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Zhou K, Liu Y, Tang C, Zhu H. Pancreatic Cancer: Pathogenesis and Clinical Studies. MedComm (Beijing) 2025; 6:e70162. [PMID: 40182139 PMCID: PMC11965705 DOI: 10.1002/mco2.70162] [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: 06/24/2024] [Revised: 03/08/2025] [Accepted: 03/12/2025] [Indexed: 04/05/2025] Open
Abstract
Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS-MAPK, PI3K-AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody-drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.
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Affiliation(s)
- Kexun Zhou
- Department of Medical OncologyCancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Yingping Liu
- Department of RadiotherapyCancer HospitalChinese Academy of Medical SciencesBeijingChina
| | - Chuanyun Tang
- The First Clinical Medical College of Nanchang UniversityNanchang UniversityNanchangChina
| | - Hong Zhu
- Department of Medical OncologyCancer CenterWest China HospitalSichuan UniversityChengduChina
- Division of Abdominal Tumor Multimodality TreatmentCancer CenterWest China HospitalSichuan UniversityChengduChina
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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [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: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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Campos F, Kasper B. Examining nirogacestat for adults with progressing desmoid tumors who require systemic treatment. Expert Opin Pharmacother 2024; 25:2115-2124. [PMID: 39414771 DOI: 10.1080/14656566.2024.2418416] [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: 09/03/2024] [Revised: 10/10/2024] [Accepted: 10/15/2024] [Indexed: 10/18/2024]
Abstract
INTRODUCTION Desmoid tumor (DT) is a rare, locally aggressive, mesenchymal neoplasm that can arise at any site in the body. Medical therapies play a major role for DT's patients requiring treatment. A novel systemic approach has recently emerged with Nirogacestat, a γ-secretase inhibitor targeting the NOTCH signaling pathway. AREAS COVERED Nirogacestat is the first drug in its class to receive approval from the Food and Drug Administration (FDA) and is the first FDA-approved treatment specifically for DTs. We reviewed the data leading to its discovery, including its mechanism of action, pharmacological properties, clinical efficacy, and its positioning within the current treatment armamentarium for DTs. EXPERT OPINION High-quality evidence for systemic therapies in the management of DTs remains an unmet need. Nirogacestat now joins sorafenib as the only drugs with efficacy in DTs demonstrated by randomized phase 3 studies. Currently, there are no comparative trials of the available systemic therapies. Therefore, physicians should consider factors such as drug accessibility, cost, toxicity profile, comorbidities, and patient preferences when selecting treatment. Long-term efficacy and safety data will be essential for evaluating the duration of treatment response and monitoring late-onset side effects of Nirogacestat.
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Affiliation(s)
- Fernando Campos
- Sarcoma Reference Center, A.C.Camargo Cancer Center (ACCCC), Sao Paulo, Brazil
| | - Bernd Kasper
- Sarcoma Unit, Mannheim Cancer Center (MCC), Mannheim University Medical Center, University of Heidelberg, Mannheim, Germany
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Shi Q, Xue C, Zeng Y, Yuan X, Chu Q, Jiang S, Wang J, Zhang Y, Zhu D, Li L. Notch signaling pathway in cancer: from mechanistic insights to targeted therapies. Signal Transduct Target Ther 2024; 9:128. [PMID: 38797752 PMCID: PMC11128457 DOI: 10.1038/s41392-024-01828-x] [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: 01/18/2024] [Revised: 03/31/2024] [Accepted: 04/15/2024] [Indexed: 05/29/2024] Open
Abstract
Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The Notch receptor and its ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical Notch signaling transduction. Accumulating evidence indicates that the Notch signaling pathway serves as both an oncogenic factor and a tumor suppressor in various cancer types. Dysregulation of this pathway promotes epithelial-mesenchymal transition and angiogenesis in malignancies, closely linked to cancer proliferation, invasion, and metastasis. Furthermore, the Notch signaling pathway contributes to maintaining stem-like properties in cancer cells, thereby enhancing cancer invasiveness. The regulatory role of the Notch signaling pathway in cancer metabolic reprogramming and the tumor microenvironment suggests its pivotal involvement in balancing oncogenic and tumor suppressive effects. Moreover, the Notch signaling pathway is implicated in conferring chemoresistance to tumor cells. Therefore, a comprehensive understanding of these biological processes is crucial for developing innovative therapeutic strategies targeting Notch signaling. This review focuses on the research progress of the Notch signaling pathway in cancers, providing in-depth insights into the potential mechanisms of Notch signaling regulation in the occurrence and progression of cancer. Additionally, the review summarizes pharmaceutical clinical trials targeting Notch signaling for cancer therapy, aiming to offer new insights into therapeutic strategies for human malignancies.
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Affiliation(s)
- Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Shuwen Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Jinzhi Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yaqi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Danhua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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5
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MacLean MR, Walker OL, Arun RP, Fernando W, Marcato P. Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways. Int J Mol Sci 2024; 25:4102. [PMID: 38612911 PMCID: PMC11012648 DOI: 10.3390/ijms25074102] [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: 02/28/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer stem cells (CSCs) represent a subpopulation within tumors that promote cancer progression, metastasis, and recurrence due to their self-renewal capacity and resistance to conventional therapies. CSC-specific markers and signaling pathways highly active in CSCs have emerged as a promising strategy for improving patient outcomes. This review provides a comprehensive overview of the therapeutic targets associated with CSCs of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog. We discuss a wide array of therapeutic modalities ranging from targeted antibodies, small molecule inhibitors, and near-infrared photoimmunotherapy to advanced genetic approaches like RNA interference, CRISPR/Cas9 technology, aptamers, antisense oligonucleotides, chimeric antigen receptor (CAR) T cells, CAR natural killer cells, bispecific T cell engagers, immunotoxins, drug-antibody conjugates, therapeutic peptides, and dendritic cell vaccines. This review spans developments from preclinical investigations to ongoing clinical trials, highlighting the innovative targeting strategies that have been informed by CSC-associated pathways and molecules to overcome therapeutic resistance. We aim to provide insights into the potential of these therapies to revolutionize cancer treatment, underscoring the critical need for a multi-faceted approach in the battle against cancer. This comprehensive analysis demonstrates how advances made in the CSC field have informed significant developments in novel targeted therapeutic approaches, with the ultimate goal of achieving more effective and durable responses in cancer patients.
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Affiliation(s)
- Maya R. MacLean
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Olivia L. Walker
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Raj Pranap Arun
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Wasundara Fernando
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Biology, Acadia University, Wolfville, NS B4P 2R6, Canada
| | - Paola Marcato
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Nova Scotia Health Authority, Halifax, NS B3H 4R2, Canada
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Sinha S, Hembram KC, Chatterjee S. Targeting signaling pathways in cancer stem cells: A potential approach for developing novel anti-cancer therapeutics. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 385:157-209. [PMID: 38663959 DOI: 10.1016/bs.ircmb.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
Cancer stem cells (CSCs) have emerged as prime players in the intricate landscape of cancer development, progression, and resistance to traditional treatments. These unique cellular subpopulations own the remarkable capability of self-renewal and differentiation, giving rise to the diverse cellular makeup of tumors and fostering their recurrence following conventional therapies. In the quest for developing more effective cancer therapeutics, the focus has now shifted toward targeting the signaling pathways that govern CSCs behavior. This chapter underscores the significance of these signaling pathways in CSC biology and their potential as pivotal targets for the development of novel chemotherapy approaches. We delve into several key signaling pathways essential for maintaining the defining characteristics of CSCs, including the Wnt, Hedgehog, Notch, JAK-STAT, NF-κB pathways, among others, shedding light on their potential crosstalk. Furthermore, we highlight the latest advancements in CSC-targeted therapies, spanning from promising preclinical models to ongoing clinical trials. A comprehensive understanding of the intricate molecular aspects of CSC signaling pathways and their manipulation holds the prospective to revolutionize cancer treatment paradigms. This, in turn, could lead to more efficacious and personalized therapies with the ultimate goal of eradicating CSCs and enhancing overall patient outcomes. The exploration of CSC signaling pathways represents a key step towards a brighter future in the battle against cancer.
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Affiliation(s)
- Saptarshi Sinha
- National Institute of Biomedical Genomics, Kalyani, West Bengal, India
| | | | - Subhajit Chatterjee
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, United States.
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7
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Yan W, Menjivar RE, Bonilla ME, Steele NG, Kemp SB, Du W, Donahue KL, Brown K, Carpenter ES, Avritt FR, Irizarry-Negron VM, Yang S, Burns WR, Zhang Y, di Magliano MP, Bednar F. Notch Signaling Regulates Immunosuppressive Tumor-Associated Macrophage Function in Pancreatic Cancer. Cancer Immunol Res 2024; 12:91-106. [PMID: 37931247 PMCID: PMC10842043 DOI: 10.1158/2326-6066.cir-23-0037] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 07/08/2023] [Accepted: 10/31/2023] [Indexed: 11/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. The poor survival of patients with PDA has been attributed to a high rate of early metastasis and low efficacy of current therapies, which partly result from its complex immunosuppressive tumor microenvironment. Previous studies from our group and others have shown that tumor-associated macrophages (TAM) are instrumental in maintaining immunosuppression in PDA. Here, we explored the role of Notch signaling, a key regulator of immune response, within the PDA microenvironment. We identified Notch pathway components in multiple immune cell types within human and mouse pancreatic cancer. TAMs, the most abundant immune cell population in the tumor microenvironment, expressed high levels of Notch receptors, with cognate ligands such as JAG1 expressed on tumor epithelial cells, endothelial cells, and fibroblasts. TAMs with activated Notch signaling expressed higher levels of immunosuppressive mediators, suggesting that Notch signaling plays a role in macrophage polarization within the PDA microenvironment. Genetic inhibition of Notch in myeloid cells led to reduced tumor size and decreased macrophage infiltration in an orthotopic PDA model. Combination of pharmacologic Notch inhibition with PD-1 blockade resulted in increased cytotoxic T-cell infiltration, tumor cell apoptosis, and smaller tumor size. Our work implicates macrophage Notch signaling in the establishment of immunosuppression and indicates that targeting the Notch pathway may improve the efficacy of immune-based therapies in patients with PDA.
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Affiliation(s)
- Wei Yan
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rosa E. Menjivar
- Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Monica E. Bonilla
- Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Nina G. Steele
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Samantha B. Kemp
- Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Wenting Du
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Katelyn L. Donahue
- Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Kristee Brown
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Eileen S. Carpenter
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI 48109, USA
| | - Faith R. Avritt
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Sion Yang
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - William R. Burns
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yaqing Zhang
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Marina Pasca di Magliano
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
- Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Filip Bednar
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
- Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
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Cao J, Zhang Z, Zhou L, Luo M, Li L, Li B, Nice EC, He W, Zheng S, Huang C. Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy. MedComm (Beijing) 2023; 4:e427. [PMID: 38045829 PMCID: PMC10693315 DOI: 10.1002/mco2.427] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 12/05/2023] Open
Abstract
Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share features with embryonic development, characterized by robust proliferation and differentiation regulated by signaling pathways such as Wnt, Notch, hedgehog, and Hippo signaling. In certain phase, these cells also mimic embryonic diapause and fertilized egg implantation to evade treatments or immune elimination and promote metastasis. Additionally, the upregulation of ATP-binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer-resistant protein (BCRP), in drug-resistant cancer cells, analogous to their role in placental development, may facilitate chemotherapy efflux, further resulting in treatment resistance. In this review, we concentrate on the underlying mechanisms that contribute to tumor development and progression from the perspective of embryonic development, encompassing the dysregulation of developmental signaling pathways, the emergence of dormant cancer cells, immune microenvironment remodeling, and the hyperactivation of ABC transporters. Furthermore, we synthesize and emphasize the connections between cancer hallmarks and embryonic development, offering novel insights for the development of innovative cancer treatment strategies.
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Affiliation(s)
- Jiangjun Cao
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Zhe Zhang
- Zhejiang Provincial Key Laboratory of Pancreatic Diseasethe First Affiliated HospitalSchool of MedicineZhejiang UniversityZhejiangChina
| | - Li Zhou
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education)Department of Infectious Diseasesthe Second Affiliated HospitalInstitute for Viral Hepatitis, Chongqing Medical UniversityChongqingChina
| | - Maochao Luo
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Lei Li
- Department of anorectal surgeryHospital of Chengdu University of Traditional Chinese Medicine and Chengdu University of Traditional Chinese MedicineChengduChina
| | - Bowen Li
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Edouard C. Nice
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVICAustralia
| | - Weifeng He
- State Key Laboratory of TraumaBurn and Combined InjuryInstitute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
| | - Shaojiang Zheng
- Hainan Cancer Medical Center of The First Affiliated Hospital, the Hainan Branch of National Clinical Research Center for Cancer, Hainan Engineering Research Center for Biological Sample Resources of Major DiseasesHainan Medical UniversityHaikouChina
- Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, Hainan Women and Children's Medical Center, Key Laboratory of Emergency and Trauma of Ministry of EducationHainan Medical UniversityHaikouChina
| | - Canhua Huang
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
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Zhou K, Liu Y, Yuan S, Zhou Z, Ji P, Huang Q, Wen F, Li Q. Signalling in pancreatic cancer: from pathways to therapy. J Drug Target 2023; 31:1013-1026. [PMID: 37869884 DOI: 10.1080/1061186x.2023.2274806] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 10/18/2023] [Indexed: 10/24/2023]
Abstract
Pancreatic cancer (PC) is a common malignant tumour in the digestive system. Due to the lack of sensitive diagnostic markers, strong metastasis ability, and resistance to anti-cancer drugs, the prognosis of PC is inferior. In the past decades, increasing evidence has indicated that the development of PC is closely related to various signalling pathways. With the exploration of RAS-driven, epidermal growth factor receptor, Hedgehog, NF-κB, TGF-β, and NOTCH signalling pathways, breakthroughs have been made to explore the mechanism of pancreatic carcinogenesis, as well as the novel therapies. In this review, we discussed the signalling pathways involved in PC and summarised current targeted agents in the treatment of PC. Furthermore, opportunities and challenges in the exploration of potential therapies targeting signalling pathways were also highlighted.
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Affiliation(s)
- Kexun Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yingping Liu
- The Second Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, China
| | | | - Ziyu Zhou
- The Second Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, China
| | - Pengfei Ji
- The Second Clinical Medical College of Lanzhou University, Lanzhou University, Lanzhou, China
| | - Qianhan Huang
- School of Public Health, Xuzhou Medical University, Xuzhou, China
| | - Feng Wen
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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10
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Chen B, Huang R, Xia T, Wang C, Xiao X, Lu S, Chen X, Ouyang Y, Deng X, Miao J, Zhao C, Wang L. The m6A reader IGF2BP3 preserves NOTCH3 mRNA stability to sustain Notch3 signaling and promote tumor metastasis in nasopharyngeal carcinoma. Oncogene 2023; 42:3564-3574. [PMID: 37853162 PMCID: PMC10673713 DOI: 10.1038/s41388-023-02865-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 09/30/2023] [Accepted: 10/04/2023] [Indexed: 10/20/2023]
Abstract
Metastasis remains the major cause of treatment failure in patients with nasopharyngeal carcinoma (NPC), in which sustained activation of the Notch signaling plays a critical role. N6-Methyladenosine (m6A)-mediated post-transcriptional regulation is involved in fine-tuning the Notch signaling output; however, the post-transcriptional mechanisms underlying NPC metastasis remain poorly understood. In the present study, we report that insulin-like growth factor 2 mRNA-binding proteins 3 (IGF2BP3) serves as a key m6A reader in NPC. IGF2BP3 expression was significantly upregulated in metastatic NPC and correlated with poor prognosis in patients with NPC. IGF2BP3 overexpression promoted, while IGF2BP3 downregulation inhibited tumor metastasis and the stemness phenotype of NPC cells in vitro and in vivo. Mechanistically, IGF2BP3 maintains NOTCH3 mRNA stability via suppression of CCR4-NOT complex-mediated deadenylation in an m6A-dependent manner, which sustains Notch3 signaling activation and increases the transcription of stemness-associated downstream genes, eventually promoting tumor metastasis. Our findings highlight the pro-metastatic function of the IGF2BP3/Notch3 axis and revealed the precise role of IGF2BP3 in post-transcriptional regulation of NOTCH3, suggesting IGF2BP3 as a novel prognostic biomarker and potential therapeutic target in NPC metastasis.
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Affiliation(s)
- Boyu Chen
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Runda Huang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Tianliang Xia
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Chunyang Wang
- Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510060, P. R. China
| | - Xiao Xiao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Shunzhen Lu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Xiangfu Chen
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Ying Ouyang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
- Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Xiaowu Deng
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Jingjing Miao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
| | - Chong Zhao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
| | - Lin Wang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.
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11
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Lacalle-Gonzalez C, Florez-Cespedes M, Sanz-Criado L, Ochieng’ Otieno M, Ramos-Muñoz E, Fernandez-Aceñero MJ, Ortega-Medina L, Garcia-Foncillas J, Martinez-Useros J. DLL3 Is a Prognostic and Potentially Predictive Biomarker for Immunotherapy Linked to PD/PD-L Axis and NOTCH1 in Pancreatic Cancer. Biomedicines 2023; 11:2812. [PMID: 37893184 PMCID: PMC10604228 DOI: 10.3390/biomedicines11102812] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/05/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplasm with very poor patient survival outcomes despite available treatments. There is an urgent need for new potential treatment options and novel biomarkers for these patients. Delta-like canonical Notch ligand 3 (DLL3) interacts with the Notch receptor and causes inhibition of Notch signaling, which confers a survival advantage to PDAC cells. Thus, DLL3 expression could affect cell survival, and its inhibition could increase a patient's survival. To test this hypothesis, a survival analysis was conducted using the progression-free and overall survival from two independent datasets of PDAC patients, with one using mRNA z-score levels and the other using the Hscore protein expression level; both were carried out using a log-rank test and plotted using Kaplan-Meier curves. DLL3 at the mRNA expression level showed an association between high mRNA expression and both a longer progression-free survival (PFS) and overall survival (OS) of patients. Then, we designed a retrospective study with resected PDAC samples. Our primary objective with this dataset was to assess the relationship between PFS and OS and DLL3 protein expression. The secondary assessment was to provide a rationale for the use of anti-DLL3-based treatments in combination with immunotherapy that is supported by the link between DLL3 and other factors that are involved in immune checkpoints. The survival analyses revealed a protective effect of high DLL3 protein expression levels in both PFS and OS. Interestingly, high DLL3 protein expression levels were significantly correlated with PD-L1/2 and negatively correlated with NOTCH1. Therefore, DLL3 could be considered a biomarker for better prognosis in resectable PDAC patients as well as a therapeutic biomarker for immunotherapy response. These facts set a rationale for testing anti-DLL3-based treatments either alone or combined with immunotherapy or other NOTCH1 inhibitors.
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Affiliation(s)
- Carlos Lacalle-Gonzalez
- Department of Medical Oncology, Fundación Jiménez Díaz University Hospital, 28040 Madrid, Spain;
| | | | - Lara Sanz-Criado
- Translational Oncology Division, Oncohealth Institute, Fundacion Jiménez Díaz University Hospital, 28040 Madrid, Spain; (L.S.-C.); (M.O.O.)
| | - Michael Ochieng’ Otieno
- Translational Oncology Division, Oncohealth Institute, Fundacion Jiménez Díaz University Hospital, 28040 Madrid, Spain; (L.S.-C.); (M.O.O.)
| | - Edurne Ramos-Muñoz
- Biomarkers and Therapeutic Targets Group and Core Facility, RICORS2040, EATRIS, Ramón y Cajal Health Research Institute, (IRYCIS), C/Carretera Colmenar Km 9,100, 28034 Madrid, Spain;
| | - Maria Jesus Fernandez-Aceñero
- Pathology Department, Clinico San Carlos University Hospital, C/Profesor Martin Lagos, 28040 Madrid, Spain; (M.J.F.-A.); (L.O.-M.)
| | - Luis Ortega-Medina
- Pathology Department, Clinico San Carlos University Hospital, C/Profesor Martin Lagos, 28040 Madrid, Spain; (M.J.F.-A.); (L.O.-M.)
| | - Jesus Garcia-Foncillas
- Department of Medical Oncology, Fundación Jiménez Díaz University Hospital, 28040 Madrid, Spain;
- Translational Oncology Division, Oncohealth Institute, Fundacion Jiménez Díaz University Hospital, 28040 Madrid, Spain; (L.S.-C.); (M.O.O.)
| | - Javier Martinez-Useros
- Translational Oncology Division, Oncohealth Institute, Fundacion Jiménez Díaz University Hospital, 28040 Madrid, Spain; (L.S.-C.); (M.O.O.)
- Area of Physiology, Department of Basic Health Sciences, Faculty of Health Sciences, Rey Juan Carlos University, 28922 Madrid, Spain
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12
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Song C, Zhang J, Xu C, Gao M, Li N, Geng Q. The critical role of γ-secretase and its inhibitors in cancer and cancer therapeutics. Int J Biol Sci 2023; 19:5089-5103. [PMID: 37928268 PMCID: PMC10620818 DOI: 10.7150/ijbs.87334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 07/22/2023] [Indexed: 11/07/2023] Open
Abstract
As a multi-substrate transmembrane protease, γ-secretase exists widely in various cells. It controls multiple important cellular activities through substrate cleavage. γ-secretase inhibitors (GSIs) play a role in cancer inhibition by blocking Notch cleavage, and are considered as potential therapeutic strategies for cancer. Currently, GSIs have encouraging performance in preclinical models, yet this success does not translate well in clinical trials. In recent years, a number of breakthrough discoveries have shown us the promise of targeting γ-secretase for the treatment of cancer. Here, we integrate a large amount of data from γ-secretase and its inhibitors and cancer in nearly 30 years, comb and discuss the close connection between γ-secretase and cancer, as well as the potential and problems of current GSIs in cancer treatment. We analyze the possible reasons for the failure performance of current GSIs in clinical trials, and make recommendations for future research areas.
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Affiliation(s)
- Congkuan Song
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jinjin Zhang
- Department of Emergency, Taihe Hospital, Shiyan, China
| | - Chenzhen Xu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Minglang Gao
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ning Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
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13
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Zhai S, Lin J, Ji Y, Zhang R, Zhang Z, Cao Y, Liu Y, Tang X, Liu J, Liu P, Lin J, Li F, Li H, Shi Y, Fu D, Deng X, Shen B. A microprotein N1DARP encoded by LINC00261 promotes Notch1 intracellular domain (N1ICD) degradation via disrupting USP10-N1ICD interaction to inhibit chemoresistance in Notch1-hyperactivated pancreatic cancer. Cell Discov 2023; 9:95. [PMID: 37714834 PMCID: PMC10504324 DOI: 10.1038/s41421-023-00592-6] [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: 01/18/2023] [Accepted: 07/28/2023] [Indexed: 09/17/2023] Open
Abstract
The extensively activated Notch signaling pathway in pancreatic cancer cells is important in carcinogenesis, chemoresistance, and recurrence. Targeting this pathway is a promising therapeutic strategy for pancreatic cancer; however, few successful approaches have been reported, and currently used molecular inhibitors of this pathway exhibit limited clinical benefits. In this study, we identified a previously uncharacterized microprotein, Notch1 degradation-associated regulatory polypeptide (N1DARP), encoded by LINC00261. N1DARP knockout accelerated tumor progression and enhanced stem cell properties in pancreatic cancer organoids and LSL-Kras, LSL-Trp53, and Pdx1-Cre (KPC) mice. Mechanistically, N1DARP suppressed canonical and non-canonical Notch1 pathways by competitively disrupting the interaction between N1ICD and ubiquitin-specific peptidase 10 (USP10), thereby promoting K11- and K48-linked polyubiquitination of N1ICD. To evaluate the therapeutic potential of N1DARP, we designed a cell-penetrating stapled peptide, SAH-mAH2-5, with a helical structure similar to that of N1DARP that confers remarkable physicochemical stability. SAH-mAH2-5 interacted with and promoted the proteasome-mediated degradation of N1ICD. SAH-mAH2-5 injection provided substantial therapeutic benefits with limited off-target and systemic adverse effects in Notch1-activated pancreatic cancer models. Taken together, these findings confirm that N1DARP acts as a tumor suppressor and chemosensitizer by regulating USP10-Notch1 oncogenic signaling, and suggest a promising therapeutic strategy targeting the N1DARP-N1ICD interaction in Notch1-activated pancreatic cancer.
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Affiliation(s)
- Shuyu Zhai
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jiewei Lin
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuchen Ji
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Ronghao Zhang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Zehui Zhang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yizhi Cao
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yang Liu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Xiaomei Tang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jia Liu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Pengyi Liu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jiayu Lin
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Fanlu Li
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Hongzhe Li
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yusheng Shi
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China.
| | - Da Fu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China.
| | - Xiaxing Deng
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China.
| | - Baiyong Shen
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China.
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14
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Deshotels L, Safa FM, Saba NS. NOTCH Signaling in Mantle Cell Lymphoma: Biological and Clinical Implications. Int J Mol Sci 2023; 24:10280. [PMID: 37373427 DOI: 10.3390/ijms241210280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Despite major progress in mantle cell lymphoma (MCL) therapeutics, MCL remains a deadly disease with a median survival not exceeding four years. No single driver genetic lesion has been described to solely give rise to MCL. The hallmark translocation t(11;14)(q13;q32) requires additional genetic alterations for the malignant transformation. A short list of recurrently mutated genes including ATM, CCND1, UBR5, TP53, BIRC3, NOTCH1, NOTCH2, and TRAF2 recently emerged as contributors to the pathogenesis of MCL. Notably, NOTCH1 and NOTCH2 were found to be mutated in multiple B cell lymphomas, including 5-10% of MCL, with most of these mutations occurring within the PEST domain of the protein. The NOTCH genes play a critical role in the early and late phases of normal B cell differentiation. In MCL, mutations in the PEST domain stabilize NOTCH proteins, rendering them resistant to degradation, which subsequently results in the upregulation of genes involved in angiogenesis, cell cycle progression, and cell migration and adhesion. At the clinical level, mutated NOTCH genes are associated with aggressive features in MCL, such as the blastoid and pleomorphic variants, a shorter response to treatment, and inferior survival. In this article, we explore in detail the role of NOTCH signaling in MCL biology and the ongoing efforts toward targeted therapeutic interventions.
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Affiliation(s)
- Leigh Deshotels
- Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Firas M Safa
- Service d'hématologie, Centre Hospitalier du Mans, 72037 Le Mans, France
| | - Nakhle S Saba
- Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University, New Orleans, LA 70112, USA
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15
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Fang YT, Yang WW, Niu YR, Sun YK. Recent advances in targeted therapy for pancreatic adenocarcinoma. World J Gastrointest Oncol 2023; 15:571-595. [PMID: 37123059 PMCID: PMC10134207 DOI: 10.4251/wjgo.v15.i4.571] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/11/2022] [Accepted: 03/16/2023] [Indexed: 04/12/2023] Open
Abstract
Pancreatic adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of 8% and a median survival of 6 mo. In PDAC, several mutations in the genes are involved, with Kirsten rat sarcoma oncogene (90%), cyclin-dependent kinase inhibitor 2A (90%), and tumor suppressor 53 (75%–90%) being the most common. Mothers against decapentaplegic homolog 4 represents 50%. In addition, the self-preserving cancer stem cells, dense tumor microenvironment (fibrous accounting for 90% of the tumor volume), and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC. Molecular targeted therapy is widely utilized and effective in several solid tumors. In PDAC, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC – erlotinib, but the absolute benefit of erlotinib in combination with gemcitabine is also minimal (2 wk). In this review, we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process, analyze possible reasons for the lack of positive results in clinical trials, and suggest ways to improve them. We also discuss emerging trends in targeted therapies for PDAC: combining targeted inhibitors of multiple pathways. The PubMed database and National Center for Biotechnology Information clinical trial website (www.clinicaltrials.gov) were queried to identify completed and published (PubMed) and ongoing (clinicaltrials.gov) clinical trials (from 2003-2022) using the keywords pancreatic cancer and targeted therapy. The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.
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Affiliation(s)
- Yu-Ting Fang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Wei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ya-Ru Niu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Kun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang 065001, Hebei Province, China
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16
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Yan W, Steele NG, Kemp SB, Menjivar RE, Du W, Carpenter ES, Donahue KL, Brown KL, Irizarry-Negron V, Yang S, Burns WR, Zhang Y, di Magliano MP, Bednar F. Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.11.523584. [PMID: 36711890 PMCID: PMC9882066 DOI: 10.1101/2023.01.11.523584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. The poor survival of patients with PDA has been attributed to a high rate of early metastasis and low efficacy of current therapies, which partly result from its complex immunosuppressive tumor microenvironment. Previous studies from our group and others have shown that tumor-associated macrophages (TAMs) are instrumental in maintaining immunosuppression in PDA. Here, we explored the role of Notch signaling, a key regulator of immune response, within the PDA microenvironment. We identified Notch pathway components in multiple immune cell types within human and mouse pancreatic cancer. TAMs, the most abundant immune cell population in the tumor microenvironment, express high levels of Notch receptors with cognate ligands such as JAG1 expressed on tumor epithelial cells, endothelial cells and fibroblasts. TAMs with activated Notch signaling expressed higher levels of immunosuppressive mediators including arginase 1 (Arg1) suggesting that Notch signaling plays a role in macrophage polarization within the PDA microenvironment. Combination of Notch inhibition with PD-1 blockade resulted in increased cytotoxic T cell infiltration, tumor cell apoptosis, and smaller tumor size. Our work implicates macrophage Notch signaling in the establishment of immunosuppression and indicates that targeting the Notch pathway may improve the efficacy of immune-based therapies in PDA patients.
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Affiliation(s)
- Wei Yan
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Nina G. Steele
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Samantha B. Kemp
- Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rosa E. Menjivar
- Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Wenting Du
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Eileen S. Carpenter
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor Ml 48109, USA
| | - Katelyn L. Donahue
- Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - Kristee L. Brown
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Sion Yang
- College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - William R. Burns
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yaqing Zhang
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Marina Pasca di Magliano
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
- Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Filip Bednar
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
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17
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Manni W, Min W. Signaling pathways in the regulation of cancer stem cells and associated targeted therapy. MedComm (Beijing) 2022; 3:e176. [PMID: 36226253 PMCID: PMC9534377 DOI: 10.1002/mco2.176] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 11/07/2022] Open
Abstract
Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self-renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well-established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor-associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy-resistant or -refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC-directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC-directed therapeutics, with a special focus on those with application approval or under clinical evaluation.
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Affiliation(s)
- Wang Manni
- Department of Biotherapy, Cancer Center, West China HospitalSichuan UniversityChengduP. R. China
| | - Wu Min
- Department of Biomedical Sciences, School of Medicine and Health SciencesUniversity of North DakotaGrand ForksNorth DakotaUSA
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18
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Zhuang L, Yao Y, Peng L, Cui F, Chen C, Zhang Y, Sun L, Yu Q, Lin K. Silencing GS Homeobox 2 Alleviates Gemcitabine Resistance in Pancreatic Cancer Cells by Activating SHH/GLI1 Signaling Pathway. Dig Dis Sci 2022; 67:3773-3782. [PMID: 34623580 DOI: 10.1007/s10620-021-07262-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 09/20/2021] [Indexed: 12/13/2022]
Abstract
Sonic hedgehog (SHH) signaling pathway and glioma-associated oncogene homolog 1 (GLI1) play important roles in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). GS homeobox 2 (GSX2, formerly GSH2) is a downstream target of SHH signaling, but its role in pancreatic cancer remains unclear. This study evaluates the role of GSH2 in the development and drug resistance of pancreatic cancer. Both cell culture and xenograft mouse model were used. Immunohistochemistry, Western blotting and quantitative RT-PCR were used to examine the expression of GSH2 and other related molecules. CCK8 assay was used to test the cell proliferation, and flow cytometry used to examine cell apoptosis upon gemcitabine treatment. It was found that GSH2 is overexpressed in human pancreatic cancer tissues and cells. The expression of SHH and GLI1 was reversely correlated with GSH2 in pancreatic cancer cells. SHH and GLI1 have protein-protein interactions with GSH2. GSH2 silencing in pancreatic cancer cells inhibited cell proliferation, migration and invasion, increased cell apoptosis and sensitized pancreatic cancer cells to gemcitabine treatment. Furthermore, in vivo study demonstrated that silencing GSH2 increased the efficacy of gemcitabine-based treatment. Our results indicate that GSH2 is overexpressed in pancreatic cancer. GSH2 silencing in pancreatic cancer alleviates gemcitabine resistance by activating SHH/GLI1 pathway. Thus, targeting GSH2 in PDAC could be a novel cancer therapeutic strategy.
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Affiliation(s)
- Lu Zhuang
- Department of Gastroenterology, Changhai Hospital, Navy Military Medical University, 168 Changhai Road, Shanghai, 200433, China
- Shanghai Hongkou District Jiaxing Road Subdistrict Community Healthcare Service Center, 1 Hongguan Road, Shanghai, 200086, China
| | - Yao Yao
- Department of Gastroenterology, Changhai Hospital, Navy Military Medical University, 168 Changhai Road, Shanghai, 200433, China
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200030, China
| | - Lisi Peng
- Department of Gastroenterology, Changhai Hospital, Navy Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Fang Cui
- Department of Gastroenterology, Changhai Hospital, Navy Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Cui Chen
- Department of Gastroenterology, Changhai Hospital, Navy Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Yang Zhang
- Department of Gastroenterology, Changhai Hospital, Navy Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Liqi Sun
- Department of Gastroenterology, Changhai Hospital, Navy Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Qihong Yu
- Department of Gastroenterology, Changhai Hospital, Navy Military Medical University, 168 Changhai Road, Shanghai, 200433, China
| | - Kun Lin
- Department of Gastroenterology, Changhai Hospital, Navy Military Medical University, 168 Changhai Road, Shanghai, 200433, China.
- Department of Gastroenterology, Zhongnan Hospital, Wuhan University, 169 Donghu Road, Wuhan, 430071, China.
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19
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Notch signaling in malignant gliomas: supporting tumor growth and the vascular environment. Cancer Metastasis Rev 2022; 41:737-747. [PMID: 35624227 DOI: 10.1007/s10555-022-10041-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 05/18/2022] [Indexed: 11/02/2022]
Abstract
Glioblastoma is the most malignant form of glioma, which is the most commonly occurring tumor of the central nervous system. Notch signaling in glioblastoma is considered to be a marker of an undifferentiated tumor cell state, associated with tumor stem cells. Notch is also known for facilitating tumor dormancy escape, recurrence and progression after treatment. Studies in vitro suggest that reducing, removing or blocking the expression of this gene triggers tumor cell differentiation, which shifts the phenotype away from stemness status and consequently facilitates treatment. In contrast, in the vasculature, Notch appears to also function as an important receptor that defines mature non-leaking vessels, and increasing its expression promotes tumor normalization in models of cancer in vivo. Failures in clinical trials with Notch inhibitors are potentially related to their opposing effects on the tumor versus the tumor vasculature, which points to the need for a greater understanding of this signaling pathway.
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20
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Identification, Culture and Targeting of Cancer Stem Cells. Life (Basel) 2022; 12:life12020184. [PMID: 35207472 PMCID: PMC8879966 DOI: 10.3390/life12020184] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Chemoresistance, tumor progression, and metastasis are features that are frequently seen in cancer that have been associated with cancer stem cells (CSCs). These cells are a promising target in the future of cancer therapy but remain largely unknown. Deregulation of pathways that govern stemness in non-tumorigenic stem cells (SCs), such as Notch, Wnt, and Hedgehog pathways, has been described in CSC pathogenesis, but it is necessary to conduct further studies to discover potential new therapeutic targets. In addition, some markers for the identification and characterization of CSCs have been suggested, but the search for specific CSC markers in many cancer types is still under development. In addition, methods for CSC cultivation are also under development, with great heterogeneity existing in the protocols used. This review focuses on the most recent aspects of the identification, characterization, cultivation, and targeting of human CSCs, highlighting the advances achieved in the clinical implementation of therapies targeting CSCs and remarking those potential areas where more research is still required.
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21
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Reddy AV, Hill CS, Sehgal S, Ding D, Hacker-Prietz A, He J, Zheng L, Herman JM, Meyer J, Narang AK. Impact of somatic mutations on clinical and pathologic outcomes in borderline resectable and locally advanced pancreatic cancer treated with neoadjuvant chemotherapy and stereotactic body radiotherapy followed by surgical resection. Radiat Oncol J 2021; 39:304-314. [PMID: 34986552 PMCID: PMC8743453 DOI: 10.3857/roj.2021.00815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/08/2021] [Accepted: 10/14/2021] [Indexed: 01/05/2023] Open
Abstract
PURPOSE The purpose of this study was to determine if somatic mutations are associated with clinical and pathologic outcomes in patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) who were treated with neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS Patients treated with neoadjuvant chemotherapy and SBRT followed by surgical resection from August 2016 to January 2019 and who underwent next generation sequencing of their primary tumor were included in the study. Next-generation sequencing was performed either in-house with a Solid Tumor Panel or with FoundationOne CDx. Univariate (UVA) and multivariable analyses (MVA) were performed to determine associations between somatic mutations and pathologic and clinical outcomes. RESULTS Thirty-five patients were included in the study. Chemotherapy consisted of modified FOLFIRINOX, gemcitabine and nab-paclitaxel, or gemcitabine and capecitabine. Patients were treated with SBRT in 33 Gy in 5 fractions. On UVA and MVA, tumors with KRAS G12V mutation demonstrated better pathologic tumor regression grade (TRG) to neoadjuvant therapy when compared to tumors with other KRAS mutations (odds ratio = 0.087; 95% confidence interval [CI], 0.009-0.860; p = 0.036). On UVA and MVA, mutations in NOTCH1/2 were associated with worse overall survival (hazard ratio [HR] = 4.15; 95% CI, 1.57-10.95; p = 0.004) and progression-free survival (HR = 3.61; 95% CI, 1.41-9.28; p = 0.008). On UVA, only mutations in NOTCH1/2 were associated with inferior distant metastasis-free survival (HR = 3.38; 95% CI, 1.25-9.16; p = 0.017). CONCLUSION In BRPC and LAPC, the KRAS G12V mutation was associated with better TRG following chemotherapy and SBRT. Additionally, NOTCH1/2 mutations were associated with worse overall survival, distant metastasis-free survival, and progression-free survival.
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Affiliation(s)
- Abhinav V. Reddy
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Colin S. Hill
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shuchi Sehgal
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ding Ding
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amy Hacker-Prietz
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jin He
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lei Zheng
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Joseph M. Herman
- Department of Radiation Oncology, Northwell Health Cancer Institute, New Hyde Park, NY, USA
| | - Jeffrey Meyer
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amol K. Narang
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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22
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Zhang H, Xing J, Zhao L. Lysine-specific demethylase 1 induced epithelial-mesenchymal transition and promoted renal fibrosis through Jagged-1/Notch signaling pathway. Hum Exp Toxicol 2021; 40:S203-S214. [PMID: 34396798 DOI: 10.1177/09603271211038743] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE TGF-β1-induced excessive deposition of extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT) process of tubular epithelial cells play critical roles in the progression of renal fibrosis. We are aimed to explore the effects of lysine-specific demethylase 1 (LSD1) in TGF-β1-treated HK-2 cells and in rats with unilateral ureteral obstruction (UUO), and to investigate the underlying molecular mechanism. METHODS TGF-β1-treated HK-2 cells and UUO-treated rats were used to establish the model of renal fibrosis in vitro and in vivo, respectively. Protein expression of LSD1, E-cadherin, a-smooth muscle actin (a-SMA), Vimentin, Jagged-1, Notch-1 and Notch-2 were detected by Western blot. The concentrations of type I collagen (Col-I) and Fibronectin (FN) were measured by ELISA. Transwell assay were used to assess cell invasion. RESULTS LSD1 was dramatically increased in TGF-β1-stimulated HK-2 cells. Knockdown of LSD1 decreased the TGF-β1-induced secretion of Col-I and FN, and suppressed TGF-β1-induced expression of E-cadherin,α-SMA and Vimentin, while suppressed cell invasion. Consistent with the in vitro data, the severe histopathological damage, collagen deposition and reduced E-cadherin, increased α-SMA induced by UUO was abated by the knockdown of LSD1 in vivo. Moreover, knockdown of LSD1 suppressed TGF-β1-induced expression of Jagged-1, Notch-1 and Notch-2. Furthermore, we found that inhibition of Notch signaling by a γ-secretase inhibitor RO4929097 almost recapitulated the effects of LSD1 knockdown in TGF-β1-induced HK-2 cells, and at least in part reversed the effects of LSD1 overexpression on EMT and ECM deposition in HK-2 cells. CONCLUSIONS Taken together, LSD1 significantly impact on the progression of TGF-β1-mediated EMT and ECM deposition in HK-2 cells, and it may represent novel target for the prevention strategies of renal fibrosis.
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Affiliation(s)
- Huali Zhang
- Gerontology Department, 586778Gansu Provincial Hospital of TCM, Lanzhou, China
| | - Jiaming Xing
- Gerontology Department, 586778Gansu Provincial Hospital of TCM, Lanzhou, China
| | - Lingwei Zhao
- Nephrology Department, Sichuan Province Forestry Center Hospital, Chengdu, China
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23
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Dardare J, Witz A, Merlin JL, Bochnakian A, Toussaint P, Gilson P, Harlé A. Epithelial to Mesenchymal Transition in Patients with Pancreatic Ductal Adenocarcinoma: State-of-the-Art and Therapeutic Opportunities. Pharmaceuticals (Basel) 2021; 14:740. [PMID: 34451837 PMCID: PMC8399337 DOI: 10.3390/ph14080740] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the malignancies with the worst prognosis despite a decade of efforts. Up to eighty percent of patients are managed at late stages with metastatic disease, in part due to a lack of diagnosis. The effectiveness of PDAC therapies is challenged by the early and widespread metastasis. Epithelial to mesenchymal transition (EMT) is a major driver of cancer progression and metastasis. This process allows cancer cells to gain invasive properties by switching their phenotype from epithelial to mesenchymal. The importance of EMT has been largely described in PDAC, and its importance is notably highlighted by the two major subtypes found in PDAC: the classical epithelial and the quasi-mesenchymal subtypes. Quasi-mesenchymal subtypes have been associated with a poorer prognosis. EMT has also been associated with resistance to treatments such as chemotherapy and immunotherapy. EMT is associated with several key molecular markers both epithelial and mesenchymal. Those markers might be helpful as a biomarker in PDAC diagnosis. EMT might becoming a key new target of interest for the treatment PDAC. In this review, we describe the role of EMT in PDAC, its contribution in diagnosis, in the orientation and treatment follow-up. We also discuss the putative role of EMT as a new therapeutic target in the management of PDAC.
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Affiliation(s)
- Julie Dardare
- Université de Lorraine, CNRS UMR7039 CRAN, Service de Biopathologie, Institut de Cancérologie de Lorraine, 54519 Vandoeuvre-lès-Nancy, France; (A.W.); (J.-L.M.); (A.B.); (P.T.); (P.G.); (A.H.)
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24
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Raghav PK, Mann Z. Cancer stem cells targets and combined therapies to prevent cancer recurrence. Life Sci 2021; 277:119465. [PMID: 33831426 DOI: 10.1016/j.lfs.2021.119465] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/01/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) control the dynamics of tumorigenesis by self-renewal ability and differentiation potential. These properties contribute towards tumor malignancy, metastasis, cellular heterogeneity, and immune escape, which are regulated by multiple signaling pathways. The CSCs are chemoresistant and cause cancer recurrence, generally recognized as a small side-population that eventually leads to tumor relapse. Despite many treatment options available, none can be considered entirely efficient due to a lack of specificity and dose limitation. This review primarily highlights the processes involved in CSCs development and maintenance. Secondly, the current effective therapies based on stem cells, cell-free therapies that involve exosomes and miRNAs, and photodynamic therapy have been discussed. Also, the inhibitors that specifically target various signaling pathways, which can be used in combination to control CSCs kinetics have been highlighted. Conclusively, this comprehensive review is a detailed study of recently developed novel treatment strategies that will facilitate in coming up with better-targeted approaches against CSCs.
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Affiliation(s)
| | - Zoya Mann
- Independent Researcher, New Delhi, India
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25
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McCaw TR, Inga E, Chen H, Jaskula‐Sztul R, Dudeja V, Bibb JA, Ren B, Rose JB. Gamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance. Oncologist 2021; 26:e608-e621. [PMID: 33284507 PMCID: PMC8018325 DOI: 10.1002/onco.13627] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/13/2020] [Indexed: 01/01/2023] Open
Abstract
Gamma secretase inhibitors (GSIs), initially developed as Alzheimer's therapies, have been repurposed as anticancer agents given their inhibition of Notch receptor cleavage. The success of GSIs in preclinical models has been ascribed to induction of cancer stem-like cell differentiation and apoptosis, while also impairing epithelial-to-mesenchymal transition and sensitizing cells to traditional chemoradiotherapies. The promise of these agents has yet to be realized in the clinic, however, as GSIs have failed to demonstrate clinical benefit in most solid tumors with the notable exceptions of CNS malignancies and desmoid tumors. Disappointing clinical performance to date reflects important questions that remain to be answered. For example, what is the net impact of these agents on antitumor immune responses, and will they require concurrent targeting of tumor-intrinsic compensatory pathways? Addressing these limitations in our current understanding of GSI mechanisms will undoubtedly facilitate their rational incorporation into combinatorial strategies and provide a valuable tool with which to combat Notch-dependent cancers. In the present review, we provide a current understanding of GSI mechanisms, discuss clinical performance to date, and suggest areas for future investigation that might maximize the utility of these agents. IMPLICATIONS FOR PRACTICE: The performance of gamma secretase inhibitors (GSIs) in clinical trials generally has not reflected their encouraging performance in preclinical studies. This review provides a current perspective on the clinical performance of GSIs across various solid tumor types alongside putative mechanisms of antitumor activity. Through exploration of outstanding gaps in knowledge as well as reasons for success in certain cancer types, the authors identify areas for future investigation that will likely enable incorporation of GSIs into rational combinatorial strategies for superior tumor control and patient outcomes.
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Affiliation(s)
- Tyler R. McCaw
- Divisions of Surgical Oncology, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - Evelyn Inga
- Divisions of Surgical Oncology, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - Herbert Chen
- Breast & Endocrine Surgery, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - Renata Jaskula‐Sztul
- Breast & Endocrine Surgery, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - Vikas Dudeja
- Divisions of Surgical Oncology, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - James A. Bibb
- Gastrointestinal Surgery, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - Bin Ren
- Vascular Surgery & Endovascular Therapy, Department of Surgery, The University of Alabama at BirminghamBirminghamAlabamaUSA
| | - J. Bart Rose
- Divisions of Surgical Oncology, The University of Alabama at BirminghamBirminghamAlabamaUSA
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26
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Liu X, Li Z, Wang Y. Advances in Targeted Therapy and Immunotherapy for Pancreatic Cancer. Adv Biol (Weinh) 2021; 5:e1900236. [PMID: 33729700 DOI: 10.1002/adbi.201900236] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 08/19/2020] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is a highly aggressive malignancy with an overall 5-year survival rate of <6% due to therapeutic resistance and late-stage diagnosis. These statistics have not changed despite 50 years of research and therapeutic development. Pancreatic cancer is predicted to become the second leading cause of cancer mortality by the year 2030. Currently, the treatment options for pancreatic cancer are limited. This disease is usually diagnosed at a late stage, which prevents curative surgical resection. Chemotherapy is the most frequently used approach for pancreatic cancer treatment and has limited effects. In many other cancer types, targeted therapy and immunotherapy have made great progress and have been shown to be very promising prospects; these treatments also provide hope for pancreatic cancer. The need for research on targeted therapy and immunotherapy is pressing due to the poor prognosis of pancreatic cancer, and in recent years, there have been some breakthroughs for targeted therapy and immunotherapy in pancreatic cancer. This review summarizes the current preclinical and clinical studies of targeted therapy and immunotherapy for pancreatic cancer and ends by describing the challenges and outlook.
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Affiliation(s)
- Xiaoxiao Liu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Zhang Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuexiang Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
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27
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Patni AP, Harishankar MK, Joseph JP, Sreeshma B, Jayaraj R, Devi A. Comprehending the crosstalk between Notch, Wnt and Hedgehog signaling pathways in oral squamous cell carcinoma - clinical implications. Cell Oncol (Dordr) 2021; 44:473-494. [PMID: 33704672 DOI: 10.1007/s13402-021-00591-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 01/17/2021] [Accepted: 01/19/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) is a malignant oral cavity neoplasm that affects many people, especially in developing countries. Despite several advances that have been made in diagnosis and treatment, the morbidity and mortality rates due to OSCC remain high. Accumulating evidence indicates that aberrant activation of cellular signaling pathways, such as the Notch, Wnt and Hedgehog pathways, occurs during the development and metastasis of OSCC. In this review, we have articulated the roles of the Notch, Wnt and Hedgehog signaling pathways in OSCC and their crosstalk during tumor development and progression. We have also examined possible interactions and associations between these pathways and treatment regimens that could be employed to effectively tackle OSCC and/or prevent its recurrence. CONCLUSIONS Activation of the Notch signaling pathway upregulates the expression of several genes, including c-Myc, β-catenin, NF-κB and Shh. Associations between the Notch signaling pathway and other pathways have been shown to enhance OSCC tumor aggressiveness. Crosstalk between these pathways supports the maintenance of cancer stem cells (CSCs) and regulates OSCC cell motility. Thus, application of compounds that block these pathways may be a valid strategy to treat OSCC. Such compounds have already been employed in other types of cancer and could be repurposed for OSCC.
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Affiliation(s)
- Anjali P Patni
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - M K Harishankar
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - Joel P Joseph
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - Bhuvanadas Sreeshma
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India
| | - Rama Jayaraj
- College of Human and Human Sciences, Charles Darwin University, Ellangowan Drive, Darwin, Northern Territory, 0909, Australia
| | - Arikketh Devi
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India.
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28
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Al-Share B, Hammad N, Diab M. Pancreatic adenocarcinoma: molecular drivers and the role of targeted therapy. Cancer Metastasis Rev 2021; 40:355-371. [PMID: 33398620 DOI: 10.1007/s10555-020-09948-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/15/2020] [Indexed: 01/05/2023]
Abstract
Prognosis from pancreatic ductal adenocarcinoma (PDAC) continues to be poor despite the many efforts channeled to improve its management. Although the mainstay treatment is still traditional chemotherapy, recent advances highlighted a promising potential for targeted therapy in the management of this disease. Those advances emphasize the significance of timely genomic profiling of tumor tissue as well as germline testing of patients to identify potential markers of targeted therapy. While targeted therapy is reserved for a relatively small subset of patients with PDAC, ongoing research is uncovering additional markers, and targeted agents, that will hopefully translate to better outcomes for patients.
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Affiliation(s)
- Bayan Al-Share
- Department of Oncology, Wayne State University, Karmanos Cancer Institute, Detroit, MI, USA
| | - Nour Hammad
- Department of Oncology, Ascension Providence Hospital and Medical Center/Michigan State University/Collage of Human Medicine, Southfield, MI, USA
| | - Maria Diab
- Department of Oncology, Emory University, Atlanta, GA, USA.
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29
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NOTCH3, a crucial target of miR-491-5p/miR-875-5p, promotes gastric carcinogenesis by upregulating PHLDB2 expression and activating Akt pathway. Oncogene 2021; 40:1578-1594. [PMID: 33452458 PMCID: PMC7932926 DOI: 10.1038/s41388-020-01579-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 01/29/2023]
Abstract
Aberrant Notch activation has been implicated in multiple malignancies and the identification of NOTCH receptors and related pathways is critical for targeted therapy. In this study, we aim to delineate the most prominent dysregulated NOTCH receptor and comprehensively reveal its deregulation in gastric cancer (GC). In the four Notch members, NOTCH3 was found uniformly upregulated and associated with poor clinical outcomes in multiple GC datasets. siRNA-mediated NOTCH3 knockdown demonstrated antitumor effects by suppressing cell proliferation, inhibiting monolayer formation, and impairing cell invasion abilities. Its depletion also induced early and late apoptosis. NOTCH3 was confirmed to be a direct target of two tumor suppressor microRNAs (miRNAs), namely miR-491-5p and miR-875-5p. The activation of NOTCH3 is partly due to the silence of these two miRNAs. Through RNA-seq profiling and functional validation, PHLDB2 was identified as a potent functional downstream modulator for NOTCH3 in gastric carcinogenesis. PHLDB2 expression demonstrated a positive correlation with NOTCH3, but was negatively correlated with miR-491-5p. Akt-mTOR was revealed as the downstream signaling of PHLDB2. The NOTCH3-PHLDB2-Akt co-activation was found in 33.7% GC patients and the activation of this axis predicted poor clinical outcome. GC cells treated with siNOTCH3, siPHLDB2, miR-491-5p, miR-875-5p, were more sensitive to Cisplatin and 5-FU. Taken together, the NOTCH3-PHLDB2-Akt cascade plays oncogenic role in gastric carcinogenesis and serves as a therapeutic target. Our study provided insights into Notch-mediated underlying molecular mechanisms and implied translational potential.
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30
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Gharaibeh L, Elmadany N, Alwosaibai K, Alshaer W. Notch1 in Cancer Therapy: Possible Clinical Implications and Challenges. Mol Pharmacol 2020; 98:559-576. [PMID: 32913140 DOI: 10.1124/molpharm.120.000006] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 08/10/2020] [Indexed: 12/19/2022] Open
Abstract
The Notch family consists of four highly conserved transmembrane receptors. The release of the active intracellular domain requires the enzymatic activity of γ-secretase. Notch is involved in embryonic development and in many physiologic processes of normal cells, in which it regulates growth, apoptosis, and differentiation. Notch1, a member of the Notch family, is implicated in many types of cancer, including breast cancer (especially triple-negative breast cancer), leukemias, brain tumors, and many others. Notch1 is tightly connected to many signaling pathways that are therapeutically involved in tumorigenesis. Together, they impact apoptosis, proliferation, chemosensitivity, immune response, and the population of cancer stem cells. Notch1 inhibition can be achieved through various and diverse methods, the most common of which are the γ-secretase inhibitors, which produce a pan-Notch inhibition, or the use of Notch1 short interference RNA or Notch1 monoclonal antibodies, which produce a more specific blockade. Downregulation of Notch1 can be used alone or in combination with chemotherapy, which can achieve a synergistic effect and a decrease in chemoresistance. Targeting Notch1 in cancers that harbor high expression levels of Notch1 offers an addition to therapeutic strategies recruited for managing cancer. Considering available evidence, Notch1 offers a legitimate target that might be incorporated in future strategies for combating cancer. In this review, the possible clinical applications of Notch1 inhibition and the obstacles that hinder its clinical application are discussed. SIGNIFICANCE STATEMENT: Notch1 plays an important role in different types of cancer. Numerous approaches of Notch1 inhibition possess potential benefits in the management of various clinical aspects of cancer. The application of different Notch1 inhibition modalities faces many challenges.
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Affiliation(s)
- L Gharaibeh
- Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan (L.G); Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.E.); Research Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia (K.A.); and Cell Therapy Center, The University of Jordan, Amman, Jordan (W.A.)
| | - N Elmadany
- Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan (L.G); Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.E.); Research Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia (K.A.); and Cell Therapy Center, The University of Jordan, Amman, Jordan (W.A.)
| | - K Alwosaibai
- Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan (L.G); Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.E.); Research Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia (K.A.); and Cell Therapy Center, The University of Jordan, Amman, Jordan (W.A.)
| | - W Alshaer
- Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan (L.G); Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (N.E.); Research Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia (K.A.); and Cell Therapy Center, The University of Jordan, Amman, Jordan (W.A.)
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Rauff B, Malik A, Bhatti YA, Chudhary SA, Qadri I, Rafiq S. Notch signalling pathway in development of cholangiocarcinoma. World J Gastrointest Oncol 2020; 12:957-974. [PMID: 33005291 PMCID: PMC7509998 DOI: 10.4251/wjgo.v12.i9.957] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/03/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) comprises of extra-hepatic cholangiocarcinoma and intrahepatic cholangiocarcinoma cancers as a result of inflammation of epithelium cell lining of the bile duct. The incidence rate is increasing dramatically worldwide with highest rates in Eastern and South Asian regions. Major risk factors involve chronic damage and inflammation of bile duct epithelium from primary sclerosing cholangitis, chronic hepatitis virus infection, gallstones and liver fluke infection. Various genetic variants have also been identified and as CCA develops on the background of biliary inflammation, diverse range of molecular mechanisms are involved in its progression. Among these, the Notch signalling pathway acts as a major driver of cholangiocarcinogenesis and its components (receptors, ligands and downstream signalling molecules) represent a promising therapeutic targets. Gamma-Secretase Inhibitors have been recognized in inhibiting the Notch pathway efficiently. A comprehensive knowledge of the molecular pathways activated by the Notch signalling cascade as well as its functional crosstalk with other signalling pathways provide better approach in developing innovative therapies against CCA.
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Affiliation(s)
- Bisma Rauff
- Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan
| | - Arif Malik
- Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan
| | - Yasir Ali Bhatti
- Institute of Molecular Biology and Biotechnology, University of Lahore, Lahore 54000, Pakistan
| | - Shafiq Ahmad Chudhary
- Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore 54000, Pakistan
| | - Ishtiaq Qadri
- Department of Biology, Faculty of Science, King Abdulaziz University Jeddah Kingdom of Saudi Arabia
| | - Shafquat Rafiq
- Department of Gastrointestinal medicine, Croydon University Hospital, Croydon CR7 7YE, United Kingdom
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32
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Mechanisms of cancer stem cell therapy. Clin Chim Acta 2020; 510:581-592. [PMID: 32791136 DOI: 10.1016/j.cca.2020.08.016] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 08/01/2020] [Accepted: 08/07/2020] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) are responsible for carcinogenesis and tumorigenesis and are involved in drug and radiation resistance, metastasis, tumor relapse and initiation. Remarkably, they have other abilities such as inheritance of self-renewal and de-differentiation. Hence, targeting CSCs is considered a potential anti-cancer therapeutic strategy. Recent advances in the identification of biomarkers to recognize CSCs and the development of new techniques to evaluate tumorigenic and carcinogenic roles of CSCs are instrumental to this approach. Elucidation of signaling pathways that regulate CSCs colony progression and drug resistance are critical in establishing effective targeted therapies. CSCs play a central key role in immunomodulation, immune evasion and effector immunity, which alters immune system balancing. These include mTOR, SHH, NOTCH and Wnt/β-catering in cancer progression. In this review article, we discuss the importance of these CSCs pathways in cancer therapy.
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Ancel J, Dewolf M, Deslée G, Nawrocky-Raby B, Dalstein V, Gilles C, Polette M. Clinical Impact of the Epithelial-Mesenchymal Transition in Lung Cancer as a Biomarker Assisting in Therapeutic Decisions. Cells Tissues Organs 2020; 211:91-109. [PMID: 32750701 DOI: 10.1159/000510103] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/11/2020] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is one of the most common solid cancers and represents the leading cause of cancer death worldwide. Over the last decade, research on the epithelial-mesenchymal transition (EMT) in lung cancer has gained increasing attention. Here, we review clinical and histological features of non-small-cell lung cancer associated with EMT. We then aimed to establish potential clinical implications of EMT in current therapeutic options, including surgery, radiation, targeted therapy against oncogenic drivers, and immunotherapy.
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Affiliation(s)
- Julien Ancel
- Inserm, Université de Reims Champagne Ardenne, P3Cell UMR-S1250, SFR CAP-SANTE, Reims, France.,Service de Pneumologie, Hôpital Maison Blanche, CHU de Reims, Reims, France
| | - Maxime Dewolf
- Service de Pneumologie, Hôpital Maison Blanche, CHU de Reims, Reims, France
| | - Gaëtan Deslée
- Inserm, Université de Reims Champagne Ardenne, P3Cell UMR-S1250, SFR CAP-SANTE, Reims, France.,Service de Pneumologie, Hôpital Maison Blanche, CHU de Reims, Reims, France
| | - Béatrice Nawrocky-Raby
- Inserm, Université de Reims Champagne Ardenne, P3Cell UMR-S1250, SFR CAP-SANTE, Reims, France
| | - Véronique Dalstein
- Inserm, Université de Reims Champagne Ardenne, P3Cell UMR-S1250, SFR CAP-SANTE, Reims, France.,Laboratoire de Pathologie, Hôpital Maison Blanche, CHU de Reims, Reims, France
| | - Christine Gilles
- Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium,
| | - Myriam Polette
- Inserm, Université de Reims Champagne Ardenne, P3Cell UMR-S1250, SFR CAP-SANTE, Reims, France.,Laboratoire de Pathologie, Hôpital Maison Blanche, CHU de Reims, Reims, France
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Moore G, Annett S, McClements L, Robson T. Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives. Cells 2020; 9:cells9061503. [PMID: 32575680 PMCID: PMC7349363 DOI: 10.3390/cells9061503] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/05/2020] [Accepted: 06/11/2020] [Indexed: 12/17/2022] Open
Abstract
Evolutionarily conserved Notch plays a critical role in embryonic development and cellular self-renewal. It has both tumour suppressor and oncogenic activity, the latter of which is widely described. Notch-activating mutations are associated with haematological malignancies and several solid tumours including breast, lung and adenoid cystic carcinoma. Moreover, upregulation of Notch receptors and ligands and aberrant Notch signalling is frequently observed in cancer. It is involved in cancer hallmarks including proliferation, survival, migration, angiogenesis, cancer stem cell renewal, metastasis and drug resistance. It is a key component of cell-to-cell interactions between cancer cells and cells of the tumour microenvironment, such as endothelial cells, immune cells and fibroblasts. Notch displays diverse crosstalk with many other oncogenic signalling pathways, and may drive acquired resistance to targeted therapies as well as resistance to standard chemo/radiation therapy. The past 10 years have seen the emergence of different classes of drugs therapeutically targeting Notch including receptor/ligand antibodies, gamma secretase inhibitors (GSI) and most recently, the development of Notch transcription complex inhibitors. It is an exciting time for Notch research with over 70 cancer clinical trials registered and the first-ever Phase III trial of a Notch GSI, nirogacestat, currently at the recruitment stage.
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Affiliation(s)
- Gillian Moore
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, Royal College of Surgeons, D02 YN77 Dublin, Ireland; (G.M.); (S.A.)
| | - Stephanie Annett
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, Royal College of Surgeons, D02 YN77 Dublin, Ireland; (G.M.); (S.A.)
| | - Lana McClements
- The School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia;
| | - Tracy Robson
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, Royal College of Surgeons, D02 YN77 Dublin, Ireland; (G.M.); (S.A.)
- Correspondence:
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Kim K, Yu J, Kang JK, Morrow JP, Pajvani UB. Liver-selective γ-secretase inhibition ameliorates diet-induced hepatic steatosis, dyslipidemia and atherosclerosis. Biochem Biophys Res Commun 2020; 527:979-984. [PMID: 32439159 DOI: 10.1016/j.bbrc.2020.04.157] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 04/30/2020] [Indexed: 01/05/2023]
Abstract
Hepatic γ-secretase regulates low-density lipoprotein receptor (LDLR) cleavage and degradation, affecting clearance of plasma triglyceride (TG)-rich lipoproteins (TRLs). In this study, we investigated whether γ-secretase inhibition modulates risk of Western (high-fat/sucrose and high-cholesterol)-type diet (WTD)-induced hepatic steatosis, dyslipidemia and atherosclerosis. We evaluated liver and plasma lipids in WTD-fed mice with hepatocyte-specific ablation of the non-redundant γ-secretase-targeting subunit Nicastrin (L-Ncst). In parallel, we investigated the effect of liver-selective Ncst antisense oligonucleotides (ASO) on lipid metabolism and atherosclerosis in wildtype (WT) and ApoE knockout (ApoE-/-) mice fed normal chow or WTD. WTD-fed L-Ncst and Ncst ASO-treated WT mice showed reduced total cholesterol and LDL-cholesterol (LDL-C), as well as reduced hepatic lipid content as compared to Cre- and control ASO-treated WT mice. Treatment of WTD-fed ApoE-/- mice with Ncst ASO markedly lowered total and LDL cholesterol, hepatic TG and attenuated atherosclerotic lesions in the aorta, as compared to control ASO-treated mice. L-Ncst and Ncst ASO similarly showed reduced plasma glucose as compared to control mice. In conclusion, inhibition of hepatic γ-secretase reduces plasma glucose, and attenuates WTD-induced dyslipidemia, hepatic fat accumulation and atherosclerosis, suggesting potential pleiotropic application for diet-induced metabolic dysfunction.
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Affiliation(s)
- KyeongJin Kim
- Department of Medicine, Columbia University, New York, NY, 10032, USA; Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, 22212, South Korea.
| | - Junjie Yu
- Department of Medicine, Columbia University, New York, NY, 10032, USA
| | - Jin Ku Kang
- Department of Medicine, Columbia University, New York, NY, 10032, USA
| | - John P Morrow
- Department of Medicine, Columbia University, New York, NY, 10032, USA
| | - Utpal B Pajvani
- Department of Medicine, Columbia University, New York, NY, 10032, USA.
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36
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Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, Zhang G, Wang X, Dong Z, Chen F, Cui H. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther 2020; 5:8. [PMID: 32296030 PMCID: PMC7005297 DOI: 10.1038/s41392-020-0110-5] [Citation(s) in RCA: 1125] [Impact Index Per Article: 225.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 12/15/2019] [Accepted: 12/19/2019] [Indexed: 12/18/2022] Open
Abstract
Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.
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Affiliation(s)
- Liqun Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Pengfei Shi
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Gaichao Zhao
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Jie Xu
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Wen Peng
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Jiayi Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Guanghui Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Xiaowen Wang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Fei Chen
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, 48201, USA
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China.
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China.
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Sardesai S, Badawi M, Mrozek E, Morgan E, Phelps M, Stephens J, Wei L, Kassem M, Ling Y, Lustberg M, Stover D, Williams N, Layman R, Reinbolt R, VanDeusen J, Cherian M, Grever M, Carson W, Ramaswamy B, Wesolowski R. A phase I study of an oral selective gamma secretase (GS) inhibitor RO4929097 in combination with neoadjuvant paclitaxel and carboplatin in triple negative breast cancer. Invest New Drugs 2020; 38:1400-1410. [PMID: 31953695 DOI: 10.1007/s10637-020-00895-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 01/10/2020] [Indexed: 12/20/2022]
Abstract
Upregulation of Notch pathway is associated with poor prognosis in breast cancer. We present the results of a phase I study of an oral selective gamma secretase (GS) inhibitor (critical to Notch signaling), RO4929097 in combination with neoadjuvant chemotherapy for operable triple negative breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) of RO4929097. Secondary objectives were to determine real-time pharmacokinetics of RO4929097 and paclitaxel, safety and pathologic (pCR) complete response to study treatment. Eligible patients, initiated carboplatin at AUC 6 administered intravenously (IV) on day 1, weekly paclitaxel at 80 mg/m2 IV and RO4929097 10 mg daily given orally (PO) on days 1-3, 8-10 and 15-17 for six 21-day cycles. RO4929097 was escalated in 10 mg increments using the 3 + 3 dose escalation design. Two DLTs were observed in 14 patients - Grade (G) 4 thrombocytopenia in dose level 1 (10 mg) and G3 hypertension in dose level 2 (20 mg). Protocol-defined MTD was not determined due to discontinuation of RO4929097 development. However, 4 of 5 patients enrolled to 20 mg dose of RO4929097 required dose reduction to 10 mg due to toxicities (including neutropenia, thrombocytopenia and hypertension) occurring during and beyond the DLT observation period. Thus, 10 mg would have been the likely dose level for further development. G3 or higher hematologic toxicities included neutropenia (N = 8, 57%) and thrombocytopenia (N = 5, 36%) patients. Six (43%) patients had G2-3 neuropathy requiring paclitaxel dose reduction. No signs of drug-drug interaction between paclitaxel and RO4929097 were evident. Five patients (36%) had pCR.
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Affiliation(s)
- Sagar Sardesai
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Mohamed Badawi
- The Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Ewa Mrozek
- Medical Oncology, Mercy Health, St. Rita's Cancer Center, Lima, OH, USA
| | - Evan Morgan
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Mitch Phelps
- The Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Julie Stephens
- Medical Oncology, Mercy Health, St. Rita's Cancer Center, Lima, OH, USA
| | - Lai Wei
- The Center for Biostatistics, Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Mahmoud Kassem
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Yonghua Ling
- The Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Maryam Lustberg
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Daniel Stover
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Nicole Williams
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Rachel Layman
- Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Raquel Reinbolt
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Jeffrey VanDeusen
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Mathew Cherian
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Michael Grever
- The Division of Hematology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - William Carson
- The Division of Surgical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Bhuvaneswari Ramaswamy
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Robert Wesolowski
- The Division of Medical Oncology, College of Medicine, The Ohio State University, Columbus, OH, USA.
- The Ohio State University Comprehensive Cancer Center, Suite 1204, Lincoln Tower, 1800 Cannon Drive, Columbus, OH, 43210, USA.
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Vincent P, Wang H, Nieskoski M, Gunn JR, Marra K, Hoopes PJ, Samkoe KS, Doyley MM, Hasan T, Pogue BW. High-Resolution Ex Vivo Elastography to Characterize Tumor Stromal Heterogeneity In Situ in Pancreatic Adenocarcinoma. IEEE Trans Biomed Eng 2020; 67:2490-2496. [PMID: 31902753 DOI: 10.1109/tbme.2019.2963562] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Tumor stiffening in pancreatic adenocarcinoma (PDAC) has been linked to cancer progression and lack of therapy response, yet current elastography tools cannot map stiffness in a whole tumor field-of-view with biologically relevant spatial resolution. Therefore, this study was developed to assess stiffness heterogeneity and geometrical patterns across whole PDAC xenograft ex vivo tumors. METHODS The ex vivo elastography (EVE) mapping system was capable of creating stiffness map at 300-micron spatial resolution under a 5-20 mm field of view relevant to whole tumor assessment. The stiffness value at each location was determined by compression testing and an absolute tumor Young's modulus map was calculated based on the calibration between the system and ultrasound elastography (R2 = 0.95). RESULTS Two PDAC tumor lines AsPC-1 and BxPC-3 implanted in xenograft models were assessed to show tumor stiffness and its linear relationship to collagen content (R2 = 0.59). EVE was able to capture stiffness heterogeneity ranging between 5 and 100 kPa in pancreatic tumors with collagen content up to 25%. More importantly, data shows the inverse relationship of local stiffness to local drug distribution (R2 = 0.66) and vessel patency (R2 = 0.61) in both PDAC tumor lines. CONCLUSION The results suggested that elastography could be utilized to predict drug penetration in PDAC tumors or assess response to biological modifying adjunct therapies. SIGNIFICANCE This study presents the first attempt to map out stiffness on a biologically relevant spatial scale across whole PDAC tumor slices with spatial resolution in the hundreds of microns.
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Clara JA, Monge C, Yang Y, Takebe N. Targeting signalling pathways and the immune microenvironment of cancer stem cells - a clinical update. Nat Rev Clin Oncol 2019; 17:204-232. [PMID: 31792354 DOI: 10.1038/s41571-019-0293-2] [Citation(s) in RCA: 473] [Impact Index Per Article: 78.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2019] [Indexed: 02/06/2023]
Abstract
Cancer stem cells (CSCs) have important roles in tumour development, relapse and metastasis; the intrinsic self-renewal characteristics and tumorigenic properties of these cells provide them with unique capabilities to resist diverse forms of anticancer therapy, seed recurrent tumours, and disseminate to and colonize distant tissues. The findings of several studies indicate that CSCs originate from non-malignant stem or progenitor cells. Accordingly, inhibition of developmental signalling pathways that are crucial for stem and progenitor cell homeostasis and function, such as the Notch, WNT, Hedgehog and Hippo signalling cascades, continues to be pursued across multiple cancer types as a strategy for targeting the CSCs hypothesized to drive cancer progression - with some success in certain malignancies. In addition, with the renaissance of anticancer immunotherapy, a better understanding of the interplay between CSCs and the tumour immune microenvironment might be the key to unlocking a new era of oncological treatments associated with a reduced propensity for the development of resistance and with enhanced antimetastatic activity, thus ultimately resulting in improved patient outcomes. Herein, we provide an update on the progress to date in the clinical development of therapeutics targeting the Notch, WNT, Hedgehog and Hippo pathways. We also discuss the interactions between CSCs and the immune system, including the potential immunological effects of agents targeting CSC-associated developmental signalling pathways, and provide an overview of the emerging approaches to CSC-targeted immunotherapy.
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Affiliation(s)
- Joseph A Clara
- National Heart Lung and Blood Institute, NIH, Bethesda, MD, USA
| | - Cecilia Monge
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Yingzi Yang
- Department of Developmental Biology, Harvard School of Dental Medicine, Dana-Farber/Harvard Cancer Center, Boston, MA, USA
| | - Naoko Takebe
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA.
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Lai E, Puzzoni M, Ziranu P, Pretta A, Impera V, Mariani S, Liscia N, Soro P, Musio F, Persano M, Donisi C, Tolu S, Balconi F, Pireddu A, Demurtas L, Pusceddu V, Camera S, Sclafani F, Scartozzi M. New therapeutic targets in pancreatic cancer. Cancer Treat Rev 2019; 81:101926. [PMID: 31739115 DOI: 10.1016/j.ctrv.2019.101926] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 11/03/2019] [Accepted: 11/04/2019] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with poor survival. Of all newly diagnosed patients, only about 20% can benefit from a potentially curative surgical resection, the remaining 80% presenting with unresectable locally advanced (LAPC) or metastatic (MPC) disease. Currently, there are limited therapeutic options for LAPC and MPC patients. Furthermore, despite intensive research efforts to better understand the molecular bases of PDAC and the biological relevance of its tumor microenvironment, treatments still largely consist of classical cytotoxic chemotherapy agents. Several studies of genetic and epigenetic sequencing have demonstrated the existence of 4 molecular PDAC subtypes, with heterogeneous genetic characteristics and different biological behaviour: squamous, pancreatic progenitor, immunogenic and aberrantly differentiated endocrine exocrine (ADEX). These distinct subtypes derive from alterations at multiple levels. Apart from the DNA repair pathway, however, none of these has so far been validated as a clinically relevant therapeutic target. Also, PDAC is unique from an immunological perspective and many studies have recently tried to elucidate the role of intratumoral effector T-cells, RAS oncogene, immunosuppressive leukocytes and desmoplastic reaction in maintaining the immunological homeostasis of this disease. However, there still remains much to be learned about the mechanisms whereby the pancreatic immune microenvironment promotes immune escape of cancer cells. Furthermore, while therapies targeting the stroma as well as immunotherapies hold promise for the future, these are not yet standard of care. This review aims to outline the state-of-the-art of LAPC and MPC treatment, highlighting data on the target therapies failure and current ongoing clinical trials on new promising therapeutic strategies.
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Affiliation(s)
- Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
| | - Andrea Pretta
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy.
| | - Valentino Impera
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy.
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
| | - Nicole Liscia
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy.
| | - Paolo Soro
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
| | - Francesca Musio
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
| | - Simona Tolu
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy.
| | - Francesca Balconi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
| | - Annagrazia Pireddu
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy.
| | - Laura Demurtas
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
| | - Silvia Camera
- Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, Italy.
| | | | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy.
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Dzobo K, Thomford NE, Senthebane DA. Targeting the Versatile Wnt/β-Catenin Pathway in Cancer Biology and Therapeutics: From Concept to Actionable Strategy. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2019; 23:517-538. [PMID: 31613700 DOI: 10.1089/omi.2019.0147] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
This expert review offers a critical synthesis of the latest insights and approaches at targeting the Wnt/β-catenin pathway in various cancers such as colorectal cancer, melanoma, leukemia, and breast and lung cancers. Notably, from organogenesis to cancer, the Wnt/β-catenin signaling displays varied and highly versatile biological functions in animals, with virtually all tissues requiring the Wnt/β-catenin signaling in one way or the other. Aberrant expression of the members of the Wnt/β-catenin has been implicated in many pathological conditions, particularly in human cancers. Mutations in the Wnt/β-catenin pathway genes have been noted in diverse cancers. Biochemical and genetic data support the idea that inhibition of Wnt/β-catenin signaling is beneficial in cancer therapeutics. The interaction of this important pathway with other signaling systems is also noteworthy, but remains as an area for further research and discovery. In addition, formation of different complexes by components of the Wnt/β-catenin pathway and the precise roles of these complexes in the cytoplasmic milieu are yet to be fully elucidated. This article highlights the latest medical technologies in imaging, single-cell omics, use of artificial intelligence (e.g., machine learning techniques), genome sequencing, quantum computing, molecular docking, and computational softwares in modeling interactions between molecules and predicting protein-protein and compound-protein interactions pertinent to the biology and therapeutic value of the Wnt/β-catenin signaling pathway. We discuss these emerging technologies in relationship to what is currently needed to move from concept to actionable strategies in translating the Wnt/β-catenin laboratory discoveries to Wnt-targeted cancer therapies and diagnostics in the clinic.
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Affiliation(s)
- Kevin Dzobo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa.,Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Nicholas Ekow Thomford
- Pharmacogenetics Research Group, Division of Human Genetics, Department of Pathology and Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Dimakatso A Senthebane
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa.,Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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Stem J, Flickinger JC, Merlino D, Caparosa EM, Snook AE, Waldman SA. Therapeutic targeting of gastrointestinal cancer stem cells. Regen Med 2019; 14:331-343. [PMID: 31025613 DOI: 10.2217/rme-2018-0146] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Gastrointestinal cancers remain a tremendous burden on society. Despite advances in therapy options, including chemotherapy and radiation, cancer mortality from recurrences and metastases occur frequently. Cancer stem cells (CSCs) drive disease recurrence and metastasis, as these cells are uniquely equipped to self-renew and evade therapy. Therefore, cancer eradication requires treatment strategies that target CSCs in addition to differentiated cancer cells. This review highlights current literature on therapies targeting CSCs in gastrointestinal cancer.
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Affiliation(s)
- Jonathan Stem
- Departments of Surgery, Sidney, 1020 Locust St, JAH368, Philadelphia, PA 19107, USA
| | - John C Flickinger
- Pharmacology & Experimental Therapeutics, Sidney, 1020 Locust St, JAH368, Philadelphia, PA 19107, USA
| | - Dante Merlino
- Pharmacology & Experimental Therapeutics, Sidney, 1020 Locust St, JAH368, Philadelphia, PA 19107, USA
| | - Ellen M Caparosa
- Departments of Surgery, Sidney, 1020 Locust St, JAH368, Philadelphia, PA 19107, USA.,Pharmacology & Experimental Therapeutics, Sidney, 1020 Locust St, JAH368, Philadelphia, PA 19107, USA
| | - Adam E Snook
- Pharmacology & Experimental Therapeutics, Sidney, 1020 Locust St, JAH368, Philadelphia, PA 19107, USA
| | - Scott A Waldman
- Pharmacology & Experimental Therapeutics, Sidney, 1020 Locust St, JAH368, Philadelphia, PA 19107, USA
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43
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Targeting Wnt Signaling via Notch in Intestinal Carcinogenesis. Cancers (Basel) 2019; 11:cancers11040555. [PMID: 31003440 PMCID: PMC6520938 DOI: 10.3390/cancers11040555] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/15/2019] [Accepted: 04/16/2019] [Indexed: 12/25/2022] Open
Abstract
Proliferation and differentiation of intestinal epithelial cells is assisted by highly specialized and well-regulated signaling cascades. The Wnt pathway, which is one of the fundamental pathways in the intestine, contributes to the organization of proliferative intestinal crypts by positioning and cycling of intestinal stem cells and their derivatives. The Wnt pathway promotes differentiation of intestinal secretory cell types along the crypt-plateau and crypt-villus axis. In contrast to the Wnt pathway, the intestinal Notch cascade participates in cellular differentiation and directs progenitor cells towards an absorptive fate with diminished numbers of Paneth and goblet cells. Opposing activities of Notch and Wnt signaling in the regulation of intestinal stem cells and the enterocytic cell fate have been elucidated recently. In fact, targeting Notch was able to overcome tumorigenesis of intestinal adenomas, prevented carcinogenesis, and counteracted Paneth cell death in the absence of caspase 8. At present, pharmacological Notch inhibition is considered as an interesting tool targeting the intrinsic Wnt pathway activities in intestinal non-neoplastic disease and carcinogenesis.
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Li H, Zhang W, Niu C, Lin C, Wu X, Jian Y, Li Y, Ye L, Dai Y, Ouyang Y, Chen J, Qiu J, Song L, Zhang Y. Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway. Int J Cancer 2019; 145:1921-1934. [PMID: 30895619 PMCID: PMC6767785 DOI: 10.1002/ijc.32293] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 02/02/2019] [Accepted: 02/21/2019] [Indexed: 12/19/2022]
Abstract
The primary challenge facing treatment of epithelial ovarian cancer (EOC) is the high frequency of chemoresistance, which severely impairs the quality of life and survival of patients with EOC. Our study aims to investigate the mechanisms by which upregulation of NR2F6 induces chemoresistance in EOC. The biological roles of NR2F6 in EOC chemoresistance were explored in vitro by Sphere, MTT and AnnexinV/PI assay, and in vivo using an ovarian cancer orthotopic transplantation model. Bioinformatics analysis, luciferase assay, CHIP and IP assays were performed to identify the mechanisms by which NR2F6 promotes chemoresistance in EOC. The expression of NR2F6 was significantly upregulated in chemoresistant EOC tissue, and NR2F6 expression was correlated with poorer overall survival. Moreover, overexpression of NR2F6 promotes the EOC cancer stem cell phenotype; conversely, knockdown of NR2F6 represses the EOC cancer stem cell phenotype and sensitizes EOC to cisplatin in vitro and in vivo. Our results further demonstrate that NR2F6 sustains activated Notch3 signaling, resulting in chemoresistance in EOC cells. Notably, NR2F6 acts as an informative biomarker to identify the population of EOC patients who are likely to experience a favorable objective response to gamma‐secretase inhibitors (GSI), which inhibit Notch signaling. Therefore, concurrent inhibition of NR2F6 and treatment with GSI and cisplatin‐based chemotherapy may be a novel therapeutic approach for NR2F6‐overexpressing EOC. In summary, we have, for the first time, identified an important role for NR2F6 in EOC cisplatin resistance. Our study suggests that GSI may serve as a potential targeted treatment for patients with NR2F6‐overexpressing EOC. What's new? Chemoresistance is a major challenge in women afflicted with epithelial ovarian cancer (EOC), but molecular mechanisms of EOC chemoresistance remain unclear. Here the authors connect nuclear receptor subfamily 2 group F member 6 (NR2F6) with this process. They find NR2F6 upregulated in tissues from chemoresistant EOC patients. High NR2F6 expression promoted a cancer stem cell phenotype and suppressed cisplatin‐induced apoptosis by transcriptionally upregulating Notch3 signaling, thereby promoting EOC chemoresistance.
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Affiliation(s)
- Han Li
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Weijing Zhang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chunhao Niu
- Department of Obsterics and Gynecology, The Third Affiliated Hospital, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Guangzhou, Guangdong, China
| | - Chuyong Lin
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xianqiu Wu
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yunting Jian
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yue Li
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Liping Ye
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yuhu Dai
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ying Ouyang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jueming Chen
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jiaqi Qiu
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Libing Song
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yanna Zhang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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45
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Daniel SK, Sullivan KM, Labadie KP, Pillarisetty VG. Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma. Clin Transl Med 2019; 8:10. [PMID: 30931508 PMCID: PMC6441665 DOI: 10.1186/s40169-019-0226-9] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 03/09/2019] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with limited response to cytotoxic chemoradiotherapy, as well as newer immunotherapies. The PDA tumor microenvironment contains infiltrating immune cells including cytotoxic T cells; however, there is an overall immunosuppressive milieu. Hypoxia is a known element of the solid tumor microenvironment and may promote tumor survival. Through various mechanisms including, but not limited to, those mediated by HIF-1α, hypoxia also leads to increased tumor proliferation and metabolic changes. Furthermore, epithelial to mesenchymal transition is promoted through several pathways, including NOTCH and c-MET, regulated by hypoxia. Hypoxia-promoted changes also contribute to the immunosuppressive phenotype seen in many different cell types within the microenvironment and thereby may inhibit an effective immune system response to PDA. Pancreatic stellate cells (PSCs) and myofibroblasts appear to contribute to the recruitment of myeloid derived suppressor cells (MDSCs) and B cells in PDA via cytokines increased due to hypoxia. PSCs also increase collagen secretion in response to HIF-1α, which promotes a fibrotic stroma that alters T cell homing and migration. In hypoxic environments, B cells contribute to cytotoxic T cell exhaustion and produce chemokines to attract more immunosuppressive regulatory T cells. MDSCs inhibit T cell metabolism by hoarding key amino acids, modulate T cell homing by cleaving L-selectin, and prevent T cell activation by increasing PD-L1 expression. Immunosuppressive M2 phenotype macrophages promote T cell anergy via increased nitric oxide (NO) and decreased arginine in hypoxia. Increased numbers of regulatory T cells are seen in hypoxia which prevent effector T cell activation through cytokine production and increased CTLA-4. Effective immunotherapy for pancreatic adenocarcinoma and other solid tumors will need to help counteract the immunosuppressive nature of hypoxia-induced changes in the tumor microenvironment. Promising studies will look at combination therapies involving checkpoint inhibitors, chemokine inhibitors, and possible targeting of hypoxia. While no model is perfect, assuring that models incorporate the effects of hypoxia on cancer cells, stromal cells, and effector immune cells will be crucial in developing successful therapies.
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Affiliation(s)
- S K Daniel
- Department of Surgery, University of Washington, Seattle, USA
| | - K M Sullivan
- Department of Surgery, University of Washington, Seattle, USA
| | - K P Labadie
- Department of Surgery, University of Washington, Seattle, USA
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46
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Cho ES, Kang HE, Kim NH, Yook JI. Therapeutic implications of cancer epithelial-mesenchymal transition (EMT). Arch Pharm Res 2019; 42:14-24. [PMID: 30649699 DOI: 10.1007/s12272-018-01108-7] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 12/27/2018] [Indexed: 12/19/2022]
Abstract
The epithelial-mesenchymal transition (EMT) comprises an essential biological process involving cancer progression as well as initiation. While the EMT has been regarded as a phenotypic conversion from epithelial to mesenchymal cells, recent evidence indicates that it plays a critical role in stemness, metabolic reprogramming, immune evasion and therapeutic resistance of cancer cells. Interestingly, several transcriptional repressors including Snail (SNAI1), Slug (SNAI2) and the ZEB family constitute key players for EMT in cancer as well as in the developmental process. Note that the dynamic conversion between EMT and epithelial reversion (mesenchymal-epithelial transition, MET) occurs through variable intermediate-hybrid states rather than being a binary process. Given the close connection between oncogenic signaling and EMT repressors, the EMT has emerged as a therapeutic target or goal (in terms of MET reversion) in cancer therapy. Here we review the critical role of EMT in therapeutic resistance and the importance of EMT as a therapeutic target for human cancer.
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Affiliation(s)
- Eunae Sandra Cho
- Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea
| | - Hee Eun Kang
- Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea
| | - Nam Hee Kim
- Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea.
| | - Jong In Yook
- Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea.
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47
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Diab M, Azmi A, Mohammad R, Philip PA. Pharmacotherapeutic strategies for treating pancreatic cancer: advances and challenges. Expert Opin Pharmacother 2018; 20:535-546. [PMID: 30592647 DOI: 10.1080/14656566.2018.1561869] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Despite many efforts to improve the outcome of pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor, which is mostly related to late diagnosis and drug resistance. Improving systemic therapy is considered the major challenge in improving the outcome of this disease. AREAS COVERED This review covers novel chemotherapy and targeted agents in the treatment of PDAC, with a focus on advanced stage disease. EXPERT OPINION Current frontline therapies used in the treatment of patients with PDAC with favorable performance status are gemcitabine (GEM) and nab-paclitaxel or 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). PDAC has a number of genetic mutations that may explain its biological behavior, such as KRAS, p53 and CDK2NA, which occur in more than 90% of cases. Unfortunately, to this day, a specific targeting agent to any of those frequent gene mutations is lacking. Emerging areas of targeted therapies include the DNA repair, stroma, metabolism, and stem cells. Immunotherapy with either vaccines or immune checkpoint inhibitors has not produced any significant improvements in outcome of PDAC. Incorporating different approaches in therapy, including conventional, immunological, and others, is key in offering patients with the best possible care.
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Affiliation(s)
- Maria Diab
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Asfar Azmi
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Ramzi Mohammad
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Philip A Philip
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA.,b Department of Pharmacology, School of Medicine , Wayne State University , Detroit , MI , USA
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48
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Saygin C, Matei D, Majeti R, Reizes O, Lathia JD. Targeting Cancer Stemness in the Clinic: From Hype to Hope. Cell Stem Cell 2018; 24:25-40. [PMID: 30595497 DOI: 10.1016/j.stem.2018.11.017] [Citation(s) in RCA: 360] [Impact Index Per Article: 51.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Tumors are composed of non-homogeneous cell populations exhibiting varying degrees of genetic and functional heterogeneity. Cancer stem cells (CSCs) are capable of sustaining tumors by manipulating genetic and non-genetic factors to metastasize, resist treatment, and maintain the tumor microenvironment. Understanding the key traits and mechanisms of CSC survival provides opportunities to improve patient outcomes via improved prognostic models and therapeutics. Here, we review the clinical significance of CSCs and results of potential CSC-targeting therapies in various cancers. We discuss barriers to translating cues from pre-clinical models into clinical applications and propose new strategies for rational design of future anti-CSC trials.
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Affiliation(s)
- Caner Saygin
- Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Daniela Matei
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Ravindra Majeti
- Division of Hematology, Department of Medicine, Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ofer Reizes
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44192, USA
| | - Justin D Lathia
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44192, USA.
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49
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Davis RB, Pahl K, Datto NC, Smith SV, Shawber C, Caron KM, Blatt J. Notch signaling pathway is a potential therapeutic target for extracranial vascular malformations. Sci Rep 2018; 8:17987. [PMID: 30573741 PMCID: PMC6302123 DOI: 10.1038/s41598-018-36628-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 11/20/2018] [Indexed: 12/22/2022] Open
Abstract
Notch expression has been shown to be aberrant in brain arteriovenous malformations (AVM), and targeting Notch has been suggested as an approach to their treatment. It is unclear whether extracranial vascular malformations follow the same patterning and Notch pathway defects. In this study, we examined human extracranial venous (VM) (n = 3), lymphatic (LM) (n = 10), and AV (n = 6) malformations, as well as sporadic brain AVMs (n = 3). In addition to showing that extracranial AVMs demonstrate interrupted elastin and that AVMs and LMs demonstrate abnormal α-smooth muscle actin just as brain AVMS do, our results demonstrate that NOTCH1, 2, 3 and 4 proteins are overexpressed to varying degrees in both the endothelial and mural lining of the malformed vessels in all types of malformations. We further show that two gamma secretase inhibitors (GSIs), DAPT (GSI-IX) and RO4929097, cause dose-dependent inhibition of Notch target gene expression (Hey1) and rate of migration of monolayer cultures of lymphatic endothelial cells (hLECs) and blood endothelial cells (HUVEC). GSIs also inhibit HUVEC network formation. hLECs are more sensitive to GSIs compared to HUVEC. GSIs have been found to be safe in clinical trials in patients with Alzheimer’s disease or cancer. Our results provide further rationale to support testing of Notch inhibitors in patients with extracranial vascular malformations.
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Affiliation(s)
- Reema B Davis
- Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kristy Pahl
- Pediatrics (Division of Pediatric Hematology Oncology), University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Nicholas C Datto
- Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Scott V Smith
- Surgical Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,Pathology and Laboratory Medicine (Translational Pathology Laboratory), University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Carrie Shawber
- Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA
| | - Kathleen M Caron
- Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Julie Blatt
- Pediatrics (Division of Pediatric Hematology Oncology), University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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50
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Chandana S, Babiker HM, Mahadevan D. Therapeutic trends in pancreatic ductal adenocarcinoma (PDAC). Expert Opin Investig Drugs 2018; 28:161-177. [DOI: 10.1080/13543784.2019.1557145] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Sreenivasa Chandana
- Phase I program, START Midwest, Grand Rapids, MI, USA
- Department of Gastrointestinal Medical Oncology, Cancer and Hematology Centers of Western Michigan, Grand Rapids, MI, USA
- Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Hani M. Babiker
- Early Phase Therapeutics Program, University of Arizona Cancer Center, Tucson, AZ, USA
| | - Daruka Mahadevan
- Early Phase Therapeutics Program, University of Arizona Cancer Center, Tucson, AZ, USA
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