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Ferrari DP, Çobanoglu Ö, Sayedipour S, Luna O, Ferkel SAM, Agorku D, Perez Y, Cruz LJ, Albericio F, Trottein F, Alves F, Markus MA, Ramos-Gomes F. Anti-Tumor Efficacy of a Mesothelin-Based Nanovaccine in a KPC Orthotopic Mouse Model of Pancreatic Cancer. Vaccines (Basel) 2025; 13:314. [PMID: 40266223 PMCID: PMC11946167 DOI: 10.3390/vaccines13030314] [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: 12/19/2024] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 04/24/2025] Open
Abstract
Background/Objectives: Immunotherapy has shown promising results in some cancers, but its efficacy remains limited in pancreatic ductal adenocarcinoma (PDAC). Vaccines in nanoparticle form (nanovaccines) can incorporate immunostimulating components to induce a potent immune response. As mesothelin (MSLN) is a tumor-associated antigen overexpressed in PDAC, we evaluated the effect of MSLN nanovaccine in a syngeneic orthotopic KPC-PDAC mouse model. Methods: An MSLN peptide combining three MSLN epitopes and two adjuvants, poly I:C and R848, was encapsulated in PLGA-chitosan nanoparticles to generate the nanovaccine. Results: The MSLN nanovaccine was successfully taken up by dendritic cells in vitro and was found in inguinal lymph nodes 24 h after subcutaneous injection into C57BL/6 mice. Nanovaccine re-stimulation of splenocytes from vaccinated mice led to increased levels of interferon-γ in vitro compared to unstimulated splenocytes. Higher levels of MSLN-specific IgM and IgG antibodies were detected in the serum of vaccinated mice compared to that of control mice. Three vaccination regimens were tested: a prophylactic scheme that included vaccination before tumor induction and two therapeutic schemes involving early and late vaccination after tumor cell inoculation. MSLN nanovaccination inhibited KPC tumor progression and metastasis and induced higher CD8+ T cell infiltration in the tumor that developed in response to prophylactic and early therapeutic schedules but not in response to a later vaccination approach. Although the nanovaccine treatment elicited higher humoral and cellular antigen-specific responses in tumor-bearing mice for both vaccination strategies, the therapeutic vaccination also increased the expression of exhaustion markers in CD8+ T cells. Conclusions: Our results support the relevance of an MSLN-based nanovaccine as a new immunotherapy treatment for PDAC and propose an innovative method of vaccine delivery using NPs.
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Affiliation(s)
- Daniele P. Ferrari
- Translational Molecular Imaging, Max-Planck-Institute for Multidisciplinary Sciences, 37075 Göttingen, Germany
| | - Özmen Çobanoglu
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Sana Sayedipour
- Department of Radiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Omar Luna
- Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain (F.A.)
| | - Sonia A. M. Ferkel
- Translational Molecular Imaging, Max-Planck-Institute for Multidisciplinary Sciences, 37075 Göttingen, Germany
| | - David Agorku
- Miltenyi Biotec B.V. & Co. KG, 51429 Bergisch Gladbach, Germany
| | | | - Luis J. Cruz
- Department of Radiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Fernando Albericio
- Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain (F.A.)
| | - François Trottein
- Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
| | - Frauke Alves
- Translational Molecular Imaging, Max-Planck-Institute for Multidisciplinary Sciences, 37075 Göttingen, Germany
- Department of Haematology and Medical Oncology, Translational Molecular Imaging, University Medical Center Göttingen, 37075 Göttingen, Germany
- Institute of Diagnostic and Interventional Radiology, Translational Molecular Imaging, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Marietta Andrea Markus
- Translational Molecular Imaging, Max-Planck-Institute for Multidisciplinary Sciences, 37075 Göttingen, Germany
| | - Fernanda Ramos-Gomes
- Translational Molecular Imaging, Max-Planck-Institute for Multidisciplinary Sciences, 37075 Göttingen, Germany
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Ramalingam PS, Premkumar T, Sundararajan V, Hussain MS, Arumugam S. Design and development of dual targeting CAR protein for the development of CAR T-cell therapy against KRAS mutated pancreatic ductal adenocarcinoma using computational approaches. Discov Oncol 2024; 15:592. [PMID: 39453574 PMCID: PMC11511808 DOI: 10.1007/s12672-024-01455-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/11/2024] [Indexed: 10/26/2024] Open
Abstract
Mutant KRAS promotes the proliferation, metastasis, and aggressiveness of various cancers including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal adenocarcinoma (CRC) respectively. Mutant KRAS therapeutics are limited, while Sotorasib and Adagrasib were the only FDA-approved drugs for the treatment of KRASG12C mutated NSCLC. Chimeric antigen receptor (CAR) T-cell therapy has been emerged as an effective strategy against hematological malignancies and being extended towards solid cancers including PDAC. mesothelin (MSLN) and Carcinoembryonic Antigen (CEA) were reported to be highly overexpressed in KRAS-mutated PDAC. Meanwhile, in clinical trials, several CAR T-cell therapy studies are mainly focused towards these two cancer antigens in PDAC, however, the dual targeting of these two neoantigens is not reported. In the present study, we have designed and developed a novel dual-targeting CAR protein by employing various bioinformatics approaches such as functional analysis (antigenicity, allergenicity, antigen binding sites & signalling cascades), qualitative analysis (physicochemical, prediction, refinement & validation of 2D and 3D structures), molecular docking, and in silico cloning. Our results revealed that the designed CAR protein specifically binds with both MSLN & CEA with significant binding affinities, and was predicted to be stable & non-allergenic. Additionally, the protein-protein interaction network reveals the T-cell mediated antitumor responses of each domain in the designed CAR. Conclusively, we have designed and developed a dual targeting (MSLN & CEA) CAR protein towards KRAS-mutated PDAC using computational approaches. Alongside, we further recommend to engineer this designed CAR in T-cells and evaluating their therapeutic efficiency in in vitro and in vivo studies in the near future.
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Affiliation(s)
- Prasanna Srinivasan Ramalingam
- Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - T Premkumar
- Integrative Multiomics Lab, School of Bio-Sciences & Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Vino Sundararajan
- Integrative Multiomics Lab, School of Bio-Sciences & Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Md Sadique Hussain
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand, 248007, India
| | - Sivakumar Arumugam
- Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
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Malla M, Deshmukh SK, Wu S, Samec T, Olevian DC, El Naili R, El-Rayes B, Xiu J, Farrell A, Lenz HJ, Lou E, Goel S, Spetzler D, Goldberg RM, Hazlehurst L. Mesothelin expression correlates with elevated inhibitory immune activity in patients with colorectal cancer. Cancer Gene Ther 2024; 31:1547-1558. [PMID: 39174744 PMCID: PMC11489080 DOI: 10.1038/s41417-024-00816-1] [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: 02/15/2024] [Revised: 06/19/2024] [Accepted: 07/24/2024] [Indexed: 08/24/2024]
Abstract
The expression of the protein Mesothelin (MSLN) is highly variable in several malignancies, including colorectal cancer (CRC), and high levels are associated with aggressive clinicopathological features and worse patient survival. Colorectal cancer is both a common and deadly cancer; being the third most common in incidence and second most common cause of cancer-related death. While systemic therapy remains the primary therapeutic option for most patients with stage IV (metastatic; m) CRC, their disease eventually becomes treatment refractory, and 85% succumb within 5 years. Microsatellite-stable (MSS) CRC tumors, which constitute more than 90% of patients with mCRC, are generally refractory to immunotherapeutic interventions. In our current work, we characterize MSLN levels in CRC, specifically correlating expression with clinical outcomes in relevant CRC subtypes, and explore how MSLN expression impacts the status of immune activation and suppression in the peritumoral microenvironment. Higher MSLN expression is prevalent in CMS1 and CMS4 CRC subtypes and correlates with higher gene mutation rates across the patient cohorts. Further, MSLN-high patients exhibit increased M1/M2 macrophage infiltration, PD-L1 staining, immune-inhibitory gene expression, enrichment in inflammatory, TGF-β, IL6/JAK/STAT3, IL2/STAT5 signaling pathways, and mutation in KRAS and FBXW7. Together, these results suggest that MSLN protein is a potential target for antigen-specific therapy and supports investigation into its tumorigenic effects to identify possible therapeutic interventions for patients with high MSLN expressing MSS CRC.
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Affiliation(s)
| | | | - Sharon Wu
- Caris Life Sciences, Phoenix, AZ, USA
| | | | - Dane C Olevian
- West Virginia University Department of Pathology, Morgantown, WV, USA
| | - Reima El Naili
- West Virginia University Department of Pathology, Morgantown, WV, USA
| | | | | | | | - Heinz-Josef Lenz
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Emil Lou
- Masonic Cancer Center/University of Minnesota Medical School, Minneapolis, MN, USA
| | - Sanjay Goel
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
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Nabeta R, Kanaya A, Shimada K, Matsuura K, Yoshimura A, Oyamada T, Azakami D, Furuya T, Uchide T. Characterization of mesothelin gene expression in dogs and overexpression in canine mesotheliomas. Front Vet Sci 2024; 11:1436621. [PMID: 39315086 PMCID: PMC11417096 DOI: 10.3389/fvets.2024.1436621] [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: 05/22/2024] [Accepted: 08/26/2024] [Indexed: 09/25/2024] Open
Abstract
Introduction Canine mesotheliomas are uncommon malignant tumors typically detected late. Minimally invasive diagnostic biomarkers would facilitate diagnosis at earlier stages, thereby improving clinical outcomes. We hypothesized that mesothelin could be used as a reliable diagnostic biomarker for canine mesotheliomas since it has been used as a cancer biomarker for human mesothelioma. We aimed to explore and characterize mesothelin gene expression in dogs and assess its use as a diagnostic biomarker for canine mesotheliomas. Materials and methods We quantified expressed canine mesothelin transcripts via reverse transcription polymerase chain reaction (RT-PCR) and sequenced them using ribonucleic acid (RNA) extracted from a canine mesothelioma cell line. After confirming mesothelin expression, we assessed its levels in major organ tissues and compared them with those in the mesothelioma tissues using quantitative PCR (qPCR). Mesothelin overexpression in mesotheliomas was detected, and we further compared its levels using qPCR between mesotheliomas and non-mesotheliomas using tumor tissues and clinical sample effusions, confirming its significance as a diagnostic biomarker for canine mesothelioma. Results Mesothelin complementary deoxyribonucleic acid (cDNA) was amplified via RT-PCR, yielding a single band of expected upon DNA electrophoresis. Sequence analyses confirmed it as a predicted canine mesothelin transcript from the genome sequence database. Comparative sequence analysis of the deduced amino acid sequence of the expressed canine mesothelin demonstrated molecular signature similarities with the human mesothelin. However, the pre-sequence of canine mesothelin lacks the mature megakaryocyte potentiating factor (MPF) portion, which is typically cleaved post-translationally with furin. Mesothelin expression was quantified via qPCR revealing low levels in the mesothelial and lung tissues, with negligible expression in the other major organs. Canine mesothelin exhibited significantly higher expression in the canine mesotheliomas than in the noncancerous tissues. Moreover, analysis of clinical samples using qPCR demonstrated markedly elevated mesothelin expression in canine mesotheliomas compared to non-mesothelioma cases. Discussion and conclusion Canine mesothelin exhibits molecular and biological characteristics akin to human mesothelin. It could serve as a vital biomarker for diagnosing canine mesotheliomas, applicable to both tissue- and effusion-based samples.
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Affiliation(s)
- Rina Nabeta
- Laboratory of Veterinary Molecular Pathology and Therapeutics, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Ami Kanaya
- Laboratory of Veterinary Molecular Pathology and Therapeutics, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Kazumi Shimada
- Laboratory of Veterinary Surgery, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Katsuhiro Matsuura
- Laboratory of Veterinary Surgery, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
- Department of Small Animal Clinical Science, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States
| | - Aritada Yoshimura
- Animal Medical Center, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Tomohiro Oyamada
- Animal Medical Center, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Daigo Azakami
- Laboratory of Veterinary Clinical Oncoogy, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Tetsuya Furuya
- Laboratory of Veterinary Infectious Diseases, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
| | - Tsuyoshi Uchide
- Laboratory of Veterinary Molecular Pathology and Therapeutics, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Japan
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Chen Q, Sun Y, Li H. Application of CAR-T cell therapy targeting mesothelin in solid tumor treatment. Discov Oncol 2024; 15:289. [PMID: 39023820 PMCID: PMC11258118 DOI: 10.1007/s12672-024-01159-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 07/15/2024] [Indexed: 07/20/2024] Open
Abstract
Chimeric antigen receptor (CAR)-T-cell therapy is one of the most effective immunotherapies. CAR-T-cell therapy has achieved great success in the treatment of hematological malignancies. However, due to the characteristics of solid malignant tumors, such as on-target effects, off-tumor toxicity, an immunosuppressive tumor microenvironment (TME), and insufficient trafficking, CAR-T-cell therapy for solid tumors is still in the exploration stage. Mesothelin (MSLN) is a molecule expressed on the surface of various solid malignant tumor cells that is suitable as a target of tumor cells with high MSLN expression for CAR-T-cell therapy. This paper briefly described the development of CAR-T cell therapy and the structural features of MSLN, and especially summarized the strategies of structure optimization of MSLN-targeting CAR-T-cells and the enhancement methods of MSLN-targeting CAR-T cell anti-tumor efficacy by summarizing some preclinical experiment and clinical trials. When considering MSLN-targeting CAR-T-cell therapy as an example, this paper summarizes the efforts made by researchers in CAR-T-cell therapy for solid tumors and summarizes feasible treatment plans by integrating the existing research results.
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Affiliation(s)
- Qiuhong Chen
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, No. 88 East Wenhua Road, Jinan, 250014, People's Republic of China
| | - Yang Sun
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, No. 88 East Wenhua Road, Jinan, 250014, People's Republic of China
| | - Hua Li
- Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, No. 88 East Wenhua Road, Jinan, 250014, People's Republic of China.
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Lee K, Perry K, Xu M, Veillard I, Kumar R, Rao TD, Rueda BR, Spriggs DR, Yeku OO. Structural basis for antibody recognition of the proximal MUC16 ectodomain. J Ovarian Res 2024; 17:41. [PMID: 38374055 PMCID: PMC10875768 DOI: 10.1186/s13048-024-01373-9] [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: 08/09/2023] [Accepted: 02/13/2024] [Indexed: 02/21/2024] Open
Abstract
BACKGROUND Mucin 16 (MUC16) overexpression is linked with cancer progression, metastasis, and therapy resistance in high grade serous ovarian cancer and other malignancies. The cleavage of MUC16 forms independent bimodular fragments, the shed tandem repeat sequence which circulates as a protein bearing the ovarian cancer biomarker (CA125) and a proximal membrane-bound component which is critical in MUC16 oncogenic behavior. A humanized, high affinity antibody targeting the proximal ectodomain represents a potential therapeutic agent against MUC16 with lower antigenic potential and restricted human tissue expression. RESULTS Here, we demonstrate the potential therapeutic versatility of the humanized antibody as a monoclonal antibody, antibody drug conjugate, and chimeric antigen receptor. We report the crystal structures of 4H11-scFv, derived from an antibody specifically targeting the MUC16 C-terminal region, alone and in complex with a 26-amino acid MUC16 segment resolved at 2.36 Å and 2.47 Å resolution, respectively. The scFv forms a robust interaction with an epitope consisting of two consecutive β-turns and a β-hairpin stabilized by 2 hydrogen bonds. The VH-VL interface within the 4H11-scFv is stabilized through an intricate network of 11 hydrogen bonds and a cation-π interaction. CONCLUSIONS Together, our studies offer insight into antibody-MUC16 ectodomain interaction and advance our ability to design agents with potentially improved therapeutic properties over anti-CA125 moiety antibodies.
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Affiliation(s)
- Kwangkook Lee
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital-Harvard Medical School, Boston, MA, USA
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Kay Perry
- Department of Chemistry and Chemical Biology, Argonne National Laboratory, NE-CAT, Cornell University, Building 436E, 9700 S. Cass Avenue, Argonne, IL, 60439, USA
| | - Mengyao Xu
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Irva Veillard
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Raj Kumar
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Thapi Dharma Rao
- Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Bo R Rueda
- Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - David R Spriggs
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital-Harvard Medical School, Boston, MA, USA
| | - Oladapo O Yeku
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital-Harvard Medical School, Boston, MA, USA.
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7
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Malla M, Kumar Deshkmukh S, Wu S, Samec T, Olevian D, Naili R, Bassel ER, Xiu J, Farrell A, Lenz HJ, Lou E, Goel S, Spetzler D, Goldberg RM, Hazlehurst L. Mesothelin expression correlates with elevated inhibitory immune activity in patients with colorectal cancer. RESEARCH SQUARE 2023:rs.3.rs-3787873. [PMID: 38234761 PMCID: PMC10793489 DOI: 10.21203/rs.3.rs-3787873/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2024]
Abstract
The expression of the protein Mesothelin (MSLN) is highly variable in several malignancies including colorectal cancer (CRC) and high levels are associated with aggressive clinicopathological features and worse patient survival. CRC is both a common and deadly cancer; being the third most common in incidence and second most common cause of cancer related death. While systemic therapy remains the primary therapeutic option for most patients with stage IV (metastatic; m) CRC, their disease eventually becomes treatment refractory, and 85% succumb within 5 years. Microsatellite-stable (MSS) CRC tumors, which affect more than 90% of patients with mCRC, are generally refractory to immunotherapeutic interventions. In our current work, we characterize MSLN levels in CRC, specifically correlating expression with clinical outcomes in relevant CRC subtypes and explore how MSLN expression impacts the status of immune activation and suppression in the peritumoral microenvironment. High MSLN expression is highly prevalent in CMS1 and CMS4 CRC subtypes as well as in mCRC tissue and correlates with higher gene mutation rates across the patient cohorts. Further, MSLN-high patients exhibit increased M1/M2 macrophage infiltration, PD-L1 staining, immune-inhibitory gene expression, enrichment in inflammatory, TGF-β, IL6/JAK/STAT3, IL2/STAT5 signaling pathways and mutation in KRAS and FBXW7. Together, these results suggest MSLN protein is a potential target for antigen-specific therapy and supports investigation into its tumorigenic effects to identify possible therapeutic interventions for patients with high MSLN expressing MSS CRC.
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8
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Hagerty BL, Takabe K. Biology of Mesothelin and Clinical Implications: A Review of Existing Literature. World J Oncol 2023; 14:340-349. [PMID: 37869242 PMCID: PMC10588497 DOI: 10.14740/wjon1655] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 08/30/2023] [Indexed: 10/24/2023] Open
Abstract
Since its discovery in 1992, mesothelin (MSLN) has generated significant interest as a therapeutic target. A number of characteristics make it ideal for this purpose. First, it is not expressed on the parenchyma of any vital organs. Second, it is differentially expressed on a number of cancer types that have relatively poor prognosis and lack effective systemic options. Third, it is expressed on the cell membrane making it accessible to large molecule targeted therapies. However, unlike other drug targets that have been exploited for therapeutic benefit, the precise function of MSLN, why it is expressed in certain cancers, and its biological role have not been clearly elucidated. Here the existing literature on the cellular function and expression patterns of MSLN across tumor types is reviewed in order to gain further understanding of this intriguing molecule. In doing so, we conclude that there remains significant ambiguity surrounding its function and role in cellular and tumor biology. Furthermore, the expression of MSLN and its relation of prognosis seems to depend on the type of tumor. Finally, the unified mechanism by which MSLN acts as a protein that conveys tumor aggressiveness remains elusive. What is clear is that there is much yet to be discovered in this realm and doing so may have large implications for treatment of otherwise lethal malignancies.
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Affiliation(s)
- Brendan L Hagerty
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, USA
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
- Department of Breast Surgery, Fukushima Medical University, Fukushima, Japan
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Marin-Muller C, Li D, Lü JM, Liang Z, Vega-Martínez O, Crawford SE, Estes MK, Fisher WE, Chen C, Yao Q. Nanoparticle-Mediated Therapy with miR-198 Sensitizes Pancreatic Cancer to Gemcitabine Treatment through Downregulation of VCP-Mediated Autophagy. Pharmaceutics 2023; 15:2038. [PMID: 37631252 PMCID: PMC10457905 DOI: 10.3390/pharmaceutics15082038] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 07/18/2023] [Accepted: 07/25/2023] [Indexed: 08/27/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains an extremely aggressive disease characterized by rapidly acquired multi-drug resistance, including to first-line chemotherapeutic agent gemcitabine. Autophagy is a process that is often exploited by cancer and is one of several intrinsic factors associated with resistance to gemcitabine. We have previously found that miR-198 acts as a tumor suppressor in PDAC through the targeting of factors including Valosin-containing protein (VCP). VCP has been reported to play an important role in autophagic flux. In this study, we investigated whether the repression of VCP through miR-198 administration disrupts the autophagy process and sensitizes PDAC cells to gemcitabine treatment in vitro. Moreover, we used LGA-PEI (LPNP) nanoparticles to effectively administer miR-198 to tumors in vivo, inducing tumor sensitization to gemcitabine and leading to a significant reduction in tumor burden and metastases and a concomitant downregulation of VCP expression and autophagy maturation. Our results indicate a potential therapeutic strategy for targeting gemcitabine resistant PDAC and establishes the use of LPNPs for effective therapeutic delivery of nucleic acids in vitro and in vivo.
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Affiliation(s)
- Christian Marin-Muller
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; (C.M.-M.)
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
- Speratum Biopharma, Inc., Dover, DE 19901, USA
| | - Dali Li
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; (C.M.-M.)
| | - Jian-Ming Lü
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; (C.M.-M.)
| | - Zhengdong Liang
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; (C.M.-M.)
| | | | - Sue E. Crawford
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Mary K. Estes
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - William E. Fisher
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; (C.M.-M.)
| | - Changyi Chen
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; (C.M.-M.)
| | - Qizhi Yao
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; (C.M.-M.)
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
- Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA
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10
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Chen Q, Wang Q, Wang Y, Chu Y, Luo Y, You H, Su B, Li C, Guo Q, Sun T, Jiang C. Penetrating Micelle for Reversing Immunosuppression and Drug Resistance in Pancreatic Cancer Treatment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2107712. [PMID: 35285149 DOI: 10.1002/smll.202107712] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/11/2022] [Indexed: 06/14/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is on of the most lethal malignant tumors with relatively poor prognosis, characterized with insufficient drug penetration, low immune response and obvious drug resistances. The therapeutic inefficiency is multifactorially related to its specific tumor microenvironment (TME), which is representatively featured as rich stroma and immunosuppression. In this work, a versatile drug delivery system is developed that can coencapsulate two prodrugs modified from gemcitabine (GEM) and a signal transducer and activator of transcription 3 (STAT3) inhibitor (HJC0152), and the gradient pH variation is further sensed in the TME of PDAC to achieve a higher penetration by reversing its surficial charges. The escorted prodrugs can release GEM intracellularly, and respond to the hypoxic condition to yield the parental STAT3 inhibitor HJC0152, respectively. By inhibiting STAT3, the tumor immunosuppression microenvironment can be re-educated through the reversion of M2-like tumor associated macrophages (M2-TAMs), recruitment of cytotoxic T lymphocytes and downregulation of regulatory T cells (Treg s). Furthermore, cytidine deaminase (CDA) and α-smooth muscle actin (α-SMA) expression can be downregulated, plus the lipid modification of GEM, the drug resistance of GEM can be greatly relieved. Based on the above design, a synergetic therapeutic efficacy in PDAC treatment can be achieved to provide more opportunity for clinical applications.
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Affiliation(s)
- Qinjun Chen
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Qingbing Wang
- Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China
| | - Yu Wang
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Yongchao Chu
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Yifan Luo
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Haoyu You
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Boyu Su
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Chao Li
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Qin Guo
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Tao Sun
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Chen Jiang
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
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11
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Taniguchi G, Kajino K, Momose S, Saeki H, Yue L, Ohtsuji N, Abe M, Shibuya T, Orimo A, Nagahara A, Watanabe S, Hino O. The Inhibitory Effects of Anti-ERC/Mesothelin Antibody 22A31 on Colorectal Adenocarcinoma Cells, within a Mouse Xenograft Model. Cancers (Basel) 2022; 14:cancers14092198. [PMID: 35565327 PMCID: PMC9101225 DOI: 10.3390/cancers14092198] [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: 03/08/2022] [Revised: 04/22/2022] [Accepted: 04/26/2022] [Indexed: 11/23/2022] Open
Abstract
Simple Summary The expression of Renal Carcinoma (ERC)/mesothelin is overexpressed in malignancies such as mesothelioma, pancreatic cancer, and ovarian cancer, and molecular-targeted therapies against ERC/mesothelin have been developed to treat them. Recently, it was revealed that ERC/mesothelin is also expressed in colorectal cancer; thus, this protein is expected to be a therapeutic target in colorectal cancer. In this study, we demonstrated that anti-ERC/mesothelin antibody 22A31 suppressed the growth of colorectal cancer cells subcutaneously xenografted on the back of mice. This is the first report to show the effectiveness of an anti-ERC/mesothelin antibody for the treatment of colorectal cancer in vivo. Abstract The expression of Renal Carcinoma (ERC)/mesothelin is enhanced in a variety of cancers. ERC/mesothelin contributes to cancer progression by modulating cell signals that regulate proliferation and apoptosis. Based on such biological insights, ERC/mesothelin has become a molecular target for the treatment of mesothelioma, pancreatic cancer, and ovarian cancer. Recent studies revealed about 50–60% of colorectal adenocarcinomas also express ERC/mesothelin. Therefore, colorectal cancer can also be a potential target of the treatment using an anti-ERC/mesothelin antibody. We previously demonstrated an anti-tumor effect of anti-ERC antibody 22A31 against mesothelioma. In this study, we investigated the effect of 22A31 on a colorectal adenocarcinoma cell line, HCT116. The cells were xenografted into BALB/c nu/nu mice. All mice were randomly allocated to either an antibody treatment group with 22A31 or isotype-matched control IgG1κ. We compared the volume of subsequent tumors, and tumors were pathologically assessed by immunohistochemistry. Tumors treated with 22A31 were significantly smaller than those treated with IgG1κ and contained significantly fewer mitotic cells with Ki67 staining. We demonstrated that 22A31 exhibited a growth inhibitory property on HCT116. Our results implied that ERC/mesothelin-targeted therapy might be a promising treatment for colorectal cancer.
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Affiliation(s)
- Gentaro Taniguchi
- Department of Molecular Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (G.T.); (L.Y.); (N.O.); (M.A.); (A.O.); (O.H.)
- Department of Gastroenterology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (T.S.); (A.N.); (S.W.)
| | - Kazunori Kajino
- Department of Molecular Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (G.T.); (L.Y.); (N.O.); (M.A.); (A.O.); (O.H.)
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan;
- Correspondence:
| | - Shuji Momose
- Department of Pathology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe 350-8550, Japan;
| | - Harumi Saeki
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan;
| | - Liang Yue
- Department of Molecular Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (G.T.); (L.Y.); (N.O.); (M.A.); (A.O.); (O.H.)
| | - Naomi Ohtsuji
- Department of Molecular Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (G.T.); (L.Y.); (N.O.); (M.A.); (A.O.); (O.H.)
- Department of Human Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan;
| | - Masaaki Abe
- Department of Molecular Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (G.T.); (L.Y.); (N.O.); (M.A.); (A.O.); (O.H.)
| | - Tomoyoshi Shibuya
- Department of Gastroenterology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (T.S.); (A.N.); (S.W.)
| | - Akira Orimo
- Department of Molecular Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (G.T.); (L.Y.); (N.O.); (M.A.); (A.O.); (O.H.)
| | - Akihito Nagahara
- Department of Gastroenterology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (T.S.); (A.N.); (S.W.)
| | - Sumio Watanabe
- Department of Gastroenterology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (T.S.); (A.N.); (S.W.)
| | - Okio Hino
- Department of Molecular Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (G.T.); (L.Y.); (N.O.); (M.A.); (A.O.); (O.H.)
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12
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Park JY, Yoo KD, Bae E, Kim KH, Lee JW, Shin SJ, Lee JS, Kim YS, Yang SH. Blockade of STAT3 signaling alleviates progression of acute kidney injury-to-chronic kidney disease through anti-apoptosis. Am J Physiol Renal Physiol 2022; 322:F553-F572. [PMID: 35311382 DOI: 10.1152/ajprenal.00595.2020] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a pivotal mediator of IL-6-type cytokine signaling. However, the roles of its full-length and truncated isoforms in acute kidney injury (AKI) and its transition to chronic kidney disease (CKD) remain elusive. Herein, the role of STAT3 isoforms in AKI-to-CKD transition was characterized using an ischemia-reperfusion injury (IRI) mouse model. IRI was induced in C57BL/6 mice. Stattic®, a STAT3 inhibitor, was administered to the mice 3 h prior to IRI. Intrarenal cytokine expression was quantified using real-time PCR, and FACS analysis was performed. The effect of Stattic® on human tubular epithelial cells (TECs) cultured under hypoxic conditions was also evaluated. Phosphorylated STAT3 isoforms were detected by western blotting. Stattic® treatment attenuated IRI-induced tubular damage and inflammatory cytokine/chemokine expression, while decreasing macrophage infiltration and fibrosis in mouse unilateral IRI and UUO models. Similarly, in vitro STAT3 inhibition downregulated fibrosis and apoptosis in 72-h hypoxia-induced human TECs and reduced pSTAT3α-mediated inflammation. Moreover, pSTAT3 expression was increased in human acute tubular necrosis and CKD tissues. STAT3 activation is associated with IRI progression, and STAT3-α may be a significant contributor. Hence, STAT3 may affect AKI-to-CKD transition, suggesting a novel strategy for AKI management with STAT3 inhibitors.
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Affiliation(s)
- Jae Yoon Park
- Department of Internal Medicine, Dongguk University College of Medicine, Dongguk University Ilsan Hospital, Goyang-si, Korea (South), Republic of
| | - Kyung Don Yoo
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea (South), Republic of
| | - Eunjin Bae
- Department of Internal Medicine, Gyeongsang National University College of Medicine, Gyeongsang University Changwon Hospital, Changwon, Korea (South), Republic of
| | - Kyu Hong Kim
- Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea (South), Republic of
| | - Jae Wook Lee
- Nephrology Clinic, National Cancer Center of Korea, Seoul, Korea (South), Republic of
| | - Sung Joon Shin
- Department of Internal Medicine, Dongguk University College of Medicine, Dongguk University Ilsan Hospital, Goyang-si, Korea (South), Republic of
| | - Jong Soo Lee
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea (South), Republic of
| | - Yon Su Kim
- Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea (South), Republic of.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea (South), Republic of.,Kidney Research Institute, Seoul National University, Seoul, Korea (South), Republic of.,Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea (South), Republic of
| | - Seung Hee Yang
- Kidney Research Institute, Seoul National University, Seoul, Korea (South), Republic of.,Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea (South), Republic of
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13
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Mesothelin: An Immunotherapeutic Target beyond Solid Tumors. Cancers (Basel) 2022; 14:cancers14061550. [PMID: 35326701 PMCID: PMC8946840 DOI: 10.3390/cancers14061550] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/12/2022] [Accepted: 03/17/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary This review summarizes the current knowledge on mesothelin’s function, its role in cancer, and opportunities for immunotherapeutic targeting of mesothelin. Immunotherapies including monoclonal antibodies, antibody–drug conjugates, chimeric antigen receptor T and NK-cells, targeted alpha therapies, and bispecific T cell engaging molecules are reviewed. We show future directions for mesothelin targeting in hematological malignancies, including acute myeloid leukemia. Abstract Modern targeted cancer therapies rely on the overexpression of tumor associated antigens with very little to no expression in normal cell types. Mesothelin is a glycosylphosphatidylinositol-anchored cell surface protein that has been identified in many different tumor types, including lung adenocarcinomas, ovarian carcinomas, and most recently in hematological malignancies, including acute myeloid leukemia (AML). Although the function of mesothelin is widely unknown, interactions with MUC16/CA125 indicate that mesothelin plays a role in the regulation of proliferation, growth, and adhesion signaling. Most research on mesothelin currently focuses on utilizing mesothelin to design targeted cancer therapies such as monoclonal antibodies, antibody–drug conjugates, chimeric antigen receptor T and NK cells, bispecific T cell engaging molecules, and targeted alpha therapies, amongst others. Both in vitro and in vivo studies using different immunotherapeutic modalities in mesothelin-positive AML models highlight the potential impact of this approach as a unique opportunity to treat hard-to-cure AML.
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14
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Li D, Lin S, Hong J, Ho M. Immunotherapy for hepatobiliary cancers: Emerging targets and translational advances. Adv Cancer Res 2022; 156:415-449. [DOI: 10.1016/bs.acr.2022.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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15
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Araújo TG, Mota STS, Ferreira HSV, Ribeiro MA, Goulart LR, Vecchi L. Annexin A1 as a Regulator of Immune Response in Cancer. Cells 2021; 10:2245. [PMID: 34571894 PMCID: PMC8464935 DOI: 10.3390/cells10092245] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/05/2021] [Accepted: 08/07/2021] [Indexed: 01/01/2023] Open
Abstract
Annexin A1 is a 37 kDa phospholipid-binding protein that is expressed in many tissues and cell types, including leukocytes, lymphocytes and epithelial cells. Although Annexin A1 has been extensively studied for its anti-inflammatory activity, it has been shown that, in the cancer context, its activity switches from anti-inflammatory to pro-inflammatory. Remarkably, Annexin A1 shows pro-invasive and pro-tumoral properties in several cancers either by eliciting autocrine signaling in cancer cells or by inducing a favorable tumor microenvironment. Indeed, the signaling of the N-terminal peptide of AnxA1 has been described to promote the switching of macrophages to the pro-tumoral M2 phenotype. Moreover, AnxA1 has been described to prevent the induction of antigen-specific cytotoxic T cell response and to play an essential role in the induction of regulatory T lymphocytes. In this way, Annexin A1 inhibits the anti-tumor immunity and supports the formation of an immunosuppressed tumor microenvironment that promotes tumor growth and metastasis. For these reasons, in this review we aim to describe the role of Annexin A1 in the establishment of the tumor microenvironment, focusing on the immunosuppressive and immunomodulatory activities of Annexin A1 and on its interaction with the epidermal growth factor receptor.
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Affiliation(s)
- Thaise Gonçalves Araújo
- Laboratory of Genetics and Biotechnology, Federal University of Uberlandia, Patos de Minas 387400-128, MG, Brazil; (T.G.A.); (S.T.S.M.); (H.S.V.F.); (M.A.R.)
- Laboratory of Nanobiotechnology, Federal University of Uberlandia, Uberlandia 38400-902, MG, Brazil;
| | - Sara Teixeira Soares Mota
- Laboratory of Genetics and Biotechnology, Federal University of Uberlandia, Patos de Minas 387400-128, MG, Brazil; (T.G.A.); (S.T.S.M.); (H.S.V.F.); (M.A.R.)
- Laboratory of Nanobiotechnology, Federal University of Uberlandia, Uberlandia 38400-902, MG, Brazil;
| | - Helen Soares Valença Ferreira
- Laboratory of Genetics and Biotechnology, Federal University of Uberlandia, Patos de Minas 387400-128, MG, Brazil; (T.G.A.); (S.T.S.M.); (H.S.V.F.); (M.A.R.)
| | - Matheus Alves Ribeiro
- Laboratory of Genetics and Biotechnology, Federal University of Uberlandia, Patos de Minas 387400-128, MG, Brazil; (T.G.A.); (S.T.S.M.); (H.S.V.F.); (M.A.R.)
| | - Luiz Ricardo Goulart
- Laboratory of Nanobiotechnology, Federal University of Uberlandia, Uberlandia 38400-902, MG, Brazil;
| | - Lara Vecchi
- Laboratory of Nanobiotechnology, Federal University of Uberlandia, Uberlandia 38400-902, MG, Brazil;
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16
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Weidemann S, Perez D, Izbicki JR, Neipp M, Mofid H, Daniels T, Nahrstedt U, Jacobsen F, Bernreuther C, Simon R, Steurer S, Burandt E, Marx AH, Krech T, Clauditz TS, Jansen K. Mesothelin is Commonly Expressed in Pancreatic Adenocarcinoma but Unrelated to Cancer Aggressiveness. Cancer Invest 2021; 39:711-720. [PMID: 34143695 DOI: 10.1080/07357907.2021.1943747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Data on Mesothelin (MSLN) expression in human normal and cancerous tissues is controversial. We employed immunohistochemistry (IHC) on a tissue microarray (TMA) from 599 pancreatic cancers and 12 large tissue sections of pancreatitis. MSLN expression was highest in pancreatic adenocarcinomas (89%) and adenocarcinomas of the ampulla Vateri (79%), infrequent in pancreatitis and absent in 6 acinus cell carcinomas and normal pancreas. MSLN expression was unrelated to pathological tumor stage, grade, metastasis, and tumor-infiltrating CD8+ lymphocytes. In conclusion, pancreatic cancer may be ideally suited for putative anti- MSLN therapies, and MSLN may represent a suitable biomarker for pancreatic cancer diagnosis, especially on small biopsies.
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Affiliation(s)
- Sören Weidemann
- 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
| | - 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
| | - Thies Daniels
- General, Visceral and Tumor Surgery Clinic, Albertinen Hospital, Hamburg, Germany
| | - Ulf Nahrstedt
- Department of General and Abdominal Surgery, Schoen Clinic Hamburg Eilbek, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Bernreuther
- 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
| | - 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
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kristina Jansen
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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17
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Chu C, Geng Y, Zhou Y, Sicinski P. Cyclin E in normal physiology and disease states. Trends Cell Biol 2021; 31:732-746. [PMID: 34052101 DOI: 10.1016/j.tcb.2021.05.001] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/29/2021] [Accepted: 05/03/2021] [Indexed: 01/17/2023]
Abstract
E-type cyclins, collectively called cyclin E, represent key components of the core cell cycle machinery. In mammalian cells, two E-type cyclins, E1 and E2, activate cyclin-dependent kinase 2 (CDK2) and drive cell cycle progression by phosphorylating several cellular proteins. Abnormally elevated activity of cyclin E-CDK2 has been documented in many human tumor types. Moreover, cyclin E overexpression mediates resistance of tumor cells to various therapeutic agents. Recent work has revealed that the role of cyclin E extends well beyond cell proliferation and tumorigenesis, and it may regulate a diverse array of physiological and pathological processes. In this review, we discuss these various cyclin E functions and the potential for therapeutic targeting of cyclin E and cyclin E-CDK2 kinase.
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Affiliation(s)
- Chen Chu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Yan Geng
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Yu Zhou
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA; Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu, China
| | - Piotr Sicinski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
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18
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Fujii Y, Kamachi H, Matsuzawa F, Mizukami T, Kobayashi N, Fukai M, Taketomi A. Early administration of amatuximab, a chimeric high-affinity anti-mesothelin monoclonal antibody, suppresses liver metastasis of mesothelin-expressing pancreatic cancer cells and enhances gemcitabine sensitivity in a xenograft mouse model. Invest New Drugs 2021; 39:1256-1266. [PMID: 33905019 DOI: 10.1007/s10637-021-01118-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 04/15/2021] [Indexed: 01/11/2023]
Abstract
Amatuximab is a promising therapeutic antibody targeting mesothelin, a 40-kDa glycoprotein that is highly expressed in pancreatic cancer. We investigated the effectiveness of early amatuximab treatment, imitating an adjuvant chemotherapy setting, and combination therapy with amatuximab and gemcitabine in liver metastasis of pancreatic cancer. Liver metastasis mouse models were established in 8-week-old male BALB/c nu/nu mice using the hemisplenic injection method. Tridaily amatuximab monotherapy or combination with gemcitabine was administered to the liver metastasis mouse model before metastatic lesions had formed huge masses. Gaussia luciferase-transfected AsPC-1 was used as a mesothelin-overexpressing pancreatic cancer cell line. The amount of liver metastases and the serum luciferase activity were significantly lower in the treatment groups than those in the control IgG group. Notably, the anti-tumor activity of gemcitabine was synergically enhanced by combination therapy with amatuximab. Furthermore, western blotting revealed that the high expression of phosphorylated c-Met and AKT in liver metastatic lesions treated with gemcitabine monotherapy was canceled by its combination with amatuximab. This result indicated that the observed synergic therapeutic effect may have occurred as a result of the inhibitory effect of amatuximab on the phosphorylation of c-Met and AKT, which were promoted by exposure to GEM. In conclusion, our study revealed that early administration of amatuximab alone or in combination with GEM significantly suppressed the liver metastases of mesothelin-expressing pancreatic cancer cells. A phase II clinical trial of amatuximab as part of an adjuvant chemotherapy regimen for resected pancreatic cancer is expected.
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Affiliation(s)
- Yuki Fujii
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan
| | - Hirofumi Kamachi
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan.
| | - Fumihiko Matsuzawa
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan
| | - Tatsuzo Mizukami
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan
| | - Nozomi Kobayashi
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery 1, Hokkaido University Graduate School of Medicine, N15W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan
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19
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Matsuzawa F, Kamachi H, Mizukami T, Einama T, Kawamata F, Fujii Y, Fukai M, Kobayashi N, Hatanaka Y, Taketomi A. Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells. BMC Cancer 2021; 21:200. [PMID: 33637083 PMCID: PMC7912898 DOI: 10.1186/s12885-020-07722-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/09/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. METHODS We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. RESULTS Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. CONCLUSIONS Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.
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Affiliation(s)
- Fumihiko Matsuzawa
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Hirofumi Kamachi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.
| | - Tatsuzo Mizukami
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takahiro Einama
- Department of Surgery, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama, 359-8513, Japan
| | - Futoshi Kawamata
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yuki Fujii
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Nozomi Kobayashi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yutaka Hatanaka
- Research Division of Companion Diagnostics, Hokkaido University Hospital, Kita 14, Nishi 5, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan
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Yang X, Huang M, Zhang Q, Chen J, Li J, Han Q, Zhang L, Li J, Liu S, Ma Y, Li L, Yang L, Zou S, Han B. Metformin Antagonizes Ovarian Cancer Cells Malignancy Through MSLN Mediated IL-6/STAT3 Signaling. Cell Transplant 2021; 30:9636897211027819. [PMID: 34238029 PMCID: PMC8274104 DOI: 10.1177/09636897211027819] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/01/2021] [Accepted: 06/08/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Ovarian cancer is the most lethal gynecological malignancy, and chemotherapy remains the cornerstone for ovarian cancer management. Due to the unsatisfactory prognosis, a better understanding of the underlying molecular carcinogenesis is urgently required. METHODS Assays for determining cell growth, cell motility, and apoptosis were employed to evaluate the potential antitumor effects of metformin against ovarian cancer cells. Molecular biological methods were employed to explore the underlying mechanism. Human ovarian cancer samples and Gene Expression Profiling Interactive Analysis (GEPIA) dataset were used for uncovering the clinical significances of mesothelin (MSLN) on ovarian cancer. RESULTS In the present work, we found that metformin treatment led to cell growth and cell migration inhibition, and induced cell apoptosis. Metformin administration also impaired cancer cell stemness and the capillary-like structure formation capacity of SKOV3 cells. On mechanism, metformin treatment remarkably reduced mesothelin (MSLN) expression, downregulated IL-6/STAT3 signaling activity, subsequently resulted in VEGF and TGFβ1 expression. We also observed an oncogenic function of MSLN on ovarian cancer. CONCLUSIONS Collectively, our findings suggested that metformin exerts anticancer effects by suppressing ovarian cancer cell malignancy, which attributed to MSLN inhibition mediated IL6/STAT3 signaling and VEGF and TGFβ1 downregulation.
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Affiliation(s)
- Xu Yang
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Mei Huang
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Qin Zhang
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Jiao Chen
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Juan Li
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Qian Han
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Lu Zhang
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - JiaQi Li
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Shuai Liu
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - YuLan Ma
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Lan Li
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Lei Yang
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - SiYing Zou
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
| | - Bin Han
- Department of Obstetrics and Gynecology, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China
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Klampatsa A, Dimou V, Albelda SM. Mesothelin-targeted CAR-T cell therapy for solid tumors. Expert Opin Biol Ther 2020; 21:473-486. [PMID: 33176519 DOI: 10.1080/14712598.2021.1843628] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Mesothelin (MSLN) is a tumor differentiation antigen normally restricted to the body's mesothelial surfaces, but significantly overexpressed in a broad range of solid tumors. For this reason, MSLN has emerged as an important target for the development of novel immunotherapies. This review focuses on anti-MSLN chimeric antigen receptor (CAR) T cell immunotherapy approaches.Areas covered: A brief overview of MSLN as a therapeutic target and existing anti-MSLN antibody-based drugs and vaccines is provided. A detailed account of anti-MSLN CAR-T cell approaches utilized in preclinical models is presented. Finally, a comprehensive summary of currently ongoing and completed anti-MSLN CAR-T cell clinical trials is discussed.Expert opinion: Initial trials using anti-MSLN CAR-T cells have been safe, but efficacy has been limited. Employing regional routes of delivery, introducing novel modifications leading to enhanced tumor infiltration and persistence, and improved safety profiles and combining anti-MSLN CAR-T cells with standard therapies, could render them more efficacious in the treatment of solid malignancies.
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Affiliation(s)
- Astero Klampatsa
- Thoracic Oncology Immunotherapy Group, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK
| | - Vivian Dimou
- Thoracic Oncology Immunotherapy Group, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK
| | - Steven M Albelda
- Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Possible reversibility between epithelioid and sarcomatoid types of mesothelioma is independent of ERC/mesothelin expression. Respir Res 2020; 21:187. [PMID: 32677949 PMCID: PMC7364551 DOI: 10.1186/s12931-020-01449-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 07/08/2020] [Indexed: 12/12/2022] Open
Abstract
Background Mesothelioma is histologically divided into three subgroups: epithelioid, sarcomatoid, and biphasic types. The epithelioid or sarcomatoid type is morphologically defined by polygonal or spindle-like forms of cells, respectively. The biphasic type consists of both components. It is not yet understood how histological differentiation of mesothelioma is regulated. ERC/mesothelin is expressed in most cases of the epithelioid type, but not in the sarcomatoid type of mesothelioma. Consequently, its expression is well correlated to the histological subtype. We hypothesized that ERC/mesothelin expression influences the histological differentiation of mesothelioma, and tested this hypothesis. Methods We performed studies using the overexpression or knockdown of ERC/mesothelin in mesothelioma cells to examine its effect on cellular morphology, growth kinetics, or migration/invasion activity, in vitro. We then transplanted ERC/mesothelin-overexpressing and control cells into the intraperitoneal space of mice. We examined the effect of ERC/mesothelin overexpression on mouse survival and tumor phenotype. Results In vitro cell culture manipulations of ERC/mesothelin expression did not affect cellular morphology or proliferation, although its overexpression enhanced cellular adhesion and the migration/invasion activity of mesothelioma cells. The survival rate of mice following intraperitoneal transplantation of ERC/mesothelin-overexpressing mesothelioma cells was significantly lower than that of mice with control cells. The histological evaluation of the tumors, however, did not show any morphological difference between two groups, and our hypothesis was not validated. Unexpectedly, both groups (ERC/mesothelin-overexpressing and control) of mesothelioma cells that were morphologically monophasic and spindle-like in vitro differentiated into a biphasic type consisting of polygonal and spindle-like components in the transplanted tumor, irrespective of ERC/mesothelin expression. Conclusions These results suggested that the histological transition of mesothelioma between epithelioid and sarcomatoid types may be reversible and regulated not by ERC/mesothelin, but by other unknown mechanisms.
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Histoepigenetic analysis of the mesothelin network within pancreatic ductal adenocarcinoma cells reveals regulation of retinoic acid receptor gamma and AKT by mesothelin. Oncogenesis 2020; 9:62. [PMID: 32616712 PMCID: PMC7332500 DOI: 10.1038/s41389-020-00245-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 06/04/2020] [Accepted: 06/09/2020] [Indexed: 12/26/2022] Open
Abstract
To enable computational analysis of regulatory networks within the cancer cell in its natural tumor microenvironment, we develop a two-stage histoepigenetic analysis method. The first stage involves iterative computational deconvolution to estimate sample-specific cancer-cell intrinsic expression of a gene of interest. The second stage places the gene within a network module. We validate the method in simulation experiments, show improved performance relative to differential expression analysis from bulk samples, and apply it to illuminate the role of the mesothelin (MSLN) network in pancreatic ductal adenocarcinoma (PDAC). The network analysis and subsequent experimental validation in a panel of PDAC cell lines suggests AKT activation by MSLN through two known activators, retinoic acid receptor gamma (RARG) and tyrosine kinase non receptor 2 (TNK2). Taken together, these results demonstrate the potential of histoepigenetic analysis to reveal cancer-cell specific molecular interactions directly from patient tumor profiles.
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Montemagno C, Cassim S, Pouyssegur J, Broisat A, Pagès G. From Malignant Progression to Therapeutic Targeting: Current Insights of Mesothelin in Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2020; 21:E4067. [PMID: 32517181 PMCID: PMC7312874 DOI: 10.3390/ijms21114067] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/19/2020] [Accepted: 05/20/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all pancreatic tumors, is a highly devastating disease with poor prognosis and rising incidence. The lack of available specific diagnostics tests and the limited treatment opportunities contribute to this pejorative issue. Over the last 10 years, a growing interest pointing towards mesothelin (MSLN) as a promising PDAC-associated antigen has emerged. The limited expression of MSLN in normal tissues (peritoneum, pleura and pericardium) and its overexpression in 80 to 90% of PDAC make it an attractive candidate for therapeutic management of PDAC patients. Moreover, its role in malignant progression related to its involvement in tumor cell proliferation and resistance to chemotherapy has highlighted the relevance of its targeting. Hence, several clinical trials are investigating anti-MSLN efficacy in PDAC. In this review, we provide a general overview of the different roles sustained by MSLN during PDAC progression. Finally, we also summarize the different MSLN-targeted therapies that are currently tested in the clinic.
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Affiliation(s)
- Christopher Montemagno
- Département de Biologie Médicale, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (S.C.); (J.P.); (G.P.)
- Institute for Research on Cancer and Aging of Nice, Université Cote d’Azur, CNRS UMR 7284, INSERM U1081, Centre Antoine Lacassagne, 06200 Nice, France
| | - Shamir Cassim
- Département de Biologie Médicale, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (S.C.); (J.P.); (G.P.)
| | - Jacques Pouyssegur
- Département de Biologie Médicale, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (S.C.); (J.P.); (G.P.)
- Institute for Research on Cancer and Aging of Nice, Université Cote d’Azur, CNRS UMR 7284, INSERM U1081, Centre Antoine Lacassagne, 06200 Nice, France
| | - Alexis Broisat
- Laboratoire Radiopharmaceutiques Biocliniques, INSERM, 1039-Université de Grenoble, 38700 La Tronche, France;
| | - Gilles Pagès
- Département de Biologie Médicale, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (S.C.); (J.P.); (G.P.)
- Institute for Research on Cancer and Aging of Nice, Université Cote d’Azur, CNRS UMR 7284, INSERM U1081, Centre Antoine Lacassagne, 06200 Nice, France
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Virus-Like Particles as an Immunogenic Platform for Cancer Vaccines. Viruses 2020; 12:v12050488. [PMID: 32349216 PMCID: PMC7291217 DOI: 10.3390/v12050488] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/21/2020] [Accepted: 04/24/2020] [Indexed: 12/11/2022] Open
Abstract
Virus-like particles (VLP) spontaneously assemble from viral structural proteins. They are naturally biocompatible and non-infectious. VLP can serve as a platform for many potential vaccine epitopes, display them in a dense repeating array, and elicit antibodies against non-immunogenic substances, including tumor-associated self-antigens. Genetic or chemical conjugation facilitates the multivalent display of a homologous or heterologous epitope. Most VLP range in diameter from 25 to 100 nm and, in most cases, drain freely into the lymphatic vessels and induce antibodies with high titers and affinity without the need for additional adjuvants. VLP administration can be performed using different strategies, regimens, and doses to improve the immunogenicity of the antigen they expose on their surface. This article summarizes the features of VLP and presents them as a relevant platform technology to address not only infectious diseases but also chronic diseases and cancer.
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26
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Le K, Wang J, Zhang T, Guo Y, Chang H, Wang S, Zhu B. Overexpression of Mesothelin in Pancreatic Ductal Adenocarcinoma (PDAC). Int J Med Sci 2020; 17:422-427. [PMID: 32174772 PMCID: PMC7053310 DOI: 10.7150/ijms.39012] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Accepted: 01/05/2020] [Indexed: 12/11/2022] Open
Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) with difficulty in early diagnosis does not respond well to conventional treatments and has not occurred significant improvement in the overall 5-year survival rates. Mesothelin (MSLN) is a tumor differentiation antigen expressed in several solid neoplasms and a limited number of healthy tissues. Its selective expression on malignant cells makes it an interesting candidate for investigation as a diagnostic and prognostic biomarker and as a therapeutic target. In this study, we detected the expression of MSLN in PDAC and analyzed the correlation between the expression of MSLN and clinicopathological data, so as to provide more theoretical basis for the role of MSLN in the diagnosis and treatment of PDAC. Patients and methods: Cancer and para-cancer tissues of 24 cases with PDAC were assessed by standardized immunohistochemical (IHC) detection with two kinds of anti-MSLN antibodies (EPR4509 and EPR19025-42) to detect their positive expression rates and study the correlation between the expression of MSLN and the clinicopathological data. Results: The two anti-MSLN antibodies of cancer tissues showed positive expression with tan yellow or tan brown granules diffusely distributed on the cell membrane in 22 of 24 cases with PDAC (positive rate of 91.67%), and the positive expression of the two antibodies EPR4509 and EPR19025-42 was completely consistent in all tissue samples. No expression of the two anti-MSLN antibodies was found in para-cancer tissues and the difference was statistically significant (χ2=40.615, p=0.000, p<0.05) when compared with PDAC tissues. There was no significant correlation between MSLN expression and clinicopathological data, such as gender, tumor size, location, pathological stage, differentiation degree and lymph node metastasis (p>0.05). Conclusion: MSLN was highly expressed in PDAC tissues, but not in paracancerous tissues. There was no significant correlation between MSLN expression and clinicopathological factors. The overexpression of MSLN may have promising prospects in diagnosis, targeted therapy and immunotherapy of PDAC.
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Affiliation(s)
- Kai Le
- Department of General Surgery, Peking University Ninth School of Clinical Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of Urology Surgery, Aerospace Center Hospital, Beijing, China
| | - Jia Wang
- Department of General Surgery, Peking University Ninth School of Clinical Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Tao Zhang
- Department of General Surgery, Liang Xiang Teaching Hospital of Capital Medical University, Beijing, China
| | - Yifan Guo
- Department of General Surgery, Peking University Ninth School of Clinical Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Hong Chang
- Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Siyuan Wang
- Department of Rehabilitation Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Bin Zhu
- Department of General Surgery, Peking University Ninth School of Clinical Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
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Sirois AR, Deny DA, Li Y, Fall YD, Moore SJ. Engineered Fn3 protein has targeted therapeutic effect on mesothelin-expressing cancer cells and increases tumor cell sensitivity to chemotherapy. Biotechnol Bioeng 2019; 117:330-341. [PMID: 31631324 DOI: 10.1002/bit.27204] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 10/05/2019] [Accepted: 10/13/2019] [Indexed: 12/12/2022]
Abstract
Mesothelin is a protein expressed at high levels on the cell surface in a variety of cancers, with limited expression in healthy tissues. The presence of mesothelin on tumor tissue correlates with increased invasion and metastasis, and resistance to traditional chemotherapies, through mechanisms that remain poorly understood. Molecules that specifically recognize mesothelin and interrupt its contribution to tumor progression have significant potential for targeted therapy and targeted drug delivery applications. A number of mesothelin-targeting therapies are in preclinical and clinical development, although none are currently approved for routine clinical use. In this work, we report the development of a mesothelin-targeting protein based on the fibronectin type-III non-antibody protein scaffold, which offers opportunities for applications where antibodies have limitations. We engineered protein variants that bind mesothelin with high affinity and selectively initiate apoptosis in tumor cells expressing mesothelin. Interestingly, apoptosis does not occur through a caspase-mediated pathway and does not require downregulation of cell-surface mesothelin, suggesting a currently unknown pathway through which mesothelin contributes to cancer progression. Importantly, simultaneous treatment with mesothelin-binding protein and chemotherapeutic mitomycin C had a greater cytotoxic effect on mesothelin-positive cells compared to either molecule alone, underscoring the potential for combination therapy including biologics targeting mesothelin.
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Affiliation(s)
- Allison R Sirois
- Molecular and Cellular Biology Program, University of Massachusetts Amherst, Amherst, Massachusetts.,Picker Engineering Program, Smith College, Northampton, Massachusetts
| | - Daniela A Deny
- Biochemistry Program, Smith College, Northampton, Massachusetts
| | - Yanxuan Li
- Picker Engineering Program, Smith College, Northampton, Massachusetts
| | - Yacine D Fall
- Biochemistry Program, Smith College, Northampton, Massachusetts
| | - Sarah J Moore
- Molecular and Cellular Biology Program, University of Massachusetts Amherst, Amherst, Massachusetts.,Picker Engineering Program, Smith College, Northampton, Massachusetts.,Department of Biological Sciences, Smith College, Northampton, Massachusetts
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Avula LR, Rudloff M, El-Behaedi S, Arons D, Albalawy R, Chen X, Zhang X, Alewine C. Mesothelin Enhances Tumor Vascularity in Newly Forming Pancreatic Peritoneal Metastases. Mol Cancer Res 2019; 18:229-239. [PMID: 31676721 DOI: 10.1158/1541-7786.mcr-19-0688] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 09/20/2019] [Accepted: 10/28/2019] [Indexed: 02/06/2023]
Abstract
Over 90% of pancreatic ductal adenocarcinomas (PDAC) express mesothelin (MSLN). Overexpression or knockdown of MSLN has been implicated in PDAC aggressiveness. This activity has been ascribed to MSLN-induced activation of MAPK or NF-κB signaling pathways and to interaction of MSLN with its only known binding partner, MUC16. Here, we used CRISPR/Cas9 gene editing to delete MSLN from PDAC, then restored expression of wild-type (WT) or Y318A mutant MSLN by viral transduction. We found that MSLN KO cells grew in culture and as subcutaneous tumors in mouse xenografts at the same rate as WT cells but formed intraperitoneal metastases poorly. Complementation with WT MSLN restored intraperitoneal growth, whereas complementation with Y318A mutant MSLN, which does not bind MUC16, was ineffective at enhancing growth in both MUC16(+) and MUC16(-) models. Restoration of WT MSLN did enhance growth but did not affect cell-to-cell binding, cell viability in suspension or signaling pathways previously identified as contributing to the protumorigenic effect of MSLN. RNA deep sequencing of tumor cells identified no changes in transcriptional profile that could explain the observed phenotype. Furthermore, no histologic changes in tumor cell proliferation or morphology were observed in mature tumors. Examination of nascent MSLN KO tumors revealed decreased microvascular density as intraperitoneal tumors were forming, followed by decreased proliferation, which resolved by 2 weeks postimplantation. These data support a model whereby MSLN expression by tumor cells contributes to metastatic colonization. IMPLICATIONS: MSLN confers a growth advantage to tumor cells during colonization of peritoneal metastasis. Therapeutic blockade of MSLN might limit peritoneal spread.
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Affiliation(s)
- Leela Rani Avula
- Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Michael Rudloff
- Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Salma El-Behaedi
- Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Danielle Arons
- Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Rakan Albalawy
- Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Xiongfong Chen
- CCR-SF Bioinformatics Group, Advanced Biomedical and Computational Sciences, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Xianyu Zhang
- Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Christine Alewine
- Laboratory of Molecular Biology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
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Nichetti F, Marra A, Corti F, Guidi A, Raimondi A, Prinzi N, de Braud F, Pusceddu S. The Role of Mesothelin as a Diagnostic and Therapeutic Target in Pancreatic Ductal Adenocarcinoma: A Comprehensive Review. Target Oncol 2019; 13:333-351. [PMID: 29656320 DOI: 10.1007/s11523-018-0567-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mesothelin is a tumor differentiation antigen, which is highly expressed in several solid neoplasms, including pancreatic cancer. Its selective expression on malignant cells and on only a limited number of healthy tissues has made it an interesting candidate for investigation as a diagnostic and prognostic biomarker and as a therapeutic target. Based on a strong preclinical rationale, a number of therapeutic agents targeting mesothelin have entered clinical trials, including immunotoxins, monoclonal antibodies, antibody-drug conjugates, cancer vaccines, and adoptive T cell therapies with chimeric antigen receptors. In pancreatic cancer, mesothelin has been investigated mainly to address two unmet issues: the urgent need for new laboratory techniques for early tumor detection and the lack of successfully targetable oncogenic alterations for patients' treatment. In this review, we describe the clinicopathological significance of mesothelin expression in pancreatic cancer initiation and progression, we summarize available studies evaluating mesothelin as a potential diagnostic and prognostic biomarker in this disease, and we discuss current evidence and future perspectives of preclinical and clinical studies testing mesothelin as a molecular target for pancreatic cancer treatment.
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Affiliation(s)
- Federico Nichetti
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy.
| | - Antonio Marra
- Medical Oncology Unit, Azienda Ospedaliera San Paolo, Milan, Italy
| | - Francesca Corti
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Alessandro Guidi
- Medical Oncology Unit, Azienda Ospedaliera San Gerardo, Monza, Italy
| | - Alessandra Raimondi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Natalie Prinzi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
| | - Filippo de Braud
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
- Department of Oncology, Università degli Studi di Milano, Milan, Italy
| | - Sara Pusceddu
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy
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30
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Shiraishi T, Shinto E, Mochizuki S, Tsuda H, Kajiwara Y, Okamoto K, Einama T, Hase K, Ueno H. Mesothelin expression has prognostic value in stage ΙΙ/ΙΙΙ colorectal cancer. Virchows Arch 2019; 474:297-307. [DOI: 10.1007/s00428-018-02514-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/08/2018] [Accepted: 12/17/2018] [Indexed: 11/24/2022]
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Hilliard TS. The Impact of Mesothelin in the Ovarian Cancer Tumor Microenvironment. Cancers (Basel) 2018; 10:E277. [PMID: 30134520 PMCID: PMC6162689 DOI: 10.3390/cancers10090277] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 08/17/2018] [Accepted: 08/18/2018] [Indexed: 01/14/2023] Open
Abstract
Ovarian cancer is the deadliest gynecological disease among U.S. women. Poor 5-year survival rates (<30%) are due to presentation of most women at diagnosis with advanced stage disease with widely disseminated intraperitoneal metastasis. However, when diagnosed before metastatic propagation the overall 5-year survival rate is >90%. Metastasizing tumor cells grow rapidly and aggressively attach to the mesothelium of all organs within the peritoneal cavity, including the parietal peritoneum and the omentum, producing secondary lesions. In this review, the involvement of mesothelin (MSLN) in the tumor microenvironment is discussed. MSLN, a 40kDa glycoprotein that is overexpressed in many cancers including ovarian and mesotheliomas is suggested to play a role in cell survival, proliferation, tumor progression, and adherence. However, the biological function of MSLN is not fully understood as MSLN knockout mice do not present with an abnormal phenotype. Conversely, MSLN has been shown to bind to the ovarian cancer antigen, CA-125, and thought to play a role in the peritoneal diffusion of ovarian tumor cells. Although the cancer-specific expression of MSLN makes it a potential therapeutic target, more studies are needed to validate the role of MSLN in tumor metastasis.
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Affiliation(s)
- Tyvette S Hilliard
- Department of Chemistry and Biochemistry, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA.
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Tsukagoshi M, Wada S, Hirono S, Yoshida S, Yada E, Sasada T, Shirabe K, Kuwano H, Yamaue H. Identification of a novel HLA-A24-restricted cytotoxic T lymphocyte epitope peptide derived from mesothelin in pancreatic cancer. Oncotarget 2018; 9:31448-31458. [PMID: 30140382 PMCID: PMC6101134 DOI: 10.18632/oncotarget.25837] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 07/12/2018] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer involves highly malignant tumors, and the development of new therapeutic strategies is critical. Mesothelin is overexpressed in infiltrating pancreatic cancer cells and plays an important role in the invasion and migration processes. In this study, we focused on mesothelin as a tumor-specific antigen target for a pancreatic cancer vaccine. We first investigated the mesothelin-derived epitope peptide restricted to HLA-A*2402. A total of 19 candidate peptides were synthesized, and we then determined their potential to induce peptide-specific cytotoxic T lymphocytes (CTLs). Peptide-specific CTLs were induced by five peptides derived from mesothelin, and these CTLs successfully exhibited peptide-specific IFN-γ production. After the expansion of each CTL, two CTL lines were established, which were induced by mesothelin-10-5 peptide (AFYPGYLCSL). These CTL lines exhibited peptide-specific cytotoxicity and IFN-γ production. Moreover, we were able to generate mesothelin-10-5 peptide-specific CTL clones. These CTL clones also had specific cytotoxic activity against HLA-A*2402-positive pancreatic cancer cells that endogenously expressed mesothelin. These results indicate that the mesothelin-10-5 peptide is a novel HLA-A*2402 restricted CTL epitope and that it is a promising candidate target for antigen-specific immunotherapy against pancreatic cancers.
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Affiliation(s)
- Mariko Tsukagoshi
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi Gunma 371-8511, Japan.,Department of Innovative Cancer Immunotherapy, Gunma University Graduate School of Medicine, Maebashi Gunma 371-8511, Japan
| | - Satoshi Wada
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi Gunma 371-8511, Japan.,Department of Cancer Immunotherapy, Kanagawa Cancer Center, Asahi-ku, Yokohama Kanagawa 241-8515, Japan
| | - Seiko Hirono
- Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan
| | - Shintaro Yoshida
- Department of Cancer Immunotherapy, Kanagawa Cancer Center, Asahi-ku, Yokohama Kanagawa 241-8515, Japan
| | - Erica Yada
- Department of Cancer Immunotherapy, Kanagawa Cancer Center, Asahi-ku, Yokohama Kanagawa 241-8515, Japan
| | - Tetsuro Sasada
- Department of Cancer Immunotherapy, Kanagawa Cancer Center, Asahi-ku, Yokohama Kanagawa 241-8515, Japan
| | - Ken Shirabe
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi Gunma 371-8511, Japan.,Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi Gunma 371-8511, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi Gunma 371-8511, Japan
| | - Hiroki Yamaue
- Second Department of Surgery, Wakayama Medical University, Wakayama 641-8510, Japan
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Tesfaye AA, Kamgar M, Azmi A, Philip PA. The evolution into personalized therapies in pancreatic ductal adenocarcinoma: challenges and opportunities. Expert Rev Anticancer Ther 2018; 18:131-148. [PMID: 29254387 PMCID: PMC6121777 DOI: 10.1080/14737140.2018.1417844] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Accepted: 12/12/2017] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer related mortality in the United States in 2030, with a 5-year overall survival of less than 10% despite decades of extensive research. Pancreatic cancer is marked by the accumulation of complex molecular changes, complex tumor-stroma interaction, and an immunosuppressive tumor microenvironment. PDAC has proven to be resistant to many cytotoxic, targeted and immunologic treatment approaches. Areas covered: In this paper, we review the major areas of research in PDAC, with highlights on the challenges and areas of opportunity for personalized treatment approaches. Expert commentary: The focus of research in pancreatic cancer has moved away from developing conventional cytotoxic combinations. The marked advances in understanding the molecular biology of this disease especially in the areas of the microenvironment, metabolism, and DNA repair have opened new opportunities for developing novel treatment strategies. Improved understanding of molecular abnormalities allows the development of personalized treatment approaches.
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Affiliation(s)
- Anteneh A Tesfaye
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI
- Barbara Ann Karmanos Cancer Institute, Detroit, MI
| | - Mandana Kamgar
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI
- Barbara Ann Karmanos Cancer Institute, Detroit, MI
| | - Asfar Azmi
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI
- Barbara Ann Karmanos Cancer Institute, Detroit, MI
| | - Philip A Philip
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI
- Barbara Ann Karmanos Cancer Institute, Detroit, MI
- Department of Pharmacology, Wayne State University, School of Medicine, Detroit, MI
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Alfaleh MA, Howard CB, Sedliarou I, Jones ML, Gudhka R, Vanegas N, Weiss J, Suurbach JH, de Bakker CJ, Milne MR, Rumballe BA, MacDiarmid JA, Brahmbhatt H, Mahler SM. Targeting mesothelin receptors with drug-loaded bacterial nanocells suppresses human mesothelioma tumour growth in mouse xenograft models. PLoS One 2017; 12:e0186137. [PMID: 29059207 PMCID: PMC5653298 DOI: 10.1371/journal.pone.0186137] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 09/26/2017] [Indexed: 12/29/2022] Open
Abstract
Human malignant mesothelioma is a chemoresistant tumour that develops from mesothelial cells, commonly associated with asbestos exposure. Malignant mesothelioma incidence rates in European countries are still rising and Australia has one of the highest burdens of malignant mesothelioma on a population basis in the world. Therapy using systemic delivery of free cytotoxic agents is associated with many undesirable side effects due to non-selectivity, and is thus dose-limited which limits its therapeutic potential. Therefore, increasing the selectivity of anti-cancer agents has the potential to dramatically enhance drug efficacy and reduce toxicity. EnGeneIC Dream Vectors (EDV) are antibody-targeted nanocells which can be loaded with cytotoxic drugs and delivered to specific cancer cells via bispecific antibodies (BsAbs) which target the EDV and a cancer cell-specific receptor, simultaneously. BsAbs were designed to target doxorubicin-loaded EDVs to cancer cells via cell surface mesothelin (MSLN). Flow cytometry was used to investigate cell binding and induction of apoptosis, and confocal microscopy to visualize internalization. Mouse xenograft models were used to assess anti-tumour effects in vivo, followed by immunohistochemistry for ex vivo evaluation of proliferation and necrosis. BsAb-targeted, doxorubicin-loaded EDVs were able to bind to and internalize within mesothelioma cells in vitro via MSLN receptors and induce apoptosis. In mice xenografts, the BsAb-targeted, doxorubicin-loaded EDVs suppressed the tumour growth and also decreased cell proliferation. Thus, the use of MSLN-specific antibodies to deliver encapsulated doxorubicin can provide a novel and alternative modality for treatment of mesothelioma.
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Affiliation(s)
- Mohamed A. Alfaleh
- Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, Queensland, Australia
- Faculty of Pharmacy; King Abdulaziz University, Jeddah, Saudi Arabia
| | - Christopher B. Howard
- Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, Queensland, Australia
- Centre for Advanced Imaging, The University of Queensland, Brisbane, Queensland, Australia
- Australian Research Council Training Centre for Biopharmaceutical Innovation, The University of Queensland, Brisbane, Queensland, Australia
- * E-mail:
| | - Ilya Sedliarou
- Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia
| | - Martina L. Jones
- Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, Queensland, Australia
- Australian Research Council Training Centre for Biopharmaceutical Innovation, The University of Queensland, Brisbane, Queensland, Australia
| | - Reema Gudhka
- Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia
| | - Natasha Vanegas
- Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia
| | - Jocelyn Weiss
- Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia
| | - Julia H. Suurbach
- Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia
| | - Christopher J. de Bakker
- Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, Queensland, Australia
| | - Michael R. Milne
- Queensland Brain Institute (QBI), The University of Queensland, Brisbane, Queensland, Australia
| | - Bree A. Rumballe
- Queensland Brain Institute (QBI), The University of Queensland, Brisbane, Queensland, Australia
| | | | | | - Stephen M. Mahler
- Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, Queensland, Australia
- Australian Research Council Training Centre for Biopharmaceutical Innovation, The University of Queensland, Brisbane, Queensland, Australia
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35
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Kim J, Choi S, Saxena N, Singh AK, Singh I, Won JS. Regulation of STAT3 and NF-κB activations by S-nitrosylation in multiple myeloma. Free Radic Biol Med 2017; 106:245-253. [PMID: 28232202 PMCID: PMC5826580 DOI: 10.1016/j.freeradbiomed.2017.02.039] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 02/09/2017] [Accepted: 02/20/2017] [Indexed: 10/20/2022]
Abstract
Numerous reports suggest that aberrant activations of STAT3 and NF-κB promote survival and proliferation of multiple myeloma (MM) cells. In the present report, we demonstrate that a synthetic S-nitrosothiol compound, S-nitroso-N-acetylcysteine (SNAC), inhibits proliferation and survival of multiple MM cells via S-nitrosylation-dependent inhibition of STAT3 and NF-κB. In human MM cells (e.g. U266, H929, and IM-9 cells), SNAC treatment increased S-nitrosylation of STAT3 and NF-κB and inhibited their activities. Consequently, SNAC treatment resulted in MM cell cycle arrest at G1/S check point and inhibited their proliferation. SNAC also decreased the expression of cell survival factors and increased the activities of caspases, thus increased sensitivity of MM cells to melphalan, a chemotherapeutic agent for MM. In U266 xenografted mice, SNAC treatment decreased the activity of STAT3 and reduced the growth of human CD138 positive cells (U266 cells) in the bone marrow and also reduced their production of human IgE into the serum. Taken together, these data document the S-nitrosylation mediated inhibition of MM cell proliferation and cell survival via inhibition of STAT3 and NF-κB pathways and its efficacy in animal model of MM.
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Affiliation(s)
- Jinsu Kim
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Seungho Choi
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Nishant Saxena
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Avtar K Singh
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, United States; Pathology and Laboratory Medicine Service, Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC 29401, United States
| | - Inderjit Singh
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, United States.
| | - Je-Seong Won
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, United States.
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DeSelm CJ, Tano ZE, Varghese AM, Adusumilli PS. CAR T-cell therapy for pancreatic cancer. J Surg Oncol 2017; 116:63-74. [PMID: 28346697 DOI: 10.1002/jso.24627] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 03/05/2017] [Indexed: 12/18/2022]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy utilizes genetic engineering to redirect a patient's own T cells to target cancer cells. The remarkable results in hematological malignancies prompted investigating this approach in solid tumors such as pancreatic cancer. The complex tumor microenvironment, stromal hindrance in limiting immune response, and expression of checkpoint blockade on T cells pose hurdles. Herein, we summarize the opportunities, challenges, and state of knowledge in targeting pancreatic cancer with CAR T-cell therapy.
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Affiliation(s)
- Carl J DeSelm
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Zachary E Tano
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Anna M Varghese
- Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Prasad S Adusumilli
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York.,Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
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37
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Han SH, Joo M, Kim H, Chang S. Mesothelin Expression in Gastric Adenocarcinoma and Its Relation to Clinical Outcomes. J Pathol Transl Med 2017; 51:122-128. [PMID: 28196410 PMCID: PMC5357757 DOI: 10.4132/jptm.2016.11.18] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 11/17/2016] [Accepted: 11/17/2016] [Indexed: 11/23/2022] Open
Abstract
Background Although surgical resection with chemotherapy is considered effective for patients with advanced gastric cancer, it remains the third leading cause of cancer-related death in South Korea. Several studies have reported that mesothelial markers including mesothelin, calretinin, and Wilms tumor protein 1 (WT1) were positive in variable carcinomas, associated with prognosis, and were evaluated as potential markers for targeted therapy. The aim of this study was to assess the immunohistochemical expression of mesothelial markers (mesothelin, calretinin, and WT1) in gastric adenocarcinoma and their relations to clinocopathological features and prognosis. Methods We evaluated calretinin, WT1, and mesothelin expression by immunohistochemical staining in 117 gastric adenocarcinomas. Results Mesothelin was positively stained in 30 cases (25.6%). Mesothelin expression was related to increased depth of invasion (p = .002), lymph node metastasis (p = .013), and presence of lymphovascular (p = .015) and perineural invasion (p = .004). Patients with mesothelin expression had significantly worse disease-free survival rate compared with that of nonmesothelin expression group (p = .024). Univariate analysis showed that mesothelin expression is related to short-term survival. None of the 117 gastric adenocarcinomas stained for calretinin or WT1. Conclusions Mesothelin expression was associated with poor prognosis. Our results suggest that mesothelin-targeted therapy should be considered as an important therapeutic alternative for gastric adenocarcinoma patients with mesothelin expression.
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Affiliation(s)
- Song-Hee Han
- Department of Pathology, Inje University Ilsan Paik Hospital, Goyang, Korea
| | - Mee Joo
- Department of Pathology, Inje University Ilsan Paik Hospital, Goyang, Korea
| | - Hanseong Kim
- Department of Pathology, Inje University Ilsan Paik Hospital, Goyang, Korea
| | - Sunhee Chang
- Department of Pathology, Inje University Ilsan Paik Hospital, Goyang, Korea
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38
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Yuan Y, Xi Y, Chen J, Zhu P, Kang J, Zou Z, Wang F, Bu S. STAT3 stimulates adipogenic stem cell proliferation and cooperates with HMGA2 during the early stage of differentiation to promote adipogenesis. Biochem Biophys Res Commun 2017; 482:1360-1366. [DOI: 10.1016/j.bbrc.2016.12.042] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 12/06/2016] [Indexed: 12/31/2022]
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39
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Overexpression of sulfatase-1 in murine hepatocarcinoma Hca-F cell line downregulates mesothelin and leads to reduction in lymphatic metastasis, both in vitro and in vivo. Oncotarget 2016; 7:75052-75063. [PMID: 27626699 PMCID: PMC5342722 DOI: 10.18632/oncotarget.11933] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 08/26/2016] [Indexed: 02/06/2023] Open
Abstract
Lymphatic vessels function as transport channels for tumor cells to metastasize from the primary site into the lymph nodes. In this experiment we evaluated the effect of Sulfatase-1 (Sulf-1) on metastasis by upregulating it in murine hepatocarcinoma cell line Hca-F with high lymph node metastatic rate of >75%. The study in vitro showed that upregulation of Sulf-1 in Hca-F cells significantly reduced cell proliferation, migration and invasion (p<0.05). Also, the forced expression of Sulf-1 downregulated Mesothelin (Msln) at both the protein and mRNA levels. The experiment in vivo further showed that up-regulation of Sulf-1 with the attendant downregulation of mesothelin delayed tumor growth and decreased lymph node metastasis. In conclusion, our findings show that Sulf-1 is an important tumor suppressor gene in hepatocellular carcinoma (HCC), and its overexpression downregulates Msln and results in a decrease in HCC cell proliferation, migration, invasion, and lymphatic metastasis. This functional relationship between Sulf-1 and Msln could be exploited for the development of a novel liver cancer therapy.
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40
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He X, Despeaux E, Stueckle TA, Chi A, Castranova V, Dinu CZ, Wang L, Rojanasakul Y. Role of mesothelin in carbon nanotube-induced carcinogenic transformation of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 2016; 311:L538-49. [PMID: 27422997 PMCID: PMC5142212 DOI: 10.1152/ajplung.00139.2016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 07/05/2016] [Indexed: 02/06/2023] Open
Abstract
Carbon nanotubes (CNTs) have been likened to asbestos in terms of morphology and toxicity. CNT exposure can lead to pulmonary fibrosis and promotion of tumorigenesis. However, the mechanisms underlying CNT-induced carcinogenesis are not well defined. Mesothelin (MSLN) is overexpressed in many human tumors, including mesotheliomas and pancreatic and ovarian carcinomas. In this study, the role of MSLN in the carcinogenic transformation of human bronchial epithelial cells chronically exposed to single-walled CNT (BSW) was investigated. MSLN overexpression was found in human lung tumors, lung cancer cell lines, and BSW cells. The functional role of MSLN in the BSW cells was then investigated by using stably transfected MSLN knockdown (BSW shMSLN) cells. MSLN knockdown resulted in significantly decreased invasion, migration, colonies on soft agar, and tumor sphere formation. In vivo, BSW shMSLN cells formed smaller primary tumors and less metastases. The mechanism by which MSLN contributes to these more aggressive behaviors was investigated by using ingenuity pathway analysis, which predicted that increased MSLN could induce cyclin E expression. We found that BSW shMSLN cells had decreased cyclin E, and their proliferation rate was reverted to nearly that of untransformed cells. Cell cycle analysis showed that the BSW shMSLN cells had an increased G2 population and a decreased S phase population, which is consistent with the decreased rate of proliferation. Together, our results indicate a novel role of MSLN in the malignant transformation of bronchial epithelial cells following CNT exposure, suggesting its utility as a potential biomarker and drug target for CNT-induced malignancies.
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Affiliation(s)
- Xiaoqing He
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia
| | - Emily Despeaux
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia
| | - Todd A Stueckle
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia; HELD, National Institute for Occupational Safety and Health, Morgantown, West Virginia
| | - Alexander Chi
- WVU Cancer Institute, West Virginia University, Morgantown, West Virginia; and
| | - Vincent Castranova
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia
| | - Cerasela Zoica Dinu
- Department of Chemical Engineering, West Virginia University, Morgantown, West Virginia
| | - Liying Wang
- HELD, National Institute for Occupational Safety and Health, Morgantown, West Virginia
| | - Yon Rojanasakul
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia; WVU Cancer Institute, West Virginia University, Morgantown, West Virginia; and
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41
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Awuah P, Bera TK, Folivi M, Chertov O, Pastan I. Reduced Shedding of Surface Mesothelin Improves Efficacy of Mesothelin-Targeting Recombinant Immunotoxins. Mol Cancer Ther 2016; 15:1648-55. [PMID: 27196771 PMCID: PMC4936933 DOI: 10.1158/1535-7163.mct-15-0863] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 05/03/2016] [Indexed: 11/16/2022]
Abstract
Mesothelin (MSLN) is a differentiation antigen that is highly expressed in many epithelial cancers. MSLN is an important therapeutic target due to its high expression in cancers and limited expression in normal human tissues. Although it has been assumed that shed antigen is a barrier to immunotoxin action, a modeling study predicted that shed MSLN may enhance the action of MSLN-targeting recombinant immunotoxins such as SS1P and similar therapeutics by facilitating their redistribution within tumors. We aimed to determine whether shed MSLN enhances or reduces the antitumor effect of MSLN-targeting immunotoxins SS1P and RG7787. We engineered a cell line, A431/G9 (TACE mutant) that expresses a mutant form of MSLN in which the TNF-converting enzyme protease site is replaced with GGGS. We compared the response of the TACE-mutant cells with immunotoxins SS1P and RG7787 with that of the parental A431/H9 cell line. We show that TACE-mutant cells shed 80% less MSLN than A431/H9 cells, that TACE-mutant cells show a 2- to 3-fold increase in MSLN-targeted immunotoxin uptake, and that they are about 5-fold more sensitive to SS1P killing in cell culture. Tumors with reduced shedding respond significantly better to treatment with SS1P and RG7787. Our data show that MSLN shedding is an impediment to the antitumor activity of SS1P and RG7787. Approaches that decrease MSLN shedding could enhance the efficacy of immunotoxins and immunoconjugates targeting MSLN-expressing tumors. Mol Cancer Ther; 15(7); 1648-55. ©2016 AACR.
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Affiliation(s)
- Prince Awuah
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Tapan K Bera
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Messan Folivi
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Oleg Chertov
- Cancer Research Technology Program, Leidos Biomedical, Inc., Frederick, Maryland
| | - Ira Pastan
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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42
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Einama T, Kawamata F, Kamachi H, Nishihara H, Homma S, Matsuzawa F, Mizukami T, Konishi Y, Tahara M, Kamiyama T, Hino O, Taketomi A, Todo S. Clinical impacts of mesothelin expression in gastrointestinal carcinomas. World J Gastrointest Pathophysiol 2016; 7:218-222. [PMID: 27190694 PMCID: PMC4867401 DOI: 10.4291/wjgp.v7.i2.218] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 12/08/2015] [Accepted: 01/29/2016] [Indexed: 02/06/2023] Open
Abstract
Mesothelin, C-ERC/mesothelin is a 40-kDa cell surface glycoprotein that is normally present on normal mesothelial cells lining the pleura, peritoneum, and pericardium. Moreover, mesothelin has been shown to be overexpressed in several human cancers, including virtually all mesothelioma and pancreatic cancer, approximately 70% of ovarian cancer and extra bile duct cancer, and 50% of lung adenocarcinomas and gastric cancer. The full-length human mesothelin gene encodes the primary product, a 71-kDa precursor protein. The 71-kDa mesothelin precursor is cleaved into two products, 40-kDa C-terminal fragment that remains membrane-bound via glycosylphosphatidylinositol anchor, and a 31-kDa N-terminal fragment, megakaryocyte potentiating factor, which is secreted into the blood. The biological functions of mesothelin remain largely unknown. However, results of recent studies have suggested that the mesothelin may play a role of cell proliferation and migration. In pancreatic cancer, mesothelin expression was immunohistochemically observed in all cases, but absent in normal pancreas and in chronic pancreatitis. Furthermore, the expression of mesothelin was correlated with an poorer patient outcome in several human cancers. The limited mesothelin expression in normal tissues and high expression in many cancers makes it an attractive candidate for cancer therapy. The present review discusses the expression and function of mesothelin in cancer cells and the utility of mesothelin as a target of cancer therapy.
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Wan C, Gong C, Ji L, Liu X, Wang Y, Wang L, Shao M, Yang L, Fan S, Xiao Y, Wang X, Li M, Zhou G, Zhang Y. NF45 overexpression is associated with poor prognosis and enhanced cell proliferation of pancreatic ductal adenocarcinoma. Mol Cell Biochem 2015; 410:25-35. [PMID: 26276310 DOI: 10.1007/s11010-015-2535-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 08/06/2015] [Indexed: 02/04/2023]
Abstract
NF45, also referred to as nuclear factor of activated T cells, has been reported to promote the progression of multiple cancer types. However, the expression and physiological significance of NF45 in pancreatic ductal adenocarcinoma (PDAC) remain largely elusive. In this study, we investigated the clinical relevance and potential role of NF45 expression in PDAC development. Western blot analysis revealed that NF45 was remarkably upregulated in PDAC tissues, compared with the adjacent non-tumorous ones. In addition, the expression of NF45 in 122 patients with PDAC was evaluated using immunohistochemistry. In this way, we found that NF45 was abundantly expressed in PDAC tissues, and the expression of NF45 was correlated with tumor size (p = 0.007), histological differentiation (p = 0.033), and TNM stage (p = 0.001). Importantly, patients with low levels of NF45 expression exhibited better postoperative prognosis as compared with those with high NF45 expression. Furthermore, using PDAC cell cultures, we found that interference of NF45 expression using siRNA oligos suppressed PDAC cell proliferation and retarded cell cycle progression. Moreover, depletion of NF45 impaired the levels of cellular cyclin E and proliferating cell nuclear antigen (PCNA). Conversely, overexpression of NF45 facilitated the cell growth and accelerated cell cycle progression. Our results establish NF45 as an important indicator of PDAC prognosis with potential utility as a therapeutic target in this lethal disease.
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Affiliation(s)
- Chunhua Wan
- Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, 226001, Jiangsu, China
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, Jiangsu, China
| | - Chen Gong
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Li Ji
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Xiaorong Liu
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, Jiangsu, China
| | - Yayun Wang
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, Jiangsu, China
| | - Liang Wang
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, Jiangsu, China
| | - Mengting Shao
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, Jiangsu, China
| | - Linlin Yang
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, Jiangsu, China
| | - Shaoqing Fan
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Yin Xiao
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Xiaotong Wang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Manhua Li
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Guoxiong Zhou
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
| | - Yixin Zhang
- Department of General Surgery, Nantong University Cancer Hospital, Nantong, 226001, Jiangsu, China.
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LPA Induces Colon Cancer Cell Proliferation through a Cooperation between the ROCK and STAT-3 Pathways. PLoS One 2015; 10:e0139094. [PMID: 26418031 PMCID: PMC4587977 DOI: 10.1371/journal.pone.0139094] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 09/09/2015] [Indexed: 12/21/2022] Open
Abstract
Lysophosphatidic acid (LPA) plays a critical role in the proliferation and migration of colon cancer cells; however, the downstream signaling events underlying these processes remain poorly characterized. The aim of this study was to investigate the signaling pathways triggered by LPA to regulate the mechanisms involved in the progression of colorectal cancer (CRC). We have used three cell line models of CRC, and initially analyzed the expression profile of LPA receptors (LPAR). Then, we treated the cells with LPA and events related to their tumorigenic potential, such as migration, invasion, anchorage-independent growth, proliferation as well as apoptosis and cell cycle were evaluated. We used the Chip array technique to analyze the global gene expression profiling that occurs after LPA treatment, and we identified cell signaling pathways related to the cell cycle. The inhibition of these pathways verified the conclusions of the transcriptomic analysis. We found that the cell lines expressed LPAR1, -2 and -3 in a differential manner and that 10 μM LPA did not affect cell migration, invasion and anchorage-independent growth, but it did induce proliferation and cell cycle progression in HCT-116 cells. Although LPA in this concentration did not induce transcriptional activity of β-catenin, it promoted the activation of Rho and STAT-3. Moreover, ROCK and STAT-3 inhibitors prevented LPA-induced proliferation, but ROCK inhibition did not prevent STAT-3 activation. Finally, we observed that LPA regulates the expression of genes related to the cell cycle and that the combined inhibition of ROCK and STAT-3 prevented cell cycle progression and increased the LPA-induced expression of cyclins E1, A2 and B1 to a greater degree than either inhibitor alone. Overall, these results demonstrate that LPA increases the proliferative potential of colon adenocarcinoma HCT-116 cells through a mechanism involving cooperation between the Rho-ROCK and STAT3 pathways involved in cell cycle control.
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Kaliyaperumal K, Sharma AK, McDonald DG, Dhindsa JS, Yount C, Singh AK, Won JS, Singh I. S-Nitrosoglutathione-mediated STAT3 regulation in efficacy of radiotherapy and cisplatin therapy in head and neck squamous cell carcinoma. Redox Biol 2015; 6:41-50. [PMID: 26177470 PMCID: PMC4511642 DOI: 10.1016/j.redox.2015.07.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 06/26/2015] [Accepted: 07/01/2015] [Indexed: 12/27/2022] Open
Abstract
S-nitrosoglutathione (GSNO) is an endogenous nitric oxide (NO) carrier that plays a critical role in redox based NO signaling. Recent studies have reported that GSNO regulates the activities of STAT3 and NF-κB via S-nitrosylation dependent mechanisms. Since STAT3 and NF-κB are key transcription factors involved in tumor progression, chemoresistance, and metastasis of head and neck cancer, we investigated the effect of GSNO in cell culture and mouse xenograft models of head and neck squamous cell carcinoma (HNSCC). For the cell culture studies, three HNSCC cell lines were tested (SCC1, SCC14a and SCC22a). All three cell lines had constitutively activated (phosphorylated) STAT3 (Tyr705). GSNO treatment of these cell lines reversibly decreased the STAT3 phosphorylation in a concentration dependent manner. GSNO treatment also decreased the basal and cytokine-stimulated activation of NF-κB in SCC14a cells and reduced the basal low degree of nitrotyrosine by inhibition of inducible NO synthase (iNOS) expression. The reduced STAT3/NF-κB activity by GSNO treatment was correlated with the decreased cell proliferation and increased apoptosis of HNSCC cells. In HNSCC mouse xenograft model, the tumor growth was reduced by systemic treatment with GSNO and was further reduced when the treatment was combined with radiation and cisplatin. Accordingly, GSNO treatment also resulted in decreased levels of phosphorylated STAT3. In summary, these studies demonstrate that GSNO treatment blocks the NF-κB and STAT3 pathways which are responsible for cell survival, proliferation and that GSNO mediated mechanisms complement cispaltin and radiation therapy, and thus could potentiate the therapeutic effect in HNSCC.
S-nitrosoglutathione (GSNO) inhibits activations of STAT3 and NF-κB in HNSCC cells. GSNO induces cell cycle arrest and apoptosis of HNSCC cells. GSNO decreases iNOS and VEGF production in HNSCC cells. GSNO enhances efficacy of chemoradiation therapy in HNSCC mouse xenograft model.
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Affiliation(s)
| | - Anand K Sharma
- Departments of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Daniel G McDonald
- Departments of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Jasdeep S Dhindsa
- Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Caroline Yount
- Departments of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Avtar K Singh
- Pathology and Laboratory Medicine Service, Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC 29401, USA
| | - Je-Seong Won
- Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
| | - Inderjit Singh
- Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
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A novel PET imaging using ⁶⁴Cu-labeled monoclonal antibody against mesothelin commonly expressed on cancer cells. J Immunol Res 2015; 2015:268172. [PMID: 25883990 PMCID: PMC4390102 DOI: 10.1155/2015/268172] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 02/14/2015] [Accepted: 02/19/2015] [Indexed: 01/27/2023] Open
Abstract
Mesothelin (MSLN) is a 40-kDa cell differentiation-associated glycoprotein appearing with carcinogenesis and is highly expressed in many human cancers, including the majority of pancreatic adenocarcinomas, ovarian cancers, and mesotheliomas, while its expression in normal tissue is limited to mesothelial cells lining the pleura, pericardium, and peritoneum. Clone 11-25 is a murine hybridoma secreting monoclonal antibody (mAb) against human MSLN. In this study, we applied the 11-25 mAb to in vivo imaging to detect MSLN-expressing tumors. In in vitro and ex vivo immunochemical studies, we demonstrated specificity of 11-25 mAb to membranous MSLN expressed on several pancreatic cancer cells. We showed the accumulation of Alexa Fluor 750-labeled 11-25 mAb in MSLN-expressing tumor xenografts in athymic nude mice. Then, 11-25 mAb was labeled with 64Cu via a chelating agent DOTA and was used in both in vitro cell binding assay and in vivo positron emission tomography (PET) imaging in the tumor-bearing mice. We confirmed that 64Cu-labeled 11-25 mAb highly accumulated in MSLN-expressing tumors as compared to MSLN-negative ones. The 64Cu-labeled 11-25 mAb is potentially useful as a PET probe capable of being used for wide range of tumors, rather than 18F-FDG that occasionally provides nonspecific accumulation into the inflammatory lesions.
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Prognostic value of mesothelin expression in patients with triple negative and HER2-positive breast cancers. Biomed Pharmacother 2015; 70:190-5. [DOI: 10.1016/j.biopha.2015.01.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2014] [Accepted: 01/05/2015] [Indexed: 11/21/2022] Open
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Tozbikian G, Brogi E, Kadota K, Catalano J, Akram M, Patil S, Ho AY, Reis-Filho JS, Weigelt B, Norton L, Adusumilli PS, Wen HY. Mesothelin expression in triple negative breast carcinomas correlates significantly with basal-like phenotype, distant metastases and decreased survival. PLoS One 2014; 9:e114900. [PMID: 25506917 PMCID: PMC4266616 DOI: 10.1371/journal.pone.0114900] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Accepted: 11/15/2014] [Indexed: 12/22/2022] Open
Abstract
Mesothelin is a cell surface associated antigen expressed on mesothelial cells and in some malignant neoplasms. Mesothelin-targeted therapies are in phase I/II clinical trials. The clinicopathologic and prognostic significance of mesothelin expression in triple negative breast carcinomas (TNBC) has not been fully assessed. We evaluated the expression of mesothelin and of basal markers in tissue microarrays of 226 TNBC and 88 non-TNBC and assessed the clinicopathologic features of mesothelin-expressing breast carcinomas. Furthermore, we investigated the impact of mesothelin expression on the disease-free and overall survival of patients with TNBC. We found that mesothelin expression is significantly more frequent in TNBC than in non-TNBC (36% vs 16%, respectively; p = 0.0006), and is significantly correlated with immunoreactivity for basal keratins, but not for EGFR. Mesothelin-positive and mesothelin-negative TNBC were not significantly different by patients’ race, tumor size, histologic grade, tumor subtype, lymphovascular invasion and lymph node metastases. Patients with mesothelin-positive TNBC were older than patients with mesothelin-negative TNBC, developed more distant metastases with a shorter interval, and had significantly lower overall and disease-free survival. Based on our results, patients with mesothelin-positive TNBC could benefit from mesothelin-targeted therapies.
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Affiliation(s)
- Gary Tozbikian
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Edi Brogi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Kyuichi Kadota
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Jeffrey Catalano
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Muzaffar Akram
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Sujata Patil
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Alice Y. Ho
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Jorge S. Reis-Filho
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Britta Weigelt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Larry Norton
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Prasad S. Adusumilli
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
| | - Hannah Yong Wen
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
- * E-mail:
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Bharadwaj U, Kasembeli MM, Eckols TK, Kolosov M, Lang P, Christensen K, Edwards DP, Tweardy DJ. Monoclonal Antibodies Specific for STAT3β Reveal Its Contribution to Constitutive STAT3 Phosphorylation in Breast Cancer. Cancers (Basel) 2014; 6:2012-34. [PMID: 25268166 PMCID: PMC4276954 DOI: 10.3390/cancers6042012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 09/15/2014] [Accepted: 09/17/2014] [Indexed: 12/04/2022] Open
Abstract
Since its discovery in mice and humans 19 years ago, the contribution of alternatively spliced Stat3, Stat3β, to the overall functions of Stat3 has been controversial. Tyrosine-phosphorylated (p) Stat3β homodimers are more stable, bind DNA more avidly, are less susceptible to dephosphorylation, and exhibit distinct intracellular dynamics, most notably markedly prolonged nuclear retention, compared to pStat3α homodimers. Overexpression of one or the other isoform in cell lines demonstrated that Stat3β acted as a dominant-negative of Stat3α in transformation assays; however, studies with mouse strains deficient in one or the other isoform indicated distinct contributions of Stat3 isoforms to inflammation. Current immunological reagents cannot differentiate Stat3β proteins derived from alternative splicing vs. proteolytic cleavage of Stat3α. We developed monoclonal antibodies that recognize the 7 C-terminal amino acids unique to Stat3β (CT7) and do not cross-react with Stat3α. Immunoblotting studies revealed that levels of Stat3β protein, but not Stat3α, in breast cancer cell lines positively correlated with overall pStat3 levels, suggesting that Stat3β may contribute to constitutive Stat3 activation in this tumor system. The ability to unambiguously discriminate splice alternative Stat3β from proteolytic Stat3β and Stat3α will provide new insights into the contribution of Stat3β vs. Stat3α to oncogenesis, as well as other biological and pathological processes.
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Affiliation(s)
- Uddalak Bharadwaj
- Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Moses M Kasembeli
- Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
| | - T Kris Eckols
- Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Mikhail Kolosov
- Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Paul Lang
- Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Kurt Christensen
- Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Dean P Edwards
- Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
| | - David J Tweardy
- Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
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50
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Kendrick ZW, Firpo MA, Repko RC, Scaife CL, Adler DG, Boucher KM, Mulvihill SJ. Serum IGFBP2 and MSLN as diagnostic and prognostic biomarkers for pancreatic cancer. HPB (Oxford) 2014; 16:670-6. [PMID: 24308545 PMCID: PMC4105906 DOI: 10.1111/hpb.12199] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 10/21/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Identification of diagnostic and prognostic biomarkers is a research priority for the improved management of pancreatic ductal adenocarcinoma (PDAC). Insulin-like growth factor binding protein 2 (IGFBP2) and mesothelin (MSLN) have shown potential as serum biomarkers in other cancers, but have not been adequately studied in PDAC. METHODS Serum IGFBP2 and MSLN levels were quantified by enzyme-linked immunosorbent assay (ELISA) in a cohort of 84 PDAC patients, 84 healthy control subjects and 40 chronic pancreatitis (ChPT) patients. Regression models related IGFBP2 and MSLN levels to diagnosis, gender, age, stage and survival. RESULTS IGFPB2 and MSLN serum levels were diagnostic for PDAC in age-adjusted models (P = 0.032 and P = 0.002, respectively) when compared with ChPT and healthy control samples. At a 95% specificity threshold, the sensitivity for IGFBP2 was 22% and the sensitivity for MSLN was 17%. Neither protein approached the diagnostic accuracy of CA 19-9. However, IGFBP2 or MSLN or both correctly identified 18 of the 28 samples misidentified by CA 19-9. In age-adjusted models, neither serum IGFBP2 (P = 0.36) nor MSLN (P = 0.29) were significant predictors of survival. DISCUSSION Serum IGFBP2 and MSLN are weak diagnostic classifiers individually, but may be useful in a diagnostic biomarker panel.
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Affiliation(s)
- Zachary W Kendrick
- Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA
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