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1
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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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2
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Chen H, Fang S, Zhu X, Liu H. Cancer-associated fibroblasts and prostate cancer stem cells: crosstalk mechanisms and implications for disease progression. Front Cell Dev Biol 2024; 12:1412337. [PMID: 39092186 PMCID: PMC11291335 DOI: 10.3389/fcell.2024.1412337] [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: 04/07/2024] [Accepted: 07/05/2024] [Indexed: 08/04/2024] Open
Abstract
The functional heterogeneity and ecological niche of prostate cancer stem cells (PCSCs), which are major drivers of prostate cancer development and treatment resistance, have attracted considerable research attention. Cancer-associated fibroblasts (CAFs), which are crucial components of the tumor microenvironment (TME), substantially affect PCSC stemness. Additionally, CAFs promote PCSC growth and survival by releasing signaling molecules and modifying the surrounding environment. Conversely, PCSCs may affect the characteristics and behavior of CAFs by producing various molecules. This crosstalk mechanism is potentially crucial for prostate cancer progression and the development of treatment resistance. Using organoids to model the TME enables an in-depth study of CAF-PCSC interactions, providing a valuable preclinical tool to accurately evaluate potential target genes and design novel treatment strategies for prostate cancer. The objective of this review is to discuss the current research on the multilevel and multitarget regulatory mechanisms underlying CAF-PCSC interactions and crosstalk, aiming to inform therapeutic approaches that address challenges in prostate cancer treatment.
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Affiliation(s)
| | | | | | - Hao Liu
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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3
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Guo Q, Zhou Y, Xie T, Yuan Y, Li H, Shi W, Zheng L, Li X, Zhang W. Tumor microenvironment of cancer stem cells: Perspectives on cancer stem cell targeting. Genes Dis 2024; 11:101043. [PMID: 38292177 PMCID: PMC10825311 DOI: 10.1016/j.gendis.2023.05.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 05/25/2023] [Indexed: 02/01/2024] Open
Abstract
There are few tumor cell subpopulations with stem cell characteristics in tumor tissue, defined as cancer stem cells (CSCs) or cancer stem-like cells (CSLCs), which can reconstruct neoplasms with malignant biological behaviors such as invasiveness via self-renewal and unlimited generation. The microenvironment that CSCs depend on consists of various cellular components and corresponding medium components. Among these factors existing at a variety of levels and forms, cytokine networks and numerous signal pathways play an important role in signaling transduction. These factors promote or maintain cancer cell stemness, and participate in cancer recurrence, metastasis, and resistance. This review aims to summarize the recent molecular data concerning the multilayered relationship between CSCs and CSC-favorable microenvironments. We also discuss the therapeutic implications of targeting this synergistic interplay, hoping to give an insight into targeting cancer cell stemness for tumor therapy and prognosis.
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Affiliation(s)
- Qianqian Guo
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450003, China
| | - Yi Zhou
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Tianyuan Xie
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yin Yuan
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Huilong Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Wanjin Shi
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Wenzhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450003, China
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4
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Pu T, Wang J, Wei J, Zeng A, Zhang J, Chen J, Yin L, Li J, Lin TP, Melamed J, Corey E, Gao AC, Wu BJ. Stromal-derived MAOB promotes prostate cancer growth and progression. SCIENCE ADVANCES 2024; 10:eadi4935. [PMID: 38335292 PMCID: PMC10857382 DOI: 10.1126/sciadv.adi4935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 01/09/2024] [Indexed: 02/12/2024]
Abstract
Prostate cancer (PC) develops in a microenvironment where the stromal cells modulate adjacent tumor growth and progression. Here, we demonstrated elevated levels of monoamine oxidase B (MAOB), a mitochondrial enzyme that degrades biogenic and dietary monoamines, in human PC stroma, which was associated with poor clinical outcomes of PC patients. Knockdown or overexpression of MAOB in human prostate stromal fibroblasts indicated that MAOB promotes cocultured PC cell proliferation, migration, and invasion and co-inoculated prostate tumor growth in mice. Mechanistically, MAOB induces a reactive stroma with activated marker expression, increased extracellular matrix remodeling, and acquisition of a protumorigenic phenotype through enhanced production of reactive oxygen species. Moreover, MAOB transcriptionally activates CXCL12 through Twist1 synergizing with TGFβ1-dependent Smads in prostate stroma, which stimulates tumor-expressed CXCR4-Src/JNK signaling in a paracrine manner. Pharmacological inhibition of stromal MAOB restricted PC xenograft growth in mice. Collectively, these findings characterize the contribution of MAOB to PC and suggest MAOB as a potential stroma-based therapeutic target.
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Affiliation(s)
- Tianjie Pu
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA
| | - Jing Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA
| | - Jing Wei
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA
| | - Alan Zeng
- Undergraduate Programs, University of Washington, Seattle, WA 98195, USA
| | - Jinglong Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA
| | - Jingrui Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA
| | - Lijuan Yin
- Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Jingjing Li
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA
| | - Tzu-Ping Lin
- Department of Urology, Taipei Veterans General Hospital, Taipei 11217, Taiwan, Republic of China
- Department of Urology, School of Medicine and Shu-Tien Urological Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan, Republic of China
| | - Jonathan Melamed
- Department of Pathology, Grossman School of Medicine, New York University, New York, NY 10016, USA
| | - Eva Corey
- Department of Urology, University of Washington, Seattle, WA 98195, USA
| | - Allen C. Gao
- Department of Urologic Surgery, University of California, Davis, Sacramento, CA 95817, USA
| | - Boyang Jason Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA
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Sailer V, von Amsberg G, Duensing S, Kirfel J, Lieb V, Metzger E, Offermann A, Pantel K, Schuele R, Taubert H, Wach S, Perner S, Werner S, Aigner A. Experimental in vitro, ex vivo and in vivo models in prostate cancer research. Nat Rev Urol 2023; 20:158-178. [PMID: 36451039 DOI: 10.1038/s41585-022-00677-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2022] [Indexed: 12/02/2022]
Abstract
Androgen deprivation therapy has a central role in the treatment of advanced prostate cancer, often causing initial tumour remission before increasing independence from signal transduction mechanisms of the androgen receptor and then eventual disease progression. Novel treatment approaches are urgently needed, but only a fraction of promising drug candidates from the laboratory will eventually reach clinical approval, highlighting the demand for critical assessment of current preclinical models. Such models include standard, genetically modified and patient-derived cell lines, spheroid and organoid culture models, scaffold and hydrogel cultures, tissue slices, tumour xenograft models, patient-derived xenograft and circulating tumour cell eXplant models as well as transgenic and knockout mouse models. These models need to account for inter-patient and intra-patient heterogeneity, the acquisition of primary or secondary resistance, the interaction of tumour cells with their microenvironment, which make crucial contributions to tumour progression and resistance, as well as the effects of the 3D tissue network on drug penetration, bioavailability and efficacy.
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Affiliation(s)
- Verena Sailer
- Institute for Pathology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Gunhild von Amsberg
- Department of Oncology and Hematology, University Cancer Center Hamburg Eppendorf and Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg Eppendorf, Hamburg, Germany
| | - Stefan Duensing
- Section of Molecular Urooncology, Department of Urology, University Hospital Heidelberg and National Center for Tumour Diseases, Heidelberg, Germany
| | - Jutta Kirfel
- Institute for Pathology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Verena Lieb
- Research Division Molecular Urology, Department of Urology and Paediatric Urology, University Hospital Erlangen, Erlangen, Germany
| | - Eric Metzger
- Department of Urology, Center for Clinical Research, University of Freiburg Medical Center, Freiburg, Germany
| | - Anne Offermann
- Institute for Pathology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | - Klaus Pantel
- Institute for Tumour Biology, Center for Experimental Medicine, University Clinics Hamburg-Eppendorf, Hamburg, Germany
- Mildred-Scheel-Nachwuchszentrum HaTRiCs4, University Cancer Center Hamburg, Hamburg, Germany
| | - Roland Schuele
- Department of Urology, Center for Clinical Research, University of Freiburg Medical Center, Freiburg, Germany
| | - Helge Taubert
- Research Division Molecular Urology, Department of Urology and Paediatric Urology, University Hospital Erlangen, Erlangen, Germany
| | - Sven Wach
- Research Division Molecular Urology, Department of Urology and Paediatric Urology, University Hospital Erlangen, Erlangen, Germany
| | - Sven Perner
- University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
- Pathology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
| | - Stefan Werner
- Institute for Tumour Biology, Center for Experimental Medicine, University Clinics Hamburg-Eppendorf, Hamburg, Germany
- Mildred-Scheel-Nachwuchszentrum HaTRiCs4, University Cancer Center Hamburg, Hamburg, Germany
| | - Achim Aigner
- Clinical Pharmacology, Rudolf-Boehm-Institute for Pharmacology and Toxicology, University of Leipzig, Medical Faculty, Leipzig, Germany.
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Rimal R, Desai P, Daware R, Hosseinnejad A, Prakash J, Lammers T, Singh S. Cancer-associated fibroblasts: Origin, function, imaging, and therapeutic targeting. Adv Drug Deliv Rev 2022; 189:114504. [PMID: 35998825 DOI: 10.1016/j.addr.2022.114504] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 07/10/2022] [Accepted: 08/17/2022] [Indexed: 02/06/2023]
Abstract
The tumor microenvironment (TME) is emerging as one of the primary barriers in cancer therapy. Cancer-associated fibroblasts (CAF) are a common inhabitant of the TME in several tumor types and play a critical role in tumor progression and drug resistance via different mechanisms such as desmoplasia, angiogenesis, immune modulation, and cancer metabolism. Due to their abundance and significance in pro-tumorigenic mechanisms, CAF are gaining attention as a diagnostic target as well as to improve the efficacy of cancer therapy by their modulation. In this review, we highlight existing imaging techniques that are used for the visualization of CAF and CAF-induced fibrosis and provide an overview of compounds that are known to modulate CAF activity. Subsequently, we also discuss CAF-targeted and CAF-modulating nanocarriers. Finally, our review addresses ongoing challenges and provides a glimpse into the prospects that can spearhead the transition of CAF-targeted therapies from opportunity to reality.
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Affiliation(s)
- Rahul Rimal
- Max Planck Institute for Medical Research (MPImF), Jahnstrasse 29, 69120 Heidelberg, Germany
| | - Prachi Desai
- DWI-Leibniz Institute for Interactive Materials, RWTH Aachen University, Forkenbeckstrasse 50, 52074 Aachen, Germany
| | - Rasika Daware
- Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Aisa Hosseinnejad
- DWI-Leibniz Institute for Interactive Materials, RWTH Aachen University, Forkenbeckstrasse 50, 52074 Aachen, Germany
| | - Jai Prakash
- Department of Advanced Organ Bioengineering and Therapeutics, Section: Engineered Therapeutics, Technical Medical Centre, University of Twente, 7500AE Enschede, the Netherlands.
| | - Twan Lammers
- Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
| | - Smriti Singh
- Max Planck Institute for Medical Research (MPImF), Jahnstrasse 29, 69120 Heidelberg, Germany.
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7
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Banik A, Sharma R, Chauhan A, Singh S. Cutting the umbilical cord: Cancer stem cell-targeted therapeutics. Life Sci 2022; 299:120502. [PMID: 35351466 DOI: 10.1016/j.lfs.2022.120502] [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: 12/30/2021] [Revised: 03/14/2022] [Accepted: 03/22/2022] [Indexed: 10/18/2022]
Abstract
Cancer Stem Cells (CSCs) are a notoriously quiescent subpopulation of cells within heterogeneous tumors exhibiting self-renewal, differentiation and drug-resistant capabilities leading to tumor relapse. Heterogeneous cell populations in tumor microenvironment develop an elaborate network of signalling and factors supporting the CSC population within a niche. Identification of specific biomarkers for CSCs facilitates their isolation. CSCs demonstrate abilities that bypass immune surveillance, exhibit resistance to therapy, and induce cancer recurrence while promoting altered metabolism of the bulk tumor, thereby encouraging metastasis. The fight against cancer is prone to relapse without discussing the issue of CSCs, making it imperative for encapsulation of current studies. In this review, we provide extensive knowledge of recent therapeutics developed that target CSCs via multiple signalling cascades, altered metabolism and the tumor microenvironment. Thorough understanding of the functioning of CSCs, their interaction with different cells in the tumor microenvironment as well as current gaps in knowledge are addressed. We present possible strategies to disrupt the cellular and molecular interplay within the tumor microenvironment and make it less conducive for CSCs, which may aid in their eradication with subsequently better treatment outcomes. In conclusion, we discuss a brief yet functional idea of emerging concepts in CSC biology to develop efficient therapeutics acting on cancer recurrence and metastasis.
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Affiliation(s)
- Ankit Banik
- Department of Biotechnology, Pondicherry University, Chinna Kalapet, Puducherry 605014, India
| | - Rishika Sharma
- Department of Biotechnology, Indian Institute of Technology, Roorkee, Roorkee 247667, India
| | - Akansha Chauhan
- Amity Institute of Physiology and Allied Sciences, Amity University, Noida, India
| | - Sandhya Singh
- Amity Institute of Physiology and Allied Sciences, Amity University, Noida, India.
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Wang X, Ye N, Xu C, Xiao C, Zhang Z, Deng Q, Li S, Li J, Li Z, Yang X. Hyperbaric oxygen regulates tumor mechanics and augments Abraxane and gemcitabine antitumor effects against pancreatic ductal adenocarcinoma by inhibiting cancer-associated fibroblasts. NANO TODAY 2022; 44:101458. [DOI: 10.1016/j.nantod.2022.101458] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
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9
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Alzeeb G, Dubreuil M, Arzur D, Rivet S, Corcos L, Grand YL, Le Jossic-Corcos C. Gastric cancer multicellular spheroid analysis by two-photon microscopy. BIOMEDICAL OPTICS EXPRESS 2022; 13:3120-3130. [PMID: 35774334 PMCID: PMC9203106 DOI: 10.1364/boe.450518] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Gastric cancer (GC) is highly deadly. Three-dimensional (3D) cancer cell cultures, known as spheroids, better mimic tumor microenvironment (TME) than standard 2D cultures. Cancer-associated fibroblasts (CAF), a major cellular component of TME, promote or restrain cancer cell proliferation, invasion and resistance to drugs. We established spheroids from two human GC cell lines mixed with human primary CAF. Spheroid organization, analyzed by two-photon microscopy, showed CAF in AGS/CAF spheroids clustered in the center, but dispersed throughout in HGT-1/CAF spheroids. Such differences may reflect clonal specificities of GC cell lines and point to the fact that GC should be considered as a highly personalized disease.
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Affiliation(s)
- George Alzeeb
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200 Brest, France
| | - Matthieu Dubreuil
- Univ Brest, Laboratory of Optics and Magnetism OPTIMAG EA 938, F-29200 Brest, France
| | - Danielle Arzur
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200 Brest, France
| | - Sylvain Rivet
- Univ Brest, Laboratory of Optics and Magnetism OPTIMAG EA 938, F-29200 Brest, France
| | - Laurent Corcos
- Inserm, Univ Brest, EFS, UMR 1078, GGB, F-29200 Brest, France
- CHU de Brest, INSERM, Univ Brest, EFS, UMR 1078, GGB, F-29200 Brest, France
| | - Yann Le Grand
- Univ Brest, Laboratory of Optics and Magnetism OPTIMAG EA 938, F-29200 Brest, France
- Equal contribution
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10
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Wan Kamarul Zaman WS, Nurul AA, Nordin F. Stem Cells and Cancer Stem Cells: The Jekyll and Hyde Scenario and Their Implications in Stem Cell Therapy. Biomedicines 2021; 9:biomedicines9091245. [PMID: 34572431 PMCID: PMC8468168 DOI: 10.3390/biomedicines9091245] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 08/31/2021] [Accepted: 09/04/2021] [Indexed: 12/12/2022] Open
Abstract
"Jekyll and Hyde" refers to persons with an unpredictably dual personality, who are battling between good and evil within themselves In this regard, even cells consist of good and evil counterparts. Normal stem cells (NSCs) and cancer stem cells (CSCs) are two types of cells that share some similar characteristics but have distinct functions that play a major role in physiological and pathophysiological development. In reality, NSCs such as the adult and embryonic stem cells, are the good cells and the ultimate treatment used in cell therapy. CSCs are the corrupted cells that are a subpopulation of cancer cells within the cancer microenvironment that grow into a massive tumour or malignancy that needs to be treated. Hence, understanding the connection between NSCs and CSCs is important not just in cancer development but also in their therapeutic implication, which is the focus of this review.
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Affiliation(s)
- Wan Safwani Wan Kamarul Zaman
- Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur 50603, Malaysia
- Centre for Innovation in Medical Engineering (CIME), Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur 50603, Malaysia
- Correspondence:
| | - Asma Abdullah Nurul
- School of Health Science, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia;
| | - Fazlina Nordin
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Universiti Kebangsaan Malaysia Medical Centre, UKM, Cheras, Kuala Lumpur 56000, Malaysia;
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11
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Qin H, Yang Y, Jiang B, Pan C, Chen W, Diao W, Ding M, Cao W, Zhang Z, Chen M, Gao J, Zhao X, Qiu X, Guo H. SOX9 in prostate cancer is upregulated by cancer-associated fibroblasts to promote tumor progression through HGF/c-Met-FRA1 signaling. FEBS J 2021; 288:5406-5429. [PMID: 33705609 DOI: 10.1111/febs.15816] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 02/14/2021] [Accepted: 03/01/2021] [Indexed: 01/13/2023]
Abstract
Transcription factor SOX9 was a biomarker for prostate cancer (Pca) with poor prognosis. Nevertheless, the regulatory mechanism underlying SOX9 upregulation still remains unclear. Several cytokines have been reported to be involved in the regulation of SOX9, suggesting that cancer-associated fibroblasts (CAFs), one of the main sources of secreted factors in the tumor microenvironment (TME), may play a role in regulating SOX9 expression. Herein, an in vitro model of paracrine interaction between primary CAFs and Pca cells was applied to investigate the molecular mechanism of SOX9 upregulation during Pca progression. The regulatory axis was validated by in vivo experiments and The Cancer Genome Atlas data. Conditional medium of CAFs (CAF-CM) upregulated the expression of SOX9, which was mutually proved to be essential for CAF-induced tumor progression. Further analysis showed that hepatocyte growth factor (HGF) secreted by CAFs was responsible for SOX9 elevation in Pca cells, via the activation of c-Met signaling. Mechanistically, HGF/c-Met signaling specifically activated MEK1/2-ERK1/2 pathway, which induced phosphorylation and upregulation of FRA1, which then transcriptionally upregulated SOX9 by binding to the promoter of SOX9 gene. Moreover, we identified that HGF/c-Met-ERK1/2-FRA1-SOX9 axis was relatively conserved between human and mouse species by validating in mouse Pca cells. Our results reveal a novel insight into the molecular mechanism that SOX9 in Pca cells is promoted by CAFs through HGF/c-Met-ERK1/2-FRA1 axis. Furthermore, SOX9 may serve as an alternative marker for the activated HGF/c-Met signaling to enroll the optimal Pca patients for HGF/c-Met inhibition treatment, since it is much more stable and easier to detect.
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Affiliation(s)
- Haixiang Qin
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, China
| | - Yang Yang
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, China
| | - Bo Jiang
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, China
| | - Chun Pan
- Immunology and Reproduction Biology Laboratory, State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, China
| | - Wei Chen
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, China
| | - Wenli Diao
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, China
| | - Meng Ding
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, China
| | - Wenmin Cao
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, China
| | - Zhenxing Zhang
- Department of Urology, The First Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Mengxia Chen
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, China
| | - Jie Gao
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, China
| | - Xiaozhi Zhao
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, China
| | - Xuefeng Qiu
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, China
| | - Hongqian Guo
- Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, China
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12
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Zhao W, Yang H, Chai J, Xing L. RUNX2 as a promising therapeutic target for malignant tumors. Cancer Manag Res 2021; 13:2539-2548. [PMID: 33758548 PMCID: PMC7981165 DOI: 10.2147/cmar.s302173] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 02/27/2021] [Indexed: 12/16/2022] Open
Abstract
The transcription factor runt-related protein 2 (RUNX2) has an important impact on the transformation of bone marrow mesenchymal stem cells to osteoblasts. Further studies have shown that RUNX2 plays a key role in the invasion and metastasis of cancers. RUNX2 is a "key" molecule in the regulatory network comprised of multiple signaling pathways upstream and its target downstream molecules. Due to the complex regulatory mechanisms of RUNX2, the specific mechanism underlying the occurrence, development and prognosis of malignant tumors has not been fully understood. Currently, RUNX2 as a promising therapeutic target for cancers has become a research hotspot. Herein, we reviewed the current literature on the modulatory functions and mechanisms of RUNX2 in the development of malignant tumors, aiming to explore its potential clinical application in the diagnosis, prognosis and treatment of tumors.
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Affiliation(s)
- Weizhu Zhao
- Department of Radiology, Cancer Hospital Affiliated to Shandong First Medical University, Shandong Cancer Hospital and Institute, Jinan, 250117, People’s Republic of China
- Department of Oncology, Binzhou People’s Hospital, Binzhou, 256610, People’s Republic of China
| | - Haiying Yang
- Department of Nursing, Binzhou People’s Hospital, Binzhou, 256610, People’s Republic of China
| | - Jie Chai
- Department of Gastrointestinal Surgery, Cancer Hospital Affiliated to Shandong First Medical University, Shandong Cancer Hospital and Institute, Jinan, 250117, People’s Republic of China
| | - Ligang Xing
- Department of Radiology, Cancer Hospital Affiliated to Shandong First Medical University, Shandong Cancer Hospital and Institute, Jinan, 250117, People’s Republic of China
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13
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Mukaida N, Tanabe Y, Baba T. Cancer non-stem cells as a potent regulator of tumor microenvironment: a lesson from chronic myeloid leukemia. MOLECULAR BIOMEDICINE 2021; 2:7. [PMID: 35006395 PMCID: PMC8607377 DOI: 10.1186/s43556-021-00030-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 02/17/2021] [Indexed: 01/10/2023] Open
Abstract
A limited subset of human leukemia cells has a self-renewal capacity and can propagate leukemia upon their transplantation into animals, and therefore, are named as leukemia stem cells, in the early 1990's. Subsequently, cell subpopulations with similar characteristics were detected in various kinds of solid cancers and were denoted as cancer stem cells. Cancer stem cells are presently presumed to be crucially involved in malignant progression of solid cancer: chemoresitance, radioresistance, immune evasion, and metastasis. On the contrary, less attention has been paid to cancer non-stem cell population, which comprise most cancer cells in cancer tissues, due to the lack of suitable markers to discriminate cancer non-stem cells from cancer stem cells. Chronic myeloid leukemia stem cells generate a larger number of morphologically distinct non-stem cells. Moreover, accumulating evidence indicates that poor prognosis is associated with the increases in these non-stem cells including basophils and megakaryocytes. We will discuss the potential roles of cancer non-stem cells in fostering tumor microenvironment, by illustrating the roles of chronic myeloid leukemia non-stem cells including basophils and megakaryocytes in the pathogenesis of chronic myeloid leukemia, a typical malignant disorder arising from leukemic stem cells.
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Affiliation(s)
- Naofumi Mukaida
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
| | - Yamato Tanabe
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
| | - Tomohisa Baba
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
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14
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Grayson KA, Jyotsana N, Ortiz-Otero N, King MR. Overcoming TRAIL-resistance by sensitizing prostate cancer 3D spheroids with taxanes. PLoS One 2021; 16:e0246733. [PMID: 33661931 PMCID: PMC7932526 DOI: 10.1371/journal.pone.0246733] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 01/25/2021] [Indexed: 11/18/2022] Open
Abstract
Three-dimensional spheroid cultures have been shown to better physiologically mimic the cell-cell and cell-matrix interactions that occur in solid tumors more than traditional 2D cell cultures. One challenge in spheroid production is forming and maintaining spheroids of uniform size. Here, we developed uniform, high-throughput, multicellular spheroids that self-assemble using microwell plates. DU145 and PC3 cells were cultured as 2D monolayers and 3D spheroids to compare sensitization of TRAIL-resistance cancer cells to TRAIL mediated apoptosis via chemotherapy based on dimensionality. Monocultured monolayers and spheroids were treated with soluble TRAIL alone (24 hr), DTX or CBZ alone (24 hr), or a combination of taxane and TRAIL (24 + 24 hr) to determine the effectiveness of taxanes as TRAIL sensitizers. Upon treatment with soluble TRAIL or taxanes solely, monolayer cells and spheroids exhibited no significant reduction in cell viability compared to the control, indicating that both cell lines are resistant to TRAIL and taxane alone in 2D and 3D. Pretreatment with CBZ or DTX followed by TRAIL synergistically amplified apoptosis in 2D and 3D DU145 cell cultures. PC3 spheroids were more resistant to the combination therapy, displaying a more additive effect in the DTX + TRAIL group compared to 2D. There was a downregulation of DR4/5 expression in spheroid form compared to monolayers in each cell line. Additionally, normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were cocultured with both PCa cell lines as spheroids to determine if CAFs confer additional resistance to chemotherapy. We determined that co-cultured spheroids show similar drug resistance to monocultured spheroids when treated with taxane plus TRAIL treatment. Collectively, these findings suggest how the third dimension and cocultures of different cell types effect the sensitization of androgen-independent prostate cancer cells to TRAIL, suggesting therapeutic targets that could overcome TRAIL-resistance in metastatic castration-resistant prostate cancer (mCRPC).
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Affiliation(s)
- Korie A. Grayson
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, United States of America
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Nidhi Jyotsana
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Nerymar Ortiz-Otero
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, United States of America
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Michael R. King
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States of America
- * E-mail:
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15
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Alzeeb G, Metges JP, Corcos L, Le Jossic-Corcos C. Three-Dimensional Culture Systems in Gastric Cancer Research. Cancers (Basel) 2020; 12:E2800. [PMID: 33003476 PMCID: PMC7601358 DOI: 10.3390/cancers12102800] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/25/2020] [Accepted: 09/27/2020] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC), which includes cancer of the esophagus, the oesophagogastric junction, and the stomach fundus, is highly deadly with strong regional influence, Asia being the most affected. GC is often detected at late stages, with 30% of metastatic cases at diagnosis. Many authors have devised models to both unravel the mechanisms of GC development and to evaluate candidate therapeutics. Among these models, 2D-cell cultures are progressively replaced by 3D-cell cultures that recapitulate, much more comprehensively, tumor cellular and genetic heterogeneity, as well as responsiveness to environmental changes, such as exposure to drugs or irradiation. With respect to the specifics of GC, there are high hopes from such model systems, especially with the aim of identifying prognostic markers and novel drug targets.
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Affiliation(s)
- George Alzeeb
- Inserm, University Brest, EFS, UMR 1078, GGB, F-29200 Brest, France; (G.A.); (L.C.)
| | - Jean-Philippe Metges
- CHU de Brest, Inserm, University Brest, EFS, UMR 1078, GGB, F-29200 Brest, France;
| | - Laurent Corcos
- Inserm, University Brest, EFS, UMR 1078, GGB, F-29200 Brest, France; (G.A.); (L.C.)
- CHU de Brest, Inserm, University Brest, EFS, UMR 1078, GGB, F-29200 Brest, France;
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16
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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: 1178] [Impact Index Per Article: 235.6] [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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17
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Nguyen EV, Pereira BA, Lawrence MG, Ma X, Rebello RJ, Chan H, Niranjan B, Wu Y, Ellem S, Guan X, Wu J, Skhinas JN, Cox TR, Risbridger GP, Taylor RA, Lister NL, Daly RJ. Proteomic Profiling of Human Prostate Cancer-associated Fibroblasts (CAF) Reveals LOXL2-dependent Regulation of the Tumor Microenvironment. Mol Cell Proteomics 2019; 18:1410-1427. [PMID: 31061140 PMCID: PMC6601211 DOI: 10.1074/mcp.ra119.001496] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 04/30/2019] [Indexed: 12/31/2022] Open
Abstract
In prostate cancer, cancer-associated fibroblasts (CAF) exhibit contrasting biological properties to non-malignant prostate fibroblasts (NPF) and promote tumorigenesis. Resolving intercellular signaling pathways between CAF and prostate tumor epithelium may offer novel opportunities for research translation. To this end, the proteome and phosphoproteome of four pairs of patient-matched CAF and NPF were characterized to identify discriminating proteomic signatures. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with a hyper reaction monitoring data-independent acquisition (HRM-DIA) workflow. Proteins that exhibited a significant increase in CAF versus NPF were enriched for the functional categories "cell adhesion" and the "extracellular matrix." The CAF phosphoproteome exhibited enhanced phosphorylation of proteins associated with the "spliceosome" and "actin binding." STRING analysis of the CAF proteome revealed a prominent interaction hub associated with collagen synthesis, modification, and signaling. It contained multiple collagens, including the fibrillar types COL1A1/2 and COL5A1; the receptor tyrosine kinase discoidin domain-containing receptor 2 (DDR2), a receptor for fibrillar collagens; and lysyl oxidase-like 2 (LOXL2), an enzyme that promotes collagen crosslinking. Increased activity and/or expression of LOXL2 and DDR2 in CAF were confirmed by enzymatic assays and Western blotting analyses. Pharmacological inhibition of CAF-derived LOXL2 perturbed extracellular matrix (ECM) organization and decreased CAF migration in a wound healing assay. Further, it significantly impaired the motility of co-cultured RWPE-2 prostate tumor epithelial cells. These results indicate that CAF-derived LOXL2 is an important mediator of intercellular communication within the prostate tumor microenvironment and is a potential therapeutic target.
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Affiliation(s)
- Elizabeth V Nguyen
- From the ‡Cancer Program, Biomedicine Discovery Institute,; Departments of §Biochemistry and Molecular Biology
| | - Brooke A Pereira
- From the ‡Cancer Program, Biomedicine Discovery Institute,; ¶Anatomy and Developmental Biology, and
| | - Mitchell G Lawrence
- From the ‡Cancer Program, Biomedicine Discovery Institute,; ¶Anatomy and Developmental Biology, and; ‖Cancer Research Division, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Parkville, Australia
| | - Xiuquan Ma
- From the ‡Cancer Program, Biomedicine Discovery Institute,; Departments of §Biochemistry and Molecular Biology
| | - Richard J Rebello
- From the ‡Cancer Program, Biomedicine Discovery Institute,; ¶Anatomy and Developmental Biology, and; ‖Cancer Research Division, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Parkville, Australia
| | - Howard Chan
- From the ‡Cancer Program, Biomedicine Discovery Institute,; Departments of §Biochemistry and Molecular Biology
| | - Birunthi Niranjan
- From the ‡Cancer Program, Biomedicine Discovery Institute,; ¶Anatomy and Developmental Biology, and
| | - Yunjian Wu
- From the ‡Cancer Program, Biomedicine Discovery Institute,; Departments of §Biochemistry and Molecular Biology
| | - Stuart Ellem
- From the ‡Cancer Program, Biomedicine Discovery Institute,; ¶Anatomy and Developmental Biology, and; **School of Health and Wellbeing, University of Southern Queensland, Ipswich, Queensland, Australia
| | - Xiaoqing Guan
- ‡‡Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Cancer Bioinformatics, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jianmin Wu
- ‡‡Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Cancer Bioinformatics, Peking University Cancer Hospital & Institute, Beijing, China
| | - Joanna N Skhinas
- §§The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, Australia
| | - Thomas R Cox
- §§The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, Australia;; ¶¶St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia
| | - Gail P Risbridger
- From the ‡Cancer Program, Biomedicine Discovery Institute,; ¶Anatomy and Developmental Biology, and; ‖Cancer Research Division, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Parkville, Australia;; ‖‖Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
| | - Renea A Taylor
- From the ‡Cancer Program, Biomedicine Discovery Institute,; ‖Cancer Research Division, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Parkville, Australia;; ‡‡‡Physiology, Monash University, Clayton, Australia
| | - Natalie L Lister
- From the ‡Cancer Program, Biomedicine Discovery Institute,; ¶Anatomy and Developmental Biology, and
| | - Roger J Daly
- From the ‡Cancer Program, Biomedicine Discovery Institute,; Departments of §Biochemistry and Molecular Biology,.
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18
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Zhao Z, Bai S, Wang R, Xiong S, Li Y, Wang X, Chen W, Cheng B. Cancer-associated fibroblasts endow stem-like qualities to liver cancer cells by modulating autophagy. Cancer Manag Res 2019; 11:5737-5744. [PMID: 31296998 PMCID: PMC6598753 DOI: 10.2147/cmar.s197634] [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: 12/12/2018] [Accepted: 05/29/2019] [Indexed: 12/24/2022] Open
Abstract
Purpose Both cancer-associated fibroblasts (CAFs) and liver cancer stem cells (LCSCs) play an important part in the tumorigenesis, development and metastasis of hepatocellular carcinoma (HCC). Moreover, the stem-like properties in HCC cells could be promoted by CAFs. However, the mechanism remains largely unknown. Patients and methods We used conditioned medium (CM) of CAFs to culture Huh7 cells. Stemness of the cells was then examined mainly by sphere formation assay while stemness-associated genes including Nanog, Sox2 and Oct4 were measured by Western blotting. Immunofluorescence staining, Transmission Electron Microscope as well as Western blotting were performed to detect the level of autophagy in Huh7 cells. Results Increased level of stemness and autophagy was observed in HCC cells cultured in CAFs-CM compared to the control group. Activation of CAFs-induced autophagic flux could be inhibited by Chloroquine (CQ), which can accumulate LC3-II protein and increase punctate distribution of LC3 localization. Treatment of HCC cells with CQ effectively reversed the CAF-induced stemness, invasion, and metastasis ability in these cells. In vivo, Huh7 cells inoculated together with CAFs developed significantly larger tumors than Huh7 cells injected alone. Moreover, blockage of autophagy in Huh7 cells by CQ greatly reduced the growth of xenografted tumors of Huh7 cells combined with CAFs. Conclusion These results reveal that CAFs are capable of promoting stemness and metastasis of HCC cells and blocking autophagy could markedly attenuate the stemness enhanced by CAFs, suggesting that targeting autophagy in HCC could be an effective strategy in HCC treatment.
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Affiliation(s)
- Zhenxiong Zhao
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Shuya Bai
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Ronghua Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Si Xiong
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Yawen Li
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Xiju Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Wei Chen
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Bin Cheng
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
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Abstract
Since the introduction of the cancer stem cell (CSC) hypothesis, accumulating evidence shows that most cancers present stem-like niches. However, therapies aimed at targeting this niche have not been as successful as expected. New evidence regarding CSCs hierarchy, similarities with normal tissue stem cells and cell plasticity might be key in understanding their role in cancer biology and how to efficiently eliminate them. In this Chapter, we discuss what is known in breast and prostate CSCs from their initial discoveries to the current therapeutic efforts in the field. Future challenges towards better CSC identification and isolation strategies will be key to shed light into how CSCs could accurately be targeted in combination to traditional therapies to ultimately prolong patient survival.
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Affiliation(s)
- Rocío G Sampayo
- Department of Chemical and Biomolecular Engineering, University of California at Berkeley, Berkeley, CA, United States
| | - Mina J Bissell
- Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, United States.
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20
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Richards Z, McCray T, Marsili J, Zenner ML, Manlucu JT, Garcia J, Kajdacsy-Balla A, Murray M, Voisine C, Murphy AB, Abdulkadir SA, Prins GS, Nonn L. Prostate Stroma Increases the Viability and Maintains the Branching Phenotype of Human Prostate Organoids. iScience 2019; 12:304-317. [PMID: 30735898 PMCID: PMC6365938 DOI: 10.1016/j.isci.2019.01.028] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 06/06/2018] [Accepted: 01/18/2019] [Indexed: 12/29/2022] Open
Abstract
The fibromuscular stroma of the prostate regulates normal epithelial differentiation and contributes to carcinogenesis in vivo. We developed and characterized a human 3D prostate organoid co-culture model that incorporates prostate stroma. Primary prostate stromal cells increased organoid formation and directed organoid morphology into a branched acini structure similar to what is observed in vivo. Organoid branching occurred distal to physical contact with stromal cells, demonstrating non-random branching. Stroma-induced phenotypes were similar in all patients examined, yet they maintained inter-patient heterogeneity in the degree of response. Stromal cells expressed growth factors involved in epithelial differentiation, which was not observed in non-prostatic fibroblasts. Organoids derived from areas of prostate cancer maintained differential expression of alpha-methylacyl-CoA racemase and showed increased viability and passaging when co-cultured with stroma. The addition of stroma to epithelial cells in vitro improves the ability of organoids to recapitulate features of the tissue and enhances the viability of organoids.
Co-culture with human primary prostate stroma improves epithelial organoid viability Stromal cell contact in co-culture directs epithelial organoid branching Prostate stromal cells express morphogenic factors unique from non-prostate fibroblasts Co-culture with stroma maintains AMACR and increases survival of cancer derived-organoids
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Affiliation(s)
- Zachary Richards
- Department of Pathology, University of Illinois at Chicago, 840 S Wood St., Chicago, IL 60612, USA
| | - Tara McCray
- Department of Pathology, University of Illinois at Chicago, 840 S Wood St., Chicago, IL 60612, USA
| | - Joseph Marsili
- Department of Pathology, University of Illinois at Chicago, 840 S Wood St., Chicago, IL 60612, USA; Department of Biology, Northeastern Illinois University, Chicago, IL 60625, USA
| | - Morgan L Zenner
- Department of Pathology, University of Illinois at Chicago, 840 S Wood St., Chicago, IL 60612, USA
| | - Jacob T Manlucu
- Department of Biology, Northeastern Illinois University, Chicago, IL 60625, USA
| | - Jason Garcia
- Department of Pathology, University of Illinois at Chicago, 840 S Wood St., Chicago, IL 60612, USA
| | - Andre Kajdacsy-Balla
- Department of Pathology, University of Illinois at Chicago, 840 S Wood St., Chicago, IL 60612, USA; University of Illinois Cancer Center, Chicago, IL 60612, USA
| | | | - Cindy Voisine
- Department of Biology, Northeastern Illinois University, Chicago, IL 60625, USA
| | - Adam B Murphy
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Sarki A Abdulkadir
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Gail S Prins
- Department of Pathology, University of Illinois at Chicago, 840 S Wood St., Chicago, IL 60612, USA; Departments of Urology, Physiology, and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA; University of Illinois Cancer Center, Chicago, IL 60612, USA
| | - Larisa Nonn
- Department of Pathology, University of Illinois at Chicago, 840 S Wood St., Chicago, IL 60612, USA; University of Illinois Cancer Center, Chicago, IL 60612, USA.
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21
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Nath D, White JR, Bratslavsky G, Kotula L. Identification, Histological Characterization, and Dissection of Mouse Prostate Lobes for In Vitro 3D Spheroid Culture Models. J Vis Exp 2018. [PMID: 30295668 DOI: 10.3791/58397] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Genetically engineered mouse models (GEMMs) serve as effective pre-clinical models for investigating most types of human cancers, including prostate cancer (PCa). Understanding the anatomy and histology of the mouse prostate is important for the efficient use and proper characterization of such animal models. The mouse prostate has four distinct pairs of lobes, each with their own characteristics. This article demonstrates the proper method of dissection and identification of mouse prostate lobes for disease analysis. Post-dissection, the prostate cells can be further cultured in vitro for mechanistic understanding. Since mouse prostate primary cells tend to lose their normal characteristics when cultured in vitro, we outline here a method for isolating the cells and growing them as 3D spheroid cultures, which is effective for preserving the physiological characteristics of the cells. These 3D cultures can be used for analyzing cell morphology and behavior in near-physiological conditions, investigating altered levels and localizations of key proteins and pathways involved in the development and progression of a disease, and looking at responses to drug treatments.
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Affiliation(s)
- Disharee Nath
- Department of Urology, SUNY Upstate Medical University; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University
| | - Julie R White
- Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center; Boulder BioPATH, Inc
| | | | - Leszek Kotula
- Department of Urology, SUNY Upstate Medical University; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University;
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22
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Abstract
Despite the high long-term survival in localized prostate cancer, metastatic prostate cancer remains largely incurable even after intensive multimodal therapy. The lethality of advanced disease is driven by the lack of therapeutic regimens capable of generating durable responses in the setting of extreme tumor heterogeneity on the genetic and cell biological levels. Here, we review available prostate cancer model systems, the prostate cancer genome atlas, cellular and functional heterogeneity in the tumor microenvironment, tumor-intrinsic and tumor-extrinsic mechanisms underlying therapeutic resistance, and technological advances focused on disease detection and management. These advances, along with an improved understanding of the adaptive responses to conventional cancer therapies, anti-androgen therapy, and immunotherapy, are catalyzing development of more effective therapeutic strategies for advanced disease. In particular, knowledge of the heterotypic interactions between and coevolution of cancer and host cells in the tumor microenvironment has illuminated novel therapeutic combinations with a strong potential for more durable therapeutic responses and eventual cures for advanced disease. Improved disease management will also benefit from artificial intelligence-based expert decision support systems for proper standard of care, prognostic determinant biomarkers to minimize overtreatment of localized disease, and new standards of care accelerated by next-generation adaptive clinical trials.
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Affiliation(s)
- Guocan Wang
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Di Zhao
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Denise J Spring
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Ronald A DePinho
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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23
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Skvortsov S, Skvortsova II, Tang DG, Dubrovska A. Concise Review: Prostate Cancer Stem Cells: Current Understanding. Stem Cells 2018; 36:1457-1474. [PMID: 29845679 DOI: 10.1002/stem.2859] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 04/05/2018] [Accepted: 05/01/2018] [Indexed: 12/29/2022]
Abstract
Prostate cancer (PCa) is heterogeneous, harboring phenotypically diverse cancer cell types. PCa cell heterogeneity is caused by genomic instability that leads to the clonal competition and evolution of the cancer genome and by epigenetic mechanisms that result in subclonal cellular differentiation. The process of tumor cell differentiation is initiated from a population of prostate cancer stem cells (PCSCs) that possess many phenotypic and functional properties of normal stem cells. Since the initial reports on PCSCs in 2005, there has been much effort to elucidate their biological properties, including unique metabolic characteristics. In this Review, we discuss the current methods for PCSC enrichment and analysis, the hallmarks of PCSC metabolism, and the role of PCSCs in tumor progression. Stem Cells 2018;36:1457-1474.
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Affiliation(s)
- Sergej Skvortsov
- Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology, Innsbruck Medical University, Innsbruck, Austria.,Tyrolean Cancer Research Institute, Innsbruck, Austria
| | - Ira-Ida Skvortsova
- Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology, Innsbruck Medical University, Innsbruck, Austria.,Tyrolean Cancer Research Institute, Innsbruck, Austria
| | - Dean G Tang
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, USA.,Cancer Stem Cell Institute, Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Anna Dubrovska
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, Dresden, Germany; German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
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24
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Bongiovanni L, Caposano F, Romanucci M, Grieco V, Malatesta D, Brachelente C, Massimini M, Benazzi C, Thomas RE, Salda LD. Survivin and Sox9: Potential Stem Cell Markers in Canine Normal, Hyperplastic, and Neoplastic Canine Prostate. Vet Pathol 2018; 56:200-207. [PMID: 30131013 DOI: 10.1177/0300985818794161] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Canine prostatic carcinoma is a relevant model for human prostatic carcinoma. Survivin is proposed as a biomarker of malignancy in human prostatic cancer. Sox9 is a stem cell marker required for prostate development and expressed in several adult tissues. The aims of the present study were to evaluate the patterns and expression levels of 2 putative stem cell markers, survivin and Sox9, in canine benign prostatic hyperplasia (BPH) and prostatic carcinoma to investigate their potential as stem cell markers. Immunohistochemistry with specific antibodies was performed on 3 samples of normal prostate gland, 18 samples of canine BPH, and 16 samples of prostatic carcinoma. The basal cell layer of normal and hyperplastic prostatic lobules had nuclear Sox9 immunolabeling and nuclear and rarely cytoplasmic survivin immunostaining, identifying them as potential stem cell markers. Significantly more frequent survivin and Sox9 expression (≥10% of nuclei) was observed in prostatic carcinoma as compared with BPH. The potential coexpression of survivin with Sox9, androgen receptor, and p63 was also investigated in selected BPH and prostatic carcinoma cases with immunofluorescence, and a partial colocalization was observed. Results indicate that Sox9 and survivin could be considered markers of stemness in canine prostate cells. Given its role in proliferation, cells in the basal cell layer with nuclear survivin expression are likely to be transit-amplifying cells that maintain some stem cell proprieties.
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Affiliation(s)
- Laura Bongiovanni
- 1 Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy.,2 Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | | | | | - Valeria Grieco
- 3 Department of Veterinary Science and Public Health, University of Milan, Milan, Italy
| | - Daniela Malatesta
- 1 Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy
| | - Chiara Brachelente
- 4 Department of Veterinary Medicine, University of Perugia, Perugia, Italy
| | | | - Cinzia Benazzi
- 5 Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy
| | - Rachel E Thomas
- 2 Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
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25
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Nilendu P, Sarode SC, Jahagirdar D, Tandon I, Patil S, Sarode GS, Pal JK, Sharma NK. Mutual concessions and compromises between stromal cells and cancer cells: driving tumor development and drug resistance. Cell Oncol (Dordr) 2018; 41:353-367. [PMID: 30027403 DOI: 10.1007/s13402-018-0388-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/08/2018] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Various cancers have been found to be associated with heterogeneous and adaptive tumor microenvironments (TMEs) and to be driven by the local TMEs in which they thrive. Cancer heterogeneity plays an important role in tumor cell survival, progression and drug resistance. The diverse cellular components of the TME may include cancer-associated fibroblasts, adipocytes, pericytes, mesenchymal stem cells, endothelial cells, lymphocytes and other immune cells. These components may support tumor development through the secretion of growth factors, evasion from immune checkpoints, metabolic adaptations, modulations of the extracellular matrix, activation of oncogenes and the acquisition of drug resistance. Here, we will address recent advances in our understanding of the molecular mechanisms underlying stromal-tumor cell interactions, with special emphasis on basic and pre-clinical information that may facilitate the design of novel personalized cancer therapies. CONCLUSIONS This review presents a holistic view on the translational potential of the interplay between stromal cells and cancer cells. This interplay is currently being employed for the development of promising preclinical and clinical biomarkers, and the design of small molecule inhibitors, antibodies and small RNAs for (combinatorial) cancer treatment options. In addition, nano-carriers, tissue scaffolds and 3-D based matrices are being developed to precisely and safely deliver these compounds.
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Affiliation(s)
- Pritish Nilendu
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India
| | - Sachin C Sarode
- Department of Oral Pathology and Microbiology, Dr. D Y Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India.
| | - Devashree Jahagirdar
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India
| | - Ishita Tandon
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan, Saudi Arabia
| | - Gargi S Sarode
- Department of Oral Pathology and Microbiology, Dr. D Y Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India
| | - Jayanta K Pal
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India
| | - Nilesh Kumar Sharma
- Cancer and Translational Research Lab, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, 411033, India.
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26
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Liao CP, Lin TP, Li PC, Geary LA, Chen K, Vaikari VP, Wu JB, Lin CH, Gross ME, Shih JC. Loss of MAOA in epithelia inhibits adenocarcinoma development, cell proliferation and cancer stem cells in prostate. Oncogene 2018; 37:5175-5190. [PMID: 29844571 DOI: 10.1038/s41388-018-0325-x] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 01/31/2018] [Accepted: 04/26/2018] [Indexed: 12/17/2022]
Abstract
Monoamine oxidase A (MAOA) is a mitochondrial enzyme, which degrades monoamine neurotransmitters and dietary amines and produces H2O2. Recent studies have shown increased MAOA expression in prostate cancer (PCa), glioma, and classical Hodgkin lymphoma. However, the biological function of MAOA in cancer development remains unknown. In this study, we investigated the role of MAOA in the development of prostate adenocarcinoma by creating a prostate-specific Pten/MAOA knockout (KO) mouse model, in which MAOA-floxP mouse was crossed with the conditional Pten KO PCa mouse that develops invasive PCa. In contrast to Pten KO mice, age-matched Pten/MAOA KO mice exhibited a significant decrease in both prostate size and the incidence of invasive cancer. We observed a significant decline in AKT phosphorylation and Ki67 expression in Pten/MAOA KO mice, which reduced epithelial cell growth and proliferation. As cancer stem cells (CSCs) are required for tumor initiation and growth, we investigated expression of OCT4 and NANOG in the setting of decreased MAOA expression. We found that both OCT4 and NANOG were significantly attenuated in the prostate epithelia of Pten/MAOA KO mice compared to Pten KO mice, which was confirmed with targeted knockdown of MAOA with a short-hairpin(sh) vector targeting MAOA compared to cells transfected with a control vector. Expression of other markers associated with the a stem cell phenotype, including CD44, α2β1, and CD133 as well as HIF-1α+CD44+ stem cells were all decreased in shMAOA PCa cells compared with empty vector-transfected control cells. We also found spheroid formation ability in PCa cells was decreased when endogenous MAOA was suppressed by siRNA or MAOA inhibitor clorgyline in a colony formation assay. Using the TCGA database, elevated MAOA expression was associated with reduced Pten levels in high Gleason grade in patient samples. Further, we found that Pten-positive PCa cells were more resistant to clorgyline treatments than Pten-null cells in tumorigenicity and stemness. Taken together, these studies suggest that MAOA expression promotes PCa development by increasing cell proliferation and CSCs and highlights the potential use of MAOA inhibitors for the treatment of PCa.
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Affiliation(s)
- Chun-Peng Liao
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089-9121, USA.,USC-Taiwan Center for Translation Research, University of Southern California, Los Angeles, CA, 90089-9121, USA.,Lawrence J. Ellison Institute for Transformative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033-9075, USA
| | - Tzu-Ping Lin
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089-9121, USA.,USC-Taiwan Center for Translation Research, University of Southern California, Los Angeles, CA, 90089-9121, USA.,Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, WA, 11221, Taiwan
| | - Pei-Chuan Li
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089-9121, USA.,USC-Taiwan Center for Translation Research, University of Southern California, Los Angeles, CA, 90089-9121, USA
| | - Lauren A Geary
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089-9121, USA.,USC-Taiwan Center for Translation Research, University of Southern California, Los Angeles, CA, 90089-9121, USA
| | - Kevin Chen
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089-9121, USA.,USC-Taiwan Center for Translation Research, University of Southern California, Los Angeles, CA, 90089-9121, USA
| | - Vijaya Pooja Vaikari
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089-9121, USA.,USC-Taiwan Center for Translation Research, University of Southern California, Los Angeles, CA, 90089-9121, USA
| | - Jason Boyang Wu
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, 99210-1495, USA
| | - Chi-Hung Lin
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, WA, 11221, Taiwan
| | - Mitchell E Gross
- Lawrence J. Ellison Institute for Transformative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033-9075, USA.,Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, 90089-9176, CA, USA
| | - Jean C Shih
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089-9121, USA. .,USC-Taiwan Center for Translation Research, University of Southern California, Los Angeles, CA, 90089-9121, USA. .,Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, 90089-9176, CA, USA. .,Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089-9037, USA. .,College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan.
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27
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Suh J, Kim DH, Surh YJ. Resveratrol suppresses migration, invasion and stemness of human breast cancer cells by interfering with tumor-stromal cross-talk. Arch Biochem Biophys 2018; 643:62-71. [DOI: 10.1016/j.abb.2018.02.011] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 01/30/2018] [Accepted: 02/17/2018] [Indexed: 01/04/2023]
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28
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Phi LTH, Sari IN, Yang YG, Lee SH, Jun N, Kim KS, Lee YK, Kwon HY. Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment. Stem Cells Int 2018; 2018:5416923. [PMID: 29681949 PMCID: PMC5850899 DOI: 10.1155/2018/5416923] [Citation(s) in RCA: 618] [Impact Index Per Article: 88.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 01/11/2018] [Indexed: 12/14/2022] Open
Abstract
Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are suggested to be responsible for drug resistance and cancer relapse due in part to their ability to self-renew themselves and differentiate into heterogeneous lineages of cancer cells. Thus, it is important to understand the characteristics and mechanisms by which CSCs display resistance to therapeutic agents. In this review, we highlight the key features and mechanisms that regulate CSC function in drug resistance as well as recent breakthroughs of therapeutic approaches for targeting CSCs. This promises new insights of CSCs in drug resistance and provides better therapeutic rationales to accompany novel anticancer therapeutics.
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Affiliation(s)
- Lan Thi Hanh Phi
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Ita Novita Sari
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Ying-Gui Yang
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Sang-Hyun Lee
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Nayoung Jun
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Kwang Seock Kim
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Yun Kyung Lee
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
| | - Hyog Young Kwon
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea
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29
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Saha A, Blando J, Fernandez I, Kiguchi K, DiGiovanni J. Linneg Sca-1high CD49fhigh prostate cancer cells derived from the Hi-Myc mouse model are tumor-initiating cells with basal-epithelial characteristics and differentiation potential in vitro and in vivo. Oncotarget 2018; 7:25194-207. [PMID: 26910370 PMCID: PMC5041897 DOI: 10.18632/oncotarget.7535] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 01/29/2016] [Indexed: 12/11/2022] Open
Abstract
A cell line was established from ventral prostate (VP) tumors of one-year-old Hi-Myc mice. These cells, called HMVP2 cells, are LinnegSca-1highCD49fhigh with high CD44 and CD29 expression and express CK14, Sca-1 and CD49f (but not CK8), suggesting basal-epithelial characteristics. Furthermore, HMVP2 cells form spheroids and both the cells and spheroids produce tumors in syngeneic mice. After four days of culture, HMVP2 spheroids underwent a gradual transition from LinnegSca-1highCD49fhigh expression to LinnegSca-1lowCD49flow while a subpopulation of the cells retained the original LinnegSca-1highCD49fhigh expression pattern. Additional cell subpopulations expressing Lin positive markers were also present suggesting further differentiation of HMVP2 spheroids. Two additional highly tumorigenic cell lines (HMVP2A1 and HMVP2A2) were isolated from HMVP2 cells after subsequent tumor formation in FVB/N mice. Concurrently, we also established cell lines from the VP of 6 months old Hi-Myc mice (named as HMVP1) and FVB/N mice (called NMVP) having less aggressive growth properties compared to the other three cell lines. AR expression was reduced in HMVP2 cells compared to NMVP and HMVP1 cells and almost absent in HMVP2A1 and HMVP2A2 cells. These cell lines will provide valuable tools for further mechanistic studies as well as preclinical studies to evaluate preventive and/or therapeutic agents for prostate cancer.
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Affiliation(s)
- Achinto Saha
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78723, USA.,Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78723, USA
| | - Jorge Blando
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78723, USA.,Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78723, USA
| | - Irina Fernandez
- Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78723, USA.,Stem Cell Transplantation Department, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA
| | - Kaoru Kiguchi
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78723, USA.,Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78723, USA
| | - John DiGiovanni
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78723, USA.,Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78723, USA
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30
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De Jaeghere E, De Vlieghere E, Van Hoorick J, Van Vlierberghe S, Wagemans G, Pieters L, Melsens E, Praet M, Van Dorpe J, Boone MN, Ghobeira R, De Geyter N, Bracke M, Vanhove C, Neyt S, Berx G, De Geest BG, Dubruel P, Declercq H, Ceelen W, De Wever O. Heterocellular 3D scaffolds as biomimetic to recapitulate the tumor microenvironment of peritoneal metastases in vitro and in vivo. Biomaterials 2017; 158:95-105. [PMID: 29306747 DOI: 10.1016/j.biomaterials.2017.12.017] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 12/20/2017] [Accepted: 12/21/2017] [Indexed: 01/01/2023]
Abstract
Peritoneal metastasis is a major cause of death and preclinical models are urgently needed to enhance therapeutic progress. This study reports on a hybrid hydrogel-polylactic acid (PLA) scaffold that mimics the architecture of peritoneal metastases at the qualitative, quantitative and spatial level. Porous PLA scaffolds with controllable pore size, geometry and surface properties are functionalized by type I collagen hydrogel. Co-seeding of cancer-associated fibroblasts (CAF) increases cancer cell adhesion, recovery and exponential growth by in situ heterocellular spheroid formation. Scaffold implantation into the peritoneum allows long-term follow-up (>14 weeks) and results in a time-dependent increase in vascularization, which correlates with cancer cell colonization in vivo. CAF, endothelial cells, macrophages and cancer cells show spatial and quantitative aspects as similarly observed in patient-derived peritoneal metastases. CAF provide long-term secretion of complementary paracrine factors implicated in spheroid formation in vitro as well as in recruitment and organization of host cells in vivo. In conclusion, the multifaceted heterocellular interactions that occur within peritoneal metastases are reproduced in this tissue-engineered implantable scaffold model.
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Affiliation(s)
- Emiel De Jaeghere
- Laboratory Experimental Cancer Research (LECR), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Elly De Vlieghere
- Laboratory Experimental Cancer Research (LECR), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Jasper Van Hoorick
- Polymer Chemistry & Biomaterials Group, Centre of Macromolecular Chemistry, Ghent University, Krijgslaan 281, S4-Bis, 9000 Ghent, Belgium
| | - Sandra Van Vlierberghe
- Polymer Chemistry & Biomaterials Group, Centre of Macromolecular Chemistry, Ghent University, Krijgslaan 281, S4-Bis, 9000 Ghent, Belgium
| | - Glenn Wagemans
- Laboratory Experimental Cancer Research (LECR), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Leen Pieters
- Department of Basic Medical Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Elodie Melsens
- Experimental Surgery Lab, Department of Surgery, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Marleen Praet
- Department of Pathology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Jo Van Dorpe
- Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Department of Pathology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Matthieu N Boone
- Department of Physics and Astronomy, Ghent University, Proeftuinstraat 86, 9000 Ghent, Belgium
| | - Rouba Ghobeira
- Department of Applied Physics, Research Unit Plasma Technology (RUPT), Ghent University, Sint-Pietersnieuwstraat 41, B4, 9000 Ghent, Belgium
| | - Nathalie De Geyter
- Department of Applied Physics, Research Unit Plasma Technology (RUPT), Ghent University, Sint-Pietersnieuwstraat 41, B4, 9000 Ghent, Belgium
| | - Marc Bracke
- Laboratory Experimental Cancer Research (LECR), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Christian Vanhove
- Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Institute Biomedical Technology, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Sara Neyt
- MOLECUBES NV, Ottergemsesteenweg-Zuid 808, 325 Ghent, Belgium
| | - Geert Berx
- Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Department of Biomedical Molecular Biology, Unit of Molecular and Cellular Oncology, Inflammation Research Center, VIB, Technologiepark Zwijnaarde 927, 9052 Ghent, Belgium
| | - Bruno G De Geest
- Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Department of Pharmaceutics, Ghent University, Ottergemstesteenweg 460, 9000 Ghent, Belgium
| | - Peter Dubruel
- Polymer Chemistry & Biomaterials Group, Centre of Macromolecular Chemistry, Ghent University, Krijgslaan 281, S4-Bis, 9000 Ghent, Belgium
| | - Heidi Declercq
- Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Department of Basic Medical Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Wim Ceelen
- Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Experimental Surgery Lab, Department of Surgery, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium
| | - Olivier De Wever
- Laboratory Experimental Cancer Research (LECR), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
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31
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Ookura M, Fujii T, Yagi H, Ogawa T, Kishi S, Hosono N, Shigemi H, Yamauchi T, Ueda T, Yoshida A. YM155 exerts potent cytotoxic activity against quiescent (G 0/G 1) multiple myeloma and bortezomib resistant cells via inhibition of survivin and Mcl-1. Oncotarget 2017; 8:111535-111550. [PMID: 29340073 PMCID: PMC5762341 DOI: 10.18632/oncotarget.22871] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 11/13/2017] [Indexed: 12/25/2022] Open
Abstract
YM155, a novel small molecule inhibitor of survivin, shows broad anticancer activity. Here, we have focused on the cytotoxic activity of YM155 against multiple myeloma (MM) including cytokinetically quiescent (G0/G1) cells and bortezomib resistant cells. YM155 strongly inhibited the growth of MM cell lines with the IC50 value of below 10 nM. YM155 also showed potent anti-myeloma activity in mouse xenograft model. YM155 suppressed the expression of survivin and rapidly directed Mcl-1 protein for proteasome degradation. YM155 abrogated the interleukin-6-induced STAT3 phosphorylation, subsequently blocked Mcl-1 expression and induced apoptosis in MM cells. Triple-color flow cytometric analysis revealed that YM155 potently induced cell death of MM cells in G0 phase. Quiescent primary MM cells were also sensitive to YM155. We established bortezomib-resistant MM cell line, U266/BTZR1, which possess a point mutation G322A. YM155 exhibited similar cytotoxic potency against U266/BTZR1 compared with parental cells. Interestingly, survivin expression was markedly elevated in U266/BTZR1 cells. Treatment with YM155 significantly down-regulated this increased survivin and Mcl-1 expression in U266/BTZR1 cells. In conclusion, our data indicate that YM155 exhibits potent cytotoxicity against quiescent (G0/G1) MM cells and bortezomib-resistant cells. These unique features of YM155 may be beneficial for the development of new therapeutic strategies to eliminate quiescent MM cells and overcome bortezomib resistance.
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Affiliation(s)
- Miyuki Ookura
- Department of Hematology and Oncology, University of Fukui, Matsuoka, Fukui 910-1193, Japan
| | - Tatsuya Fujii
- Department of Hematology and Oncology, University of Fukui, Matsuoka, Fukui 910-1193, Japan
| | - Hideki Yagi
- Department of Pharmaceutical Sciences, International University of Health and Welfare, Otawara, Tochigi 324-8501, Japan
| | - Takuya Ogawa
- Department of Pharmaceutical Sciences, International University of Health and Welfare, Otawara, Tochigi 324-8501, Japan
| | - Shinji Kishi
- Department of Hematology and Oncology, University of Fukui, Matsuoka, Fukui 910-1193, Japan
| | - Naoko Hosono
- Department of Hematology and Oncology, University of Fukui, Matsuoka, Fukui 910-1193, Japan
| | - Hiroko Shigemi
- Department of Hematology and Oncology, University of Fukui, Matsuoka, Fukui 910-1193, Japan
| | - Takahiro Yamauchi
- Department of Hematology and Oncology, University of Fukui, Matsuoka, Fukui 910-1193, Japan
| | - Takanori Ueda
- Department of Hematology and Oncology, University of Fukui, Matsuoka, Fukui 910-1193, Japan
| | - Akira Yoshida
- Department of Hematology, International University of Health and Welfare Hospital, Iguchi, Nasushiobara, Tochigi, 329-2763, Japan
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Cell surface Thomsen-Friedenreich proteome profiling of metastatic prostate cancer cells reveals potential link with cancer stem cell-like phenotype. Oncotarget 2017; 8:98598-98608. [PMID: 29228713 PMCID: PMC5716753 DOI: 10.18632/oncotarget.21985] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 09/29/2017] [Indexed: 02/04/2023] Open
Abstract
The tumor-associated Thomsen-Friedenreich glycoantigen (TF-Ag) plays an important role in hematogenous metastasis of multiple cancers. The LTQ Orbitrap LC-MS/MS mass spectrometry analysis of cell surface TF-Ag proteome of metastatic prostate cancer cells reveals that several cell surface glycoproteins expressing this carbohydrate antigen in prostate cancer (CD44, α2 integrin, β1 integrin, CD49f, CD133, CD59, EphA2, CD138, transferrin receptor, profilin) are either known as stem cell markers or control important cancer stem-like cell functions. This outcome points to a potential link between TF-Ag expression and prostate cancer stem-like phenotype. Indeed, selecting prostate cancer cells for TF-Ag expression resulted in the enrichment of cells with stem-like properties such as enhanced clonogenic survival and growth, prostasphere formation under non-differentiating and differentiating conditions, and elevated expression of stem cell markers such as CD44 and CD133. Further, the analysis of the recent literature demonstrates that TF-Ag is a common denominator for multiple prostate cancer stem-like cell populations identified to date and otherwise characterized by distinct molecular signatures. The current paradigm suggests that dissemination of tumor cells with stem-like properties to bone marrow that occurred before surgery and/or radiation therapy is largely responsible for disease recurrence years after radical treatment causing a massive clinical problem in prostate cancer. Thus, developing means for destroying disseminated prostate cancer stem-like cells is an important goal of modern cancer research. The results presented in this study suggest that multiple subpopulation of putative prostate cancer stem-like cells characterized by distinct molecular signatures can be attacked using a single target commonly expressed on these cells, the TF-Ag.
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Ishiguro T, Ohata H, Sato A, Yamawaki K, Enomoto T, Okamoto K. Tumor-derived spheroids: Relevance to cancer stem cells and clinical applications. Cancer Sci 2017; 108:283-289. [PMID: 28064442 PMCID: PMC5378268 DOI: 10.1111/cas.13155] [Citation(s) in RCA: 354] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 12/13/2016] [Accepted: 12/28/2016] [Indexed: 02/06/2023] Open
Abstract
Recently, many types of in vitro 3‐D culture systems have been developed to recapitulate the in vivo growth conditions of cancer. The cancer 3‐D culture methods aim to preserve the biological characteristics of original tumors better than conventional 2‐D monolayer cultures, and include tumor‐derived organoids, tumor‐derived spheroids, organotypic multicellular spheroids, and multicellular tumor spheroids. The 3‐D culture methods differ in terms of cancer cell sources, protocols for cell handling, and the required time intervals. Tumor‐derived spheroids are unique because they are purposed for the enrichment of cancer stem cells (CSCs) or cells with stem cell‐related characteristics. These spheroids are grown as floating spheres and have been used as surrogate systems to evaluate the CSC‐related characteristics of solid tumors in vitro. Because eradication of CSCs is likely to be of clinical importance due to their association with the malignant nature of cancer cells, such as tumorigenicity or chemoresistance, the investigation of tumor‐derived spheroids may provide invaluable clues to fight against cancer. Spheroid cultures have been established from cancers including glioma, breast, colon, ovary, and prostate cancers, and their biological and biochemical characteristics have been investigated by many research groups. In addition to the investigation of CSCs, tumor‐derived spheroids may prove to be instrumental for a high‐throughput screening platform or for the cultivation of CSC‐related tumor cells found in the circulation or body fluids.
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Affiliation(s)
- Tatsuya Ishiguro
- Department of Obstetrics and Gynecology, Niigata University Medical School, Niigata, Japan
| | - Hirokazu Ohata
- Division of Cancer Differentiation, National Cancer Center Research Institute, Tokyo, Japan
| | - Ai Sato
- Division of Cancer Differentiation, National Cancer Center Research Institute, Tokyo, Japan
| | - Kaoru Yamawaki
- Department of Obstetrics and Gynecology, Niigata University Medical School, Niigata, Japan.,Division of Cancer Differentiation, National Cancer Center Research Institute, Tokyo, Japan
| | - Takayuki Enomoto
- Department of Obstetrics and Gynecology, Niigata University Medical School, Niigata, Japan
| | - Koji Okamoto
- Division of Cancer Differentiation, National Cancer Center Research Institute, Tokyo, Japan
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34
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Liao CP, Chen LY, Luethy A, Kim Y, Kani K, MacLeod AR, Gross ME. Androgen receptor in cancer-associated fibroblasts influences stemness in cancer cells. Endocr Relat Cancer 2017; 24:157-170. [PMID: 28264911 PMCID: PMC5453797 DOI: 10.1530/erc-16-0138] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Accepted: 02/06/2017] [Indexed: 12/16/2022]
Abstract
Androgen receptor (AR) regulation pathways are essential for supporting the growth and survival of prostate cancer cells. Recently, sub-populations of prostate cancer cells have been identified with stem cell features and are associated with the emergence of treatment-resistant prostate cancer. Here, we explored the function of AR in prostate cancer-associated fibroblasts (CAFs) relative to growth and stem cell-associated characteristics. CAFs were isolated from the murine cPten-/-L prostate cancer model and cultured with human prostate cancer epithelial (hPCa) cells. A murine-specific AR antisense oligonucleotide (ASO) was used to suppress the expression of AR in the CAF cells. CAFs express low, but significant levels of AR relative to fibroblasts derived from non-malignant tissue. CAFs promoted growth and colony formation of hPCa cells, which was attenuated by the suppression of AR expression. Surprisingly, AR-depleted CAFs promoted increased stem cell marker expression in hPCa cells. Interferon gamma (IFN-γ) and macrophage colony-stimulating factor (M-CSF) were increased in AR-depleted CAF cells and exhibited similar effects on stem cell marker expression as seen in the CAF co-culture systems. Clinically, elevated IFN-γ expression was found to correlate with histologic grade in primary prostate cancer samples. In summary, AR and androgen-dependent signaling are active in CAFs and exert significant effects on prostate cancer cells. IFN-γ and M-CSF are AR-regulated factors secreted by CAF cells, which promote the expression of stem cell markers in prostate cancer epithelial cells. Understanding how CAFs and other constituents of stromal tissue react to anti-cancer therapies may provide insight into the development and progression of prostate cancer.
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Affiliation(s)
- Chun-Peng Liao
- Lawrence J. Ellison Institute for Transformative MedicineKeck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Leng-Ying Chen
- Lawrence J. Ellison Institute for Transformative MedicineKeck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Andrea Luethy
- Lawrence J. Ellison Institute for Transformative MedicineKeck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Youngsoo Kim
- Ionis Pharmaceuticals Inc.Carlsbad, California, USA
| | - Kian Kani
- Lawrence J. Ellison Institute for Transformative MedicineKeck School of Medicine, University of Southern California, Los Angeles, California, USA
| | | | - Mitchell E Gross
- Lawrence J. Ellison Institute for Transformative MedicineKeck School of Medicine, University of Southern California, Los Angeles, California, USA
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35
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Adamowicz J, Pakravan K, Bakhshinejad B, Drewa T, Babashah S. Prostate cancer stem cells: from theory to practice. Scand J Urol 2017. [DOI: 10.1080/21681805.2017.1283360] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- Jan Adamowicz
- Chair of Urology, Department of Regenerative Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Katayoon Pakravan
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Babak Bakhshinejad
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Tomasz Drewa
- Chair of Urology, Department of Regenerative Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Sadegh Babashah
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
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36
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Strand DW, Aaron L, Henry G, Franco OE, Hayward SW. Isolation and analysis of discreet human prostate cellular populations. Differentiation 2016; 91:139-51. [PMID: 26546040 PMCID: PMC4854811 DOI: 10.1016/j.diff.2015.10.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 10/27/2015] [Indexed: 02/03/2023]
Abstract
The use of lineage tracing in transgenic mouse models has revealed an abundance of subcellular phenotypes responsible for maintaining prostate homeostasis. The ability to use fresh human tissues to examine the hypotheses generated by these mouse experiments has been greatly enhanced by technical advances in tissue processing, flow cytometry and cell culture. We describe in detail the optimization of protocols for each of these areas to facilitate research on solving human prostate diseases through the analysis of human tissue.
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Affiliation(s)
- Douglas W Strand
- Department of Urology, UT Southwestern University Medical Center, Dallas, TX, USA
| | - LaTayia Aaron
- Department of Cancer Biology, Meharry Medical College, Nashville, TN, USA
| | - Gervaise Henry
- Department of Urology, UT Southwestern University Medical Center, Dallas, TX, USA
| | - Omar E Franco
- Department of Surgery, NorthShore University Health System, Research Institute, Evanston, IL, USA
| | - Simon W Hayward
- Department of Surgery, NorthShore University Health System, Research Institute, Evanston, IL, USA.
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37
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Small molecules modulating tumor-stromal cell interactions: new candidates for anti-tumor drugs. J Antibiot (Tokyo) 2016; 69:411-4. [PMID: 27005556 DOI: 10.1038/ja.2016.37] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 02/23/2016] [Accepted: 03/01/2016] [Indexed: 11/08/2022]
Abstract
The tumor microenvironment comprises tumor cells surrounding normal cells and the extracellular matrix. The surrounding normal cells have critical roles in the regulation of growth and metastasis of cancers, including the maintenance of cancer stem cells and the formation of cancer metastatic niches. Recent anti-tumor strategies targeting the tumor microenvironment have included inhibition of angiogenesis and the augmentation of immune reactions. However, in this review, we will focus on stromal cells (fibroblast-like cells), a common constituent of the tumor microenvironment. Since stromal cells regulate the growth of cancer cells positively and negatively through adhesion and secreted factors, anti-tumor strategies should consider modulating tumor-stromal cell interactions through use of small molecules.
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38
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Ferreira JA, Peixoto A, Neves M, Gaiteiro C, Reis CA, Assaraf YG, Santos LL. Mechanisms of cisplatin resistance and targeting of cancer stem cells: Adding glycosylation to the equation. Drug Resist Updat 2016; 24:34-54. [DOI: 10.1016/j.drup.2015.11.003] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 11/09/2015] [Accepted: 11/18/2015] [Indexed: 02/06/2023]
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39
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Shibata M, Shen MM. Stem cells in genetically-engineered mouse models of prostate cancer. Endocr Relat Cancer 2015; 22:T199-208. [PMID: 26341780 PMCID: PMC4618022 DOI: 10.1530/erc-15-0367] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/04/2015] [Indexed: 12/24/2022]
Abstract
The cancer stem cell model proposes that tumors have a hierarchical organization in which tumorigenic cells give rise to non-tumorigenic cells, with only a subset of stem-like cells able to propagate the tumor. In the case of prostate cancer, recent analyses of genetically engineered mouse (GEM) models have provided evidence supporting the existence of cancer stem cells in vivo. These studies suggest that cancer stem cells capable of tumor propagation exist at various stages of tumor progression from prostatic intraepithelial neoplasia (PIN) to advanced metastatic and castration-resistant disease. However, studies of stem cells in prostate cancer have been limited by available approaches for evaluating their functional properties in cell culture and transplantation assays. Given the role of the tumor microenvironment and the putative cancer stem cell niche, future studies using GEM models to analyze cancer stem cells in their native tissue microenvironment are likely to be highly informative.
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Affiliation(s)
- Maho Shibata
- Departments of MedicineGenetics and Development, Urology, and Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032, USA
| | - Michael M Shen
- Departments of MedicineGenetics and Development, Urology, and Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032, USA
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40
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Novel Implications of DNA Damage Response in Drug Resistance of Malignant Cancers Obtained from the Functional Interaction between p53 Family and RUNX2. Biomolecules 2015; 5:2854-76. [PMID: 26512706 PMCID: PMC4693260 DOI: 10.3390/biom5042854] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 09/17/2015] [Accepted: 10/16/2015] [Indexed: 12/31/2022] Open
Abstract
During the lifespan of cells, their genomic DNA is continuously exposed to the endogenous and exogenous DNA insults. Thus, the appropriate cellular response to DNA damage plays a pivotal role in maintaining genomic integrity and also acts as a molecular barrier towards DNA legion-mediated carcinogenesis. The tumor suppressor p53 participates in an integral part of proper regulation of DNA damage response (DDR). p53 is frequently mutated in a variety of human cancers. Since mutant p53 displays a dominant-negative behavior against wild-type p53, cancers expressing mutant p53 sometimes acquire drug-resistant phenotype, suggesting that mutant p53 prohibits the p53-dependent cell death pathway following DNA damage, and thereby contributing to the acquisition and/or maintenance of drug resistance of malignant cancers. Intriguingly, we have recently found that silencing of pro-oncogenic RUNX2 enhances drug sensitivity of aggressive cancer cells regardless of p53 status. Meanwhile, cancer stem cells (CSCs) have stem cell properties such as drug resistance. Therefore, the precise understanding of the biology of CSCs is quite important to overcome their drug resistance. In this review, we focus on molecular mechanisms behind DDR as well as the serious drug resistance of malignant cancers and discuss some attractive approaches to improving the outcomes of patients bearing drug-resistant cancers.
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41
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Albini A, Bruno A, Gallo C, Pajardi G, Noonan DM, Dallaglio K. Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity. Connect Tissue Res 2015; 56:414-25. [PMID: 26291921 PMCID: PMC4673538 DOI: 10.3109/03008207.2015.1066780] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Tumor cells able to recapitulate tumor heterogeneity have been tracked, isolated and characterized in different tumor types, and are commonly named Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC). CSC/CIC are disseminated in the tumor mass and are resistant to anti-cancer therapies and adverse conditions. They are able to divide into another stem cell and a "proliferating" cancer cell. They appear to be responsible for disease recurrence and metastatic dissemination even after apparent eradication of the primary tumor. The modulation of CSC/CIC activities by the tumor microenvironment (TUMIC) is still poorly known. CSC/CIC may mutually interact with the TUMIC in a special and unique manner depending on the TUMIC cells or proteins encountered. The TUMIC consists of extracellular matrix components as well as cellular players among which endothelial, stromal and immune cells, providing and responding to signals to/from the CSC/CIC. This interplay can contribute to the mechanisms through which CSC/CIC may reside in a dormant state in a tissue for years, later giving rise to tumor recurrence or metastasis in patients. Different TUMIC components, including the connective tissue, can differentially activate CIC/CSC in different areas of a tumor and contribute to the generation of cancer heterogeneity. Here, we review possible networking activities between the different components of the tumor microenvironment and CSC/CIC, with a focus on its role in tumor heterogeneity and progression. We also summarize novel therapeutic options that could target both CSC/CIC and the microenvironment to elude resistance mechanisms activated by CSC/CIC, responsible for disease recurrence and metastases.
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Affiliation(s)
- Adriana Albini
- Department of Research and Statistics, IRCCS Arcispedale Santa Maria Nuova,
Reggio Emilia,
Italy,Correspondence: Adriana Albini, Director of the Department of Research and Statistics,
IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Viale Risorgimento 80, 42123,
Reggio Emilia,
Italy. E-mail:
| | - Antonino Bruno
- Scientific and Technology Park, IRCCS MultiMedica,
Milan,
Italy
| | - Cristina Gallo
- Department of Research and Statistics, IRCCS Arcispedale Santa Maria Nuova,
Reggio Emilia,
Italy
| | - Giorgio Pajardi
- Department of Hand Surgery, San Giuseppe MultiMedica Hospital of Milan,
Milan,
Italy,Department of Clinical Sciences and Community, Plastic Surgery School, University of Milan,
Milan,
Italy
| | - Douglas M. Noonan
- Scientific and Technology Park, IRCCS MultiMedica,
Milan,
Italy,Department of Biotechnology and Life Sciences, University of Insubria,
Varese,
Italy
| | - Katiuscia Dallaglio
- Department of Research and Statistics, IRCCS Arcispedale Santa Maria Nuova,
Reggio Emilia,
Italy
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42
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Sackmann-Sala L, Angelergues A, Boutillon F, d'Acremont B, Maidenberg M, Oudard S, Goffin V. Human and murine prostate basal/stem cells are not direct targets of prolactin. Gen Comp Endocrinol 2015; 220:133-42. [PMID: 25888939 DOI: 10.1016/j.ygcen.2015.04.007] [Citation(s) in RCA: 3] [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: 09/03/2014] [Revised: 03/25/2015] [Accepted: 04/07/2015] [Indexed: 10/23/2022]
Abstract
Local overexpression of prolactin (PRL) in the prostate of Pb-PRL transgenic mice induces benign prostate tumors exhibiting marked amplification of the epithelial basal/stem cell compartment. However, PRL-activated intracellular signaling seems to be restricted to luminal cells, suggesting that basal/stem cells may not be direct targets of PRL. Given their described role as prostate cancer-initiating cells, it is important to understand the mechanisms that regulate basal/stem cells. In this study, we evaluated whether PRL can act directly on these cells, by growing them as prostaspheres. For this, primary 3D prostasphere cultures were prepared from unfractionated cells isolated from freshly harvested human and mouse benign prostate tissues and subjected to PRL stimulation in vitro. None of the various concentrations of PRL tested showed any effects on the sizes or numbers of the prostaspheres generated. In addition, neither activation of canonical PRL-induced signaling pathways (Stat5, Stat3 or Erk1/2) nor increased expression of the proliferation marker Ki-67 were detected by immunostaining in PRL-stimulated prostaspheres. Consistent with the absence of response, PRL receptor mRNA levels were generally undetectable in mouse sphere cells. We conclude that human and mouse prostate basal/stem cells are not direct targets of PRL action. The observed amplification of basal/stem cells in Pb-PRL prostates might be due to paracrine mechanisms originating from PRL action on other cell compartments. Our current efforts are aimed at unraveling these mechanisms.
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Affiliation(s)
- Lucila Sackmann-Sala
- Institut Necker Enfants Malades (INEM), Inserm U1151 - CNRS UMR 8253, Equipe "Physiopathologie des hormones PRL/GH", Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 14 rue Maria Helena Vieira da Silva - CS 61431, Bâtiment Leriche, 75993 Paris Cedex 14, France.
| | - Antoine Angelergues
- Institut Necker Enfants Malades (INEM), Inserm U1151 - CNRS UMR 8253, Equipe "Physiopathologie des hormones PRL/GH", Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 14 rue Maria Helena Vieira da Silva - CS 61431, Bâtiment Leriche, 75993 Paris Cedex 14, France; Service de Cancérologie Médicale, Hôpital Européen Georges Pompidou, Université Paris Descartes, 20 rue Leblanc, 75015 Paris, France.
| | - Florence Boutillon
- Institut Necker Enfants Malades (INEM), Inserm U1151 - CNRS UMR 8253, Equipe "Physiopathologie des hormones PRL/GH", Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 14 rue Maria Helena Vieira da Silva - CS 61431, Bâtiment Leriche, 75993 Paris Cedex 14, France
| | - Bruno d'Acremont
- Service d'Urologie, Fondation Saint Jean de Dieu - Clinique Oudinot, 19 rue Oudinot, 75007 Paris, France.
| | - Marc Maidenberg
- Service d'Urologie, Fondation Saint Jean de Dieu - Clinique Oudinot, 19 rue Oudinot, 75007 Paris, France.
| | - Stéphane Oudard
- Service de Cancérologie Médicale, Hôpital Européen Georges Pompidou, Université Paris Descartes, 20 rue Leblanc, 75015 Paris, France.
| | - Vincent Goffin
- Institut Necker Enfants Malades (INEM), Inserm U1151 - CNRS UMR 8253, Equipe "Physiopathologie des hormones PRL/GH", Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 14 rue Maria Helena Vieira da Silva - CS 61431, Bâtiment Leriche, 75993 Paris Cedex 14, France.
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43
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Gandellini P, Andriani F, Merlino G, D'Aiuto F, Roz L, Callari M. Complexity in the tumour microenvironment: Cancer associated fibroblast gene expression patterns identify both common and unique features of tumour-stroma crosstalk across cancer types. Semin Cancer Biol 2015; 35:96-106. [PMID: 26320408 DOI: 10.1016/j.semcancer.2015.08.008] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 08/17/2015] [Accepted: 08/21/2015] [Indexed: 12/21/2022]
Abstract
Cancer is a complex disease, driven by the accumulation of several somatic aberrations but fostered by a two-way interaction between tumour cells and the surrounding microenvironment. Cancer associated fibroblasts (CAFs) represent one of the major players in tumour-stroma crosstalk. Recent in vitro and in vivo studies, often conducted by employing high throughput approaches, have started unravelling the key pathways involved in their functional effects. This review focus on open challenges in the study of CAF properties and function, highlighting at the same time the existence of common mechanisms as well as peculiarities in different cancer types (breast, prostate and lung cancer). Although still limited by current experimental models, which are unable to deal with the full level of complexity of the tumour microenvironment, a better understanding of these mechanisms may enable the identification of new biomarkers and therapeutic targets, to improve current strategies for cancer diagnosis and treatment.
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Affiliation(s)
- Paolo Gandellini
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca Andriani
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giuseppe Merlino
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca D'Aiuto
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luca Roz
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maurizio Callari
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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44
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Liang M, Adisetiyo H, Liu X, Liu R, Gill P, Roy-Burman P, Jones JO, Mulholland DJ. Identification of Androgen Receptor Splice Variants in the Pten Deficient Murine Prostate Cancer Model. PLoS One 2015. [PMID: 26196517 PMCID: PMC4510390 DOI: 10.1371/journal.pone.0131232] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Androgen receptor (AR) variants are associated with resistance to anti androgen therapy both in human prostate cancer cell lines and clinical samples. These observations support the hypothesis that AR isoform accumulation is a consequence of selective therapeutic pressure on the full length AR. The Pten deficient prostate cancer model proceeds with well-defined kinetics including progression to castration resistant prostate cancer (CRPC). While surgical castration and enzalutamide treatments yield an initial therapeutic response, Pten-/-epithelia continue to proliferate yielding locally invasive primary tumor pathology. That most epithelium remains AR positive, but ligand independent, suggests the presence of oncogenic AR variants. To address this hypothesis, we have used a panel of recently described Pten-/- tumor cell lines derived from both from hormone intact (E4, E8) and castrated Pten mutants (cE1, cE2) followed by RACE PCR to identify and characterize three novel truncated, amino terminus containing AR variants (mAR-Va, b, c). Variants appear not only conserved throughout progression but are correlated with nearly complete loss of full length AR (AR-FL) at castrate androgen levels. The overexpression of variants leads to enhanced transcriptional activity of AR while knock down studies show reduced transcriptional output. Collectively, the identification of truncated AR variants in the conditional PTEN deletion model supports a role for maintaining the CRPC phenotype and provides further therapeutic applications of this preclinical model.
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Affiliation(s)
- Mengmeng Liang
- Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Helty Adisetiyo
- Children’s Hospital of Los Angeles, Los Angeles, California, United States of America
| | - Xiuqing Liu
- St. Luke's Hospital, Internal medicine resident, Chesterfield, Missouri, United States of America
| | - Ren Liu
- Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America
| | - Parkash Gill
- Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America
| | - Pradip Roy-Burman
- Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California, United States of America
| | - Jeremy O. Jones
- Beckman Research Institute, City of Hope, Duarte, California, United States of America
- * E-mail: (DJM); (JJ)
| | - David J. Mulholland
- Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- * E-mail: (DJM); (JJ)
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Stromal cells positively and negatively modulate the growth of cancer cells: stimulation via the PGE2-TNFα-IL-6 pathway and inhibition via secreted GAPDH-E-cadherin interaction. PLoS One 2015; 10:e0119415. [PMID: 25785838 PMCID: PMC4364666 DOI: 10.1371/journal.pone.0119415] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 01/13/2015] [Indexed: 02/04/2023] Open
Abstract
Fibroblast-like stromal cells modulate cancer cells through secreted factors and adhesion, but those factors are not fully understood. Here, we have identified critical stromal factors that modulate cancer growth positively and negatively. Using a cell co-culture system, we found that gastric stromal cells secreted IL-6 as a growth and survival factor for gastric cancer cells. Moreover, gastric cancer cells secreted PGE2 and TNFα that stimulated IL-6 secretion by the stromal cells. Furthermore, we found that stromal cells secreted glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Extracellular GAPDH, or its N-terminal domain, inhibited gastric cancer cell growth, a finding confirmed in other cell systems. GAPDH bound to E-cadherin and downregulated the mTOR-p70S6 kinase pathway. These results demonstrate that stromal cells could regulate cancer cell growth through the balance of these secreted factors. We propose that negative regulation of cancer growth using GAPDH could be a new anti-cancer strategy.
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Han Y, Zhang Y, Jia T, Sun Y. Molecular mechanism underlying the tumor-promoting functions of carcinoma-associated fibroblasts. Tumour Biol 2015; 36:1385-94. [PMID: 25680413 DOI: 10.1007/s13277-015-3230-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Accepted: 02/05/2015] [Indexed: 12/16/2022] Open
Abstract
Tumor microenvironment is composed of all the untransformed elements in the vicinity of tumor, mainly including a large number of stromal cells and extracellular matrix proteins, which play an active role in most solid tumor initiation and progression. Carcinoma-associated fibroblasts (CAFs), one of the most common stromal cell types in the tumor microenvironment, have been demonstrated to be involved in tumor growth, invasion, and metastasis. Therefore, they are becoming a promising target for anti-cancer therapies. In this review, we firstly summarize the current understandings of CAFs' molecular biology, including the heterogeneous cellular origins and molecular markers, and then, we focus on reviewing their various tumor-promoting phenotypes involved in complex mechanisms, which can be summarized to the CAF-conveyed paracrine signals in tumor cells, cancer stem cells, and metastasis-initiating cancer cells, as well as the CAF-enhanced extrinsic tumor-promoting processes including angiogenesis, extracellular matrix remodeling, and tumor-related inflammation; finally, we describe the available directions of CAF-based target therapy and suggest research areas which need to be further explored so as to deepen the understanding of tumor evolution and provide new therapeutic targets for cancer treatment.
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Affiliation(s)
- Yali Han
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, 250013, Shandong, China,
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Huang L, Xu AM, Liu S, Liu W, Li TJ. Cancer-associated fibroblasts in digestive tumors. World J Gastroenterol 2014; 20:17804-17818. [PMID: 25548479 PMCID: PMC4273131 DOI: 10.3748/wjg.v20.i47.17804] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2014] [Revised: 06/22/2014] [Accepted: 07/11/2014] [Indexed: 02/07/2023] Open
Abstract
The significant influence of tumor stroma on malignant cells has been extensively investigated in this era of targeted therapy. The tumor microenvironment, as a dynamic system, is orchestrated by various cells including tumor vascular composing cells, inflammatory cells and fibroblasts. As a major and important component in tumor stroma, increasing evidence has shown that spindle-shaped cancer-associated fibroblasts (CAFs) are a significant modifier of cancer evolution, and promote tumorigenesis, tumor invasion and metastasis by stimulating angiogenesis, malignant cell survival, epithelial-mesenchymal transition (EMT) and proliferation via direct cell-to-cell contact or secretion of soluble factors in most digestive solid tumors. CAFs are thought to be activated, characterized by the expression of α-smooth muscle actin, fibroblast activated protein, fibroblast specific protein, vimentin, fibronectin, etc. They are hypothesized to originate from normal or aged fibroblasts, bone marrow-derived mesenchymal cells, or vascular endothelial cells. EMT may also be an important process generating CAFs, and most probably, CAFs may originate from multiple cells. A close link exists between EMT, tumor stem cells, and chemo-resistance of tumor cells, which is largely orchestrated by CAFs. CAFs significantly induce immunosuppression, and may be a prognostic marker in various malignancies. Targeted therapy toward CAFs has displayed promising anticancer efficacy, which further reinforces the necessity to explore the relationship between CAFs and their hosts.
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Adisetiyo H, Liang M, Liao CP, Jeong JH, Cohen MB, Roy-Burman P, Frenkel B. Dependence of castration-resistant prostate cancer (CRPC) stem cells on CRPC-associated fibroblasts. J Cell Physiol 2014; 229:1170-6. [PMID: 24752784 DOI: 10.1002/jcp.24546] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Accepted: 12/20/2013] [Indexed: 01/24/2023]
Abstract
We previously established a role for cancer-associated fibroblasts (CAF) in enhancing the self-renewal and differentiation potentials of putative prostate cancer stem cells (CSC). Our published work focused on androgen-dependent prostate cancer (ADPC) using the conditional Pten deletion mouse model. Employing the same model, we now describe the interaction of CAF and CSC in castration-resistant prostate cancer (CRPC). CAF isolated from ADPC (ADPCAF) and from CRPC (CRPCAF) were compared in terms of their ability to support organoid formation and tumor initiation by CSC from CRPC (CRPCSC) in vitro and in vivo. CRPCSC formed spheroids in vitro and well-differentiated glandular structures under the renal capsules of recipient mice in vivo more effectively in the presence of CRPCAF compared to ADPCAF. Furthermore, whereas CSC with CAF from ADPC formed mostly well-differentiated tumors in our previous study, we now show that CRPCSC, when combined with CRPCAF (but not ADPCAF), can form aggressive, poorly-differentiated tumors. The potential of CRPCAF to support organoid/tumor formation by CRPCSC remained greater even when compared to 10-fold more ADPCAF, suggesting that paracrine factors produced specifically by CRPCAF preferentially potentiate the stemness and tumorigenic properties of the corresponding CSC. This apparently unique property of CRPCAF was notable when the CAF and CSC were grafted in either intact or castrated recipient mice. In both environments, CRPCAF induced in the epithelial compartment higher proliferative activity compared to ADPCAF, indicated by a higher Ki67 index. Factors released by CRPCAF to regulate CRPCSC may be targeted to develop novel therapeutic approaches to manage advanced prostate cancer.
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Affiliation(s)
- Helty Adisetiyo
- Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California; Institute for Genetic Medicine, University of Southern California, Los Angeles, California
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Geary LA, Nash KA, Adisetiyo H, Liang M, Liao CP, Jeong JH, Zandi E, Roy-Burman P. CAF-secreted annexin A1 induces prostate cancer cells to gain stem cell-like features. Mol Cancer Res 2014; 12:607-21. [PMID: 24464914 DOI: 10.1158/1541-7786.mcr-13-0469] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
UNLABELLED Annexin A1 (AnxA1), a phospholipid-binding protein and regulator of glucocorticoid-induced inflammatory signaling, has implications in cancer. Here, a role for AnxA1 in prostate adenocarcinoma was determined using primary cultures and a tumor cell line (cE1), all derived from the conditional Pten deletion mouse model of prostate cancer. AnxA1 secretion by prostate-derived cancer-associated fibroblasts (CAF) was significantly higher than by normal prostate fibroblasts (NPF). Prostate tumor cells were sorted to enrich for epithelial subpopulations based on nonhematopoietic lineage, high SCA-1, and high or medium levels of CD49f. Compared with controls, AnxA1 enhanced stem cell-like properties in high- and medium-expression subpopulations of sorted cE1 and primary cells, in vitro, through formation of greater number of spheroids with increased complexity, and in vivo, through generation of more, larger, and histologically complex glandular structures, along with increased expression of p63, a basal/progenitor marker. The differentiated medium-expression subpopulations from cE1 and primary cells were most susceptible to gain stem cell-like properties as shown by increased spheroid and glandular formation. Further supporting this increased plasticity, AnxA1 was shown to regulate epithelial-to-mesenchymal transition in cE1 cells. These results suggest that CAF-secreted AnxA1 contributes to tumor stem cell dynamics via two separate but complementary pathways: induction of a dedifferentiation process leading to generation of stem-like cells from a subpopulation of cancer epithelial cells and stimulation of proliferation and differentiation of the cancer stem-like cells. IMPLICATIONS AnxA1 participates in a paradigm in which malignant prostate epithelial cells that are not cancer stem cells are induced to gain cancer stem cell-like properties.
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Affiliation(s)
- Lauren A Geary
- Department of Pathology, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR 210B, Los Angeles, CA 90033.
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