays an important role in regulating intestinal motility and its expression is a diagnostic hallmark of gastrointestinal stromal tumors (GIST). Data on a possible role of DOG1 in pancreatic cancer are rare and controversial. The aim of our study was to clarify the prevalence of DOG1 expression in pancreatic cancer and to study its association with parameters of cancer aggressiveness. METHODS DOG1 expression was analyzed by immunohistochemistry in 599 pancreatic cancers in a tissue microarray format and in 12 cases of pancreatitis on large tissue sections. RESULTS DOG1 expression was always absent in normal pancreas but a focal weak expression was seen in four of 12 cases of pancreatitis. DOG1 expression was, however, common in pancreatic cancer. Membranous and cytoplasmic DOG1 expression in tumor cells was highest in pancreatic ductal adenocarcinomas (61% of 444 interpretable cases), followed by cancers of the ampulla Vateri (43% of 51 interpretable cases), and absent in 6 acinus cell carcinomas. DOG1 expression in tumor associated stroma cells was seen in 76 of 444 (17%) pancreatic ductal adenocarcinomas and in seven of 51 (14%) cancers of the ampulla Vateri. Both tumoral and stromal DOG1 expression were unrelated to tumor stage, grade, lymph node and distant metastasis, mismatch repair protein deficiency and the density of CD8 positive cytotoxic T-lymphocytes in the subgroups of ductal adenocarcinomas and cancers of ampulla Vateri. Overall, the results of our study indicate that DOG1 may represent a potential biomarker for pancreatic cancer diagnosis and a putative therapeutic target in pancreatic cancer. However, DOG1 expression is unrelated to pancreatic cancer aggressiveness.
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Affiliation(s)
- Kristina Jansen
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | | | - Martina Kluth
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | | | - Daniel Perez
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob Izbicki
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | | | | | | | | | - Frank Jacobsen
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Patrick Lebok
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ria Uhlig
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Ronald Simon
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas Marx
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Academic Hospital Fuerth, Fuerth, Germany
| | - Till Krech
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrück, Germany
| | - Till Clauditz
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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47
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Pinto MC, Silva IAL, Figueira MF, Amaral MD, Lopes-Pacheco M. Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis. J Exp Pharmacol 2021; 13:693-723. [PMID: 34326672 PMCID: PMC8316759 DOI: 10.2147/jep.s255377] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, an anion channel that transports chloride and bicarbonate across epithelia. Despite clinical progress in delaying disease progression with symptomatic therapies, these individuals still develop various chronic complications in lungs and other organs, which significantly restricts their life expectancy and quality of life. The development of high-throughput assays to screen drug-like compound libraries have enabled the discovery of highly effective CFTR modulator therapies. These novel therapies target the primary defect underlying CF and are now approved for clinical use for individuals with specific CF genotypes. However, the clinically approved modulators only partially reverse CFTR dysfunction and there is still a considerable number of individuals with CF carrying rare CFTR mutations who remain without any effective CFTR modulator therapy. Accordingly, additional efforts have been pursued to identify novel and more potent CFTR modulators that may benefit a larger CF population. The use of ex vivo individual-derived specimens has also become a powerful tool to evaluate novel drugs and predict their effectiveness in a personalized medicine approach. In addition to CFTR modulators, pro-drugs aiming at modulating alternative ion channels/transporters are under development to compensate for the lack of CFTR function. These therapies may restore normal mucociliary clearance through a mutation-agnostic approach (ie, independent of CFTR mutation) and include inhibitors of the epithelial sodium channel (ENaC), modulators of the calcium-activated channel transmembrane 16A (TMEM16, or anoctamin 1) or of the solute carrier family 26A member 9 (SLC26A9), and anionophores. The present review focuses on recent progress and challenges for the development of ion channel/transporter-modulating drugs for the treatment of CF.
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Affiliation(s)
- Madalena C Pinto
- Biosystems & Integrative Sciences Institute (BioISI), Faculty of Sciences, University of Lisboa, Lisboa, Portugal
| | - Iris A L Silva
- Biosystems & Integrative Sciences Institute (BioISI), Faculty of Sciences, University of Lisboa, Lisboa, Portugal
| | - Miriam F Figueira
- Marsico Lung Institute/Cystic Fibrosis Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Margarida D Amaral
- Biosystems & Integrative Sciences Institute (BioISI), Faculty of Sciences, University of Lisboa, Lisboa, Portugal
| | - Miquéias Lopes-Pacheco
- Biosystems & Integrative Sciences Institute (BioISI), Faculty of Sciences, University of Lisboa, Lisboa, Portugal
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Wang T, Wang H, Yang F, Gao K, Luo S, Bai L, Ma K, Liu M, Wu S, Wang H, Chen Z, Xiao Q. Honokiol inhibits proliferation of colorectal cancer cells by targeting anoctamin 1/TMEM16A Ca 2+ -activated Cl - channels. Br J Pharmacol 2021; 178:4137-4154. [PMID: 34192810 DOI: 10.1111/bph.15606] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 05/25/2021] [Accepted: 06/06/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Ca2+ -activated Cl- channels (Ano1 channels) contribute to the pathogenesis of colorectal cancer. Honokiol is known to inhibit cell proliferation and tumour growth in colorectal cancer. However, the molecular target of honokiol remains unclear. This study aimed to investigate whether honokiol inhibited cell proliferation of colorectal cancer by targeting Ano1 channels. EXPERIMENTAL APPROACH Patch-clamp techniques were performed to study the effect of honokiol on Ca2+ -activated Cl- currents in HEK293 cells overexpressing Ano1- or Ano2-containing plasmids or in human colorectal carcinoma SW620 cells. Site-directed mutagenesis was used to identify the critical residues for honokiol-induced Ano1 inhibition. Proliferation of SW620 cells or human intestinal epithelial NCM460 cells by CCK-8 assays. KEY RESULTS Honokiol blocked Ano1 currents in Ano1-overexpressing HEK293 cells and SW620 cells. Honokiol more potently inhibited Ano1 currents than Ano2 currents. Three amino acids (R429, K430 and N435) were critical for honokiol-induced Ano1 inhibition. The R429A/K430L/N435G mutation reduced the sensitivity of Ano1 to honokiol. Honokiol inhibited SW620 cell proliferation, and this effect was reduced by Ano1-shRNAs. Furthermore, Ano1 overexpression promoted proliferation in NCM460 cells with low Ano1 endogenous expression and resulted in an increased sensitivity to honokiol. Overexpression of the R429A/K430L/N435G mutation reduced WT Ano1-induced increase in the sensitivity of NCM460 cells to honokiol. CONCLUSION AND IMPLICATIONS We identified a new anticancer mechanism of honokiol, through the inhibition of cell proliferation, by targeting Ano1 Ca2+ -activated Cl- channels.
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Affiliation(s)
- Tianyu Wang
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Hui Wang
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Fan Yang
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Kuan Gao
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Shuya Luo
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Lichuan Bai
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Ke Ma
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Mei Liu
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Shuwei Wu
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Huijie Wang
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Zaixing Chen
- Pharmaceutical Teaching and Experimental Center, School of Pharmacy, China Medical University, Shenyang, China
| | - Qinghuan Xiao
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
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Al-Maqrashi Z, Burney IA, Taqi KM, Al-Sawafi Y, Qureshi A, Lakhtakia R, Mehdi I, Al-Bahrani B, Kumar S, Al-Moundhri M. Clinicopathological Features and Outcomes of Gastrointestinal Stromal Tumours in Oman: A multi-centre study. Sultan Qaboos Univ Med J 2021; 21:e237-e243. [PMID: 34221471 PMCID: PMC8219329 DOI: 10.18295/squmj.2021.21.02.012] [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: 05/11/2020] [Revised: 08/13/2020] [Accepted: 09/09/2020] [Indexed: 11/16/2022] Open
Abstract
Objectives This study aimed to report the clinicopathological features, management and long-term outcomes of patients with gastrointestinal stromal tumours (GISTs) in Oman. Methods This retrospective study was conducted on patients treated for GIST between January 2003 and December 2017 at three tertiary referral centres in Muscat, Oman. All patients with confirmed histopathological diagnoses of GIST and followed-up at the centres during this period were included. Relevant information was retrieved from hospital records until April 2019. Results A total of 44 patients were included in the study. The median age was 55.5 years and 56.8% were female. The most common primary site of disease was the stomach (63.6%) followed by the jejunum/ileum (18.2%). Two patients (4.5%) had c-Kit-negative, discovered on GIST-1-positive disease. A total of 24 patients (54.5%) presented with localised disease and eight (33.3%) were classified as being at high risk of relapse. Patients with metastatic disease received imatinib in a palliative setting, whereas those with completely resected disease in the intermediate and high-risk groups were treated with adjuvant imatinib. Of the six patients (13.6%) with progressive metastatic disease, of which four had mutations on exon 11 and one on exon 9, while one had wild-type disease. Overall, rates of progression-free survival and overall survival (OS) at 100 months were 77.4% and 80.4%, respectively. Rates of OS for patients with localised and metastatic disease were 89.9% and 80.2%, respectively. Conclusion The presenting features and outcomes of patients with GISTs in Oman were comparable to those reported in the regional and international literature.
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Affiliation(s)
| | - Ikram A Burney
- Department of Medicine, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Kadhim M Taqi
- Division of General Surgery, Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Yaqoob Al-Sawafi
- Department of General Surgery, Armed Forces Hospital, Muscat, Oman
| | - Asim Qureshi
- Department of Pathology, King's Mill Hospital, Sherwood Forest Hospitals National Health Service Foundation Trust, Mansfield, Nottinghamshire, UK.,Department of Pathology, Sultan Qaboos University Hospital, Muscat, Oman
| | - Ritu Lakhtakia
- Department of Pathology, Mohammed bin Rashid University of Medicine & Health Sciences, Dubai, United Arab Emirates
| | - Itrat Mehdi
- National Oncology Centre, Royal Hospital, Muscat, Oman
| | | | - Shiyam Kumar
- Department of Medical Oncology, Yeovil District Hospital NHS Foundation Trust, Somerset, UK
| | - Mansour Al-Moundhri
- Department of Medicine, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman
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50
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Shrestha BM, Shrestha S, Kharel S, Adhikari S, Tiwari SB, Kandel BP, Lakhey PJ. Cecal gastrointestinal stromal tumor causing ileocolic intussusception in an adult: A rare case report. Int J Surg Case Rep 2021; 84:106097. [PMID: 34139427 PMCID: PMC8219755 DOI: 10.1016/j.ijscr.2021.106097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/06/2021] [Accepted: 06/06/2021] [Indexed: 11/04/2022] Open
Abstract
Introduction and importance Cecal gastrointestinal stromal tumors (GIST) constitute a rarer subtype of all GISTs. Rarely, it can present with ileocolic intussusception in adults making it a challenging diagnosis due to non-specific clinical features. Case presentation A 30-year previously healthy woman presented with lower abdominal pain and a distended abdomen who was subsequently diagnosed with ileocolic intussusception on a CT scan. Intraoperatively, a pedunculated polypoid hard mass was identified in the cecum and thus, a standard right hemicolectomy was performed with the suspicion of malignancy. Histopathology of the resected mass confirmed CD117 negative, spindle type GIST. Discussion Cecal GIST presenting in the form of ileocolic intussusception is rare. Contrast-enhanced CT scan is the preferred imaging modality for the evaluation of patients with suspected GIST to determine the extent of the tumor, the presence or absence of metastatic disease alongside evaluation of the possibility of complete resection. Adjuvant imatinib therapy following complete resection decreases the disease recurrence. Conclusion Intussusception in an adult can be the first manifestation of underlying malignancy like GIST. Complete surgical resection of the tumor with a negative margin offers long-term survival.
Ileocolic intussusception is rare in adult and often associated with pathological lead points like neoplasm. Cecal GIST is an uncommon cause of ileocolic intussusception in adults. Diagnosis of this entity is challenging because of its non-specific presenting features.
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Affiliation(s)
| | - Suraj Shrestha
- Maharajgunj Medical Campus, Institute of Medicine, Kathmandu, Nepal
| | - Sanjeev Kharel
- Maharajgunj Medical Campus, Institute of Medicine, Kathmandu, Nepal
| | - Shankar Adhikari
- Department of GI and General Surgery, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal
| | - Sansar Babu Tiwari
- Department of Pathology, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal
| | - Bishnu Prasad Kandel
- Department of GI and General Surgery, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal
| | - Paleswan Joshi Lakhey
- Department of GI and General Surgery, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal
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