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Feng QS, Shan XF, Yau V, Cai ZG, Xie S. Facilitation of Tumor Stroma-Targeted Therapy: Model Difficulty and Co-Culture Organoid Method. Pharmaceuticals (Basel) 2025; 18:62. [PMID: 39861125 PMCID: PMC11769033 DOI: 10.3390/ph18010062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 12/28/2024] [Accepted: 01/05/2025] [Indexed: 01/27/2025] Open
Abstract
Background: Tumors, as intricate ecosystems, comprise oncocytes and the highly dynamic tumor stroma. Tumor stroma, representing the non-cancerous and non-cellular composition of the tumor microenvironment (TME), plays a crucial role in oncogenesis and progression, through its interactions with biological, chemical, and mechanical signals. This review aims to analyze the challenges of stroma mimicry models, and highlight advanced personalized co-culture approaches for recapitulating tumor stroma using patient-derived tumor organoids (PDTOs). Methods: This review synthesizes findings from recent studies on tumor stroma composition, stromal remodeling, and the spatiotemporal heterogeneities of the TME. It explores popular stroma-related models, co-culture systems integrating PDTOs with stromal elements, and advanced techniques to improve stroma mimicry. Results: Stroma remodeling, driven by stromal cells, highlights the dynamism and heterogeneity of the TME. PDTOs, derived from tumor tissues or cancer-specific stem cells, accurately mimic the tissue-specific and genetic features of primary tumors, making them valuable for drug screening. Co-culture models combining PDTOs with stromal elements effectively recreate the dynamic TME, showing promise in personalized anti-cancer therapy. Advanced co-culture techniques and flexible combinations enhance the precision of tumor-stroma recapitulation. Conclusions: PDTO-based co-culture systems offer a promising platform for stroma mimicry and personalized anti-cancer therapy development. This review underscores the importance of refining these models to advance precision medicine and improve therapeutic outcomes.
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Affiliation(s)
- Qiu-Shi Feng
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22# Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (Q.-S.F.); (X.-F.S.)
| | - Xiao-Feng Shan
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22# Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (Q.-S.F.); (X.-F.S.)
| | - Vicky Yau
- Division of Oral and Maxillofacial Surgery, Columbia Irving Medical Center, New York City, NY 10027, USA;
| | - Zhi-Gang Cai
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22# Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (Q.-S.F.); (X.-F.S.)
| | - Shang Xie
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, 22# Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (Q.-S.F.); (X.-F.S.)
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Lianos GD, Kyrochristou GD, Lianou AD, Tatsis V, Schizas D, Vlachos K, Mitsis M. Gastric Juice Biomarkers in Gastric Cancer: New Trends? MAEDICA 2024; 19:775-779. [PMID: 39974454 PMCID: PMC11834849 DOI: 10.26574/maedica.2024.19.4.775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
As gastric cancer represents the fifth most common cancer diagnosis and the third leading cause of cancer death worldwide, it remains a current social and health issue. A variety of genetic, epigenetic and environmental factors contribute to the development of gastric cancer, although the etiology remains unclear. Timely diagnosis and appropriate treatment play the most crucial role not only in the containment of morbidity and mortality but also in the prognosis. The establishment of novel non-invasive biomarkers into patient management protocols represents a very promising and challenging approach. In this article, we focus on gastric cancer biomarkers with a special interest in gastric juice that may represent a novel, non-invasive, cost-effective 'liquid biopsy'.
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Affiliation(s)
- Georgios D Lianos
- Department of Surgery, University Hospital of Ioannina, Ioannina, Greece
| | | | | | - Vasileios Tatsis
- Department of Surgery, University Hospital of Ioannina, Ioannina, Greece
| | - Dimitrios Schizas
- 1st Department of Surgery, National and Kapodistrian University of Athens,Laikon General Hospital, 11527 Athens, Greece
| | | | - Michail Mitsis
- Department of Surgery, University Hospital of Ioannina, Ioannina, Greece
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Li ZF, Li Z, Zhang XJ, Sun CY, Fei H, Du CX, Guo CG, Zhao DB. Perioperative chemotherapy improves survival of patients with locally advanced diffuse gastric cancer. World J Gastrointest Surg 2024; 16:2878-2892. [PMID: 39351555 PMCID: PMC11438797 DOI: 10.4240/wjgs.v16.i9.2878] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/21/2024] [Accepted: 07/26/2024] [Indexed: 09/18/2024] Open
Abstract
BACKGROUND Whether patients with diffuse gastric cancer, which is insensitive to chemotherapy, can benefit from neoadjuvant or adjuvant chemotherapy has long been controversial. AIM To investigate whether perioperative chemotherapy can improve survival of patients with locally advanced diffuse gastric cancer. METHODS A total of 2684 patients with locally advanced diffuse gastric cancer from 18 population-based cancer registries in the United States were analyzed. RESULTS Compared with surgery alone, perioperative chemotherapy improved the prognosis of patients with locally advanced gastric cancer. Before stabilized inverse probability of treatment weighting (IPTW), the median overall survival (OS) times were 40.0 months and 13.0 months (P < 0.001), respectively. After IPTW, the median OS times were 33.0 months and 17.0 months (P < 0.001), respectively. Neoadjuvant chemotherapy did not improve the prognosis of patients with locally advanced gastric cancer compared with adjuvant chemotherapy after IPTW. After IPTW, the median OS times were 38.0 months in the neoadjuvant chemotherapy group and 42.0 months in the adjuvant chemotherapy group (P = 0.472). CONCLUSION Patients with diffuse gastric cancer can benefit from perioperative chemotherapy. There was no significant difference in survival between patients who received neoadjuvant chemotherapy and those who received adjuvant chemotherapy.
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Affiliation(s)
- Ze-Feng Li
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zheng Li
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xiao-Jie Zhang
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Chong-Yuan Sun
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - He Fei
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Chun-Xia Du
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Chun-Guang Guo
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Dong-Bing Zhao
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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Ooki A, Osumi H, Yoshino K, Yamaguchi K. Potent therapeutic strategy in gastric cancer with microsatellite instability-high and/or deficient mismatch repair. Gastric Cancer 2024; 27:907-931. [PMID: 38922524 PMCID: PMC11335850 DOI: 10.1007/s10120-024-01523-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024]
Abstract
Gastric cancer (GC) is a common malignancy that presents challenges in patient care worldwide. The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that protects genome integrity during replication. Deficient MMR (dMMR) results in an increased accumulation of genetic errors in microsatellite sequences, leading to the development of a microsatellite instability-high (MSI-H) phenotype. Most MSI-H/dMMR GCs arise sporadically, mainly due to MutL homolog 1 (MLH1) epigenetic silencing. Unlike microsatellite-stable (MSS)/proficient MMR (pMMR) GCs, MSI-H/dMMR GCs are relatively rare and represent a distinct subtype with genomic instability, a high somatic mutational burden, favorable immunogenicity, different responses to treatment, and prognosis. dMMR/MSI-H status is a robust predictive biomarker for treatment with immune checkpoint inhibitors (ICIs) due to high neoantigen load, prominent tumor-infiltrating lymphocytes, and programmed cell death ligand 1 (PD-L1) overexpression. However, a subset of MSI-H/dMMR GC patients does not benefit from immunotherapy, highlighting the need for further research into predictive biomarkers and resistance mechanisms. This review provides a comprehensive overview of the clinical, molecular, immunogenic, and therapeutic aspects of MSI-H/dMMR GC, with a focus on the impact of ICIs in immunotherapy and their potential as neoadjuvant therapies. Understanding the complexity and diversity of the molecular and immunological profiles of MSI-H/dMMR GC will drive the development of more effective therapeutic strategies and molecular targets for future precision medicine.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan.
| | - Hiroki Osumi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Koichiro Yoshino
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
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Liu D, Guo L, Waasdorp C, Meijer SL, Bootsma S, Oyarce C, Bijlsma MF, van Laarhoven HWM. Hyaluronidase improves the efficacy of nab-paclitaxel after prolonged angiogenesis inhibition in preclinical models for esophagogastric cancer. Biomed Pharmacother 2024; 178:117261. [PMID: 39106708 DOI: 10.1016/j.biopha.2024.117261] [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: 05/06/2024] [Revised: 08/01/2024] [Accepted: 08/02/2024] [Indexed: 08/09/2024] Open
Abstract
BACKGROUND Long-term anti-angiogenesis leads to pruned vasculature, densely deposited extracellular matrix (ECM), and consequently reduced chemotherapy delivery in esophagogastric cancer (EGC). To address this issue, we evaluated the efficacy of adding a hyaluronidase or a NO-donor to the regimen of chemotherapy and anti-angiogenic drugs. METHODS A patient-derived EGC xenograft model was developed. Grafted mice were randomly assigned to four experimental groups and one control group. The experimental groups received DC101, a murine angiogenesis inhibitor, and nab-paclitaxel (NPTX), with the addition of hyaluronidase (PEGPH20), or NO-donor (nitroglycerine, NTG), or their combination, respectively. We compared tumor growth during 17 days of treatment. We performed immunohistochemistry for ECM components hyaluronan (HA) and collagen, CD31 for endothelial cells, and γH2AX for DNA damage. The positively stained areas were quantified, and vessel diameters were measured using QuPath software. RESULTS Prolonged DC101 treatment induced deposition of HA (p<0.01) and collagen (p<0.01). HA was effectively degraded by PEGPH20 (p<0.001), but not by NTG as expected. Both PEGPH20 (p<0.05) and NTG (p<0.01) dilated vessels collapsed in response to long-term DC101 treatment. However, only PEGPH20 (rather than NTG) was found to significantly inhibit tumor growth (p<0.05) in combination with NPTX and DC101. CONCLUSIONS These findings suggest that the mechanical barrier of HA is the major reason responsible for the resistance developed during prolonged anti-angiogenesis in EGC. Incorporating PEGPH20 into the existing treatment regimen is promising to improve outcomes for patients with EGC.
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Affiliation(s)
- Dajia Liu
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Amsterdam UMC location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Lihui Guo
- Amsterdam UMC location University of Amsterdam, Department Experimental Immunology, Amsterdam Infection and Immunity Center, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands
| | - Cynthia Waasdorp
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Sybren L Meijer
- Amsterdam UMC Location University of Amsterdam, Department of Pathology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands
| | - Sanne Bootsma
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Amsterdam UMC location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Cesar Oyarce
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Maarten F Bijlsma
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Hanneke W M van Laarhoven
- Amsterdam UMC location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands.
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Herrera Kok JH, Marano L, van den Berg JW, Shetty P, Vashist Y, Lorenzon L, Rau B, van Hillegersberg R, de Manzoni G, Spallanzani A, Seo WJ, Nagata H, Eveno C, Mönig S, van der Sluis K, Solaini L, Wijnhoven BP, Puccetti F, Chevallay M, Lee E, D'Ugo D. Current trends in the management of Gastro-oEsophageal cancers: Updates to the ESSO core curriculum (ESSO-ETC-UGI-WG initiative). EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:108387. [PMID: 38796969 DOI: 10.1016/j.ejso.2024.108387] [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: 03/04/2024] [Revised: 04/26/2024] [Accepted: 05/02/2024] [Indexed: 05/29/2024]
Abstract
Gastro-oEsophageal Cancers (GECs) are severe diseases whose management is rapidly evolving. The European Society of Surgical Oncology (ESSO) is committed to the generation and spread of knowledge, and promotes the multidisciplinary management of cancer patients through its core curriculum. The present work discusses the approach to GECs, including the management of oligometastatic oesophagogastric cancers (OMEC), the diagnosis and management of peritoneal metastases from gastric cancer (GC), the management of Siewert Type II tumors, the importance of mesogastric excision, the role of robotic surgery, textbook outcomes, organ preserving options, the use of molecular markers and immune check-point inhibitors in the management of patients with GECs, as well as the improvement of current clinical practice guidelines for the management of patients with GECs. The aim of the present review is to provide a concise overview of the state-of-the-art on the management of patients with GECs and, at the same time, to share the latest advancements in the field and to foster the debate between surgical oncologists treating GECs worldwide. We are sure that our work will, at the same time, give an update to the advanced surgical oncologists and help the training surgical oncologists to settle down the foundations for their future practice.
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Affiliation(s)
- Johnn Henry Herrera Kok
- European Society of Surgical Oncology (ESSO), Education and Training Committee (ETC), Upper Gastrointestinal (UGI), Working Group (WG), Belgium; ESSO-European Young Surgeons and Alumni Club (EYSAC), Research Academy (RA), Belgium; Department of General and Digestive Surgery, Upper GI Unit, University Hospital of León, León, Spain.
| | - Luigi Marano
- European Society of Surgical Oncology (ESSO), Education and Training Committee (ETC), Upper Gastrointestinal (UGI), Working Group (WG), Belgium; Department of Medicine, Academy of Applied Medical and Social Sciences (AMiSNS), Akademia Medycznych i Społecznych Nauk Stosowanych, Elbląg, Poland
| | - Jan Willem van den Berg
- European Society of Surgical Oncology (ESSO), Education and Training Committee (ETC), Upper Gastrointestinal (UGI), Working Group (WG), Belgium; Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Preethi Shetty
- European Society of Surgical Oncology (ESSO), Education and Training Committee (ETC), Upper Gastrointestinal (UGI), Working Group (WG), Belgium; Department of Surgical Oncology, Kasturba Medical College, MAHE Manipal, India
| | - Yogesh Vashist
- European Society of Surgical Oncology (ESSO), Education and Training Committee (ETC), Upper Gastrointestinal (UGI), Working Group (WG), Belgium; Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Laura Lorenzon
- ESSO-European Young Surgeons and Alumni Club (EYSAC), Research Academy (RA), Belgium; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Beate Rau
- Department of Surgery, Campus Virchow-Klinikum and Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Germany
| | | | - Giovanni de Manzoni
- Department of General Surgery, Upper GI Unit, University Hospital of Verona, Verona, Italy
| | - Andrea Spallanzani
- Department of Oncology and Hematology, University of Modena and Reggio Emilia Hospital, Modena, Italy
| | - Won Jun Seo
- Department of Surgery, Korea University Guro Hospital, Seoul, Republic of Korea; PIPS-GC Study Group, Republic of Korea
| | - Hiromi Nagata
- Department of Gastric Surgery, National Cancer Center Hospital East, Chiba, Japan
| | - Clarisse Eveno
- Department of Surgery, Lille University Hospital, Lille, France
| | - Stefan Mönig
- Department of Surgery, University Hospitals of Geneva, Geneva, Switzerland
| | - Karen van der Sluis
- Department of Surgery, The Netherlands Cancer Institute Antoni van Leewenhoek, Amsterdam, the Netherlands
| | - Leonardo Solaini
- Department of General and Oncologic Surgery, Morgagni Pierantoni Hospital, Forli, Italy
| | - Bas Pl Wijnhoven
- Department of Surgery, Erasmus Medical Center Cancer Institute, Amsterdam, the Netherlands
| | - Francesco Puccetti
- Gastrointestinal Surgery Unit, Department of Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Mickael Chevallay
- Department of Surgery, University Hospitals of Geneva, Geneva, Switzerland
| | - Eunju Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea; Department of Surgery, Chung-Ang University Gwangmyeong Hospital, Gwangmyeong-si, Republic of Korea
| | - Domenico D'Ugo
- European Society of Surgical Oncology (ESSO), Education and Training Committee (ETC), Upper Gastrointestinal (UGI), Working Group (WG), Belgium; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; ESSO Past-President, Republic of Korea
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Piraino F, Costa M, Meyer M, Cornish G, Ceroni C, Garnier V, Hoehnel-Ka S, Brandenberg N. Organoid models: the future companions of personalized drug development. Biofabrication 2024; 16:032009. [PMID: 38608454 DOI: 10.1088/1758-5090/ad3e30] [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: 11/30/2023] [Accepted: 04/12/2024] [Indexed: 04/14/2024]
Abstract
High failure rates of the current drug development process are driving exemplary changes toward methodologies centered on human diseasein-vitromodeling. Organoids are self-organized tissue sub-units resembling their organ of origin and are widely acknowledged for their unique potential in recapitulating human physio-pathological mechanisms. They are transformative for human health by becoming the platform of choice to probe disease mechanisms and advance new therapies. Furthermore, the compounds' validation as therapeutics represents another point of the drug development pipeline where organoids may provide key understandings and help pharma organizations replace or reduce animal research. In this review, we focus on gastrointestinal organoid models, which are currently the most advanced organoid models in drug development. We focus on experimental validations of their value, and we propose avenues to enhance their use in drug discovery and development, as well as precision medicine and diagnostics.
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Affiliation(s)
| | - Mariana Costa
- Doppl SA, EPFL Innovation Park, Lausanne, Switzerland
| | - Marine Meyer
- Doppl SA, EPFL Innovation Park, Lausanne, Switzerland
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Jiang K, Cao F, Yin L, Hu Y, Zhao X, Huang X, Ma X, Li J, Lu M, Sun Y. Claudin 18.2 expression in digestive neuroendocrine neoplasms: a clinicopathological study. J Endocrinol Invest 2024; 47:1251-1260. [PMID: 38060154 DOI: 10.1007/s40618-023-02245-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 11/09/2023] [Indexed: 12/08/2023]
Abstract
BACKGROUND Claudin 18.2-targeted therapy has shown significant efficacy in treating claudin 18.2-positive cancers. However, limited systematic studies have investigated characteristics of claudin 18.2 expression in neuroendocrine neoplasms (NENs). METHODS Data and specimens from 403 cases of digestive NENs were retrospectively collected, and claudin 18.2 expression was detected using immunochemical staining. RESULTS Claudin 18.2 was positive in 19.6% (79/403) of the digestive NENs. The highest positive rate of claudin 18.2 was observed in gastric NENs (72/259, 27.8%), accounting for 91.1% (72/79) of all positive cases. The positivity rate was significantly higher in gastric NENs compared to pancreatic (2/78, 2.6%) or colorectal NENs (2/38, 5.3%; p < 0.05). For digestive NENs, claudin 18.2 positivity was significantly higher in neuroendocrine carcinomas (NECs) (37/144, 25.7%) than in neuroendocrine tumours (NETs; 14/160, 8.8%; p < 0.001), but no significant difference was found between gastric NECs (59/213, 27.7%) and gastric NETs (13/46, 28.3%; p > 0.05). The positivity was significantly higher in large-cell NECs (LCNECs; 28/79, 35.4%) and MiNEN (mixed neuroendocrine-non- neuroendocrine neoplasms)-LCNECs (23/66, 34.8%) compared to small-cell NECs (SCNECs; 9/65, 13.8%) and MiNEN-SCNECs (5/33, 15.2%; p < 0.05). Claudin 18.2 expression was more prevalent in gastric NENs than in pancreatic (12.5 ×; p = 0.001) and colorectal NENs (5.9 ×; p = 0.021). Claudin 18.2 staining was a useful method for identify the gastric origins of NETs, with a sensitivity of 28.3% and a specificity of 99.1%. CONCLUSION The expression characteristics of claudin 18.2 in NENs were characterized, which may provide a clinicopathological reference for targeted therapies in patients with NENs.
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Affiliation(s)
- K Jiang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - F Cao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - L Yin
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Y Hu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - X Zhao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - X Huang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - X Ma
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - J Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - M Lu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
| | - Y Sun
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
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Nie Z, Zeng K, Yan Q, Liu Y, Bian Y, Zhu J, Guo Z, He F, Shi H, Guo Y. The Relationship Between Gene Mutations and the Clinicopathological Features and Prognosis of Gastric Cancer. Int J Surg Pathol 2024; 32:486-495. [PMID: 37545327 DOI: 10.1177/10668969231188421] [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: 08/08/2023]
Abstract
Current treatments for gastric cancer (GC) are suboptimal. Potential therapeutic targets for GC were screened using next-generation sequencing. We examined many mutation genes linked to GC, including TP53 (60%), PIK3CA (19%), LRP1B (13%), and ERBB2 (12%), ARID1A (9%), KMT2C (9%), and KRAS (7%). The KMT2C, KRAS, CDK6, and ARID1A wild-type genes were dominant in diffuse-type GC (P < .05), but mutations did not influence prognosis. Patients with APC (6%) and CDH1 (8%) wild-type GC presented with vascular invasion (P < .05). Patients with ATR (2%) wild-type GC were prone to lymph node metastasis (P < .05). Patients with ARID1A (9%) wild-type GC had reduced programmed death ligand 1 expression (<1, P < .05). We found that patients who received chemotherapy had a better prognosis than those who did not (although there was no statistical difference), with platinum-based group having better prognosis and uracil combined with paclitaxel group having worse prognosis.
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Affiliation(s)
- Zunzhen Nie
- Department of Pathology, Xi'an Daxing Hospital, Xi'an, China
| | - Kaixuan Zeng
- Precision Medical Research Institute, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qingguo Yan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China
| | - Yuangang Liu
- Department of Pathology, Xi'an Daxing Hospital, Xi'an, China
| | - Yawei Bian
- Department of Pathology, Xi'an Daxing Hospital, Xi'an, China
| | - Jin Zhu
- Department of Pathology, Xi'an Daxing Hospital, Xi'an, China
| | - Zhenzhen Guo
- Department III of General Surgery, Xi'an Daxing Hospital, Xi'an, China
| | - Furong He
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China
| | - Hai Shi
- Department of Gastrointestinal Surgery, Xi'an Daxing Hospital, Xi'an, China
| | - Ying Guo
- Department of Pathology, Xi'an Daxing Hospital, Xi'an, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China
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10
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Zou G, Huang Y, Zhang S, Ko KP, Kim B, Zhang J, Venkatesan V, Pizzi MP, Fan Y, Jun S, Niu N, Wang H, Song S, Ajani JA, Park JI. E-cadherin loss drives diffuse-type gastric tumorigenesis via EZH2-mediated reprogramming. J Exp Med 2024; 221:e20230561. [PMID: 38411616 PMCID: PMC10899090 DOI: 10.1084/jem.20230561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 09/27/2023] [Accepted: 01/29/2024] [Indexed: 02/28/2024] Open
Abstract
Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 mutations, the role of CDH1/E-cadherin inactivation in sporadic DGAC tumorigenesis remains elusive. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that Cdh1 knock-out (KO), KrasG12D, Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared with KrasG12D, Trp53 KO (KP). We also identified EZH2 as a key mediator promoting CDH1 loss-associated DGAC tumorigenesis. These findings highlight DGAC's molecular diversity and potential for personalized treatment in CDH1-inactivated patients.
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Affiliation(s)
- Gengyi Zou
- Division of Radiation Oncology, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yuanjian Huang
- Division of Radiation Oncology, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shengzhe Zhang
- Division of Radiation Oncology, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kyung-Pil Ko
- Division of Radiation Oncology, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bongjun Kim
- Division of Radiation Oncology, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jie Zhang
- Division of Radiation Oncology, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vishwa Venkatesan
- Division of Radiation Oncology, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Melissa P. Pizzi
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yibo Fan
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sohee Jun
- Division of Radiation Oncology, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Na Niu
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Huamin Wang
- Division of Pathology/Lab Medicine, Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shumei Song
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaffer A. Ajani
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jae-Il Park
- Division of Radiation Oncology, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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11
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de Moraes FCA, Pasqualotto E, Chavez MP, Ferreira ROM, De Castria TB, Burbano RMR. Efficacy and safety of Zolbetuximab plus chemotherapy for advanced CLDN18.2-positive gastric or gastro-oesophageal adenocarcinoma: a meta-analysis of randomized clinical trials. BMC Cancer 2024; 24:240. [PMID: 38383390 PMCID: PMC10882870 DOI: 10.1186/s12885-024-11980-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 02/07/2024] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND The benefit of adding Zolbetuximab to the treatment in patients with Claudin-18 isoform 2 (CLDN18.2)-positive, human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GC/GEJ) is not yet fully elucidated. METHODS We searched PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs) that investigated Zolbetuximab plus chemotherapy versus chemotherapy alone for GC or GEJ adenocarcinoma. We computed hazard-ratios (HRs) or odds-ratios (ORs) for binary endpoints, with 95% confidence intervals (CIs). RESULTS Three studies and 1,233 patients were included. Comparing with Zolbetuximab plus chemotherapy versus chemotherapy alone, progression-free survival (PFS) rate (HR 0.64; 95% CI 0.49-0.84; p < 0.01) and overall survival (OS) rate (HR 0.72; 95% CI 0.62-0.83; p < 0.01) were significant in favor of the Zolbetuximab group. Regarding effectiveness, the Objective Response Rate (ORR) was (OR 1.15; 95% CI 0.87-1.53; p = 0.34). CONCLUSIONS In this comprehensive systematic review and meta-analysis of RCTs, the incorporation of Zolbetuximab alongside chemotherapy offers a promising prospect for reshaping the established treatment paradigms for patients diagnosed with advanced CLDN18.2-positive GC/GEJ cancer.
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Affiliation(s)
| | - Eric Pasqualotto
- Federal University of Santa Catarina, 88040-900, Florianópolis, Santa Catarina, Brazil
| | | | | | - Tiago Biachi De Castria
- Moffitt Cancer Center, 12902 USF Magnolia Drive, 33612, Tampa, FL, USA
- Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., 33612, Tampa, FL, USA
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12
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Costache S, de Havilland R, Diaz McLynn S, Sajin M, Baltan A, Wedden S, D’Arrigo C. Implementing an On-Slide Molecular Classification of Gastric Cancer: A Tissue Microarray Study. Cancers (Basel) 2023; 16:55. [PMID: 38201483 PMCID: PMC10778243 DOI: 10.3390/cancers16010055] [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: 10/21/2023] [Revised: 11/25/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
Background and Objectives: Gastric cancer (GC) is one of the most commonly diagnosed cancers and the fourth cause of cancer death worldwide. Personalised treatment improves GC outcomes. A molecular classification is needed to choose the appropriate therapy. A classification that uses on-slide biomarkers and formalin-fixed and paraffin-embedded (FFPE) tissue is preferable to comprehensive genomic analysis. In 2016, Setia and colleagues proposed an on-slide classification; however, this is not in widespread use. We propose a modification of this classification that has six subgroups: GC associated with Epstein-Barr virus (GC EBV+), GC with mismatch-repair deficiency (GC dMMR), GC with epithelial-mesenchymal transformation (GC EMT), GC with chromosomal instability (GC CIN), CG that is genomically stable (GC GS) and GC not otherwise specified (GC NOS). This classification also has a provision for biomarkers for current or emerging targeted therapies (Her2, PD-L1 and Claudin18.2). Here, we assess the implementation and feasibility of this inclusive working classification. Materials and Methods: We constructed a tissue microarray library from a cohort of 79 resection cases from FFPE tissue archives. We used a restricted panel of on-slide markers (EBER, MMR, E-cadherin, beta-catenin and p53), defined their interpretation algorithms and assigned each case to a specific molecular subtype. Results: GC EBV(+) cases were 6%, GC dMMR cases were 20%, GC EMT cases were 14%, GC CIN cases were 23%, GC GS cases were 29%, and GC NOS cases were 8%. Conclusions: This working classification uses markers that are widely available in histopathology and are easy to interpret. A diagnostic subgroup is obtained for 92% of the cases. The proportion of cases in each subgroup is in keeping with other published series. Widescale implementation appears feasible. A study using endoscopic biopsies is warranted.
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Affiliation(s)
- Simona Costache
- Pathology Department, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania; (M.S.); (A.B.)
- Poundbury Cancer Institute, Dorchester DT1 3BJ, UK; (R.d.H.); (S.D.M.); (C.D.)
| | | | - Sofia Diaz McLynn
- Poundbury Cancer Institute, Dorchester DT1 3BJ, UK; (R.d.H.); (S.D.M.); (C.D.)
| | - Maria Sajin
- Pathology Department, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania; (M.S.); (A.B.)
- Pathology Department, University Emergency Hospital, 050098 Bucharest, Romania
| | - Adelina Baltan
- Pathology Department, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania; (M.S.); (A.B.)
- Poundbury Cancer Institute, Dorchester DT1 3BJ, UK; (R.d.H.); (S.D.M.); (C.D.)
| | - Sarah Wedden
- Cancer Diagnostic Quality Assurance Services (CADQAS), Dorchester DT1 3BJ, UK;
| | - Corrado D’Arrigo
- Poundbury Cancer Institute, Dorchester DT1 3BJ, UK; (R.d.H.); (S.D.M.); (C.D.)
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13
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Cho SY, Kim Y, Hwang H, Kwon Y, Son SR, Baek JG, Park I, Kang YJ, Rhee H, Kwon HC, Kwon J, Kim WK, Jang DS. Saponins Derived from the Korean Endemic Plant Heloniopsis koreana Inhibit Diffuse-type Gastric Cancer Cells. ACS OMEGA 2023; 8:48019-48027. [PMID: 38144078 PMCID: PMC10734036 DOI: 10.1021/acsomega.3c06714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/10/2023] [Accepted: 11/23/2023] [Indexed: 12/26/2023]
Abstract
Diffuse-type gastric cancer (GC) is a type of stomach cancer that occurs in small clusters of cells that are widely spread. It does not typically manifest with symptoms until the advanced stages and often goes undetected in routine imaging tests. In addition, there is no specific targeted therapy for diffuse-type GC and it has a high mortality risk. Hence, it is worthwhile to discover molecules against this cancer. In this study, the extract of Heloniopsis koreana, which is endemic to Korea, exhibited cytotoxicity against two diffuse-type GC cell lines, MKN1 and SNU668. This led to the isolation of 10 compounds, including a new cinnamic acid glycoside. Of the compounds, saponin Th (4) and SNF 11 (5) showed potent activities with IC50 values of 3.66 and 3.85 μM, respectively, in MKN1 cells, and 1.8 and 1.98 μM, respectively, in SNU668 cells. These compounds prevented cancer cell division, invasion, and colony formation in both cell lines. In addition, these compounds induced cancer cell death through conventional cell death pathways, showing an increase in ADP-ribose polymerase, caspase 3, and BAX and a decrease in BCL2.
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Affiliation(s)
- Su-Yeon Cho
- KIST
Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea
- Division
of Bio-Medical Science &Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
| | - Yejin Kim
- Department
of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- College
of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hoseong Hwang
- KIST
Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea
| | - Yujin Kwon
- KIST
Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea
- Division
of Bio-Medical Science &Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
| | - So-Ri Son
- Department
of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- College
of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jong Gwon Baek
- KIST
Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea
| | - InWha Park
- KIST
Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea
| | - Yoon Jin Kang
- KIST
Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea
| | - Hyungjin Rhee
- Department
of Radiology, Research Institute of Radiological Science, Center for
Clinical Imaging Data Science, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Hak Cheol Kwon
- KIST
Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea
| | - Jaeyoung Kwon
- KIST
Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea
- Division
of Bio-Medical Science &Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
| | - Won Kyu Kim
- KIST
Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea
- Department
of Medical Science, Yonsei University Wonju
College of Medicine, Wonju 26426, Republic
of Korea
| | - Dae Sik Jang
- Department
of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- College
of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
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14
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Taieb J, Bennouna J, Penault-Llorca F, Basile D, Samalin E, Zaanan A. Treatment of gastric adenocarcinoma: A rapidly evolving landscape. Eur J Cancer 2023; 195:113370. [PMID: 37948843 DOI: 10.1016/j.ejca.2023.113370] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/11/2023] [Accepted: 09/26/2023] [Indexed: 11/12/2023]
Abstract
Gastric adenocarcinoma (GC) and gastroesophageal junction adenocarcinoma represent frequent and severe diseases whose management has radically changed over the last 10 years. With the advent of second- and third-line standard therapies for metastatic GC patients in the 2010s, the molecular dismemberment of the disease and positive trials with immunotherapy and targeted agents will mark the 2020s. New treatment options have emerged in the neoadjuvant, adjuvant, and metastatic setting. In addition to improved multimodal treatment in operable patients, new subgroups have emerged depending on molecular alterations (HER2, Microsatellite instability) or expression of specific proteins in the tumour (PDL1, Claudin 18.2) making immunohistochemistry central in profiling the tumour for an optimal individualised management. The aim of this review is to describe the current standards of management of early and late stage GC and the molecular markers needed today to optimally manage our patients together with future perspectives on this disease.
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Affiliation(s)
- Julien Taieb
- Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Institut du Cancer Paris CARPEM, Université Paris Cité, Paris, Hôpital Européen Georges Pompidou, Department of Tumor and Cancer Genomic Medicine, Paris, France.
| | - Jaafar Bennouna
- Department of Medical Oncology, Hopital Foch, Suresnes, France
| | | | - Debora Basile
- Department of Medical Oncology, San Giovanni di Dio Hospital, Crotone, Italy
| | - Emmanuelle Samalin
- Department of Medical Oncology, Institut du Cancer de Montpellier, Univ. Montpellier (ICM), Montpellier, France
| | - Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Institut du Cancer Paris CARPEM, Université Paris Cité, Paris, Hôpital Européen Georges Pompidou, Department of Tumor and Cancer Genomic Medicine, Paris, France
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15
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Ji K, Li L, Liu H, Shen Y, Jiang J, Zhang M, Teng H, Yan X, Zhang Y, Cai Y, Zhou H. Unveiling the role of GAS41 in cancer progression. Cancer Cell Int 2023; 23:245. [PMID: 37853482 PMCID: PMC10583379 DOI: 10.1186/s12935-023-03098-z] [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: 05/10/2023] [Accepted: 10/12/2023] [Indexed: 10/20/2023] Open
Abstract
GAS41, a member of the human YEATS domain family, plays a pivotal role in human cancer development. It serves as a highly promising epigenetic reader, facilitating precise regulation of cell growth and development by recognizing essential histone modifications, including histone acetylation, benzoylation, succinylation, and crotonylation. Functional readouts of these histone modifications often coincide with cancer progression. In addition, GAS41 functions as a novel oncogene, participating in numerous signaling pathways. Here, we summarize the epigenetic functions of GAS41 and its role in the carcinoma progression. Moving forward, elucidating the downstream target oncogenes regulated by GAS41 and the developing small molecule inhibitors based on the distinctive YEATS recognition properties will be pivotal in advancing this research field.
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Affiliation(s)
- Kangkang Ji
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Li Li
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Hui Liu
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Yucheng Shen
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Jian Jiang
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Minglei Zhang
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Hongwei Teng
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Xun Yan
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Yanhua Zhang
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Yong Cai
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China
| | - Hai Zhou
- Department of Central Laboratory, Binhai County People's Hospital, Yancheng, 224000, China.
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16
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Zou G, Huang Y, Zhang S, Ko KP, Kim B, Zhang J, Venkatesan V, Pizzi MP, Fan Y, Jun S, Niu N, Wang H, Song S, Ajani JA, Park JI. CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.23.533976. [PMID: 36993615 PMCID: PMC10055394 DOI: 10.1101/2023.03.23.533976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 gene mutations, causing E-Cadherin loss, its role in sporadic DGAC is unclear. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that Cdh1 knock-out (KO), KrasG12D, Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared to KrasG12D, Trp53 KO (KP). We also identified EZH2 as a key mediator promoting CDH1 loss-associated DGAC tumorigenesis. These findings highlight DGAC's molecular diversity and potential for personalized treatment in CDH1-inactivated patients.
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Affiliation(s)
- Gengyi Zou
- Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yuanjian Huang
- Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Shengzhe Zhang
- Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kyung-Pil Ko
- Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Bongjun Kim
- Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jie Zhang
- Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Vishwa Venkatesan
- Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Melissa P. Pizzi
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yibo Fan
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Sohee Jun
- Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Na Niu
- Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA
| | - Huamin Wang
- Department of Pathology, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Shumei Song
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jaffer A. Ajani
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jae-Il Park
- Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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17
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Ooki A, Osumi H, Fukuda K, Yamaguchi K. Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma. Cancer Metastasis Rev 2023; 42:1021-1054. [PMID: 37422534 PMCID: PMC10584733 DOI: 10.1007/s10555-023-10121-2] [Citation(s) in RCA: 8] [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: 04/30/2023] [Accepted: 06/16/2023] [Indexed: 07/10/2023]
Abstract
Neuroendocrine neoplasms (NENs), which are characterized by neuroendocrine differentiation, can arise in various organs. NENs have been divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) based on morphological differentiation, each of which has a distinct etiology, molecular profile, and clinicopathological features. While the majority of NECs originate in the pulmonary organs, extrapulmonary NECs occur most predominantly in the gastro-entero-pancreatic (GEP) system. Although platinum-based chemotherapy is the main therapeutic option for recurrent or metastatic GEP-NEC patients, the clinical benefits are limited and associated with a poor prognosis, indicating the clinically urgent need for effective therapeutic agents. The clinical development of molecular-targeted therapies has been hampered due to the rarity of GEP-NECs and the paucity of knowledge on their biology. In this review, we summarize the biology, current treatments, and molecular profiles of GEP-NECs based on the findings of pivotal comprehensive molecular analyses; we also highlight potent therapeutic targets for future precision medicine based on the most recent results of clinical trials.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.
| | - Hiroki Osumi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Koshiro Fukuda
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
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18
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Wang C, Wang Y, Chen J, Wang Y, Pang C, Liang C, Yuan L, Ma Y. CLDN18.2 expression and its impact on prognosis and the immune microenvironment in gastric cancer. BMC Gastroenterol 2023; 23:283. [PMID: 37582713 PMCID: PMC10428652 DOI: 10.1186/s12876-023-02924-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 08/10/2023] [Indexed: 08/17/2023] Open
Abstract
BACKGROUND The investigational use of zolbetuximab (IMAB362), a groundbreaking monoclonal antibody medication targeting claudin 18.2 (CLDN18.2), for treatment of advanced gastrointestinal cancers is currently underway. The unclear clinicopathological characteristics and tumour immune microenvironment of CLDN18.2-positive gastric cancer (GC) make it difficult to develop and optimize CLDN18.2-targeted therapies. METHODS A total of 451 tumour tissues, 342 matched paraneoplastic tissues, and 107 matched metastatic lymph nodes were collected from GC patients. These specimens were stained for CLDN18.2 expression and quantified using immunohistochemistry (IHC). Correlations between CLDN18.2 expression and clinicopathological features as well as immune-related factors were analysed. Survival curves were drawn using the Kaplan‒Meier approach, and independent factors affecting GC prognosis were identified using Cox regression analysis. Information from relevant databases was used for corroboration. RESULTS Expression of the CLDN18.2 gene was significantly lower in gastric tumour tissues than in normal tissues (p < 0.001) but comparable in metastatic lymph nodes (p = 0.851). CLDN18.2 expression was significantly associated with Borrmann type, degree of differentiation, PD-L1 expression, and survival in GC patients and was identified as an independent risk factor for patient prognosis (HR = 1.57, 95% CI 1.16-2.11, p = 0.003). There was no correlation between CLDN18.2 expression and HER2, Lauren type, tumour size, TNM stage, or any other clinicopathological characteristic. In CLDN18.2-positive tumours, fractions of CD4 + T cells and CD8 + T cells were significantly higher than those in CLDN18.2-negative tumours. Patients with CLDN18.2-negative expression and significant CD4 + T-cell or CD8 + T-cell infiltration had the best prognosis (5-year OS: 61.0%, P = 0.036; 5-year OS: 62.2%, P = 0.034). CONCLUSIONS CLDN18.2 is expressed at a low level in tumour tissues and serves as an independent prognostic factor for patients with GC. Furthermore, CLDN18.2 correlates with immune infiltrating cells and PD-L1 expression.
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Affiliation(s)
- Canming Wang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Yukai Wang
- The First Clinical Medical College of Zunyi Medical University, Zunyi, 563006, Guizhou, China
| | - Jinxia Chen
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Yi Wang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Chuhong Pang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Chen Liang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Li Yuan
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
| | - Yubo Ma
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.
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Xu X, Li Y, Zhang R, Chen X, Shen J, Yuan M, Chen Y, Chen M, Liu S, Wu J, Sun Q. Jianpi Yangzheng decoction suppresses gastric cancer progression via modulating the miR-448/CLDN18.2 mediated YAP/TAZ signaling. JOURNAL OF ETHNOPHARMACOLOGY 2023; 311:116450. [PMID: 37023839 DOI: 10.1016/j.jep.2023.116450] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/23/2023] [Accepted: 03/30/2023] [Indexed: 06/19/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Developing complementary and effective drugs with less toxicity is urgent for gastric cancer (GC) therapy. Jianpi Yangzheng Decoction (JPYZ) is a curative medical plants formula against GC in clinic while its molecular mechanism remains to be further elucidated. AIM OF THE STUDY To evaluate the in vitro and in vivo anticancer efficacy of JPYZ against GC and its potential mechanisms. MATERIALS AND METHODS The effect of JPYZ on regulating the candidate targets were screened and examined by RNA-Seq, qRT-PCR, luciferase reporter assay, and immunoblotting. Rescue experiment was conducted to authenticate the regulation of JPYZ on the target gene. Molecular interaction, intracellular localization and function of target genes were elucidated via Co-IP and cytoplasmic-nuclear fractionation. The impact of JPYZ on the abundance of target gene in clinical specimens of GC patients was evaluated by IHC. RESULTS JPYZ treatment suppressed the proliferation and metastasis of GC cells. RNA seq revealed JPYZ significantly downregulated miR-448. A reporter plasmid containing CLDN18 3'-UTR WT exhibited significant decrease in luciferase activity when co-transfected with miR-448 mimic in GC cells. CLDN18.2 deficiency promoted the proliferation and metastasis of GC cells in vitro, as well as intensified the growth of GC xenograft in mice. JPYZ reduced the proliferation and metastasis of GC cells with CLDN18.2 abrogation. Mechanically, suppressed activities of transcriptional coactivator YAP/TAZ and its downstream targets were observed in GC cells with CLDN18.2 overexpression and those under JPYZ treatment, leading to cytoplasmic retention of phosphorylated YAP at site Ser-127. High abundance of CLDN18.2 was detected in more GC patients who received chemotherapy combined with JPYZ. CONCLUSION JPYZ has an inhibitory effect on GC growth and metastasis partly by elevating CLDN18.2 abundance in GC cells, indicating more patients may benefit from combination therapy of JPYZ and the upcoming CLDN18.2 target agents.
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Affiliation(s)
- Xintian Xu
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, China.
| | - Yaqi Li
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, China; No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
| | - Ruijuan Zhang
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, China; No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
| | - Xu Chen
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, China; No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
| | - Junyu Shen
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, China; No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
| | - Mengyun Yuan
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, China; No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
| | - Yuxuan Chen
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, China; No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
| | - Menglin Chen
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, China; No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
| | - Shenlin Liu
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, China.
| | - Jian Wu
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, China.
| | - Qingmin Sun
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210029, China.
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20
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Zhang D, Huang G, Liu J, Wei W. Claudin18.2-targeted cancer theranostics. AMERICAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 2023; 13:64-69. [PMID: 37214268 PMCID: PMC10193197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 04/02/2023] [Indexed: 05/24/2023]
Abstract
Claudin 18.2 (CLDN18.2) is an emerging target for the treatment of CLDN18.2-expressing cancers such as gastric and pancreatic cancers. Cell and antibody therapies targeting CLDN18.2 are under intensive clinical trials. In this setting, how to efficiently and specifically detect CLDN18.2 expression before and after the therapies is a clinical challenge. In recent years, molecular imaging with radiolabeled antibodies or antibody fragments have shown promise in noninvasively annotating antigen expression across the body. In this Perspective, we will bring together the most recent progress on CLDN18.2-targeted imaging and therapy of solid tumors.
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Affiliation(s)
- Di Zhang
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China
| | - Gang Huang
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China
| | - Jianjun Liu
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China
| | - Weijun Wei
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, China
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Sadeghi M, Karimi MR, Karimi AH, Ghorbanpour Farshbaf N, Barzegar A, Schmitz U. Network-Based and Machine-Learning Approaches Identify Diagnostic and Prognostic Models for EMT-Type Gastric Tumors. Genes (Basel) 2023; 14:genes14030750. [PMID: 36981021 PMCID: PMC10048224 DOI: 10.3390/genes14030750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/10/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023] Open
Abstract
The microsatellite stable/epithelial-mesenchymal transition (MSS/EMT) subtype of gastric cancer represents a highly aggressive class of tumors associated with low rates of survival and considerably high probabilities of recurrence. In the era of precision medicine, the accurate and prompt diagnosis of tumors of this subtype is of vital importance. In this study, we used Weighted Gene Co-expression Network Analysis (WGCNA) to identify a differentially expressed co-expression module of mRNAs in EMT-type gastric tumors. Using network analysis and linear discriminant analysis, we identified mRNA motifs and microRNA-based models with strong prognostic and diagnostic relevance: three models comprised of (i) the microRNAs miR-199a-5p and miR-141-3p, (ii) EVC/EVC2/GLI3, and (iii) PDE2A/GUCY1A1/GUCY1B1 gene expression profiles distinguish EMT-type tumors from other gastric tumors with high accuracy (Area Under the Receiver Operating Characteristic Curve (AUC) = 0.995, AUC = 0.9742, and AUC = 0.9717; respectively). Additionally, the DMD/ITGA1/CAV1 motif was identified as the top motif with consistent relevance to prognosis (hazard ratio > 3). Molecular functions of the members of the identified models highlight the central roles of MAPK, Hh, and cGMP/cAMP signaling in the pathology of the EMT subtype of gastric cancer and underscore their potential utility in precision therapeutic approaches.
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Affiliation(s)
- Mehdi Sadeghi
- Department of Cell & Molecular Biology, Semnan University, Semnan 3513119111, Iran
| | - Mohammad Reza Karimi
- Department of Cell & Molecular Biology, Semnan University, Semnan 3513119111, Iran
| | - Amir Hossein Karimi
- Department of Cell & Molecular Biology, Semnan University, Semnan 3513119111, Iran
| | | | - Abolfazl Barzegar
- Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz 5166616471, Iran
| | - Ulf Schmitz
- Department of Molecular & Cell Biology, James Cook University, Townsville, QLD 4811, Australia
- Centre for Tropical Bioinformatics and Molecular Biology, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4878, Australia
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22
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Dai J, Zheng H, Jin J, Cheng Y, Xu H. Claudin18.2 expression and clinicopathological features in cytology effusion specimens from gastric adenocarcinoma: A comparative study with tissue specimens. Cancer Cytopathol 2023. [PMID: 36793190 DOI: 10.1002/cncy.22688] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 12/30/2022] [Accepted: 01/25/2023] [Indexed: 02/17/2023]
Abstract
BACKGROUND Zolbetuximab (IMAB362) is under investigation for treating advanced gastrointestinal tumors because it targets Claudin18.2 (CLDN18.2). CLDN18.2 is a promising molecule along with the presence of human epidermal growth factor receptor 2 in gastric cancer. This study evaluated cell block (CB) preparations of serous cavity effusions for the feasibility for CLDN18.2 protein expression and compared the results with those of biopsy or resection specimens. The association of CLDN18.2 expression in effusion samples and the clinicopathological features were also investigated. METHODS Cytological effusion specimens and matched surgical pathology biopsy or resection specimens of 43 gastric and gastroesophageal junctional cancer cases were stained for CLDN18.2 expression and quantified using immunohistochemistry based on the manufacturer's instructions. RESULTS Positive staining was detected in 34 (79.1%) tissue and 27 (62.8%) effusion CB samples in this study. When "positivity" was defined as moderate-to-strong staining in ≥40% viable tumor cells, CLDN18.2 expression was observed in 24 (55.8%) tissue and 22 (51.2%) effusion CB samples. A cutoff of 40% for CLDN18.2 positivity was used to demonstrate high concordance (83.7%) between cytology CB and tissue specimens. The results showed that CLDN18.2 expression in effusion specimens correlated with tumor size (p = .021) but not with sex, age at diagnosis, primary tumor location, staging, Lauren phenotype, cytomorphologic features, or Epstein-Barr virus infection. Cytological effusions with or without CLDN18.2 expression did not significantly affect overall survival. CONCLUSIONS This study's results show that serous body cavity effusions may be suitable for CLDN18.2 biomarker testing; however, discordant cases should be interpreted cautiously.
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Affiliation(s)
- Jiao Dai
- Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.,The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Heng Zheng
- Graduate School, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Ju Jin
- Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Ye Cheng
- Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Haimiao Xu
- Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China
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23
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Anti-Claudin18.2-IL-21 fusion protein bifunctional molecule has more powerful anti-tumor effect and better safety. Int Immunopharmacol 2023; 115:109634. [PMID: 36584573 DOI: 10.1016/j.intimp.2022.109634] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/19/2022] [Accepted: 12/21/2022] [Indexed: 12/30/2022]
Abstract
Antibody or antibody-like protein drugs related to tumor immunotherapy are now widely used. Here, we describe an antibody-fusion protein drug IMAB362-mIL-21 with mouse IL-21 (mIL-21) fused into the C-terminal domain of IMAB362 (a clinical antibody drug against Claudin18.2), that we expect can achieve tumor targeting and activate local anti-tumor immune response more effectively, while reducing the systemic side effects of individual cytokines. In vitro assays comparing the fusion protein IMAB362-mIL-21 to IMAB362 and mIL-21, IMAB362-mIL-21 was able to recognize its cognate antigen Claudin18.2 and natural receptor mIL-21R with similar binding affinities, mediate equivalent ADCC activity and activate IL-21R-mediated downstream signal pathway. In in vivo assays, IMAB362-mIL-21 produced stronger anti-tumor effects compared with IMAB362 or mIL-21 or their combination at equimolar concentrations. Moreover, according to routine blood indicators, mIL-21-Fc and the combined treatment group had significant decreases (P < 0.01) in red blood cells (RBC), hemoglobin (HGB) and hematocrit (HCT), while the IMAB362-mIL-21 group did not. The above results have shown that IMAB362-mIL-21 can produce better anti-tumor effects without obvious hematological toxicity, which is sufficient to show that this kind of antibody-cytokine protein has better application value than IMAB362 or IL-21 as single drugs or in combination. Therefore, this bifunctional molecule combined tumor-targeting and immune activation effectively and has good application prospects.
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24
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Pavlakis N, Tincknell G, Lim LE, Muro K, Obermannova R, Lorenzen S, Chua YJ, Jackson C, Karapetis CS, Price T, Chantrill L, Segelov E, Lordick F. European-Australasian consensus on the management of advanced gastric and gastro-oesophageal junction cancer: current practice and new directions. Ther Adv Med Oncol 2022; 14:17588359221118874. [PMID: 36051471 PMCID: PMC9425884 DOI: 10.1177/17588359221118874] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 07/25/2022] [Indexed: 11/17/2022] Open
Abstract
Gastric carcinoma and gastro-oesophageal junction (GC/GEJ) carcinoma remain a significant global problem, with patients presenting with symptoms often found to have advanced or metastatic disease. Treatment options for these patients have broadened in recent years with new chemotherapy agents, agents targeting angiogenic pathways and the development of immune checkpoint inhibitors (ICIs). Most initial advances have occurred in the refractory setting, where it is important to balance treatment benefits versus toxicity and patient quality of life. In the first-line treatment of advanced/metastatic GC/GEJ, platinum- and fluoropyrimidine-based chemotherapy protocols remain the backbone of therapy (with or without HER2-targeted therapy), with the FOLFIRI regimen offering an alternative in patients deemed unsuitable for a platinum agent. Microsatellite instability-high or mismatch repair-deficient cancers have been shown to benefit most from ICIs. In unselected patients previously treated with doublet or triplet platinum- and fluoropyrimidine-based chemotherapy and second-line chemotherapy with irinotecan or taxanes have formed the backbone of therapy with or without the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab in addition to paclitaxel. Beyond this, efficacy has been demonstrated with oral trifluridine/tipiracil and with single-agent nivolumab, in selected refractory patients. In this review, we highlight the positive evidence from key trials that have led to our current practice algorithm, with particular focus on the refractory advanced disease setting, discussing the areas of active research and highlighting the factors, including biomarkers and the influence of ethnicity, that contribute to therapeutic decision-making.
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Affiliation(s)
- Nick Pavlakis
- The Australasian Gastrointestinal Trials Group (AGITG), Camperdown, NSW, AustraliaDepartment of Medical Oncology, Royal North Shore Hospital, Sydney University, Reserve Road, St Leonards, Sydney, NSW 2065, AustraliaGenesis Care, North Shore Health Hub, St Leonards, NSW, Australia
| | - Gary Tincknell
- The Australasian Gastrointestinal Trials Group (AGITG), Camperdown, NSW, AustraliaIllawarra Cancer Care Centre, Wollongong Hospital, Wollongong, NSW, Australia
| | - Lisi Elizabeth Lim
- The Australasian Gastrointestinal Trials Group (AGITG), Camperdown, NSW, AustraliaBallarat Regional Integrated Cancer Centre, Ballarat, VIC, Australia
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | | | - Sylvie Lorenzen
- Department of Hematology and Oncology, Technical University, Munich, Germany
| | - Yu Jo Chua
- The Australasian Gastrointestinal Trials Group (AGITG), Camperdown, NSW, AustraliaDepartment of Medical Oncology, Canberra Hospital
| | - Chris Jackson
- The Australasian Gastrointestinal Trials Group (AGITG), Camperdown, NSW, AustraliaDepartment of Medicine, Otago Medical School, University of Otago, Dunedin, New Zealand
| | - Christos Stelios Karapetis
- The Australasian Gastrointestinal Trials Group (AGITG), Camperdown, NSW, AustraliaFlinders Medical Centre and Flinders University, Adelaide, SA, Australia
| | - Timothy Price
- The Australasian Gastrointestinal Trials Group (AGITG), Camperdown, NSW, AustraliaQueen Elizabeth Hospital, Adelaide, SA, Australia
| | - Lorraine Chantrill
- The Australasian Gastrointestinal Trials Group (AGITG), Camperdown, NSW, AustraliaIllawarra Cancer Care Centre, Wollongong Hospital, Wollongong, NSW, Australia
| | - Eva Segelov
- The Australasian Gastrointestinal Trials Group (AGITG), Camperdown, NSW, AustraliaDepartment of Medical Oncology, Monash Health and Monash University, Clayton, VIC, Australia
| | - Florian Lordick
- University Cancer Centre, Leipzig University Medical Centre, Germany
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25
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Receptor Tyrosine Kinases Amplified in Diffuse-Type Gastric Carcinoma: Potential Targeted Therapies and Novel Downstream Effectors. Cancers (Basel) 2022; 14:cancers14153750. [PMID: 35954414 PMCID: PMC9367326 DOI: 10.3390/cancers14153750] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/28/2022] [Accepted: 07/28/2022] [Indexed: 11/28/2022] Open
Abstract
Simple Summary Diffuse-type gastric carcinoma (DGC) is an aggressive subtype of gastric carcinoma with an extremely poor prognosis due to frequent peritoneal metastasis and high probability of recurrence. Its pathogenesis is poorly understood, and consequently, no effective molecular targeted therapy is available. The importance of oncogenic receptor tyrosine kinase (RTK) signaling has been recently demonstrated in the malignant progression of DGC. In particular, RTK gene amplification appears to accelerate peritoneal metastasis. In this review, we provide an overview of RTK gene amplification in DGC and the potential of related targeted therapies. Abstract Gastric cancer (GC) is a major cause of cancer-related death worldwide. Patients with an aggressive subtype of GC, known as diffuse-type gastric carcinoma (DGC), have extremely poor prognoses. DGC is characterized by rapid infiltrative growth, massive desmoplastic stroma, frequent peritoneal metastasis, and high probability of recurrence. These clinical features and progression patterns of DGC substantially differ from those of other GC subtypes, suggesting the existence of specific oncogenic signals. The importance of gene amplification and the resulting aberrant activation of receptor tyrosine kinase (RTK) signaling in the malignant progression of DGC is becoming apparent. Here, we review the characteristics of RTK gene amplification in DGC and its importance in peritoneal metastasis. These insights may potentially lead to new targeted therapeutics.
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Ooki A, Satoh T, Muro K, Takashima A, Kadowaki S, Sakai D, Ichimura T, Mitani S, Kudo T, Chin K, Kitano S, Thai D, Zavodovskaya M, Liu J, Boku N, Yamaguchi K. A phase 1b study of andecaliximab in combination with S-1 plus platinum in Japanese patients with gastric adenocarcinoma. Sci Rep 2022; 12:11007. [PMID: 35773363 PMCID: PMC9246925 DOI: 10.1038/s41598-022-13801-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 05/27/2022] [Indexed: 12/24/2022] Open
Abstract
Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. In preclinical models, MMP9 inhibitors have been shown to enhance the cytotoxic effects of chemotherapeutic agents and to suppress distant metastasis. In this phase Ib, multicenter study, the safety and efficacy of ADX combined with S-1 plus cisplatin (SP) or S-1 plus oxaliplatin (SOX) as a first-line treatment were evaluated in Japanese patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. ADX was administrated at a dose of 800 mg every 2 weeks for the SP cohort and 1200 mg every three weeks for the SOX cohort. As of December 2019, 16 patients were enrolled (six patients in the SP cohort and 10 patients in the SOX cohort). Peripheral sensory neuropathy (69%), anorexia (63%), nausea (56%), and decreased neutrophil counts (44%) were the most common adverse events (AEs). The grade 3 or higher AEs attributed to ADX were stomatitis and abnormal hepatic function (each one patient) in the SP cohort and decreased neutrophil counts (two patients) in the SOX cohort. The objective response rate in 11 patients with measurable target lesions was 73% (8/11), based on the investigator's evaluation. Median progression-free survival was11.9 months (90% confidence interval, 5.6-16.6), and median overall survival was not reached. In conclusion, ADX combined with S-1 plus platinum demonstrated a manageable safety profile and promising clinical activity in the first-line treatment of patients with advanced gastric or GEJ adenocarcinoma.Clinical Trial Registration information: ClinicalTrials.gov Identifier: NCT02862535 (11/08/2016) and protocol ID: GS-US-296-1884.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Taroh Satoh
- Palliative and Supportive Care Center, Osaka University Hospital, Osaka, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Atsuo Takashima
- Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Daisuke Sakai
- Palliative and Supportive Care Center, Osaka University Hospital, Osaka, Japan
| | - Takashi Ichimura
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Seiichiro Mitani
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Toshihiro Kudo
- Department of Medical Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Keisho Chin
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Shigehisa Kitano
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | - Dung Thai
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | | | - Narikazu Boku
- Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
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