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Ziranu P, Pretta A, Aimola V, Cau F, Mariani S, D’Agata AP, Codipietro C, Rizzo D, Dell’Utri V, Sanna G, Moledda G, Cadoni A, Lai E, Puzzoni M, Pusceddu V, Castagnola M, Scartozzi M, Faa G. CD44: A New Prognostic Marker in Colorectal Cancer? Cancers (Basel) 2024; 16:1569. [PMID: 38672650 PMCID: PMC11048923 DOI: 10.3390/cancers16081569] [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: 01/18/2024] [Revised: 03/19/2024] [Accepted: 04/13/2024] [Indexed: 04/28/2024] Open
Abstract
Cluster of differentiation 44 (CD44) is a non-kinase cell surface glycoprotein. It is overexpressed in several cell types, including cancer stem cells (CSCs). Cells overexpressing CD44 exhibit several CSC traits, such as self-renewal, epithelial-mesenchymal transition (EMT) capability, and resistance to chemo- and radiotherapy. The role of CD44 in maintaining stemness and the CSC function in tumor progression is accomplished by binding to its main ligand, hyaluronan (HA). The HA-CD44 complex activates several signaling pathways that lead to cell proliferation, adhesion, migration, and invasion. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The different functional roles of CD44s and specific CD44v isoforms still need to be fully understood. The clinicopathological impact of CD44 and its isoforms in promoting tumorigenesis suggests that CD44 could be a molecular target for cancer therapy. Furthermore, the recent association observed between CD44 and KRAS-dependent carcinomas and the potential correlations between CD44 and tumor mutational burden (TMB) and microsatellite instability (MSI) open new research scenarios for developing new strategies in cancer treatment. This review summarises current research regarding the different CD44 isoform structures, their roles, and functions in supporting tumorigenesis and discusses its therapeutic implications.
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Affiliation(s)
- Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Valentina Aimola
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (V.A.); (F.C.)
| | - Flaviana Cau
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (V.A.); (F.C.)
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Alessandra Pia D’Agata
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Claudia Codipietro
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Daiana Rizzo
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Veronica Dell’Utri
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Giorgia Sanna
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Giusy Moledda
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Andrea Cadoni
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Massimo Castagnola
- Proteomics Laboratory, Centro Europeo di Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, 00013 Rome, Italy;
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio per Sestu, Monserrato, 09042 Cagliari, Italy; (A.P.); (S.M.); (A.P.D.); (C.C.); (D.R.); (V.D.); (G.S.); (G.M.); (A.C.); (E.L.); (M.P.); (V.P.); (M.S.)
| | - Gavino Faa
- Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy;
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
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Wei Y, Chen Q, Chen J, Zhou C, Geng S, Shi D, Huang S, Liang Z, Chen X, Ren N, Jiang J. Loss of α-1,2-mannosidase MAN1C1 promotes tumorigenesis of intrahepatic cholangiocarcinoma through enhancing CD133-FIP200 interaction. Cell Rep 2023; 42:113588. [PMID: 38117655 DOI: 10.1016/j.celrep.2023.113588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/31/2023] [Accepted: 11/30/2023] [Indexed: 12/22/2023] Open
Abstract
CD133 is widely used as a marker to isolate tumor-initiating cells in many types of cancers. The structure of N-glycan on CD133 is altered during the differentiation of tumor-initiating cells. However, the relationship between CD133 N-glycosylation and stem cell characteristics remains elusive. Here, we found that the level of α-1,2-mannosylated CD133 was associated with the level of stemness genes in intrahepatic cholangiocarcinoma (iCCA) tissues. α-1,2-mannosylated CD133+ cells possessed the characteristics of tumor-initiating cells. The loss of the Golgi α-mannosidase I coding gene MAN1C1 resulted in the formation of α-1,2-mannosylated CD133 in iCCA-initiating cells. Mechanistically, α-1,2-mannosylation promoted the cytoplasmic distribution of CD133 and enhanced the interaction between CD133 and the autophagy gene FIP200, subsequently promoting the tumorigenesis of α-1,2-mannosylated CD133+ cells. Analysis of iCCA samples showed that the level of cytoplasmic CD133 was associated with poor iCCA prognosis. Collectively, α-1,2-mannosylated CD133 is a functional marker of iCCA-initiating cells.
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Affiliation(s)
- Yuanyan Wei
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China.
| | - Qihang Chen
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Jiayue Chen
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Chenhao Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China; Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai 201199, P.R. China
| | - Shuting Geng
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Danfang Shi
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Sijing Huang
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Zhiwei Liang
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Xiaoning Chen
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Ning Ren
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China; Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer of Shanghai Municipal Health Commission, Shanghai 201199, P.R. China; Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201199, P.R. China.
| | - Jianhai Jiang
- NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China.
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Martinez Lyons A, Boulter L. NOTCH signalling - a core regulator of bile duct disease? Dis Model Mech 2023; 16:dmm050231. [PMID: 37605966 PMCID: PMC10461466 DOI: 10.1242/dmm.050231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2023] Open
Abstract
The Notch signalling pathway is an evolutionarily conserved mechanism of cell-cell communication that mediates cellular proliferation, fate determination and maintenance of stem/progenitor cell populations across tissues. Although it was originally identified as a critical regulator of embryonic liver development, NOTCH signalling activation has been associated with the pathogenesis of a number of paediatric and adult liver diseases. It remains unclear, however, what role NOTCH actually plays in these pathophysiological processes and whether NOTCH activity represents the reactivation of a conserved developmental programme that is essential for adult tissue repair. In this Review, we explore the concepts that NOTCH signalling reactivation in the biliary epithelium is a reiterative and essential response to bile duct damage and that, in disease contexts in which biliary epithelial cells need to be regenerated, NOTCH signalling supports ductular regrowth. Furthermore, we evaluate the recent literature on NOTCH signalling as a critical factor in progenitor-mediated hepatocyte regeneration, which indicates that the mitogenic role for NOTCH signalling in biliary epithelial cell proliferation has also been co-opted to support other forms of epithelial regeneration in the adult liver.
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Affiliation(s)
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, Edinburgh EH4 2XU, UK
- CRUK Scottish Centre, Institute of Genetics and Cancer, Edinburgh EH4 2XU, UK
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Mesenchymal/stromal stem cells: necessary factors in tumour progression. Cell Death Discov 2022; 8:333. [PMID: 35869057 PMCID: PMC9307857 DOI: 10.1038/s41420-022-01107-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 06/21/2022] [Accepted: 06/28/2022] [Indexed: 11/08/2022] Open
Abstract
Mesenchymal/stromal stem cells (MSCs) are a crucial component of the tumour microenvironment (TME). They can be recruited from normal tissues into the TME and educated by tumour cells to transform into tumour-associated MSCs, which are oncogenic cells that promote tumour development and progression by impacting or transforming into various kinds of cells, such as immune cells and endothelial cells. Targeting MSCs in the TME is a novel strategy to prevent malignant processes. Exosomes, as communicators, carry various RNAs and proteins and thus link MSCs and the TME, which provides options for improving outcomes and developing targeted treatment.
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Ghatak S, Hascall VC, Karamanos N, Markwald RR, Misra S. Interplay Between Chemotherapy-Activated Cancer Associated Fibroblasts and Cancer Initiating Cells Expressing CD44v6 Promotes Colon Cancer Resistance. Front Oncol 2022; 12:906415. [PMID: 35982950 PMCID: PMC9380598 DOI: 10.3389/fonc.2022.906415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/22/2022] [Indexed: 11/14/2022] Open
Abstract
Cancer-initiating cells (CICs) drive colorectal tumor growth by their supportive niches where CICs interact with multiple cell types within the microenvironment, including cancer-associated fibroblasts (CAFs). We investigated the interplay between the CICs and the clinically relevant chemotherapeutic FOLFOX that creates the persistent tumorigenic properties of colorectal CICs, and stimulates the microenvironmental factors derived from the CAFs. We found that the CICs expressing an immunophenotype (CD44v6[+]) promote FOLFOX-resistance and that the CIC-immunophenotype was enhanced by factors secreted by CAFs after FOLFOX treatment These secreted factors included periostin, IL17A and WNT3A, which induced CD44v6 expression by activating WNT3A/β-catenin signaling. Blocking the interaction between CICs with any of these CAF-derived factors through tissue-specific conditional silencing of CD44v6 significantly reduced colorectal tumorigenic potential. To achieve this, we generated two unique vectors (floxed-pSico-CD44v6 shRNA plus Fabpl-Cre) that were encapsulated into transferrin coated PEG-PEI/(nanoparticles), which when introduced in vivo reduced tumor growth more effectively than using CD44v6-blocking antibodies. Notably, this tissue-specific conditional silencing of CD44v6 resulted in long lasting effects on self-renewal and tumor growth associated with a positive feedback loop linking WNT3A signaling and alternative-splicing of CD44. These findings have crucial clinical implications suggesting that therapeutic approaches for modulating tumor growth that currently focus on cell-autonomous mechanisms may be too limited and need to be broadened to include mechanisms that recognize the interplay between the stromal factors and the subsequent CIC-immunophenotype enrichment. Thus, more specific therapeutic approaches may be required to block a chemotherapy induced remodeling of a microenvironment that acts as a paracrine regulator to enrich CD44v6 (+) in colorectal CICs.
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Affiliation(s)
- Shibnath Ghatak
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
- Department Natural Sciences, Trident Technical College, North Charleston, SC, United States
| | - Vincent C. Hascall
- Department of Biomedical Engineering/ND20, Cleveland Clinic, Cleveland, OH, United States
| | - Nikos Karamanos
- Department of Chemistry, University of Patras, Matrix Pathobiology Research Group, Patras, Greece
| | - Roger R. Markwald
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
| | - Suniti Misra
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States
- Department Natural Sciences, Trident Technical College, North Charleston, SC, United States
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Hongu T, Pein M, Insua-Rodríguez J, Gutjahr E, Mattavelli G, Meier J, Decker K, Descot A, Bozza M, Harbottle R, Trumpp A, Sinn HP, Riedel A, Oskarsson T. Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs. NATURE CANCER 2022; 3:486-504. [PMID: 35469015 PMCID: PMC9046090 DOI: 10.1038/s43018-022-00353-6] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 02/24/2022] [Indexed: 02/07/2023]
Abstract
Disseminated cancer cells frequently lodge near vasculature in secondary organs. However, our understanding of the cellular crosstalk invoked at perivascular sites is still rudimentary. Here, we identify intercellular machinery governing formation of a pro-metastatic vascular niche during breast cancer colonization in the lung. We show that specific secreted factors, induced in metastasis-associated endothelial cells (ECs), promote metastasis in mice by enhancing stem cell properties and the viability of cancer cells. Perivascular macrophages, activated via tenascin C (TNC) stimulation of Toll-like receptor 4 (TLR4), were shown to be crucial in niche activation by secreting nitric oxide (NO) and tumor necrosis factor (TNF) to induce EC-mediated production of niche components. Notably, this mechanism was independent of vascular endothelial growth factor (VEGF), a key regulator of EC behavior and angiogenesis. However, targeting both macrophage-mediated vascular niche activation and VEGF-regulated angiogenesis resulted in added potency to curb lung metastasis in mice. Together, our findings provide mechanistic insights into the formation of vascular niches in metastasis.
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Affiliation(s)
- Tsunaki Hongu
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
- Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Maren Pein
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
- Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Jacob Insua-Rodríguez
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
- Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Ewgenija Gutjahr
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Greta Mattavelli
- Mildred Scheel Early Career Center, University Hospital of Würzburg, Würzburg, Germany
| | - Jasmin Meier
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
- Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Kristin Decker
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
- Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Arnaud Descot
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
- Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Matthias Bozza
- DNA Vector Laboratory, German Cancer Research Center, Heidelberg, Germany
| | - Richard Harbottle
- DNA Vector Laboratory, German Cancer Research Center, Heidelberg, Germany
| | - Andreas Trumpp
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
- Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany
- DKFZ-ZMBH Alliance, Heidelberg, Germany
- German Cancer Consortium, Heidelberg, Germany
| | - Hans-Peter Sinn
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Angela Riedel
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
- Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany
- Mildred Scheel Early Career Center, University Hospital of Würzburg, Würzburg, Germany
| | - Thordur Oskarsson
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
- Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany.
- German Cancer Consortium, Heidelberg, Germany.
- Department of Molecular Oncology and Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
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Martinez P, Ballarin L, Ereskovsky AV, Gazave E, Hobmayer B, Manni L, Rottinger E, Sprecher SG, Tiozzo S, Varela-Coelho A, Rinkevich B. Articulating the "stem cell niche" paradigm through the lens of non-model aquatic invertebrates. BMC Biol 2022; 20:23. [PMID: 35057814 PMCID: PMC8781081 DOI: 10.1186/s12915-022-01230-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 01/12/2022] [Indexed: 12/13/2022] Open
Abstract
Stem cells (SCs) in vertebrates typically reside in "stem cell niches" (SCNs), morphologically restricted tissue microenvironments that are important for SC survival and proliferation. SCNs are broadly defined by properties including physical location, but in contrast to vertebrates and other "model" organisms, aquatic invertebrate SCs do not have clearly documented niche outlines or properties. Life strategies such as regeneration or asexual reproduction may have conditioned the niche architectural variability in aquatic or marine animal groups. By both establishing the invertebrates SCNs as independent types, yet allowing inclusiveness among them, the comparative analysis will allow the future functional characterization of SCNs.
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Affiliation(s)
- P Martinez
- Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
- Institut Català de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
| | - L Ballarin
- Department of Biology, University of Padova, Via U. Bassi 58/B, 35100, Padova, Italy
| | - A V Ereskovsky
- Aix Marseille University, Avignon Université, CNRS, IRD, IMBE, Marseille, France
- St. Petersburg State University, Biological Faculty, Universitetskaya emb. 7/9, St. Petersburg, 199034, Russia
- N. K. Koltzov Institute of Developmental Biology, Russian Academy of Sciences, Vavilova Street 26, Moscow, 119334, Russia
| | - E Gazave
- Université de Paris, CNRS, Institut Jacques Monod, F-75006, Paris, France
| | - B Hobmayer
- Department of Zoology and Center of Molecular Biosciences, University of Innsbruck, Technikerstr. 25, 6020, Innsbruck, Austria
| | - L Manni
- Department of Biology, University of Padova, Via U. Bassi 58/B, 35100, Padova, Italy
| | - E Rottinger
- Université Côte d'Azur, CNRS, INSERM, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
- Université Côte d'Azur, Federative Research Institute - Marine Resources (IFR MARRES), Nice, France
| | - S G Sprecher
- Department of Biology, University of Fribourg, Chemin du Musee 10, 1700, Fribourg, Switzerland
| | - S Tiozzo
- Sorbonne Université, CNRS, Laboratoire de Biologie du Développement de Villefranche-sur-mer (LBDV), Paris, France
| | - A Varela-Coelho
- ITQB NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Av. da República, 2780-157, Oeiras, Portugal
| | - B Rinkevich
- Israel Oceanography and Limnological Research, National Institute of Oceanography, Tel Shikmona, P.O. Box 8030, 31080, Haifa, Israel.
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Wang Y, Gong X, Li J, Wang H, Xu X, Wu Y, Wang J, Wang S, Li Y, Zhang Z. M2 macrophage microvesicle-inspired nanovehicles improve accessibility to cancer cells and cancer stem cells in tumors. J Nanobiotechnology 2021; 19:397. [PMID: 34838042 PMCID: PMC8627085 DOI: 10.1186/s12951-021-01143-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/14/2021] [Indexed: 12/14/2022] Open
Abstract
Cancer cells and cancer stem cells (CSCs) are the major players of cancer malignancy and metastasis, but they are extremely difficult to access. Inspired by the vital role of macrophages and microvesicle-mediated cell–cell communication in tumors, we herein designed M2 macrophage microvesicle-inspired nanovehicle of cabazitaxel (M-CFN) to promote accessibility to cancer cells and CSCs in tumors. In the 4T1 tumor model, M-CFN flexibly permeated the tumor mass, accessed cancer cells and CD90-positive cells, and significantly promoted their entry into CSC fractions in tumors. Moreover, M-CFN treatment profoundly eliminated aldehyde dehydrogenase (ALDH)-expressing CSCs in 4T1 and MCF-7 tumors, produced notable depression of tumor growth and caused 93.86% suppression of lung metastasis in 4T1 models. Therefore, the M2 macrophage microvesicle-inspired nanovehicle provides an encouraging strategy to penetrate the tumor tissues and access these insult cells in tumors for effective cancer therapy. ![]()
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Affiliation(s)
- Yuqi Wang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.,State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xiang Gong
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jie Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Hong Wang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xiaoxuan Xu
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yao Wu
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jiaoying Wang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Siling Wang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.
| | - Yaping Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Zhiwen Zhang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. .,Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, 264000, China.
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9
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Al-Hassan JM, Wei D, Chakraborty S, Conway T, Rhea P, Wei B, Tran M, Gagea M, Afzal M, Oommen S, Nair D, Paul BM, Yang P. Fraction B From Catfish Epidermal Secretions Kills Pancreatic Cancer Cells, Inhibits CD44 Expression and Stemness, and Alters Cancer Cell Metabolism. Front Pharmacol 2021; 12:659590. [PMID: 34349642 PMCID: PMC8326461 DOI: 10.3389/fphar.2021.659590] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 06/10/2021] [Indexed: 01/02/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in western countries. The successful treatment of PDAC remains limited. We investigated the effect of Fraction B, which is a fraction purified from catfish (Arius bilineatus, Val.) skin secretions containing proteins and lipids, on PDAC biology both in-vivo and in-vitro. We report here that Fraction B potently suppressed the proliferation of both human and mouse pancreatic cancer cells in vitro and significantly reduced the growth of their relevant xenograft (Panc02) and orthotopic tumors (human Panc-1 cells) (p < 0.05). The Reverse Phase Protein Array (RPPA) data obtained from the tumor tissues derived from orthotopic tumor bearing mice treated with Fraction B showed that Fraction B altered the cancer stem cells related pathways and regulated glucose and glutamine metabolism. The down-regulation of the cancer stem cell marker CD44 expression was further confirmed in Panc-1 cells. CBC and blood chemistry analyses showed no systemic toxicity in Fraction B treated Panc-1 tumor bearing mice compared to that of control group. Our data support that Fraction B is a potential candidate for PDAC treatment.
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Affiliation(s)
- Jassim M Al-Hassan
- Department of Biological Sciences, Faculty of Science, Kuwait University, Kuwait City, Kuwait
| | - Daoyan Wei
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sharmistha Chakraborty
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Tara Conway
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Patrea Rhea
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Bo Wei
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Megan Tran
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mihai Gagea
- Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Mohammad Afzal
- Department of Biological Sciences, Faculty of Science, Kuwait University, Kuwait City, Kuwait
| | - Sosamma Oommen
- Department of Biological Sciences, Faculty of Science, Kuwait University, Kuwait City, Kuwait
| | - Divya Nair
- Department of Biological Sciences, Faculty of Science, Kuwait University, Kuwait City, Kuwait
| | - Bincy M Paul
- Department of Biological Sciences, Faculty of Science, Kuwait University, Kuwait City, Kuwait
| | - Peiying Yang
- Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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10
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Shen Q, Hill T, Cai X, Bui L, Barakat R, Hills E, Almugaiteeb T, Babu A, Mckernan PH, Zalles M, Battiste JD, Kim YT. Physical confinement during cancer cell migration triggers therapeutic resistance and cancer stem cell-like behavior. Cancer Lett 2021; 506:142-151. [PMID: 33639204 PMCID: PMC8112468 DOI: 10.1016/j.canlet.2021.01.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/22/2020] [Accepted: 01/13/2021] [Indexed: 01/06/2023]
Abstract
Metastasized cancer cells have an increased resistance to therapies leading to a drastic decrease in patient survival rates. However, our understanding of the cause for this enhanced resistance is lacking. In this study, we report that physically tight confinement during cancer cell migration triggers therapeutic resistance and induces cancer stem cell-like behavior including up-regulation in efflux proteins and in cancer stem cell related markers. Moreover, the re-localization of Yes-associated protein (YAP) to the cell nucleus indicated an elevated level of cytoskeletal tension. The increased cytoskeletal tension suggested that mechanical interactions between cancer cells and tight surroundings during metastasis is one of the factors that contributes to therapeutic resistance and acquisition of cancer stem cell (CSC) like features. With this system and supporting data, we are able to study cells with therapeutic resistance and CSC-like properties for the future purpose of developing new strategies for the treatment of metastatic cancer.
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Affiliation(s)
- Qionghua Shen
- Neuroengineering Lab, Department of Bioengineering, University of Texas at Arlington, TX, USA
| | - Tamara Hill
- Neuroengineering Lab, Department of Bioengineering, University of Texas at Arlington, TX, USA
| | - Xue Cai
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, OK, USA
| | - Loan Bui
- Department of Aerospace & Mechanical Engineering, University of Notre Dame, IN, USA
| | - Rami Barakat
- Neuroengineering Lab, Department of Bioengineering, University of Texas at Arlington, TX, USA
| | - Emily Hills
- Neuroengineering Lab, Department of Bioengineering, University of Texas at Arlington, TX, USA
| | | | - Anish Babu
- Department of Neurology, University of Oklahoma Health Sciences Center, OK, USA
| | - Patrick H Mckernan
- Department of Neurology, University of Oklahoma Health Sciences Center, OK, USA
| | | | - James D Battiste
- Department of Neurology, University of Oklahoma Health Sciences Center, OK, USA.
| | - Young-Tae Kim
- Neuroengineering Lab, Department of Bioengineering, University of Texas at Arlington, TX, USA; Department of Urology, UT Southwestern Medical Center, TX, USA.
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11
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Stem Cells an Overview. Stem Cells 2021. [DOI: 10.1007/978-981-16-1638-9_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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12
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Liu Y, Yang M, Luo J, Zhou H. Radiotherapy targeting cancer stem cells "awakens" them to induce tumour relapse and metastasis in oral cancer. Int J Oral Sci 2020; 12:19. [PMID: 32576817 PMCID: PMC7311531 DOI: 10.1038/s41368-020-00087-0] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 06/02/2020] [Accepted: 06/03/2020] [Indexed: 02/05/2023] Open
Abstract
Radiotherapy is one of the most common treatments for oral cancer. However, in the clinic, recurrence and metastasis of oral cancer occur after radiotherapy, and the underlying mechanism remains unclear. Cancer stem cells (CSCs), considered the “seeds” of cancer, have been confirmed to be in a quiescent state in most established tumours, with their innate radioresistance helping them survive more easily when exposed to radiation than differentiated cancer cells. There is increasing evidence that CSCs play an important role in recurrence and metastasis post-radiotherapy in many cancers. However, little is known about how oral CSCs cause tumour recurrence and metastasis post-radiotherapy. In this review article, we will first summarise methods for the identification of oral CSCs and then focus on the characteristics of a CSC subpopulation induced by radiation, hereafter referred to as “awakened” CSCs, to highlight their response to radiotherapy and potential role in tumour recurrence and metastasis post-radiotherapy as well as potential therapeutics targeting CSCs. In addition, we explore potential therapeutic strategies targeting these “awakened” CSCs to solve the serious clinical challenges of recurrence and metastasis in oral cancer after radiotherapy.
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Affiliation(s)
- Yangfan Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Miao Yang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jingjing Luo
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Preventive Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
| | - Hongmei Zhou
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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13
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Exploiting Cancer's Tactics to Make Cancer a Manageable Chronic Disease. Cancers (Basel) 2020; 12:cancers12061649. [PMID: 32580319 PMCID: PMC7352192 DOI: 10.3390/cancers12061649] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/17/2020] [Accepted: 06/19/2020] [Indexed: 12/26/2022] Open
Abstract
The history of modern oncology started around eighty years ago with the introduction of cytotoxic agents such as nitrogen mustard into the clinic, followed by multi-agent chemotherapy protocols. Early success in radiation therapy in Hodgkin lymphoma gave birth to the introduction of radiation therapy into different cancer treatment protocols. Along with better understanding of cancer biology, we developed drugs targeting cancer-related cellular and genetic aberrancies. Discovery of the crucial role of vasculature in maintenance, survival, and growth of a tumor opened the way to the development of anti-angiogenic agents. A better understanding of T-cell regulatory pathways advanced immunotherapy. Awareness of stem-like cancer cells and their role in cancer metastasis and local recurrence led to the development of drugs targeting them. At the same time, sequential and rapidly accelerating advances in imaging and surgical technology have markedly increased our ability to safely remove ≥90% of tumor cells. While we have advanced our ability to kill cells from multiple directions, we have still failed to stop most types of cancer from recurring. Here we analyze the tactics employed in cancer evolution; namely, chromosomal instability (CIN), intra-tumoral heterogeneity (ITH), and cancer-specific metabolism. These tactics govern the resistance to current cancer therapeutics. It is time to focus on maximally delaying the time to recurrence, with drugs that target these fundamental tactics of cancer evolution. Understanding the control of CIN and the optimal state of ITH as the most important tactics in cancer evolution could facilitate the development of improved cancer therapeutic strategies designed to transform cancer into a manageable chronic disease.
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14
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Abstract
The extracellular matrix is part of the microenvironment and its functions are associated with the physical and chemical properties of the tissue. Among the extracellular components, the glycosaminoglycan hyaluronan is a key component, defining both the physical and biochemical characteristics of the healthy matrices. The hyaluronan metabolism is strictly regulated in physiological conditions, but in the tumoral tissues, its expression, size and binding proteins interaction are dysregulated. Hyaluronan from the tumor microenvironment promotes tumor cell proliferation, invasion, immune evasion, stemness alterations as well as drug resistance. This chapter describes data regarding novel concepts of hyaluronan functions in the tumor. Additionally, we discuss potential clinical applications of targeting HA metabolism in cancer therapy.
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15
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Heldin P, Kolliopoulos C, Lin CY, Heldin CH. Involvement of hyaluronan and CD44 in cancer and viral infections. Cell Signal 2019; 65:109427. [PMID: 31654718 DOI: 10.1016/j.cellsig.2019.109427] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 09/19/2019] [Accepted: 09/19/2019] [Indexed: 02/07/2023]
Abstract
Hyaluronan and its major receptor CD44 are ubiquitously distributed. They have important structural as well as signaling roles, regulating tissue homeostasis, and their expression levels are tightly regulated. In addition to signaling initiated by the interaction of the intracellular domain of CD44 with cytoplasmic signaling molecules, CD44 has important roles as a co-receptor for different types of receptors of growth factors and cytokines. Dysregulation of hyaluronan-CD44 interactions is seen in diseases, such as inflammation and cancer. In the present communication, we discuss the mechanism of hyaluronan-induced signaling via CD44, as well as the involvement of hyaluronan-engaged CD44 in malignancies and in viral infections.
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Affiliation(s)
- Paraskevi Heldin
- Department of Medical Biochemistry and Microbiology, Box 582, Uppsala University, SE-751 23 Uppsala, Sweden.
| | - Constantinos Kolliopoulos
- Department of Medical Biochemistry and Microbiology, Box 582, Uppsala University, SE-751 23 Uppsala, Sweden
| | - Chun-Yu Lin
- Department of Medical Biochemistry and Microbiology, Box 582, Uppsala University, SE-751 23 Uppsala, Sweden; Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University Department of Surgery, Uppsala University, Sweden; Department of Surgical Sciences, Uppsala University, Akademiska Hospital, 751 85 Uppsala, Sweden
| | - Carl-Henrik Heldin
- Department of Medical Biochemistry and Microbiology, Box 582, Uppsala University, SE-751 23 Uppsala, Sweden.
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16
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Chowdhury FN, Reisinger J, Gomez KE, Chimed TS, Thomas CM, Le PN, Miller B, Morton JJ, Nieto CM, Somerset HL, Wang XJ, Keysar SB, Jimeno A. Leading edge or tumor core: Intratumor cancer stem cell niches in oral cavity squamous cell carcinoma and their association with stem cell function. Oral Oncol 2019; 98:118-124. [PMID: 31586893 DOI: 10.1016/j.oraloncology.2019.09.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 09/02/2019] [Accepted: 09/10/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVES To describe differences in cancer stem cell (CSC) presence and behavior associated with their intratumor compartment of origin using a patient-derived xenograft (PDX) model of oral cavity squamous cell carcinoma (OCSCC). MATERIALS AND METHODS Four HPV-negative OCSCC PDX cases were selected (CUHN004, CUHN013, CUHN096, CUHN111) and the percentage of CSCs (ALDH+CD44high) was measured in the tumor Leading Edge (LE) and Core compartments of each PDX tumor case via fluorescence activated cell sorting (FACS). The fraction of cells in the proliferative phase was measured by Ki-67 labelling index of paraffin embedded tissue. The proliferation and invasion of LE versus Core CSCs were compared using sphere and Matrigel invasion assays, respectively. RESULTS Both CUHN111 and CUHN004 demonstrate CSC enrichment in their LE compartments while CUHN013 and CUHN096 show no intratumor difference. Cases with LE CSC enrichment demonstrate greater Ki-67 labelling at the LE. CSC proliferative potential, assessed by sphere formation, reveals greater sphere formation in CUHN111 LE CSCs, but no difference between CUHN013 LE and Core CSCs. CUHN111 CSCs do not demonstrate an intratumor difference in invasiveness while CUHN013 LE CSCs are more invasive than Core CSCs. CONCLUSION A discrete intratumor CSC niche is present in a subset of OCSCC PDX tumors. The CSC functional phenotype with regard to proliferation and invasion is associated with the intratumor compartment of origin of the CSC: LE or Core. These individual functional characteristics appear to be modulated independently of one another and independently of the presence of an intratumor CSC niche.
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Affiliation(s)
- Farshad N Chowdhury
- Department of Otolaryngology, University of Colorado Denver School of Medicine (UCDSOM), Aurora, CO 80045, USA
| | - Julie Reisinger
- Division of Medical Oncology, Department of Medicine, UCDSOM, Aurora, CO 80045, USA
| | - Karina E Gomez
- Division of Medical Oncology, Department of Medicine, UCDSOM, Aurora, CO 80045, USA
| | - Tugs-Saikhan Chimed
- Division of Medical Oncology, Department of Medicine, UCDSOM, Aurora, CO 80045, USA
| | - Carissa M Thomas
- Department of Otolaryngology - Head and Neck Surgery, University of Toronto, University Health Network/Princess Margaret Cancer Centre, Toronto, ON M4Y 2X5, Canada
| | - Phuong N Le
- Division of Medical Oncology, Department of Medicine, UCDSOM, Aurora, CO 80045, USA
| | - Bettina Miller
- Division of Medical Oncology, Department of Medicine, UCDSOM, Aurora, CO 80045, USA
| | - John J Morton
- Division of Medical Oncology, Department of Medicine, UCDSOM, Aurora, CO 80045, USA
| | - Cera M Nieto
- Division of Medical Oncology, Department of Medicine, UCDSOM, Aurora, CO 80045, USA
| | | | | | - Stephen B Keysar
- Division of Medical Oncology, Department of Medicine, UCDSOM, Aurora, CO 80045, USA.
| | - Antonio Jimeno
- Department of Otolaryngology, University of Colorado Denver School of Medicine (UCDSOM), Aurora, CO 80045, USA; Division of Medical Oncology, Department of Medicine, UCDSOM, Aurora, CO 80045, USA.
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17
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Hu M, Xie P, Lee NY, Li M, Ho F, Lian M, Zhao S, Yang G, Fu Z, Zheng J, Ma L, Yu J. Hypoxia with 18F-fluoroerythronitroimidazole integrated positron emission tomography and computed tomography (18F-FETNIM PET/CT) in locoregionally advanced head and neck cancer: Hypoxia changes during chemoradiotherapy and impact on clinical outcome. Medicine (Baltimore) 2019; 98:e17067. [PMID: 31577699 PMCID: PMC6783245 DOI: 10.1097/md.0000000000017067] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Hypoxia is a well-recognized biological characteristic to therapy resistance and negative prognostic factor in patients with head and neck squamous cell carcinoma (HNSCC). This study aims to investigate the changes of hypoxia measured by F-fluoroerythronitroimidazole (FETNIM) uptake on integrated positron emission tomography and computed tomography (PET/CT) during chemoradiotherapy and its prognostic value of clinical outcome in locoregionally advanced HNSCC.Thirty-two patients with locoregionally advanced HNSCC who received definitive treatment with concurrent chemoradiotherapy underwent FETNIM PET/CT scans before and after 5 weeks of treatment. The intensity of hypoxia using the maximum standardized uptake value (SUVmax) was evaluated both on primary lesion and metastatic lymph node (MLN). The pre-SUVmax and mid-SUVmax were defined as SUVmax on pre- and mid-FETNIM PET/CT. The local control (LC), regional control (RC), distant metastatic-free survival (DMFS), and overall survival (OS) were collected in patient follow-ups.Mid-SUVmax decreased significantly both in the primary tumor (t = 8.083, P < .001) and MLN (t = 6.808, P < .001) compared to pre-SUVmax. With a median follow-up of 54 months, the 5-year LC, RC, DMFS, and OS rates were 55%, 66.7%, 64.7%, and 55%, respectively, for all of the patients. On univariate analysis, patients with high pre-SUVmax in primary tumor had significantly worse LC (56.3% vs 87.5%, P = .046) and OS (43.8% vs 87.5%, P = .023) than other patients. Patients with high mid-SUVmax had significantly worse DMFS (50% vs 84.6%, P = .049) and OS (33.3% vs 73.1%, P = .028) than other patients. The tumor grade and mid-SUVmax were the significant predictors of OS on multivariate analysis.In this study, hypoxia in tumor significantly decreased during chemoradiotherapy. The persistent hypoxia predicted poor OS. The data provided evidence that FETNIM PET/CT could be used dynamically for selecting appropriate patients and optimal timing of hypoxia-adapted therapeutic regimens.
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Affiliation(s)
- Man Hu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Peng Xie
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Nancy Y. Lee
- Departments of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Min Li
- Department of Radiology, General Hospital of Jinan Military Command
| | - Felix Ho
- Departments of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Ming Lian
- Departments of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Shuqiang Zhao
- Department of Nuclear Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Guoren Yang
- Department of Nuclear Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Zheng Fu
- Department of Nuclear Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jinsong Zheng
- Department of Nuclear Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Li Ma
- Department of Nuclear Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
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Herheliuk T, Perepelytsina O, Ugnivenko A, Ostapchenko L, Sydorenko M. Investigation of multicellular tumor spheroids enriched for a cancer stem cell phenotype. Stem Cell Investig 2019; 6:21. [PMID: 31559308 DOI: 10.21037/sci.2019.06.07] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 06/12/2019] [Indexed: 12/12/2022]
Abstract
Background Cancer stem cells (CSCs) provide self-renewal of the tumor after radiation and chemotherapy. These cells are important during tumor development. The in vitro model of avascular tumor that enriched of cells with stem like characteristics is critical to understanding of the role CSCs in the tumor. Methods Cell viability was evaluated by MTT assay. The expression of cancer stem cells markers (CD133, CD44, CD24 and bmi-1) in 2D cell culture and multicellular tumor spheroids (MCTS) of MCF-7 cells was evaluated. The Stemi2000 software AxioVisionRed 4.7 was used for image processing. The volume of spheroids was calculated by Bjerkvig formula. Results The highest expression of CD133, CD44, CD24 and bmi-1 receptors was detected in MCTS, enriched with cancer stem cells (eMCTS). Cell aggregates of eMCTS culture were returned from suspension to adhesive conditions. It was found that the cells of the MCTS surface layers were enriched with CD133, CD44, CD24, bmi-1, EpCAM, vim markers, but not adherent cells. eMCTS are less sensitive to anticancer drugs (cisplatin, methotrexate and doxorubicin), than adhesive cell culture and MCTS cultured under standard conditions in a complete nutrient medium (P<0.05). Conclusions We observed that eMCTS population possesses aggressive phenotypic characteristics such as invasion, cancer stem cell markers and chemoresistance. eMCTS model could improve the screening efficiency of therapeutical agents against CSCs.
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Affiliation(s)
- Tetiana Herheliuk
- Department of Biotechnical Problems of Diagnostics, Institute for Problems of Cryobiology and Cryomedicine, National Academy of Science of Ukraine, 03028, Kyiv, Ukraine.,Educational and Scientific Centre "Institute of Biology & Medicine", 03187, Kyiv, Ukraine
| | - Olena Perepelytsina
- Department of Biotechnical Problems of Diagnostics, Institute for Problems of Cryobiology and Cryomedicine, National Academy of Science of Ukraine, 03028, Kyiv, Ukraine
| | - Andriy Ugnivenko
- Department of Biotechnical Problems of Diagnostics, Institute for Problems of Cryobiology and Cryomedicine, National Academy of Science of Ukraine, 03028, Kyiv, Ukraine
| | - Lyudmila Ostapchenko
- Educational and Scientific Centre "Institute of Biology & Medicine", 03187, Kyiv, Ukraine
| | - Mykhailo Sydorenko
- Department of Biotechnical Problems of Diagnostics, Institute for Problems of Cryobiology and Cryomedicine, National Academy of Science of Ukraine, 03028, Kyiv, Ukraine
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Műzes G, Sipos F. Issues and opportunities of stem cell therapy in autoimmune diseases. World J Stem Cells 2019; 11:212-221. [PMID: 31110602 PMCID: PMC6503459 DOI: 10.4252/wjsc.v11.i4.212] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 01/23/2019] [Accepted: 03/12/2019] [Indexed: 02/06/2023] Open
Abstract
The purpose of regenerative medicine is to restore or enhance the normal function of human cells, tissues, and organs. From a clinical point of view, the use of stem cells is more advantageous than differentiated cells because they can be collected more easily and in larger quantities, their proliferation capacity is more pronounced, they are more resistant in cell culture, their aging is delayed, they are able to form a number of cell lines, and they are able to promote vascularization of tissue carriers. The therapeutic use of stem cells for disease modification, immunomodulation, or regenerative purposes are undoubtedly encouraging, but most studies are still in their early stages, and the clinical results reported are not clear with regard to therapeutic efficacy and potential side effects. Uniform regulation of the clinical application of stem cells is also indispensable for this highly customizable, minimally invasive, individualized therapeutic method to become a successful and safe treatment alternative in many different autoimmune and autoinflammatory disorders.
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Affiliation(s)
- Györgyi Műzes
- Immunology Team, 2 Department of Internal Medicine, Semmelweis University, Szentkirályi Street 46, Budapest 1088, Hungary
| | - Ferenc Sipos
- Immunology Team, 2 Department of Internal Medicine, Semmelweis University, Szentkirályi Street 46, Budapest 1088, Hungary.
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20
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Brown Y, Hua S, Tanwar PS. Extracellular matrix-mediated regulation of cancer stem cells and chemoresistance. Int J Biochem Cell Biol 2019; 109:90-104. [DOI: 10.1016/j.biocel.2019.02.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 02/03/2019] [Accepted: 02/05/2019] [Indexed: 12/12/2022]
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Herheliuk T, Perepelytsina O, Ostapchenko L, Sydorenko M. Effect of Interferon α-2b on Multicellular Tumor Spheroids of MCF-7 Cell Line Enriched with Cancer Stem Cells. INNOVATIVE BIOSYSTEMS AND BIOENGINEERING 2019. [DOI: 10.20535/ibb.2019.3.1.157388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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22
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Abstract
The survival, proliferation, and differentiation of cells in culture are determined not only by their intrinsic potential but also by cues provided by the permissive or restrictive microenvironment in which they reside. The robustness and reproducibility of cell culture assays and endpoints relies on the stability of that microenvironment and vigilant attention to the control of variables that affect cell behavior during culture. These often underappreciated variables include, but are not limited to, medium pH and buffering, osmolarity, composition of the gas phase, the timing and periodicity of refeeding and subculture, and the impact of fluctuations in temperature and gas phase composition on frequent opening and closing of incubator doors. This chapter briefly describes the impact of these and other variables on the behavior of cultured cells.
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HIC1 and RassF1A Methylation Attenuates Tubulin Expression and Cell Stiffness in Cancer. Int J Mol Sci 2018; 19:ijms19102884. [PMID: 30249017 PMCID: PMC6212922 DOI: 10.3390/ijms19102884] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 09/19/2018] [Indexed: 12/12/2022] Open
Abstract
Cell stiffness is a potential biomarker for monitoring cellular transformation, metastasis, and drug resistance development. Environmental factors relayed into the cell may result in formation of inheritable markers (e.g., DNA methylation), which provide selectable advantages (e.g., tumor development-favoring changes in cell stiffness). We previously demonstrated that targeted methylation of two tumor suppressor genes, hypermethylated in cancer 1 (HIC1) and Ras-association domain family member 1A (RassF1A), transformed mesenchymal stem cells (MSCs). Here, transformation-associated cytoskeleton and cell stiffness changes were evaluated. Atomic force microscopy (AFM) was used to detect cell stiffness, and immunostaining was used to measure cytoskeleton expression and distribution in cultured cells as well as in vivo. HIC1 and RassF1A methylation (me_HR)-transformed MSCs developed into tumors that clonally expanded in vivo. In me_HR-transformed MSCs, cell stiffness was lost, tubulin expression decreased, and F-actin was disorganized; DNA methylation inhibitor treatment suppressed their tumor progression, but did not fully restore their F-actin organization and stiffness. Thus, me_HR-induced cell transformation was accompanied by the loss of cellular stiffness, suggesting that somatic epigenetic changes provide inheritable selection markers during tumor propagation, but inhibition of oncogenic aberrant DNA methylation cannot restore cellular stiffness fully. Therefore, cell stiffness is a candidate biomarker for cells' physiological status.
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24
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Al-Hashimi F, J. Diaz-Cano S. Multi-target analysis of neoplasms for the evaluation of tumor progression: stochastic approach of biologic processes. AIMS MOLECULAR SCIENCE 2018. [DOI: 10.3934/molsci.2018.1.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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25
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Lisson CS, Lisson CG, Flosdorf K, Mayer-Steinacker R, Schultheiss M, von Baer A, Barth TFE, Beer AJ, Baumhauer M, Meier R, Beer M, Schmidt SA. Diagnostic value of MRI-based 3D texture analysis for tissue characterisation and discrimination of low-grade chondrosarcoma from enchondroma: a pilot study. Eur Radiol 2017; 28:468-477. [DOI: 10.1007/s00330-017-5014-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 07/20/2017] [Accepted: 08/01/2017] [Indexed: 01/21/2023]
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26
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Archer LK, Frame FM, Maitland NJ. Stem cells and the role of ETS transcription factors in the differentiation hierarchy of normal and malignant prostate epithelium. J Steroid Biochem Mol Biol 2017; 166:68-83. [PMID: 27185499 DOI: 10.1016/j.jsbmb.2016.05.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 04/25/2016] [Accepted: 05/07/2016] [Indexed: 12/18/2022]
Abstract
Prostate cancer is the most common cancer of men in the UK and accounts for a quarter of all new cases. Although treatment of localised cancer can be successful, there is no cure for patients presenting with invasive prostate cancer and there are less treatment options. They are generally treated with androgen-ablation therapies but eventually the tumours become hormone resistant and patients develop castration-resistant prostate cancer (CRPC) for which there are no further successful or curative treatments. This highlights the need for new treatment strategies. In order to prevent prostate cancer recurrence and treatment resistance, all the cell populations in a heterogeneous prostate tumour must be targeted, including the rare cancer stem cell (CSC) population. The ETS transcription factor family members are now recognised as a common feature in multiple cancers including prostate cancer; with aberrant expression, loss of tumour suppressor function, inactivating mutations and the formation of fusion genes observed. Most notably, the TMPRSS2-ERG gene fusion is present in approximately 50% of prostate cancers and in prostate CSCs. However, the role of other ETS transcription factors in prostate cancer is less well understood. This review will describe the prostate epithelial cell hierarchy and discuss the evidence behind prostate CSCs and their inherent resistance to conventional cancer therapies. The known and proposed roles of the ETS family of transcription factors in prostate epithelial cell differentiation and regulation of the CSC phenotype will be discussed, as well as how they might be targeted for therapy.
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Affiliation(s)
- Leanne K Archer
- Cancer Research Unit, Department of Biology, University of York, York, YO10 5DD, United Kingdom
| | - Fiona M Frame
- Cancer Research Unit, Department of Biology, University of York, York, YO10 5DD, United Kingdom
| | - Norman J Maitland
- Cancer Research Unit, Department of Biology, University of York, York, YO10 5DD, United Kingdom.
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27
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Melzer C, von der Ohe J, Lehnert H, Ungefroren H, Hass R. Cancer stem cell niche models and contribution by mesenchymal stroma/stem cells. Mol Cancer 2017; 16:28. [PMID: 28148265 PMCID: PMC5286787 DOI: 10.1186/s12943-017-0595-x] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 01/18/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The initiation and progression of malignant tumors is driven by distinct subsets of tumor-initiating or cancer stem-like cells (CSCs) which develop therapy/apoptosis resistance and self-renewal capacity. In order to be able to eradicate these CSCs with novel classes of anti-cancer therapeutics, a better understanding of their biology and clinically-relevant traits is mandatory. MAIN BODY Several requirements and functions of a CSC niche physiology are combined with current concepts for CSC generation such as development in a hierarchical tumor model, by stochastic processes, or via a retrodifferentiation program. Moreover, progressive adaptation of endothelial cells and recruited immune and stromal cells to the tumor site substantially contribute to generate a tumor growth-permissive environment resembling a CSC niche. Particular emphasis is put on the pivotal role of multipotent mesenchymal stroma/stem cells (MSCs) in supporting CSC development by various kinds of interaction and cell fusion to form hybrid tumor cells. CONCLUSION A better knowledge of CSC niche physiology may increase the chances that cancer stemness-depleting interventions ultimately result in arrest of tumor growth and metastasis.
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Affiliation(s)
- Catharina Melzer
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, Medical University Hannover, Carl-Neuberg-Str. 1, D – 30625 Hannover, Germany
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, Medical University Hannover, Carl-Neuberg-Str. 1, D – 30625 Hannover, Germany
| | - Hendrik Lehnert
- First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, Lübeck, Germany
| | - Hendrik Ungefroren
- First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, Lübeck, Germany
- Department of General, Visceral-, Thoracic-Transplantation- and Pediatric Surgery, UKSH, Campus Kiel, Kiel, Germany
| | - Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, Medical University Hannover, Carl-Neuberg-Str. 1, D – 30625 Hannover, Germany
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28
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Qin H, Bao D, Tong X, Hu Q, Sun G, Huang X. The role of stem cells in benign tumors. Tumour Biol 2016; 37:15349–15357. [PMID: 27655284 DOI: 10.1007/s13277-016-5370-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Accepted: 09/08/2016] [Indexed: 12/15/2022] Open
Abstract
As stem cells contribute to the development and homeostasis of normal adult tissues, malfunction of stem cells in self-renewal and differentiation has been associated with tumorigenesis. A growing number of evidences indicating that tumor initiating cells play a crucial role, not only in malignancies, but also in generation and development of benign tumors. Here we offer an overview of the identification and functional characterization of benign tumor initiating cells in several tissues and organs, which typically show capacities of uncontrolled self-renewal to fuel the tumor growth and abnormal differentiation to give rise to tumor heterogeneity. They may originate from alteration of normal stem cells, which confer the benign tumor initiating cells with different repertoire of "stemness". The plastic functions of benign tumor initiating cells are determined by niche regulation mediated via several signaling and epigenetic cues. Therefore, targeting stem cell function represents an important strategy for understanding the biology and management of benign tumors.
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Affiliation(s)
- Haiyan Qin
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008, People's Republic of China.
- Nanjing Key Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008, People's Republic of China.
| | - Dongyu Bao
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008, People's Republic of China
- Nanjing Key Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008, People's Republic of China
| | - Xin Tong
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008, People's Republic of China
| | - Qingang Hu
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008, People's Republic of China
| | - Guowen Sun
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008, People's Republic of China
| | - Xiaofeng Huang
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, 210008, People's Republic of China
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29
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Wei Q, Tang YJ, Voisin V, Sato S, Hirata M, Whetstone H, Han I, Ailles L, Bader GD, Wunder J, Alman BA. Identification of CD146 as a marker enriched for tumor-propagating capacity reveals targetable pathways in primary human sarcoma. Oncotarget 2016; 6:40283-94. [PMID: 26517673 PMCID: PMC4741895 DOI: 10.18632/oncotarget.5375] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 08/28/2015] [Indexed: 01/24/2023] Open
Abstract
Tumor-propagating cells (TPCs) are believed to drive cancer initiation, progression and recurrence. These cells are characterized by enhanced tumorigenicity and self-renewal. The ability to identify such cells in primary human sarcomas relies on the dye exclusion ability of tumor side population (SP) cells. Here, we performed a high-throughput cell surface antigen screen and found that CD146 is enriched in the SP population. In vivo serial transplantation assays showed that CD146+ cells are highly tumorigenic, capable of self-renewal and thus enriches for the TPC population. In addition, depletion of SP cells from the CD146+ population show that CD146+ cells and SP cells are a distinct and overlapping TPC populations. Gene expression profiling of CD146+ and SP cells revealed multiple pathways commonly upregulated in both of these populations. Inhibition of one of these upregulated pathways, Notch signaling, significantly reduced tumor growth and self-renewal. Our data demonstrate that CD146 is an effective cell surface marker for enriching TPCs in primary human sarcomas. Targeting differentially activated pathways in TPCs may provide new therapeutic strategies for treating sarcoma.
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Affiliation(s)
- Qingxia Wei
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
| | - Yuning J Tang
- Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.,Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | | | - Shingo Sato
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
| | - Makoto Hirata
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
| | - Heather Whetstone
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
| | - Ilkyu Han
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
| | - Laurie Ailles
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Gary D Bader
- The Donnelly Centre, University of Toronto, Toronto, ON, Canada.,Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Jay Wunder
- Samuel Lunenfeld Research Institute, Division of Orthopaedic Surgery, Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada.,University Musculoskeletal Oncology Unit, Division of Orthopaedic Surgery, Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada
| | - Benjamin A Alman
- Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.,Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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30
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Carnero A, Lleonart M. The hypoxic microenvironment: A determinant of cancer stem cell evolution. Bioessays 2016; 38 Suppl 1:S65-74. [DOI: 10.1002/bies.201670911] [Citation(s) in RCA: 133] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 10/28/2015] [Accepted: 10/29/2015] [Indexed: 12/18/2022]
Affiliation(s)
- Amancio Carnero
- Oncohematology and Genetic Department, Molecular Biology of Cancer Group; Instituto de Biomedicina de Sevilla (IBIS/HUVR/CSIC/Universidad de Sevilla); Seville Spain
| | - Matilde Lleonart
- Pathology Department, Oncology and Pathology Group; Institut de Recerca Hospital Vall d'Hebron; Barcelona Spain
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31
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Som A, Bloch S, Ippolito JE, Achilefu S. Acidic extracellular pH of tumors induces octamer-binding transcription factor 4 expression in murine fibroblasts in vitro and in vivo. Sci Rep 2016; 6:27803. [PMID: 27302093 PMCID: PMC4908587 DOI: 10.1038/srep27803] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 05/20/2016] [Indexed: 12/22/2022] Open
Abstract
Octamer-binding transcription factor 4 (OCT-4) is an important marker of cellular de-differentiation that can be induced by environmental stressors, such as acidity. Here we demonstrate that chronic acidic stress in solid tumors induced OCT-4 expression in fibroblasts and other stromal cells in four tumor models. The results have implications for how tumors utilize pH modulation to recruit associated stromal cells, induce partial reprogramming of tumor-associated stromal cells, and respond to therapy.
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Affiliation(s)
- Avik Som
- Department of Radiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, 63110, USA.,Department of Biomedical Engineering, Washington University in St. Louis School of Medicine, St. Louis, Missouri, 63110, USA
| | - Sharon Bloch
- Department of Radiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, 63110, USA
| | - Joseph E Ippolito
- Department of Radiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, 63110, USA.,Department of Genetics, Washington University in St. Louis School of Medicine, St. Louis, Missouri, 63110, USA
| | - Samuel Achilefu
- Department of Radiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, 63110, USA.,Department of Biomedical Engineering, Washington University in St. Louis School of Medicine, St. Louis, Missouri, 63110, USA.,Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis School of Medicine, St. Louis, Missouri, 63110, USA
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32
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Yao T, Lu R, Zhang Y, Zhang Y, Zhao C, Lin R, Lin Z. Cervical cancer stem cells. Cell Prolif 2016; 48:611-25. [PMID: 26597379 DOI: 10.1111/cpr.12216] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Accepted: 07/18/2015] [Indexed: 12/13/2022] Open
Abstract
The concept of cancer stem cells (CSC) has been established over the past decade or so, and their role in carcinogenic processes has been confirmed. In this review, we focus on cervical CSCs, including (1) their purported origin, (2) markers used for cervical CSC identification, (3) alterations to signalling pathways in cervical cancer and (4) the cancer stem cell niche. Although cervical CSCs have not yet been definitively identified and characterized, future studies pursuing them as therapeutic targets may provide novel insights for treatment of cervical cancer.
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Affiliation(s)
- Tingting Yao
- Department of Gynecological Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.,Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen University, Guangzhou, 510120, China
| | - Rongbiao Lu
- Department of Dermatology and Venereology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, China
| | - Yizhen Zhang
- Department of Clinical Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Ya Zhang
- Department of Clinical Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Chenyang Zhao
- Department of Clinical Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Rongchun Lin
- Department of Gynecological Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Zhongqiu Lin
- Department of Gynecological Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
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33
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Abstract
Based on an analysis of a large number of sources of literature, the paper gives general information on the markers for cancer stem cells (CSCs), which allow the detection of this rare cell subpopulation, on the possibilities of estimating their immunohistochemical or immunofluorescent expression in tumors, and on the prognostic and predictive values of these molecules. For their detection, investigators generally use definite molecules, the so-called markers of CSCs, among which there are CD44, CD133, CD24, aldehyde dehydrogenase, and others. The expression of these molecules in the tumor tissue obtained from patients affects survival rates and permits the prediction of a response to therapy. A better insight into the immunophenotype of CSCs, the role of CSC markers in retaining the special properties of this call population, and the clinical significance of the expression of CSC markers will be able to elaborate new approaches to therapy for malignancies.
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Affiliation(s)
- M V Puchinskaya
- Belarusian State Medical University, Minsk, Republic of Belarus
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34
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Kokubu Y, Tabu K, Muramatsu N, Wang W, Murota Y, Nobuhisa I, Jinushi M, Taga T. Induction of protumoral CD11chighmacrophages by glioma cancer stem cells through GM-CSF. Genes Cells 2016; 21:241-51. [DOI: 10.1111/gtc.12333] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 11/29/2015] [Indexed: 12/29/2022]
Affiliation(s)
- Yasuhiro Kokubu
- Department of Stem Cell Regulation; Medical Research Institute, Tokyo Medical and Dental University (TMDU); 1-5-45, Yushima Bunkyo-ku Tokyo 113-8510 Japan
| | - Kouichi Tabu
- Department of Stem Cell Regulation; Medical Research Institute, Tokyo Medical and Dental University (TMDU); 1-5-45, Yushima Bunkyo-ku Tokyo 113-8510 Japan
| | - Nozomi Muramatsu
- Department of Stem Cell Regulation; Medical Research Institute, Tokyo Medical and Dental University (TMDU); 1-5-45, Yushima Bunkyo-ku Tokyo 113-8510 Japan
| | - Wenqian Wang
- Department of Stem Cell Regulation; Medical Research Institute, Tokyo Medical and Dental University (TMDU); 1-5-45, Yushima Bunkyo-ku Tokyo 113-8510 Japan
| | - Yoshitaka Murota
- Department of Stem Cell Regulation; Medical Research Institute, Tokyo Medical and Dental University (TMDU); 1-5-45, Yushima Bunkyo-ku Tokyo 113-8510 Japan
| | - Ikuo Nobuhisa
- Department of Stem Cell Regulation; Medical Research Institute, Tokyo Medical and Dental University (TMDU); 1-5-45, Yushima Bunkyo-ku Tokyo 113-8510 Japan
| | - Masahisa Jinushi
- Research Center for Infection-Associated Cancer; Institute for Genetic Medicine, Hokkaido University; Kita 15, Nishi 7, Kita-ku Sapporo Hokkaido 060-0815 Japan
- Institute for Advanced Medical Research, Keio University School of Medicine; Shinano-machi 35 Shinjuku-ku Tokyo 160-8582 Japan
| | - Tetsuya Taga
- Department of Stem Cell Regulation; Medical Research Institute, Tokyo Medical and Dental University (TMDU); 1-5-45, Yushima Bunkyo-ku Tokyo 113-8510 Japan
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35
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Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 2016; 16:225-38. [PMID: 25748930 DOI: 10.1016/j.stem.2015.02.015] [Citation(s) in RCA: 1156] [Impact Index Per Article: 128.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cancer stem cells (CSCs) are tumor cells that have the principal properties of self-renewal, clonal tumor initiation capacity, and clonal long-term repopulation potential. CSCs reside in niches, which are anatomically distinct regions within the tumor microenvironment. These niches maintain the principle properties of CSCs, preserve their phenotypic plasticity, protect them from the immune system, and facilitate their metastatic potential. In this perspective, we focus on the CSC niche and discuss its contribution to tumor initiation and progression. Since CSCs survive many commonly employed cancer therapies, we examine the prospects of targeting the niche components as preferable therapeutic targets.
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Affiliation(s)
- Vicki Plaks
- Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA
| | - Niwen Kong
- Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA
| | - Zena Werb
- Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA.
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36
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Abstract
Stem cells possess the extraordinary capacity of self-renewal and differentiation to various cell types, thus to form original tissues and organs. Stem cell heterogeneity including genetic and nongenetic mechanisms refers to biological differences amongst normal and stem cells originated within the same tissue. Cell differentiation hierarchy and stochasticity in gene expression and signaling pathways may result in phenotypic differences of stem cells. The maintenance of stemness and activation of differentiation potential are fundamentally orchestrated by microenvironmental stem cell niche-related cellular and humoral signals.
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Affiliation(s)
- Györgyi Műzes
- 2nd Department of Medicine, Immunology Division, Semmelweis University, Szentkirályi u. 46., Budapest, 1088, Hungary.
| | - Ferenc Sipos
- 2nd Department of Medicine, Immunology Division, Semmelweis University, Szentkirályi u. 46., Budapest, 1088, Hungary
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37
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[Cancer stem cells: Radiotherapeutic features and therapeutic targets]. Bull Cancer 2015; 103:48-54. [PMID: 26702506 DOI: 10.1016/j.bulcan.2015.10.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 10/27/2015] [Accepted: 10/30/2015] [Indexed: 02/08/2023]
Abstract
Recent evidences suggest that many types of cancers contain a cell population presenting stem cell properties. While the great majority of tumor cells are destined to differentiate, and eventually stop dividing, only a minority population of cells, termed cancer stem cells (CSCs), possesses extensive self-renewal capability and can recapitulate tumor pathophysiology in an immune-compromised animal model. Tumor initiating cells have been identified and isolated in many tumor types including brain, colon and prostate. They are virtually resistant to radiation and may contribute to treatment resistance and recurrence. Therefore, therapies specifically targeting CSCs will likely be needed for complete tumor eradication. The present study reviews published reports identifying the mechanisms of radioresistance of CSCs and potential targets based on the pathways of self-renewal. Further elucidation of pathways that regulate CSCs may provide insights into the development of novel innovative therapies.
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38
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Vinogradova TV, Chernov IP, Monastyrskaya GS, Kondratyeva LG, Sverdlov ED. Cancer Stem Cells: Plasticity Works against Therapy. Acta Naturae 2015; 7:46-55. [PMID: 26798491 PMCID: PMC4717249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Great successes in identification and deciphering of mechanisms of the adult stem cells regulation have given rise to the idea that stem cells can also function in tumors as central elements of their development, starting from the initial stage and continuing until metastasis. Such cells were called cancer stem cells (CSCs). Over the course of intense discussion, the CSCs hypothesis gradually began to be perceived as an obvious fact. Recently, the existence of CSCs has been indeed confirmed in a number of works. However, when are CSCs universal prerequisites of tumors and to what extent their role is essential for tumor evolution remains an issue far from resolved. Likewise, the problem of potential use of CSCs as therapeutic targets remains unsolved. The present review attempts to analyze the issue of cancer stem cells and the potential of targeting them in tumor therapy.
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Affiliation(s)
- T. V. Vinogradova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
| | - I. P. Chernov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
| | - G. S. Monastyrskaya
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
| | - L. G. Kondratyeva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
| | - E. D. Sverdlov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
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39
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Tirinato L, Liberale C, Di Franco S, Candeloro P, Benfante A, La Rocca R, Potze L, Marotta R, Ruffilli R, Rajamanickam VP, Malerba M, De Angelis F, Falqui A, Carbone E, Todaro M, Medema JP, Stassi G, Di Fabrizio E. Lipid droplets: a new player in colorectal cancer stem cells unveiled by spectroscopic imaging. Stem Cells 2015; 33:35-44. [PMID: 25186497 PMCID: PMC4311668 DOI: 10.1002/stem.1837] [Citation(s) in RCA: 179] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Accepted: 08/12/2014] [Indexed: 12/14/2022]
Abstract
The cancer stem cell (CSC) model is describing tumors as a hierarchical organized system and CSCs are suggested to be responsible for cancer recurrence after therapy. The identification of specific markers of CSCs is therefore of paramount importance. Here, we show that high levels of lipid droplets (LDs) are a distinctive mark of CSCs in colorectal (CR) cancer. This increased lipid content was clearly revealed by label-free Raman spectroscopy and it directly correlates with well-accepted CR-CSC markers as CD133 and Wnt pathway activity. By xenotransplantation experiments, we have finally demonstrated that CR-CSCs overexpressing LDs retain most tumorigenic potential. A relevant conceptual advance in this work is the demonstration that a cellular organelle, the LD, is a signature of CSCs, in addition to molecular markers. A further functional characterization of LDs could lead soon to design new target therapies against CR-CSCs. Stem Cells2015;33:35–44
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Affiliation(s)
- Luca Tirinato
- PSE Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia; BioNEM Lab, Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy
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Yan Y, Zuo X, Wei D. Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target. Stem Cells Transl Med 2015; 4:1033-1043. [PMID: 26136504 PMCID: PMC4542874 DOI: 10.5966/sctm.2015-0048] [Citation(s) in RCA: 463] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 05/26/2015] [Indexed: 12/12/2022] Open
Abstract
UNLABELLED The reception and integration of the plethora of signals a cell receives from its microenvironment determines the cell's fate. CD44 functions as a receptor for hyaluronan and many other extracellular matrix components, as well as a cofactor for growth factors and cytokines, and thus, CD44 is a signaling platform that integrates cellular microenvironmental cues with growth factor and cytokine signals and transduces signals to membrane-associated cytoskeletal proteins or to the nucleus to regulate a variety of gene expression levels related to cell-matrix adhesion, cell migration, proliferation, differentiation, and survival. Accumulating evidence indicates that CD44, especially CD44v isoforms, are cancer stem cell (CSC) markers and critical players in regulating the properties of CSCs, including self-renewal, tumor initiation, metastasis, and chemoradioresistance. Furthermore, there is ample evidence that CD44, especially CD44v isoforms, are valuable prognostic markers in various types of tumors. Therefore, therapies that target CD44 may destroy the CSC population, and this holds great promise for the cure of life-threatening cancers. However, many challenges remain to determining how best to use CD44 as a biomarker and therapeutic target. Here we summarize the current findings concerning the critical role of CD44/CD44v in the regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer. We also discuss the current challenges and future directions that may lead to the best use of CD44/CD44v for clinical applications. SIGNIFICANCE Mounting evidence indicates that cancer stem cells (CSCs) are mainly responsible for cancer aggressiveness, drug resistance, and tumor relapse. CD44, especially CD44v isoforms, have been identified as CSC surface markers for isolating and enriching CSCs in different types of cancers. The current findings concerning the critical role of CD44/CD44v in regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer are summarized. The current challenges and future directions that may lead to best use of CD44/CD44v for clinical applications are also discussed.
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Affiliation(s)
- Yongmin Yan
- Departments of Gastroenterology, Hepatology & Nutrition and Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; School of Medical Sciences and Laboratory Medicine, Jiangsu University, Zhenjiang, People's Republic of China
| | - Xiangsheng Zuo
- Departments of Gastroenterology, Hepatology & Nutrition and Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; School of Medical Sciences and Laboratory Medicine, Jiangsu University, Zhenjiang, People's Republic of China
| | - Daoyan Wei
- Departments of Gastroenterology, Hepatology & Nutrition and Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; School of Medical Sciences and Laboratory Medicine, Jiangsu University, Zhenjiang, People's Republic of China
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41
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Eckert RL, Fisher ML, Grun D, Adhikary G, Xu W, Kerr C. Transglutaminase is a tumor cell and cancer stem cell survival factor. Mol Carcinog 2015; 54:947-58. [PMID: 26258961 DOI: 10.1002/mc.22375] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 07/06/2015] [Accepted: 07/09/2015] [Indexed: 12/15/2022]
Abstract
Recent studies indicate that cancer cells express elevated levels of type II transglutaminase (TG2), and that expression is further highly enriched in cancer stem cells derived from these cancers. Moreover, elevated TG2 expression is associated with enhanced cancer stem cell marker expression, survival signaling, proliferation, migration, invasion, integrin-mediated adhesion, epithelial-mesenchymal transition, and drug resistance. TG2 expression is also associated with formation of aggressive and metastatic tumors that are resistant to conventional therapeutic intervention. This review summarizes the role of TG2 as a cancer cell survival factor in a range of tumor types, and as a target for preventive and therapeutic intervention. The literature supports the idea that TG2, in the closed/GTP-binding/signaling conformation, drives cancer cell and cancer stem cell survival, and that TG2, in the open/crosslinking conformation, is associated with cell death.
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Affiliation(s)
- Richard L Eckert
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.,Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland.,Department of Reproductive Biology, University of Maryland School of Medicine, Baltimore, Maryland.,The Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
| | - Matthew L Fisher
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Dan Grun
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Gautam Adhikary
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Wen Xu
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Candace Kerr
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.,The Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
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42
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Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression. Proc Natl Acad Sci U S A 2015; 112:E4055-64. [PMID: 26159421 DOI: 10.1073/pnas.1501967112] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The available evidence suggests that the lethality of glioblastoma is driven by small subpopulations of cells that self-renew and exhibit tumorigenicity. It remains unclear whether tumorigenicity exists as a static property of a few cells or as a dynamically acquired property. We used tumor-sphere and xenograft formation as assays for tumorigenicity and examined subclones isolated from established and primary glioblastoma lines. Our results indicate that glioblastoma tumorigenicity is largely deterministic, yet the property can be acquired spontaneously at low frequencies. Further, these dynamic transitions are governed by epigenetic reprogramming through the lysine-specific demethylase 1 (LSD1). LSD depletion increases trimethylation of histone 3 lysine 4 at the avian myelocytomatosis viral oncogene homolog (MYC) locus, which elevates MYC expression. MYC, in turn, regulates oligodendrocyte lineage transcription factor 2 (OLIG2), SRY (sex determining region Y)-box 2 (SOX2), and POU class 3 homeobox 2 (POU3F2), a core set of transcription factors required for reprogramming glioblastoma cells into stem-like states. Our model suggests epigenetic regulation of key transcription factors governs transitions between tumorigenic states and provides a framework for glioblastoma therapeutic development.
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43
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Kode A, Mosialou I, Manavalan SJ, Rathinam CV, Friedman RA, Teruya-Feldstein J, Bhagat G, Berman E, Kousteni S. FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice. Leukemia 2015; 30:1-13. [PMID: 26108693 PMCID: PMC4691220 DOI: 10.1038/leu.2015.161] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 05/29/2015] [Accepted: 06/11/2015] [Indexed: 01/08/2023]
Abstract
Osteoblasts, the bone forming cells, affect self-renewal and expansion of hematopoietic stem cells (HSCs), as well as homing of healthy hematopoietic cells and tumor cells into the bone marrow. Constitutive activation of β-catenin in osteoblasts is sufficient to alter the differentiation potential of myeloid and lymphoid progenitors and to initiate the development of acute myeloid leukemia (AML) in mice. We show here that Notch1 is the receptor mediating the leukemogenic properties of osteoblast-activated β-catenin in HSCs. Moreover, using cell-specific gene inactivation mouse models, we show that FoxO1 expression in osteoblasts is required for and mediates the leukemogenic properties of β-catenin. At the molecular level, FoxO1 interacts with β-catenin in osteoblasts to induce expression of the Notch ligand, Jagged-1. Subsequent activation of Notch signaling in long-term repopulating HSC progenitors induces the leukemogenic transformation of HSCs and ultimately leads to the development of AML. These findings identify FoxO1 expressed in osteoblasts as a factor affecting hematopoiesis and provide a molecular mechanism whereby the FoxO1/activated β-catenin interaction results in AML. These observations support the notion that the bone marrow niche is an instigator of leukemia and raise the prospect that FoxO1 oncogenic properties may occur in other tissues.
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Affiliation(s)
- A Kode
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - I Mosialou
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - S J Manavalan
- Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - C V Rathinam
- Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - R A Friedman
- Biomedical Informatics Shared Resource, Department of Biomedical Informatics, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - J Teruya-Feldstein
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - G Bhagat
- Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.,Department of Pathology, Institute for Cancer Genetics Irving Cancer Research Center, Columbia University, New York, NY, USA
| | - E Berman
- Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - S Kousteni
- Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
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44
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Dobbin ZC, Katre AA, Steg AD, Erickson BK, Shah MM, Alvarez RD, Conner MG, Schneider D, Chen D, Landen CN. Using heterogeneity of the patient-derived xenograft model to identify the chemoresistant population in ovarian cancer. Oncotarget 2015; 5:8750-64. [PMID: 25209969 PMCID: PMC4226719 DOI: 10.18632/oncotarget.2373] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
A cornerstone of preclinical cancer research has been the use of clonal cell lines. However, this resource has underperformed in its ability to effectively identify novel therapeutics and evaluate the heterogeneity in a patient's tumor. The patient-derived xenograft (PDX) model retains the heterogeneity of patient tumors, allowing a means to not only examine efficacy of a therapy, but also basic tenets of cancer biology in response to treatment. Herein we describe the development and characterization of an ovarian-PDX model in order to study the development of chemoresistance. We demonstrate that PDX tumors are not simply composed of tumor-initiating cells, but recapitulate the original tumor's heterogeneity, oncogene expression profiles, and clinical response to chemotherapy. Combined carboplatin/paclitaxel treatment of PDX tumors enriches the cancer stem cell populations, but persistent tumors are not entirely composed of these populations. RNA-Seq analysis of six pair of treated PDX tumors compared to untreated tumors demonstrates a consistently contrasting genetic profile after therapy, suggesting similar, but few, pathways are mediating chemoresistance. Pathways and genes identified by this methodology represent novel approaches to targeting the chemoresistant population in ovarian cancer
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Affiliation(s)
- Zachary C Dobbin
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham. NIH Medical Scientist Training Program, University of Alabama at Birmingham
| | - Ashwini A Katre
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham
| | - Adam D Steg
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham
| | - Britt K Erickson
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham
| | - Monjri M Shah
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham
| | - Ronald D Alvarez
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham
| | | | - David Schneider
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham
| | - Dongquan Chen
- Division of Preventative Medicine, Department of Medicine, University of Alabama at Birmingham
| | - Charles N Landen
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Virginia, Charlottesville, VA
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45
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Protracted dormancy of pre-leukemic stem cells. Leukemia 2015; 29:2202-7. [PMID: 26017033 PMCID: PMC4564945 DOI: 10.1038/leu.2015.132] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 05/12/2015] [Accepted: 05/13/2015] [Indexed: 12/18/2022]
Abstract
Cancer stem cells can escape therapeutic killing by adopting a quiescent or dormant state. The reversibility of this condition provides the potential for later recurrence or relapse, potentially many years later. We describe the genomics of a rare case of childhood BCR-ABL1-positive, B-cell precursor acute lymphoblastic leukemia that relapsed, with an acute myeloblastic leukemia immunophenotype, 22 years after the initial diagnosis, sustained remission and presumed cure. The primary and relapsed leukemias shared the identical BCR-ABL1 fusion genomic sequence and two identical immunoglobulin gene rearrangements, indicating that the relapse was a derivative of the founding clone. All other mutational changes (single-nucleotide variant and copy number alterations) were distinct in diagnostic or relapse samples. These data provide unambiguous evidence that leukemia-propagating cells, most probably pre-leukemic stem cells, can remain covert and silent but potentially reactivatable for more than two decades.
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46
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Lu C, Huang T, Chen W, Lu H. GnRH participates in the self-renewal of A549-derived lung cancer stem-like cells through upregulation of the JNK signaling pathway. Oncol Rep 2015; 34:244-50. [PMID: 25955300 DOI: 10.3892/or.2015.3956] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Accepted: 02/03/2015] [Indexed: 11/06/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality in humans. Exploration of the mechanisms underlying the self-renewal and stemness maintenance of cancer stem-like cells (CSLCs) will open new avenues in lung cancer diagnosis and therapy. Here, we isolated and identified a subpopulation of lung cancer stem-like cells (LCSLCs) from non-small cell lung carcinoma (NSCLC) A549 cells with features including self-renewal capacity in vitro, elevated tumorigenic activity in vivo, and high expression of stemness markers CD44, CD133, aldehyde dehydrogenase 1 (ALDH1) and Sox2, using a serum-free suspension sphere-forming culture method. We then found a higher expression level of gonadotropin-releasing hormone (GnRH) in the LCSLCs using a microarray assay, suggesting that GnRH may play a role in the self-renewal capacity and stemness maintenance in lung cancer cells. In addition, the suppression of GnRH capacity negatively regulated self-renewal and stemness maintenance in the LCSLCs. Overexpression of GnRH promoted stemness properties of A549-derived LCSLCs, indicating that GnRH expression is essential for the self-renewal and stemness maintenance in LCSLCs. Moreover, further investigations demonstrated that the promotion of GnRH functions of self-renewal and stemness maintenance in LCSLCs was associated with the JNK signaling pathway. Therefore, our results showed that GnRH participates in the self-renewal capacity and stemness maintenance of LCSLCs by upregulating the JNK signaling pathway, and GnRH may be useful as an alternative LCSLC therapy.
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Affiliation(s)
- Chi Lu
- Department of Oncology, The Central Hospital of Wuhan, Wuhan, Hubei 430014, P.R. China
| | - Ting Huang
- Department of Oncology, The Central Hospital of Wuhan, Wuhan, Hubei 430014, P.R. China
| | - Weiqun Chen
- Cancer Research Institute of Wuhan, Wuhan, Hubei 430014, P.R. China
| | - Hongda Lu
- Department of Oncology, The Central Hospital of Wuhan, Wuhan, Hubei 430014, P.R. China
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47
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Yang L, Qian Y, Eksioglu E, Epling-Burnette PK, Wei S. The inflammatory microenvironment in MDS. Cell Mol Life Sci 2015; 72:1959-66. [PMID: 25662443 PMCID: PMC11113192 DOI: 10.1007/s00018-015-1846-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 12/23/2014] [Accepted: 01/26/2015] [Indexed: 12/16/2022]
Abstract
Myelodysplastic syndromes (MDS) are a collection of pre-malignancies characterized by impaired proliferation and differentiation of hematopoietic stem cells and a tendency to evolve into leukemia. Among MDS's pathogenic mechanisms are genetic, epigenetic, apoptotic, differentiation, and cytokine milieu abnormalities. Inflammatory changes are a prominent morphologic feature in some cases, with increased populations of plasma cells, mast cells, and lymphocytes in bone marrow aspirates. Accumulating evidence suggests that the bone marrow microenvironment contributes to MDS disease pathology, with microenvironment alterations and abnormality preceding, and facilitating clonal evolution in MDS patients. In this review, we focus on the inflammatory changes involved in the pathology of MDS, with an emphasis on immune dysfunction, stromal microenvironment, and cytokine imbalance in the microenvironment as well as activation of innate immune signaling in MDS patients. A better understanding of the mechanism of MDS pathophysiology will be beneficial to the development of molecular-targeted therapies in the future.
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Affiliation(s)
- Lili Yang
- Department of Immunology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin, China
| | - Yaqin Qian
- Department of Immunology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin, China
| | - Erika Eksioglu
- Immunology Program at the H Lee Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL 33612 USA
| | | | - Sheng Wei
- Department of Immunology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin, China
- Immunology Program at the H Lee Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL 33612 USA
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48
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Saltarella I, Lamanuzzi A, Reale A, Vacca A, Ria R. Identify multiple myeloma stem cells: Utopia? World J Stem Cells 2015; 7:84-95. [PMID: 25621108 PMCID: PMC4300939 DOI: 10.4252/wjsc.v7.i1.84] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/14/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.
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49
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[The stem cell niche in glioblastoma: from fundamental aspects to targeted therapies]. Bull Cancer 2015; 102:24-33. [PMID: 25609493 DOI: 10.1016/j.bulcan.2014.07.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2014] [Accepted: 07/21/2014] [Indexed: 12/11/2022]
Abstract
The concept of cancer stem cell (CSC) was established from models of leukemogenesis explaining tumor repopulation by the clonogenic properties of this specific population of tumoral cells. Among solid tumors, glioblastoma are currently the most documented models. Cancer stem cells reside in specific locations within tumors called niches. Anatomically, two complementary niches have been described in glioblastoma. The first one is a perivascular niche composed of vessels (endothelial cells, pericytes) and their microenvironment (integrins, interleukins) constitutive the nest of "normal" neural stem cells and cancer stem cells. The second one is a hypoxic niche found in regions with low oxygen tension such as the core of the tumor. In these niches, mutual interactions between CSC and their microenvironment involving the activation of multiple signaling pathways promote stemness maintenance and tumor propagation. The median overall survival of glioblastoma does not exceed 15 months despite an aggressive multimodal treatment, thus the therapeutic targeting of these niches, by systemic agents or radiotherapy, in order to inhibit the signaling pathways involved in the maintenance of the CSC niches, represents a major challenge. The combination of these two strategies appears promising and many clinical trials are underway.
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50
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Ding J. Oncolytic virus as a cancer stem cell killer: progress and challenges. Stem Cell Investig 2014; 1:22. [PMID: 27358868 DOI: 10.3978/j.issn.2306-9759.2014.12.02] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 12/21/2014] [Indexed: 01/15/2023]
Abstract
Oncolytic viruses (OVs), which were discovered more than one century ago, have been used in multiple clinical trials for cancer therapy. OVs specifically target cancer cells when sparing normal cells by exploiting biochemical differences between normal and tumor cells. Hence oncolytic virotherapy is more specific at targeting cancer cells compared with conventional anti-cancer therapy. Apart from the lack of specificity, conventional anti-cancer therapies also often witness relapse and incomplete cure of cancer. One hypothesis explaining this phenomenon is that a subpopulation of cancer cells, known as cancer stem cells (CSCs), are resistant to conventional therapies, possibly due to its self-renewal and differentiation abilities. With the discovery of CSCs, researchers have been trying to explain whether OVs are well suited to eliminate CSCs. Two explanations for postulating OVs as ideal candidates for cancer therapy have been proposed: first, OVs are not subject to the same mechanisms responsible for chemotherapy and radiation resistance; second, viruses could be harnessed to express therapeutic transgenes that specifically target the features unique to CSCs or the properties CSCs rely on for self-renewal and differentiation. Indeed, initial studies suggest that OVs could effectively target CSCs in multiple tumor types. The focus of this review is to highlight recent studies related to the application of OVs on targeting CSCs, based on which, the challenges and perspectives for further research in this field will also be discussed.
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Affiliation(s)
- Jingzhen Ding
- Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093, USA
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