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Zuo R, Guo X, Song X, Gao X, Zhang J, Jiang S, Adam V, Kuca K, Wu W, Guo D. New uses of halofuginone to treat cancer. J Pharm Anal 2025; 15:101080. [PMID: 40099206 PMCID: PMC11910366 DOI: 10.1016/j.jpha.2024.101080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 08/09/2024] [Accepted: 08/21/2024] [Indexed: 03/19/2025] Open
Abstract
The small-molecule alkaloid halofuginone (HF) is obtained from febrifugine. Recent studies on HF have aroused widespread attention owing to its universal range of noteworthy biological activities and therapeutic functions, which range from parasite infections and fibrosis to autoimmune diseases. In particular, HF is believed to play an excellent anticancer role by suppressing the proliferation, adhesion, metastasis, and invasion of cancers. This review supports the goal of demonstrating various anticancer effects and molecular mechanisms of HF. In the studies covered in this review, the anticancer molecular mechanisms of HF mainly included transforming growth factor-β (TGF-β)/Smad-3/nuclear factor erythroid 2-related factor 2 (Nrf2), serine/threonine kinase proteins (Akt)/mechanistic target of rapamycin complex 1(mTORC1)/wingless/integrated (Wnt)/β-catenin, the exosomal microRNA-31 (miR-31)/histone deacetylase 2 (HDAC2) signaling pathway, and the interaction of the extracellular matrix (ECM) and immune cells. Notably, HF, as a novel type of adenosine triphosphate (ATP)-dependent inhibitor that is often combined with prolyl transfer RNA synthetase (ProRS) and amino acid starvation therapy (AAS) to suppress the formation of ribosome, further exerts a significant effect on the tumor microenvironment (TME). Additionally, the combination of HF with other drugs or therapies obtained universal attention. Our results showed that HF has significant potential for clinical cancer treatment.
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Affiliation(s)
- Runan Zuo
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
- Animal-Derived Food Safety Innovation Team, Anhui Province Key Lab of Veterinary Pathobiology and Disease Control, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Xinyi Guo
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China
| | - Xinhao Song
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Xiuge Gao
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Junren Zhang
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Shanxiang Jiang
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Vojtech Adam
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, 61300, Czech Republic
- Central European Institute of Technology, Brno University of Technology, Brno, 60200, Czech Republic
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, 50003, Czech Republic
- Malaysia-Japan International Institute of Technology (MJIIT), University Teknologi Malaysia, Kuala Lumpur, 50200, Malaysia
| | - Wenda Wu
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China
| | - Dawei Guo
- Engineering Center of Innovative Veterinary Drugs, Center for Veterinary Drug Research and Evaluation, Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
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2
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Mancini A, Gentile MT, Pentimalli F, Cortellino S, Grieco M, Giordano A. Multiple aspects of matrix stiffness in cancer progression. Front Oncol 2024; 14:1406644. [PMID: 39015505 PMCID: PMC11249764 DOI: 10.3389/fonc.2024.1406644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 05/27/2024] [Indexed: 07/18/2024] Open
Abstract
The biophysical and biomechanical properties of the extracellular matrix (ECM) are crucial in the processes of cell differentiation and proliferation. However, it is unclear to what extent tumor cells are influenced by biomechanical and biophysical changes of the surrounding microenvironment and how this response varies between different tumor forms, and over the course of tumor progression. The entire ensemble of genes encoding the ECM associated proteins is called matrisome. In cancer, the ECM evolves to become highly dysregulated, rigid, and fibrotic, serving both pro-tumorigenic and anti-tumorigenic roles. Tumor desmoplasia is characterized by a dramatic increase of α-smooth muscle actin expressing fibroblast and the deposition of hard ECM containing collagen, fibronectin, proteoglycans, and hyaluronic acid and is common in many solid tumors. In this review, we described the role of inflammation and inflammatory cytokines, in desmoplastic matrix remodeling, tumor state transition driven by microenvironment forces and the signaling pathways in mechanotransduction as potential targeted therapies, focusing on the impact of qualitative and quantitative variations of the ECM on the regulation of tumor development, hypothesizing the presence of matrisome drivers, acting alongside the cell-intrinsic oncogenic drivers, in some stages of neoplastic progression and in some tumor contexts, such as pancreatic carcinoma, breast cancer, lung cancer and mesothelioma.
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Affiliation(s)
- Alessandro Mancini
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
- BioUp Sagl, Lugano, Switzerland
| | - Maria Teresa Gentile
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, Caserta, Italy
| | - Francesca Pentimalli
- Department of Medicine and Surgery, LUM University “Giuseppe De Gennaro,” Casamassima, Bari, Italy
| | - Salvatore Cortellino
- Laboratory of Molecular Oncology, Responsible Research Hospital, Campobasso, Italy
- Scuola Superiore Meridionale (SSM), Clinical and Translational Oncology, Naples, NA, Italy
- Sbarro Health Research Organization (S.H.R.O.) Italia Foundation ETS, Candiolo, TO, Italy
| | - Michele Grieco
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, Caserta, Italy
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, United States
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
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3
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Mi L, Zhang Y, Su A, Tang M, Xing Z, He T, Wu W, Li Z. Halofuginone for cancer treatment: A systematic review of efficacy and molecular mechanisms. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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4
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Gillson J, Abd El-Aziz YS, Leck LYW, Jansson PJ, Pavlakis N, Samra JS, Mittal A, Sahni S. Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target. Cancers (Basel) 2022; 14:3528. [PMID: 35884592 PMCID: PMC9315706 DOI: 10.3390/cancers14143528] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/10/2022] [Accepted: 07/11/2022] [Indexed: 01/18/2023] Open
Abstract
Pancreatic cancer is known to have the lowest survival outcomes among all major cancers, and unfortunately, this has only been marginally improved over last four decades. The innate characteristics of pancreatic cancer include an aggressive and fast-growing nature from powerful driver mutations, a highly defensive tumor microenvironment and the upregulation of advantageous survival pathways such as autophagy. Autophagy involves targeted degradation of proteins and organelles to provide a secondary source of cellular supplies to maintain cell growth. Elevated autophagic activity in pancreatic cancer is recognized as a major survival pathway as it provides a plethora of support for tumors by supplying vital resources, maintaining tumour survival under the stressful microenvironment and promoting other pathways involved in tumour progression and metastasis. The combination of these features is unique to pancreatic cancer and present significant resistance to chemotherapeutic strategies, thus, indicating a need for further investigation into therapies targeting this crucial pathway. This review will outline the autophagy pathway and its regulation, in addition to the genetic landscape and tumor microenvironment that contribute to pancreatic cancer severity. Moreover, this review will also discuss the mechanisms of novel therapeutic strategies that inhibit autophagy and how they could be used to suppress tumor progression.
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Affiliation(s)
- Josef Gillson
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
| | - Yomna S. Abd El-Aziz
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
- Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta 31527, Egypt
| | - Lionel Y. W. Leck
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Patric J. Jansson
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Nick Pavlakis
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
| | - Jaswinder S. Samra
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, St Leonards, Sydney, NSW 2065, Australia
- Australian Pancreatic Centre, St Leonards, Sydney, NSW 2065, Australia
| | - Anubhav Mittal
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, St Leonards, Sydney, NSW 2065, Australia
- Australian Pancreatic Centre, St Leonards, Sydney, NSW 2065, Australia
- School of Medicine, University of Notre Dame, Darlinghurst, Sydney, NSW 2010, Australia
| | - Sumit Sahni
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
- Australian Pancreatic Centre, St Leonards, Sydney, NSW 2065, Australia
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5
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Tian X, Zhang S, Zhou L, Seyhan AA, Hernandez Borrero L, Zhang Y, El-Deiry WS. Targeting the Integrated Stress Response in Cancer Therapy. Front Pharmacol 2021; 12:747837. [PMID: 34630117 PMCID: PMC8498116 DOI: 10.3389/fphar.2021.747837] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/10/2021] [Indexed: 12/11/2022] Open
Abstract
The integrated stress response (ISR) is an evolutionarily conserved intra-cellular signaling network which is activated in response to intrinsic and extrinsic stresses. Various stresses are sensed by four specialized kinases, PKR-like ER kinase (PERK), general control non-derepressible 2 (GCN2), double-stranded RNA-dependent protein kinase (PKR) and heme-regulated eIF2α kinase (HRI) that converge on phosphorylation of serine 51 of eIF2α. eIF2α phosphorylation causes a global reduction of protein synthesis and triggers the translation of specific mRNAs, including activating transcription factor 4 (ATF4). Although the ISR promotes cell survival and homeostasis, when stress is severe or prolonged the ISR signaling will shift to regulate cellular apoptosis. We review the ISR signaling pathway, regulation and importance in cancer therapy.
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Affiliation(s)
- Xiaobing Tian
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States.,Cancer Center at Brown University, Providence, RI, United States
| | - Shengliang Zhang
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States.,Cancer Center at Brown University, Providence, RI, United States
| | - Lanlan Zhou
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States.,Cancer Center at Brown University, Providence, RI, United States
| | - Attila A Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States.,Cancer Center at Brown University, Providence, RI, United States
| | - Liz Hernandez Borrero
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
| | - Yiqun Zhang
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
| | - Wafik S El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States.,Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States.,Cancer Center at Brown University, Providence, RI, United States.,Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, RI, United States
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6
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Biffi G, Tuveson DA. Diversity and Biology of Cancer-Associated Fibroblasts. Physiol Rev 2021; 101:147-176. [PMID: 32466724 PMCID: PMC7864232 DOI: 10.1152/physrev.00048.2019] [Citation(s) in RCA: 733] [Impact Index Per Article: 183.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 05/19/2020] [Accepted: 05/20/2020] [Indexed: 02/08/2023] Open
Abstract
Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation.
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Affiliation(s)
- Giulia Biffi
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York; and Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
| | - David A Tuveson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York; and Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
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7
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Involvement of eIF2α in halofuginone-driven inhibition of TGF-β1-induced EMT. J Biosci 2020. [DOI: 10.1007/s12038-020-00042-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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8
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Demiroglu-Zergeroglu A, Turhal G, Topal H, Ceylan H, Donbaloglu F, Karadeniz Cerit K, Odongo RR. Anticarcinogenic effects of halofuginone on lung-derived cancer cells. Cell Biol Int 2020; 44:1934-1944. [PMID: 32437065 DOI: 10.1002/cbin.11399] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 05/04/2020] [Accepted: 05/18/2020] [Indexed: 02/06/2023]
Abstract
Malignant mesothelioma is a rare but aggressive form of malignancy, which is difficult to diagnose and is resistant to current chemotherapeutic treatment options. Molecular techniques have been used to investigate the mechanisms of action and the beneficial therapeutic effects of halofuginone (HF) in several cancers but not malignant mesotheliomas. In this study, the antiproliferative and apoptotic effects of HF were investigated through its ability to deregulate EGFR downstream signalling cascade proteins in the pathologically aggressive malignant mesothelioma and non-small-cell lung cancer cells. We showed that administration of HF at nanomolar concentrations induced a dose-dependent reduction in the viability of cancer cells, made cell cycle arrest, inhibited proliferation of cancer cells via STAT3 and ERK1/2 pathways and triggered the apoptotic cascade via p38MAPK. We demonstrated that the apoptotic cell death mechanism was mediated by enhanced activation of caspase-3 and concomitant PARP cleavage, downregulation of Bcl-2 and upregulation of Bax in both malignant mesothelioma and lung cancer cells. In particular, we demonstrated that cancer cells were more sensitive to HF treatment than normal mesothelial cells. Taken together, this study suggests that HF exerts its anticancer effects in lung-derived cancers by targeting signal transduction pathways mainly through deregulation of ERK1/2, STAT3 and p38MAPK to reduce cancer cell viability, induce cell cycle arrest and apoptotic cell death. Thus, HF might be considered as a potential agent against malignant mesothelioma and/or lung cancer cells.
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Affiliation(s)
- Asuman Demiroglu-Zergeroglu
- Department of Molecular Biology & Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey
| | - Gulseren Turhal
- Department of Molecular Biology & Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey
| | - Halime Topal
- Department of Molecular Biology & Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey
| | - Hurmuz Ceylan
- Department of Molecular Biology & Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey
| | - Fadime Donbaloglu
- Department of Molecular Biology & Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey
| | - Kivilcim Karadeniz Cerit
- Department of Pediatric Surgery, School of Medicine, Marmara University, Pendik, Istanbul, Turkey
| | - Ronald R Odongo
- Department of Molecular Biology & Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Turkey
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9
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Hauge A, Rofstad EK. Antifibrotic therapy to normalize the tumor microenvironment. J Transl Med 2020; 18:207. [PMID: 32434573 PMCID: PMC7240990 DOI: 10.1186/s12967-020-02376-y] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/13/2020] [Indexed: 02/07/2023] Open
Abstract
Most tumors develop abnormal fibrotic regions consisting of fibroblasts, immune cells, and a dense extracellular matrix (ECM) immersed in a viscous interstitial fluid, and an abundant fibrotic tumor microenvironment (TME) is associated with poor outcome of treatment. It has been hypothesized that the treatment of cancer may be improved by interventions aiming to normalize this TME. The approaches used in attempts to normalize the fibrotic TME can be categorized into three strategies of targeted antifibrotic therapy: targeting of components of the ECM, targeting of the producers of the ECM components-the activated cancer-associated fibroblasts (CAFs), and targeting of the signaling pathways activating CAFs. To target the ECM, enzymes against components of the ECM have been used, including collagenase, relaxin, hyaluronidase, and lyxyl oxidase. Targeting of CAFs have been investigated by using agents aiming to eliminate or reprogram CAFs. CAFs are activated primarily by transforming growth factor-β (TGF-β), hedgehog, or focal adhesion kinase signaling, and several agents have been used to target these signaling pathways, including angiotensin II receptor I blockers (e.g., losartan) to inhibit the TGF-β pathway. Taken together, these studies have revealed that antifibrotic therapy is a two-edged sword: while some studies suggest enhanced response to treatment after antifibrotic therapy, others suggest that antifibrotic therapy may lead to increased tumor growth, metastasis, and impaired outcome of treatment. There are several possible explanations of these conflicting observations. Most importantly, tumors contain different subpopulations of CAFs, and while some subpopulations may promote tumor growth and metastasis, others may inhibit malignant progression. Furthermore, the outcome of antifibrotic therapy may depend on stage of disease, duration of treatment, treatment-induced activation of alternative profibrotic signaling pathways, and treatment-induced recruitment of tumor-supporting immune cells. Nevertheless, losartan-induced suppression of TGF-β signaling appears to be a particularly promising strategy. Losartan is a widely prescribed antihypertensive drug and highly advantageous therapeutic effects have been observed after losartan treatment of pancreatic cancer. However, improved understanding of the mechanisms governing the development of fibrosis in tumors is needed before safe antifibrotic treatments can be established.
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Affiliation(s)
- Anette Hauge
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Einar K Rofstad
- Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
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10
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D'Aniello C, Patriarca EJ, Phang JM, Minchiotti G. Proline Metabolism in Tumor Growth and Metastatic Progression. Front Oncol 2020; 10:776. [PMID: 32500033 PMCID: PMC7243120 DOI: 10.3389/fonc.2020.00776] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 04/21/2020] [Indexed: 12/15/2022] Open
Abstract
Cancer cells show a formidable capacity to survive under stringent conditions, to elude mechanisms of control, such as apoptosis, and to resist therapy. Cancer cells reprogram their metabolism to support uncontrolled proliferation and metastatic progression. Phenotypic and functional heterogeneity are hallmarks of cancer cells, which endow them with aggressiveness, metastatic capacity, and resistance to therapy. This heterogeneity is regulated by a variety of intrinsic and extrinsic stimuli including those from the tumor microenvironment. Increasing evidence points to a key role for the metabolism of non-essential amino acids in this complex scenario. Here we discuss the impact of proline metabolism in cancer development and progression, with particular emphasis on the enzymes involved in proline synthesis and catabolism, which are linked to pathways of energy, redox, and anaplerosis. In particular, we emphasize how proline availability influences collagen synthesis and maturation and the acquisition of cancer cell plasticity and heterogeneity. Specifically, we propose a model whereby proline availability generates a cycle based on collagen synthesis and degradation, which, in turn, influences the epigenetic landscape and tumor heterogeneity. Therapeutic strategies targeting this metabolic-epigenetic axis hold great promise for the treatment of metastatic cancers.
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Affiliation(s)
- Cristina D'Aniello
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, Naples, Italy
| | - Eduardo J. Patriarca
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, Naples, Italy
| | - James M. Phang
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD, United States
| | - Gabriella Minchiotti
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, Naples, Italy
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11
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Liu T, Zhou L, Li D, Andl T, Zhang Y. Cancer-Associated Fibroblasts Build and Secure the Tumor Microenvironment. Front Cell Dev Biol 2019; 7:60. [PMID: 31106200 PMCID: PMC6492564 DOI: 10.3389/fcell.2019.00060] [Citation(s) in RCA: 315] [Impact Index Per Article: 52.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 04/05/2019] [Indexed: 12/13/2022] Open
Abstract
Tumor cells reside in a highly complex and heterogeneous tumor microenvironment (TME), which is composed of a myriad of genetically stable non-cancer cells, including fibroblasts, immune cells, endothelial cells, and epithelial cells, and a tumor-specific extracellular matrix (ECM). Cancer-associated fibroblasts (CAFs), as an abundant and active stromal cell population in the TME, function as the signaling center and remodeling machine to aid the creation of a desmoplastic tumor niche. Although there is no denial that the TME and CAFs may have anti-tumor effects as well, a great deal of findings reported in recent years have convincingly revealed the tumor-promoting effects of CAFs and CAF-derived ECM proteins, enzymes, chemical factors and other downstream effectors. While there is growing enthusiasm for the development of CAF-targeting therapies, a better understanding of the complexities of CAF-ECM and CAF-cancer cell interactions is necessary before novel therapeutic strategies targeting the malignant tumor “soil” can be successfully implemented in the clinic.
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Affiliation(s)
- Tianyi Liu
- Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States
| | - Linli Zhou
- Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States
| | - Danni Li
- College of Chemistry and Chemical Engineering, Guangxi University for Nationalities, Nanning, China
| | - Thomas Andl
- Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, United States
| | - Yuhang Zhang
- Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States
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Elahi-Gedwillo KY, Carlson M, Zettervall J, Provenzano PP. Antifibrotic Therapy Disrupts Stromal Barriers and Modulates the Immune Landscape in Pancreatic Ductal Adenocarcinoma. Cancer Res 2019; 79:372-386. [PMID: 30401713 PMCID: PMC6335156 DOI: 10.1158/0008-5472.can-18-1334] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 10/04/2018] [Accepted: 11/01/2018] [Indexed: 12/18/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA) remains one of the deadliest forms of cancer, in part, because it is largely refractory to current therapies. The failure of most standard therapies in PDA, as well as promising immune therapies, may be largely ascribed to highly unique and protective stromal microenvironments that present significant biophysical barriers to effective drug delivery, that are immunosuppressive, and that can limit the distribution and function of antitumor immune cells. Here, we utilized stromal reengineering to disrupt these barriers and move the stroma toward normalization using a potent antifibrotic agent, halofuginone. In an autochthonous genetically engineered mouse model of PDA, halofuginone disrupted physical barriers to effective drug distribution by decreasing fibroblast activation and reducing key extracellular matrix elements that drive stromal resistance. Concomitantly, halofuginone treatment altered the immune landscape in PDA, with greater immune infiltrate into regions of low hylauronan, which resulted in increased number and distribution of both classically activated inflammatory macrophages and cytotoxic T cells. In concert with a direct effect on carcinoma cells, this led to widespread intratumoral necrosis and reduced tumor volume. These data point to the multifunctional and critical role of the stroma in tumor protection and survival and demonstrate how compromising tumor integrity to move toward a more normal physiologic state through stroma-targeting therapy will likely be an instrumental component in treating PDA. SIGNIFICANCE: This work demonstrates how focused stromal re-engineering approaches to move toward normalization of the stroma disrupt physical barriers to effective drug delivery and promote antitumor immunity.See related commentary by Huang and Brekken, p. 328.
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Affiliation(s)
- Kianna Y Elahi-Gedwillo
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota
- University of Minnesota Physical Sciences in Oncology Center, Minneapolis, Minnesota
| | - Marjorie Carlson
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota
| | - Jon Zettervall
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota
| | - Paolo P Provenzano
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota.
- University of Minnesota Physical Sciences in Oncology Center, Minneapolis, Minnesota
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
- Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota
- Institute for Engineering in Medicine, University of Minnesota, Minneapolis, Minnesota
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13
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Nielsen MFB, Mortensen MB, Detlefsen S. Typing of pancreatic cancer-associated fibroblasts identifies different subpopulations. World J Gastroenterol 2018; 24:4663-4678. [PMID: 30416314 PMCID: PMC6224473 DOI: 10.3748/wjg.v24.i41.4663] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 10/12/2018] [Accepted: 10/21/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To determine whether it is possible to identify different immune phenotypic subpopulations of cancer-associated fibroblasts (CAFs) in pancreatic cancer (PC).
METHODS We defined four different stromal compartments in surgical specimens with PC: The juxtatumoural, peripheral, lobular and septal stroma. Tissue microarrays were produced containing all pre-defined PC compartments, and the expression of 37 fibroblast (FB) and 8 extracellular matrix (ECM) markers was evaluated by immunohistochemistry, immunofluorescence (IF), double-IF, and/or in situ hybridization. The compartment-specific mean labelling score was determined for each marker using a four-tiered scoring system. DOG1 gene expression was examined by quantitative reverse transcription PCR (qPCR).
RESULTS CD10, CD271, cytoglobin, DOG1, miR-21, nestin, and tenascin C exhibited significant differences in expression profiles between the juxtatumoural and peripheral compartments. The expression of CD10, cytoglobin, DOG1, nestin, and miR-21 was moderate/strong in juxtatumoural CAFs (j-CAFs) and barely perceptible/weak in peripheral CAFs (p-CAFs). The upregulation of DOG1 gene expression in PC compared to normal pancreas was verified by qPCR. Tenascin C expression was strong in the juxtatumoural ECM and barely perceptible/weak in the peripheral ECM. CD271 expression was barely perceptible in j-CAFs but moderate in the other compartments. Galectin-1 was stronger expressed in j-CAFs vs septal fibroblasts, PDGF-Rβ, tissue transglutaminase 2, and hyaluronic acid were stronger expressed in lobular fibroblasts vs p-CAFs, and plectin-1 was stronger expressed in j-CAFs vs l-FBs. The expression of the remaining 33 markers did not differ significantly when related to the quantity of CAFs/FBs or the amount of ECM in the respective compartments.
CONCLUSION Different immune phenotypic CAF subpopulations can be identified in PC, using markers such as cytoglobin, CD271, and miR-21. Future studies should determine whether CAF subpopulations have different functional properties.
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Affiliation(s)
- Michael Friberg Bruun Nielsen
- Department of Pathology, Odense University Hospital, Department of Clinical Research, University of Southern Denmark, Odense Pancreas Center (OPAC), Odense C 5000, Denmark
| | - Michael Bau Mortensen
- Department of Surgery, HPB Section, Odense University Hospital, Department of Clinical Research, University of Southern Denmark, Odense Pancreas Center (OPAC), Odense C 5000, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, Department of Clinical Research, University of Southern Denmark, Odense Pancreas Center (OPAC), Odense C 5000, Denmark
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14
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Mu W, Xu B, Ma H, Li J, Ji B, Zhang Z, Amat A, Cao L. Halofuginone Attenuates Osteoarthritis by Rescuing Bone Remodeling in Subchondral Bone Through Oral Gavage. Front Pharmacol 2018; 9:269. [PMID: 29636687 PMCID: PMC5881118 DOI: 10.3389/fphar.2018.00269] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 03/09/2018] [Indexed: 12/13/2022] Open
Abstract
Osteoarthritis (OA) is a common debilitating joint disorder worldwide without effective medical therapy. Articular cartilage and subchondral bone act in concert as a functional unit with the onset of OA. Halofuginone is an analog of the alkaloid febrifugine extracted from the plant Dichroa febrifuga, which has been demonstrated to exert inhibition of SMAD 2/3 phosphorylation downstream of the TGF-β signaling pathway and osteoclastogenesis. To investigate whether halofuginone (HF) alleviates OA after administration by oral gavage, 3-month-old male mice were allocated to the Sham group, vehicle-treated anterior cruciate ligament transection (ACLT) group, and HF-treated ACLT group. The immunostaining analysis indicated that HF reduced the number of matrix metalloproteinase 13 (MMP-13) and collagen X (Col X) positive cells in the articular cartilage. Moreover, HF lowered histologic OA score and prevented articular cartilage degeneration. The micro-computed tomography (μCT) scan showed that HF maintained the subchondral bone microarchitecture, demonstrated by the restoration of bone volume fraction (BV/TV), subchondral bone plate thickness (SBP.Th.), and trabecular pattern factor (Tb.Pf) to a level comparable to that of the Sham group. Immunostaining for CD31 and μCT based angiography showed that the number and volume of vessels in subchondral bone was restored by HF. HF administered by oral gavage recoupled bone remodeling and inhibited aberrant angiogenesis in the subchondral bone, further slowed the progression of OA. Therefore, HF administered by oral gavage could be a potential therapy for OA.
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Affiliation(s)
- Wenbo Mu
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Boyong Xu
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Hairong Ma
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asian Xinjiang Key Laboratory of Echinococcosis, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Jiao Li
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Baochao Ji
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Zhendong Zhang
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Abdusami Amat
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Li Cao
- Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
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15
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Luo L, Gao Y, Yang C, Shao Z, Wu X, Li S, Xiong L, Chen C. Halofuginone attenuates intervertebral discs degeneration by suppressing collagen I production and inactivating TGFβ and NF-кB pathway. Biomed Pharmacother 2018. [PMID: 29524883 DOI: 10.1016/j.biopha.2018.01.100] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Most low back pain is caused by intervertebral discs (IVD) degeneration, a disease that prevalence is increasing with age. Halofuginone, an analog of ferbrifugine isolated from plant Dichroa febrifuga, has drawn much attention in recent years for the wide range of bioactivities in malaria, cancer, fibrotic and autoimmune diseases. In this study, we evaluated the benefit effects of halofuginone in IVD degeneration treatment in a validated rabbit puncture model. Halofuginone treatment could attenuate disc degeneration by suppressing the decrease of discs height and nucleus pulposus signal strength. Besides, halofuginone treatment could suppress mRNA and protein expression of collagen I in nucleus pulposus. This might possibly due to the inactivation of transform growth factor-β (TGFβ) signal pathway by down-regulating p-Samd3 and up-regulating inhibitory Smad7. Then, we evaluated the effects of halofuginone treatment on nuclear factor of kappa B (NF-κB) signal pathway and its downstream pro-inflammatory cytokines. The level of p-p65 and p-IκBα was down-regulated in halofuginone treated group, indicating the inactivation of NF-κB signal pathway. The mRNA expression of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and interleukin 8 (IL-8) was decreased in nucleus pulposus too, indicating the down-regulation of pro-inflammatory cytokines. In conclusion, halofuginone treatment could attenuate IVD degeneration and this was possibly due to suppressing of collagen I production and inactivation of TGFβ and NF-κB signal pathway in nucleus pulposus of degenerated discs. These results suggest that halofuginone has the potential for IVD degeneration treatment, but more research is needed to validate this.
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Affiliation(s)
- Linghui Luo
- Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yong Gao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Cao Yang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xinghuo Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shuai Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Liming Xiong
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chao Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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16
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Juárez P, Fournier PGJ, Mohammad KS, McKenna RC, Davis HW, Peng XH, Niewolna M, Mauviel A, Chirgwin JM, Guise TA. Halofuginone inhibits TGF-β/BMP signaling and in combination with zoledronic acid enhances inhibition of breast cancer bone metastasis. Oncotarget 2017; 8:86447-86462. [PMID: 29156807 PMCID: PMC5689697 DOI: 10.18632/oncotarget.21200] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 08/04/2017] [Indexed: 11/25/2022] Open
Abstract
More efficient therapies that target multiple molecular mechanisms are needed for the treatment of incurable bone metastases. Halofuginone is a plant alkaloid-derivative with antiangiogenic and antiproliferative effects. Here we demonstrate that halofuginone is an effective therapy for the treatment of bone metastases, through multiple actions that include inhibition of TGFβ and BMP-signaling. Halofuginone blocked TGF-β-signaling in MDA-MB-231 and PC3 cells showed by inhibition of TGF-β–induced Smad-reporter, phosphorylation of Smad-proteins, and expression of TGF-β-regulated metastatic genes. Halofuginone increased inhibitory Smad7-mRNA and reduced TGF-β-receptor II protein. Proline supplementation but not Smad7-knockdown reversed halofuginone-inhibition of TGF-β-signaling. Halofuginone also decreased BMP-signaling. Treatment of MDA-MB-231 and PC3 cells with halofuginone reduced the BMP-Smad-reporter (BRE)4, Smad1/5/8-phosphorylation and mRNA of the BMP-regulated gene Id-1. Halofuginone decreased immunostaining of phospho-Smad2/3 and phospho-Smad1/5/8 in cancer cells in vivo. Furthermore, halofuginone decreased tumor-take and growth of orthotopic-tumors. Mice with breast or prostate bone metastases treated with halofuginone had significantly less osteolysis than control mice. Combined treatment with halofuginone and zoledronic-acid significantly reduced osteolytic area more than either treatment alone. Thus, halofuginone reduces breast and prostate cancer bone metastases in mice and combined with treatment currently approved by the FDA is an effective treatment for this devastating complication of breast and prostate-cancer.
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Affiliation(s)
- Patricia Juárez
- Division of Endocrinology, Department of Medicine, Indiana University Purdue University at Indianapolis, Indiana, USA.,Ensenada Center for Scientific Research and Higher Education, Ensenada, Mexico
| | - Pierrick G J Fournier
- Division of Endocrinology, Department of Medicine, Indiana University Purdue University at Indianapolis, Indiana, USA.,Ensenada Center for Scientific Research and Higher Education, Ensenada, Mexico
| | - Khalid S Mohammad
- Division of Endocrinology, Department of Medicine, Indiana University Purdue University at Indianapolis, Indiana, USA
| | | | - Holly W Davis
- University of Virginia, Charlottesville, Virginia, USA
| | - Xiang H Peng
- Division of Endocrinology, Department of Medicine, Indiana University Purdue University at Indianapolis, Indiana, USA
| | - Maria Niewolna
- Division of Endocrinology, Department of Medicine, Indiana University Purdue University at Indianapolis, Indiana, USA
| | - Alain Mauviel
- Institute Curie, Orsay, France.,INSERM U1021, Orsay, France.,CNRS UMR3347, Orsay, France.,Université Paris XI, Orsay, France
| | - John M Chirgwin
- Division of Endocrinology, Department of Medicine, Indiana University Purdue University at Indianapolis, Indiana, USA
| | - Theresa A Guise
- Division of Endocrinology, Department of Medicine, Indiana University Purdue University at Indianapolis, Indiana, USA
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17
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Nielsen MFB, Mortensen MB, Detlefsen S. Identification of markers for quiescent pancreatic stellate cells in the normal human pancreas. Histochem Cell Biol 2017; 148:359-380. [PMID: 28540429 DOI: 10.1007/s00418-017-1581-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/13/2017] [Indexed: 12/16/2022]
Abstract
Pancreatic stellate cells (PSCs) play a central role as source of fibrogenic cells in pancreatic cancer and chronic pancreatitis. In contrast to quiescent hepatic stellate cells (qHSCs), a specific marker for quiescent PSCs (qPSCs) that can be used in formalin-fixed and paraffin embedded (FFPE) normal human pancreatic tissue has not been identified. The aim of this study was to identify a marker enabling the identification of qPSCs in normal human FFPE pancreatic tissue. Immunohistochemical (IHC), double-IHC, immunofluorescence (IF) and double-IF analyses were carried out using a tissue microarray consisting of cores with normal human pancreatic tissue. Cores with normal human liver served as control. Antibodies directed against adipophilin, α-SMA, CD146, CRBP-1, cytoglobin, desmin, GFAP, nestin, S100A4 and vinculin were examined, with special emphasis on their expression in periacinar cells in the normal human pancreas and perisinusoidal cells in the normal human liver. The immunolabelling capacity was evaluated according to a semiquantitative scoring system. Double-IF of the markers of interest together with markers for other periacinar cells was performed. Moreover, the utility of histochemical stains for the identification of human qPSCs was examined, and their ultrastructure was revisited by electron microscopy. Adipophilin, CRBP-1, cytoglobin and vinculin were expressed in qHSCs in the liver, whereas cytoglobin and adipophilin were expressed in qPSCs in the pancreas. Adipophilin immunohistochemistry was highly dependent on the preanalytical time interval (PATI) from removal of the tissue to formalin fixation. Cytoglobin, S100A4 and vinculin were expressed in periacinar fibroblasts (FBs). The other examined markers were negative in human qPSCs. Our data indicate that cytoglobin and adipophilin are markers of qPSCs in the normal human pancreas. However, the use of adipophilin as a qPSC marker may be limited due to its high dependence on optimal PATI. Cytoglobin, on the other hand, is a sensitive marker for qPSCs but is expressed in FBs as well.
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Affiliation(s)
- Michael Friberg Bruun Nielsen
- Department of Pathology, Odense University Hospital, J.B. Winsløws Vej 15, 5000, Odense C, Denmark.,Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 19, 5000, Odense C, Denmark
| | - Michael Bau Mortensen
- Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 19, 5000, Odense C, Denmark.,Department of Surgery, HPB Section, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, J.B. Winsløws Vej 15, 5000, Odense C, Denmark. .,Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 19, 5000, Odense C, Denmark.
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18
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Manzanares MÁ, Usui A, Campbell DJ, Dumur CI, Maldonado GT, Fausther M, Dranoff JA, Sirica AE. Transforming Growth Factors α and β Are Essential for Modeling Cholangiocarcinoma Desmoplasia and Progression in a Three-Dimensional Organotypic Culture Model. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1068-1092. [PMID: 28315313 DOI: 10.1016/j.ajpath.2017.01.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 12/19/2016] [Accepted: 01/17/2017] [Indexed: 12/12/2022]
Abstract
To gain insight into the cellular and molecular interactions mediating the desmoplastic reaction and aggressive malignancy of mass-forming intrahepatic cholangiocarcinoma (ICC), we modeled ICC desmoplasia and progression in vitro. A unique three-dimensional (3D) organotypic culture model was established; within a dilute collagen-type I hydrogel, a novel clonal strain of rat cancer-associated myofibroblasts (TDFSM) was co-cultured with a pure rat cholangiocarcinoma cell strain (TDECC) derived from the same ICC type as TDFSM. This 3D organotypic culture model reproduced key features of desmoplastic reaction that closely mimicked those of the in situ tumor, as well as promoted cholangiocarcinoma cell growth and progression. Our results supported a resident liver mesenchymal cell origin of the TDFSM cells, which were not neoplastically transformed. Notably, 3D co-culturing of TDECC cells with TDFSM cells provoked the formation of a dense fibrocollagenous stroma in vitro that was associated with significant increases in both proliferative TDFSM myofibroblastic cells and TDECC cholangiocarcinoma cells accumulating within the gel matrix. This dramatic desmoplastic ICC-like phenotype, which was not observed in the TDECC or TDFSM controls, was highly dependent on transforming growth factor (TGF)-β, but not promoted by TGF-α. However, TGF-α was determined to be a key factor for promoting cholangiocarcinoma cell anaplasia, hyperproliferation, and higher malignant grading in this 3D culture model of desmoplastic ICC.
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Affiliation(s)
- Miguel Á Manzanares
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University, Richmond, Virginia
| | - Akihiro Usui
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University, Richmond, Virginia
| | - Deanna J Campbell
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University, Richmond, Virginia
| | - Catherine I Dumur
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University, Richmond, Virginia
| | - Gabrielle T Maldonado
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University, Richmond, Virginia
| | - Michel Fausther
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Jonathan A Dranoff
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Alphonse E Sirica
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University, Richmond, Virginia.
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19
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Lamora A, Mullard M, Amiaud J, Brion R, Heymann D, Redini F, Verrecchia F. Anticancer activity of halofuginone in a preclinical model of osteosarcoma: inhibition of tumor growth and lung metastases. Oncotarget 2016; 6:14413-27. [PMID: 26015407 PMCID: PMC4546476 DOI: 10.18632/oncotarget.3891] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 04/24/2015] [Indexed: 12/11/2022] Open
Abstract
Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastases are present at diagnosis. Because we recently demonstrated that TGF-β/Smad cascade plays a crucial role in osteosarcoma metastatic progression, we investigated the effect of halofuginone, identified as an inhibitor of the TGF-β/Smad3 cascade, on osteosarcoma progression. A preclinical model of osteosarcoma was used to evaluate the impact of halofuginone on tumor growth, tumor microenvironment and metastasis development. In vivo experiments showed that halofuginone reduces primary tumor growth and lung metastases development. In vitro experiments demonstrated that halofuginone decreases cell viability mainly by its ability to induce caspase-3 dependent cell apoptosis. Moreover, halofuginone inhibits the TGF-β/Smad3 cascade and the response of TGF-β key targets involved in the metastases dissemination process such as MMP-2. In addition, halofuginone treatment affects the “vicious cycle” established between tumor and bone cells, and therefore the tumor-associated bone osteolysis. Together, these results demonstrate that halofuginone decreased primary osteosarcoma development and associated lung metastases by targeting both the tumor cells and the tumor microenvironment. Using halofuginone may be a promising therapeutic strategy against tumor progression of osteosarcoma specifically against lung metastases dissemination.
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Affiliation(s)
- Audrey Lamora
- INSERM, UMR 957, Equipe Labellisée Ligue contre le Cancer 2012, Nantes, France.,Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.,CHU Hôtel Dieu, Nantes, France.,Inserm Liliane Bettencourt School, France
| | - Mathilde Mullard
- INSERM, UMR 957, Equipe Labellisée Ligue contre le Cancer 2012, Nantes, France.,Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.,CHU Hôtel Dieu, Nantes, France
| | - Jérôme Amiaud
- INSERM, UMR 957, Equipe Labellisée Ligue contre le Cancer 2012, Nantes, France.,Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.,CHU Hôtel Dieu, Nantes, France
| | - Régis Brion
- INSERM, UMR 957, Equipe Labellisée Ligue contre le Cancer 2012, Nantes, France.,Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.,CHU Hôtel Dieu, Nantes, France
| | - Dominique Heymann
- INSERM, UMR 957, Equipe Labellisée Ligue contre le Cancer 2012, Nantes, France.,Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.,CHU Hôtel Dieu, Nantes, France
| | - Françoise Redini
- INSERM, UMR 957, Equipe Labellisée Ligue contre le Cancer 2012, Nantes, France.,Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.,CHU Hôtel Dieu, Nantes, France
| | - Franck Verrecchia
- INSERM, UMR 957, Equipe Labellisée Ligue contre le Cancer 2012, Nantes, France.,Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.,CHU Hôtel Dieu, Nantes, France
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20
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Koohestani F, Qiang W, MacNeill AL, Druschitz SA, Serna VA, Adur M, Kurita T, Nowak RA. Halofuginone suppresses growth of human uterine leiomyoma cells in a mouse xenograft model. Hum Reprod 2016; 31:1540-51. [PMID: 27130615 DOI: 10.1093/humrep/dew094] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 04/06/2016] [Indexed: 12/14/2022] Open
Abstract
STUDY QUESTION Does halofuginone (HF) inhibit the growth of human uterine leiomyoma cells in a mouse xenograft model? SUMMARY ANSWER HF suppresses the growth of human uterine leiomyoma cells in a mouse xenograft model through inhibiting cell proliferation and inducing apoptosis. WHAT IS KNOWN ALREADY Uterine leiomyomas are the most common benign tumors of the female reproductive tract. HF can suppress the growth of human uterine leiomyoma cells in vitro. The mouse xenograft model reflects the characteristics of human leiomyomas. STUDY DESIGN, SIZE, DURATION Primary leiomyoma smooth muscle cells from eight patients were xenografted under the renal capsule of adult, ovariectomized NOD-scid IL2Rγ(null) mice (NSG). Mice were treated with two different doses of HF or vehicle for 4 weeks with six to eight mice per group. PARTICIPANTS/MATERIALS, SETTING, METHODS Mouse body weight measurements and immunohistochemical analysis of body organs were carried out to assess the safety of HF treatment. Xenografted tumors were measured and analyzed for cellular and molecular changes induced by HF. Ovarian steroid hormone receptors were evaluated for possible modulation by HF. MAIN RESULTS AND THE ROLE OF CHANCE Treatment of mice carrying human UL xenografts with HF at 0.25 or 0.50 mg/kg body weight for 4 weeks resulted in a 35-40% (P < 0.05) reduction in tumor volume. The HF-induced volume reduction was accompanied by increased apoptosis and decreased cell proliferation. In contrast, there was no significant change in the collagen content either at the transcript or protein level between UL xenografts in control and HF groups. HF treatment did not change the expression level of ovarian steroid hormone receptors. No adverse pathological effects were observed in other tissues from mice undergoing treatment at these doses. LIMITATIONS, REASONS FOR CAUTION While this study did test the effects of HF on human leiomyoma cells in an in vivo model, HF was administered to mice whose tolerance and metabolism of the drug may differ from that in humans. Also, the longer term effects of HF treatment are yet unclear. WIDER IMPLICATIONS OF THE FINDINGS The results of this study showing the effectiveness of HF in reducing UL tumor growth by interfering with the main cellular processes regulating cell proliferation and apoptosis are in agreement with previous studies on the effects of HF on other fibrotic diseases. HF can be considered as a candidate for reducing the size of leiomyomas, particularly prior to surgery. STUDY FUNDING/COMPETING INTERESTS This project was funded by NIH PO1HD057877 and R01 HD064402. Authors report no competing interests.
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Affiliation(s)
- Faezeh Koohestani
- Department of Animal Sciences, University of Illinois, Urbana, IL 61801, USA Present address: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Wenan Qiang
- Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA Department of Pathology, Northwestern University, Chicago, IL 60611, USA Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Amy L MacNeill
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois, Urbana, IL 61801, USA Present address: Department of Microbiology, Immunology and Pathology, Colorado State University, Ft. Collins, CO 80523, USA
| | - Stacy A Druschitz
- Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA
| | - Vanida A Serna
- Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA Present address: Department of Molecular & Cellular Biochemistry, The Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
| | - Malavika Adur
- Department of Animal Sciences, University of Illinois, Urbana, IL 61801, USA
| | - Takeshi Kurita
- Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60611, USA Present address: Department of Molecular & Cellular Biochemistry, The Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
| | - Romana A Nowak
- Department of Animal Sciences, University of Illinois, Urbana, IL 61801, USA
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Lin R, Yi S, Gong L, Liu W, Wang P, Liu N, Zhao L, Wang P. Inhibition of TGF-β signaling with halofuginone can enhance the antitumor effect of irradiation in Lewis lung cancer. Onco Targets Ther 2015; 8:3549-59. [PMID: 26664138 PMCID: PMC4671802 DOI: 10.2147/ott.s92518] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Purpose It was reported that halofuginone has inhibitory effects on transforming growth factor-beta (TGF-β) signaling pathway. The study was aimed to: 1) evaluate the antitumor effects of halofuginone in combination with radiation therapy; and 2) preliminarily explore the possible mechanisms associated with these effects. Materials and methods Lewis lung cancer (LLC) cell lines and xenograft model mice randomly received ionizing radiation, halofuginone, or combination treatment. The changes associated with antitumor effect of halofuginone, including hepatic and pulmonary metastases and survival, were observed. The migratory and invasive capabilities of LLC cells were investigated by using scratch assay and transwell chamber assay. The expression level of TGF-β and its activation were assessed with enzyme-linked immunosorbent assay, immunohistochemistry, and Western blotting. Chi-square test and survival analysis were performed for statistical analysis. P<0.05 was regarded as statistically significant. Unless otherwise specified, data were expressed as mean ± standard deviation
(x¯±s). Results After irradiation, the migratory and invasive capabilities of LLC cells were strengthened, and the TGF-β pathway was activated. The addition of halofuginone can significantly inhibit the migratory and invasive trend induced by irradiation, and the TGF-β pathway was also inhibited. In animal xenograft model, the addition of halofuginone to irradiation inhibited the growth of subcutaneously implanted xenografts, reduced hepatic and pulmonary metastases, and improved survival of the mice. The effect was accompanied by a decrease in TGF-β levels. In addition, halofuginone inhibited type I collagen expression and angiopoiesis. Conclusion Halofuginone treatment not only produces significant radiation-sensitizing effects but also inhibits hepatic and pulmonary metastases. The underlying mechanisms of these phenomena warrant additional studies.
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Affiliation(s)
- Runlong Lin
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Shuai Yi
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Linlin Gong
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Weishuai Liu
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Peng Wang
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Ningbo Liu
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Lujun Zhao
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Ping Wang
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
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Abstract
Halofuginone is an analog of febrifugine-an alkaloid originally isolated from the plant Dichroa febrifuga. During recent years, halofuginone has attracted much attention because of its wide range of beneficial biological activities, which encompass malaria, cancer, and fibrosis-related and autoimmune diseases. At present two modes of halofuginone actions have been described: (1) Inhibition of Smad3 phosphorylation downstream of the TGFβ signaling pathway results in inhibition of fibroblasts-to-myofibroblasts transition and fibrosis. (2) Inhibition of prolyl-tRNA synthetase (ProRS) activity in the blood stage of malaria and inhibition of Th17 cell differentiation thereby inhibiting inflammation and the autoimmune reaction by activation of the amino acid starvation and integrated stress responses. This review deals with the history and origin of this natural product, its synthesis, its known modes of action, and it's various biological activities in pre-clinical animal models and in humans.
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Affiliation(s)
- Mark Pines
- The Volcani Center, Institute of Animal Science, P.O. Box 6, Bet Dagan 50250, Israel.
| | - Itai Spector
- The Volcani Center, Institute of Animal Science, P.O. Box 6, Bet Dagan 50250, Israel.
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Plant-derived anticancer agents: a promising treatment for bone metastasis. BONEKEY REPORTS 2014; 3:599. [PMID: 28243436 DOI: 10.1038/bonekey.2014.94] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 09/10/2014] [Indexed: 02/07/2023]
Abstract
Bone metastasis is a very frequent complication of advanced cancer, and it remains an incurable disease. Current therapies that have been approved for the treatment of bone metastases delay the occurrence of skeletal-related events and can extend the patient's lifespan by a few years. However, they will not cure or cause the regression of established bone metastases, and new side effects are emerging after prolonged treatment. Thus, new therapies are severely needed. There are compelling evidences from in vitro and in vivo preclinical studies that support the use of compounds derived from plants to treat several forms of cancers including bone metastasis. More than 25% of the drugs used during the past 20 years were directly derived from plants, whereas another 25% are chemically altered natural products. Still, only 5-15% of the ∼250 000 higher plants have ever been investigated for bioactive compounds. There is a growing interest for the study of anticancer drugs with relatively low side effects that target specific key signaling pathways that control the establishment and progression of the cancer metastasis. Therefore, further studies are needed to identify new natural compounds with high efficiency in cancer prevention and treatment. Extensive reviews about plant-derived agents and their use in cancer have been published, but none when it comes to the treatment of bone metastases. Only a few of these compounds have been evaluated for the treatment of bone metastasis; here we describe some of the most prominent ones that are having the potential to reach the clinic soon.
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Pines M. Halofuginone for fibrosis, regeneration and cancer in the gastrointestinal tract. World J Gastroenterol 2014; 20:14778-14786. [PMID: 25356039 PMCID: PMC4209542 DOI: 10.3748/wjg.v20.i40.14778] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2014] [Revised: 05/01/2014] [Accepted: 06/13/2014] [Indexed: 02/06/2023] Open
Abstract
Organ fibrosis and architectural remodeling can severely disrupt tissue function, often with fatal consequences. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli, and the key cellular mediator of fibrosis comprises the myofibroblasts which, when activated, serve as the primary collagen-producing cells. Complex links exist between fibrosis, regeneration and carcinogenesis, and the concept that all organs contain common tissue fibrosis pathways that could be potential therapeutic targets is an attractive one. Because of the major impact of fibrosis on human health there is an unmet need for safe and effective therapies that directly target fibrosis. Halofuginone inhibits tissue fibrosis and regeneration, and thereby affects the development of tumors in various tissues along the gastrointestinal tract. The high efficacy of halofuginone in reducing the fibrosis that affects tumor growth and tissue regeneration is probably due to its dual role in inhibiting the signaling pathway of transforming growth factor β, on the one hand, and inhibiting the development of Th17 cells, on the other hand. At present halofuginone is being evaluated in a clinical trial for other fibrotic indication, and any clinical success in that trial would allow the use of halofuginone, also for all other fibrotic indications, including those of the gastrointestinal tract.
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Park MK, Park JS, Park EM, Lim MA, Kim SM, Lee DG, Baek SY, Yang EJ, Woo JW, Lee J, Kwok SK, Kim HY, Cho ML, Park SH. Halofuginone ameliorates autoimmune arthritis in mice by regulating the balance between Th17 and Treg cells and inhibiting osteoclastogenesis. Arthritis Rheumatol 2014; 66:1195-207. [PMID: 24782183 DOI: 10.1002/art.38313] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Accepted: 12/05/2013] [Indexed: 12/19/2022]
Abstract
OBJECTIVE The small molecule halofuginone has been shown to inhibit fibrosis, angiogenesis, and tumor progression. This study was undertaken to evaluate the effects of halofuginone in preventing autoimmune arthritis in mice. METHODS The effects of halofuginone on joint diseases were assessed by clinical scoring and histologic analysis. Protein expression levels were confirmed by immunohistochemistry, enzyme-linked immunosorbent assay, flow cytometry, and/or Western blotting. The expression levels of messenger RNA (mRNA) for various molecules were determined by real-time polymerase chain reaction (PCR). Proliferation of osteoclast precursors was assessed by bromodeoxyuridine uptake. Osteoclast differentiation and activity were determined by quantifying tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and area of resorbed bone. RESULTS Treatment with halofuginone suppressed the development of autoimmune arthritis and reciprocally regulated Th17 cells and FoxP3+ Treg cells. These effects of halofuginone on Th17 differentiation involved increased signaling of ERK and reduction of STAT-3 and NF-ATc1 expression. Furthermore, halofuginone induced the expression of indoleamine 2,3-dioxygenase (IDO) in dendritic cells, leading to reduced production of Th17 cells. In addition, halofuginone prevented the formation and activity of osteoclasts through suppression of transcription factors, such as activator protein 1 and NF-ATc1, and inhibited cell cycle arrest by the committed osteoclast precursors via expression of Ccnd1 encoding cyclin D1. CONCLUSION Taken together, our results suggest that halofuginone is a promising therapeutic agent for the treatment of Th17 cell-mediated inflammatory diseases and bone diseases.
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Haqq J, Howells LM, Garcea G, Metcalfe MS, Steward WP, Dennison AR. Pancreatic stellate cells and pancreas cancer: current perspectives and future strategies. Eur J Cancer 2014; 50:2570-82. [PMID: 25091797 DOI: 10.1016/j.ejca.2014.06.021] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 06/25/2014] [Accepted: 06/30/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis. To date patient outcomes have not improved principally due to the limited number of patients suitable for surgical resections and the radiation and chemotherapy resistance of these tumours. In the last decade, a failure of conventional therapies has forced researchers to re-examine the environment of PDAC. The tumour environment has been demonstrated to consist of an abundance of stroma containing many cells but predominantly pancreatic stellate cells (PSCs). Recent research has focused on understanding the interaction between PSCs and PDAC cells in vitro and in vivo. It is believed that the interaction between these cells is responsible for supporting tumour growth, invasion and metastasis and creating the barrier to delivery of chemotherapeutics. Novel approaches which focus on the interactions between PDAC and PSCs which sustain the tumour microenvironment may achieve significant patient benefits. This manuscript reviews the current evidence regarding PSCs, their interaction with PDAC cells and the potential implication this may have for future therapies. METHODS A PubMed search was carried out for the terms 'pancreas cancer' OR 'pancreatic cancer', AND 'pancreatic stellate cells', NOT 'hepatic stellate cells'. All studies were screened and assessed for their eligibility and manuscripts exploring the relationship between PSCs and PDAC were included. The studies were subdivided into in vitro and in vivo groups. RESULTS One hundred and sixty-six manuscripts were identified and reduced to seventy-three in vitro and in vivo studies for review. The manuscripts showed that PDAC cells and PSCs interact with each other to enhance proliferation, reduce apoptosis and increase migration and invasion of cancer cells. The pathways through which they facilitate these actions provide potential targets for future novel therapies. CONCLUSION There is accumulating evidence supporting the multiple roles of PSCs in establishing the tumour microenvironment and supporting the survival of PDAC. To further validate these findings there is a need for greater use of physiologically relevant models of pancreatic cancer in vitro such as three dimensional co-cultures and the use of orthotopic and genetically engineered murine (GEM) models in vivo.
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Affiliation(s)
- Jonathan Haqq
- Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom.
| | - Lynne M Howells
- Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom
| | - Giuseppe Garcea
- Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom
| | - Matthew S Metcalfe
- Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom
| | - Will P Steward
- Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom
| | - Ashley R Dennison
- Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom
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Chen H, Mrazek AA, Wang X, Ding C, Ding Y, Porro LJ, Liu H, Chao C, Hellmich MR, Zhou J. Design, synthesis, and characterization of novel apigenin analogues that suppress pancreatic stellate cell proliferation in vitro and associated pancreatic fibrosis in vivo. Bioorg Med Chem 2014; 22:3393-404. [PMID: 24837156 DOI: 10.1016/j.bmc.2014.04.043] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 04/14/2014] [Accepted: 04/22/2014] [Indexed: 02/07/2023]
Abstract
Accumulating evidence suggests that activated pancreatic stellate cells (PSC) play an important role in chronic pancreatitis (CP), and inhibition of the activated PSC is considered as a potential strategy for the treatment and prevention of CP. Herein, we disclose our findings that apigenin and its novel analogues suppress the proliferation and induce apoptosis in PSC, which reduce the PSC-mediated fibrosis in CP. Chemical modifications of apigenin have been directed to build a focused library of O-alkylamino-tethered apigenin derivatives at 4'-O position of the ring C with the attempt to enhance the potency and drug-like properties including aqueous solubility. A number of compounds such as 14, 16, and 24 exhibited potent antiproliferative effects as well as improved aqueous solubility. Intriguingly, apigenin, new analogues 23 and 24 displayed significant efficacy to reduce pancreatic fibrosis even at a low dose of 0.5mg/kg in our proof-of-concept study using a preclinical in vivo mouse model of CP.
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Affiliation(s)
- Haijun Chen
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Amy A Mrazek
- Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Xiaofu Wang
- Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Chunyong Ding
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Ye Ding
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Laura J Porro
- Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Huiling Liu
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Celia Chao
- Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Mark R Hellmich
- Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, United States.
| | - Jia Zhou
- Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
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Reduction of burn scar formation by halofuginone-eluting silicone gel sheets: a controlled study on nude mice. Ann Plast Surg 2014; 72:489. [PMID: 24618743 DOI: 10.1097/sap.0b013e318281ad59] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Tang D, Zhang J, Yuan Z, Gao J, Wang S, Ye N, Li P, Gao S, Miao Y, Wang D, Jiang K. Pancreatic satellite cells derived galectin-1 increase the progression and less survival of pancreatic ductal adenocarcinoma. PLoS One 2014; 9:e90476. [PMID: 24595374 PMCID: PMC3942444 DOI: 10.1371/journal.pone.0090476] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2013] [Accepted: 01/31/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Galectin-1, a member of carbohydrate-binding proteins with a polyvalent function on tumor progression, was found strongly expressed in pancreatic satellite cells (PSCs), which partner in crime with cancer cells and promote the development of pancreatic ductal adenocarcinoma (PDAC). We evaluated the effects of PSCs derived Galectin-1 on the progression of PDAC, as well as the tumor establishment and development in mouse xenografts. METHODS The relationship between immunohistochemistry staining intensity of Galectin-1 and clinicopathologic variables were assessed in 66 PDAC tissues, 18 chronic pancreatitis tissues and 10 normal controls. The roles of PSCs isolated from PDAC and normal pancreas on the proliferative activity, MMP2 and MMP9 expression, and the invasion of CFPAC-1 in the co-cultured system, as well as on the tumor establishment and development in mouse xenografts by mixed implanting with CFPAC-1 subcutaneously were evaluated. RESULTS Galectin-1 expression was gradually increased from normal pancreas (negative), chronic pancreatitis (weak) to PDAC (strong), in which Galectin-1 expression was also increased from well, moderately to poorly differentiated PDAC. Galectin-1 staining intensity of pancreatic cancer tissue was associated with increase in tumor size, lymph node metastasis, perineural invasion and differentiation and UICC stage, and served as the independent prognostic indicator of poor survival of pancreatic cancer. In vitro and in vivo experiments indicated that TGF-β1 upregulated Galectin-1 expression in PSCs, which could further promotes the proliferative activity, MMP2 and MMP9 expression, and invasion of pancreatic cancer cells, as well as the tumor establishment and growth. CONCLUSION Galectin-1 expression in stromal cells of pancreatic cancer suggests that this protein plays a role in the promotion of cancer cells invasion and metastasis and provides a therapeutic target for the treatment of pancreatic cancer.
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Affiliation(s)
- Dong Tang
- Department of General Surgery, Subei People's Hospital of Jiangsu Province (Clinic Medical College of Yang Zhou University), Yangzhou, Jiangsu Province, China
| | - Jingqiu Zhang
- Department of Digestive System, Subei People's Hospital of Jiangsu Province (Clinic Medical College of Yang Zhou University), Yangzhou, Jiangsu Province, China
| | - Zhongxu Yuan
- Department of General Surgery, Anhui no. 2 Provincial People's Hospital, Hefei, Anhui Province, China
| | - Jun Gao
- Department of General Surgery, Subei People's Hospital of Jiangsu Province (Clinic Medical College of Yang Zhou University), Yangzhou, Jiangsu Province, China
| | - Sen Wang
- College of Clinical Medicine, Nanjing Medical University (the First Affiliated Hospital of Nanjing Medical University), Nanjing, Jiangsu Province, China
| | - Nianyuan Ye
- Department of General Surgery, Subei People's Hospital of Jiangsu Province (Clinic Medical College of Yang Zhou University), Yangzhou, Jiangsu Province, China
| | - Ping Li
- Department of General Surgery, Subei People's Hospital of Jiangsu Province (Clinic Medical College of Yang Zhou University), Yangzhou, Jiangsu Province, China
| | - Sujun Gao
- Department of Digestive System, Subei People's Hospital of Jiangsu Province (Clinic Medical College of Yang Zhou University), Yangzhou, Jiangsu Province, China
| | - Yi Miao
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Daorong Wang
- Department of General Surgery, Subei People's Hospital of Jiangsu Province (Clinic Medical College of Yang Zhou University), Yangzhou, Jiangsu Province, China
| | - Kuirong Jiang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
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McLaughlin NP, Evans P, Pines M. The chemistry and biology of febrifugine and halofuginone. Bioorg Med Chem 2014; 22:1993-2004. [PMID: 24650700 DOI: 10.1016/j.bmc.2014.02.040] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Revised: 02/14/2014] [Accepted: 02/18/2014] [Indexed: 12/11/2022]
Abstract
The trans-2,3-disubstituted piperidine, quinazolinone-containing natural product febrifugine (also known as dichroine B) and its synthetic analogue, halofuginone, possess antimalarial activity. More recently studies have also shown that halofuginone acts as an agent capable of reducing fibrosis, an indication with clinical relevance for several disease states. This review summarizes historical isolation studies and the chemistry performed which culminated in the correct structural elucidation of naturally occurring febrifugine and its isomer isofebrifugine. It also includes the range of febrifugine analogues prepared for antimalarial evaluation, including halofuginone. Finally, a section detailing current opinion in the field of halofuginone's human biology is included.
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Affiliation(s)
- Noel P McLaughlin
- Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland
| | - Paul Evans
- Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland.
| | - Mark Pines
- Agricultural Research Organization, The Volcani Center, Institute of Animal Science, P.O. Box 6, Bet Dagan 50250, Israel.
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Tang D, Wang D, Yuan Z, Xue X, Zhang Y, An Y, Chen J, Tu M, Lu Z, Wei J, Jiang K, Miao Y. Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma. Int J Cancer 2013; 132:993-1003. [PMID: 22777597 DOI: 10.1002/ijc.27715] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Revised: 06/20/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumors with poor prognosis due to extremely high malignancy, low rate of eligibility for surgical resection and chemoradiation resistance. Increasing evidence indicate that the interaction between activated pancreatic stellate cells (PSCs) and PDAC cells plays an important role in the development of PDAC. By producing high levels of cytokines, chemotactic factors, growth factors and excessive extracellular matrix (ECM), PSCs create desmoplasia and a hypoxic microenvironment that promote the initiation, development, evasion of immune surveillance, invasion, metastasis and resistance to chemoradiation of PDAC. Therefore, targeting the interaction between PSCs and PDAC cells may represent a novel therapeutic approach to advanced PDAC, especially therapies that target PSCs of the pancreatic tumor microenvironment.
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Affiliation(s)
- Dong Tang
- Department of Gastrointestinal Surgery, Subei People's Hospital of Jiangsu Province (Clinical Medical College of Yangzhou University), Yangzhou, People's Republic of China
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Hong S, Kim HY, Kim J, Ha HT, Kim YM, Bae E, Kim TH, Lee KC, Kim SJ. Smad7 protein induces interferon regulatory factor 1-dependent transcriptional activation of caspase 8 to restore tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. J Biol Chem 2012; 288:3560-70. [PMID: 23255602 DOI: 10.1074/jbc.m112.400408] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Smad7 has been known as a negative regulator for the transforming growth factor-β (TGF-β) signaling pathway through feedback regulation. However, Smad7 has been suspected to have other biological roles through the regulation of gene transcription. By screening differentially regulated genes, we found that the caspase 8 gene was highly up-regulated in Smad7-expressing cells. Smad7 was able to activate the caspase 8 promoter through recruitment of the interferon regulatory factor 1 (IRF1) transcription factor to the interferon-stimulated response element (ISRE) site. Interaction of Smad7 on the caspase 8 promoter was confirmed with electrophoretic mobility shift assay and chromatin immunoprecipitation experiment. Interestingly, Smad7 did not directly interact with the ISRE site, but it increased the binding activity of IRF1 with ISRE. These results support that Smad7 recruits IRF1 protein on the caspase 8 promoter and functions as a transcriptional coactivator. To confirm the biological significance of caspase 8 up-regulation, we tested tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated cell death assay in breast cancer cells. Smad7 in apoptosis-resistant MCF7 cells markedly sensitized the cells to TRAIL-induced cell death by restoring the caspase cascade. Furthermore, restoration of caspase 8-mediated apoptosis pathway repressed the tumor growth in the xenograft model. In conclusion, we suggest a novel role for Smad7 as a transcriptional coactivator for caspase 8 through the interaction with IRF1 in regulation of the cell death pathway.
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Affiliation(s)
- Suntaek Hong
- Department of Molecular Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 406-840, Republic of Korea.
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Juárez P, Mohammad KS, Yin JJ, Fournier PGJ, McKenna RC, Davis HW, Peng XH, Niewolna M, Javelaud D, Chirgwin JM, Mauviel A, Guise TA. Halofuginone inhibits the establishment and progression of melanoma bone metastases. Cancer Res 2012; 72:6247-56. [PMID: 23002206 DOI: 10.1158/0008-5472.can-12-1444] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
TGF-β derived from bone fuels melanoma bone metastases by inducing tumor secretion of prometastatic factors that act on bone cells to change the skeletal microenvironment. Halofuginone is a plant alkaloid derivative that blocks TGF-β signaling with antiangiogenic and antiproliferative properties. Here, we show for the first time that halofuginone therapy decreases development and progression of bone metastasis caused by melanoma cells through the inhibition of TGF-β signaling. Halofuginone treatment of human melanoma cells inhibited cell proliferation, phosphorylation of SMAD proteins in response to TGF-β, and TGF-β-induced SMAD-driven transcription. In addition, halofuginone reduced expression of TGF-β target genes that enhance bone metastases, including PTHrP, CTGF, CXCR4, and IL11. Also, cell apoptosis was increased in response to halofuginone. In nude mice inoculated with 1205 Lu melanoma cells, a preventive protocol with halofuginone inhibited bone metastasis. The beneficial effects of halofuginone treatment were comparable with those observed with other anti-TGF-β strategies, including systemic administration of SD208, a small-molecule inhibitor of TGF-β receptor I kinase, or forced overexpression of Smad7, a negative regulator of TGF-β signaling. Furthermore, mice with established bone metastases treated with halofuginone had significantly less osteolysis than mice receiving placebo assessed by radiography. Thus, halofuginone is also effective in reducing the progression of melanoma bone metastases. Moreover, halofuginone treatment reduced melanoma metastasis to the brain, showing the potential of this novel treatment against cancer metastasis.
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Affiliation(s)
- Patricia Juárez
- Division of Endocrinology and Metabolism, Department of Medicine, Indiana University-Purdue University Indianapolis, Walther Hall, C132 980 W Walnut Street, Indianapolis, IN 46202, USA
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Spector I, Zilberstein Y, Lavy A, Nagler A, Genin O, Pines M. Involvement of host stroma cells and tissue fibrosis in pancreatic tumor development in transgenic mice. PLoS One 2012; 7:e41833. [PMID: 22848627 PMCID: PMC3404977 DOI: 10.1371/journal.pone.0041833] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Accepted: 06/26/2012] [Indexed: 12/11/2022] Open
Abstract
Introduction Stroma cells and extracellular matrix (ECM) components provide the pivotal microenvironment for tumor development. The study aimed to evaluate the importance of the pancreatic stroma for tumor development. Methods Pancreatic tumor cells were implanted subcutaneously into green fluorescent protein transgenic mice, and stroma cells invading the tumors were identified through immunohistochemistry. Inhibition of tumor invasion by stroma cells was achieved with halofuginone, an inhibitor of TGFβ/Smad3 signaling, alone or in combination with chemotherapy. The origin of tumor ECM was evaluated with species-specific collagen I antibodies and in situ hybridization of collagen α1(I) gene. Pancreatic fibrosis was induced by cerulean injection and tumors by spleen injection of pancreatic tumor cells. Results Inhibition of stroma cell infiltration and reduction of tumor ECM levels by halofuginone inhibited development of tumors derived from mouse and human pancreatic cancer cells. Halofuginone reduced the number only of stroma myofibroblasts expressing both contractile and collagen biosynthesis markers. Both stroma myofibroblasts and tumor cells generated ECM that contributes to tumor growth. Combination of treatments that inhibit stroma cell infiltration, cause apoptosis of myofibroblasts and inhibit Smad3 phosphorylation, with chemotherapy that increases tumor-cell apoptosis without affecting Smad3 phosphorylation was more efficacious than either treatment alone. More tumors developed in fibrotic than in normal pancreas, and prevention of tissue fibrosis greatly reduced tumor development. Conclusions The utmost importance of tissue fibrosis and of stroma cells for tumor development presents potential new therapy targets, suggesting combination therapy against stroma and neoplastic cells as a treatment of choice.
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Affiliation(s)
- Itai Spector
- Institute of Animal Sciences, The Volcani Center, Bet Dagan, Israel
- Department of Animal Sciences, Hebrew University of Jerusalem, Rehovot, Israel
| | - Yael Zilberstein
- The Sackler Cellular and Molecular Imaging Center (SCMIC), Tel Aviv University, Tel Aviv, Israel
| | - Adi Lavy
- Institute of Animal Sciences, The Volcani Center, Bet Dagan, Israel
- Department of Animal Sciences, Hebrew University of Jerusalem, Rehovot, Israel
| | - Arnon Nagler
- Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Olga Genin
- Institute of Animal Sciences, The Volcani Center, Bet Dagan, Israel
| | - Mark Pines
- Institute of Animal Sciences, The Volcani Center, Bet Dagan, Israel
- * E-mail:
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Leiba M, Jakubikova J, Klippel S, Mitsiades CS, Hideshima T, Tai YT, Leiba A, Pines M, Richardson PG, Nagler A, Anderson KC. Halofuginone inhibits multiple myeloma growth in vitro and in vivo and enhances cytotoxicity of conventional and novel agents. Br J Haematol 2012; 157:718-31. [PMID: 22533681 DOI: 10.1111/j.1365-2141.2012.09120.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2012] [Accepted: 03/06/2012] [Indexed: 12/13/2022]
Abstract
Multiple Myeloma (MM), a malignancy of plasma cells, remains incurable despite the use of conventional and novel therapies. Halofuginone (HF), a synthetic derivative of quinazolinone alkaloid, has recently been shown to have anti-cancer activity in various preclinical settings. This study demonstrated the anti-tumour activity of HF against a panel of human MM cell lines and primary patient-derived MM cells, regardless of their sensitivity to conventional therapy or novel agents. HF showed anti-MM activity in vivo using a myeloma xenograft mouse model. HF suppressed proliferation of myeloma cells alone and when co-cultured with bone marrow stromal cells. Similarly, HF induced apoptosis in MM cells even in the presence of insulin-like growth factor 1 or interleukin 6. Importantly, HF, even at high doses, did not induce cytotoxicity against CD40 activated peripheral blood mononuclear cells from normal donors. HF treatment induced accumulation of cells in the G(0) /G(1) cell cycle and induction of apoptotic cell death associated with depletion of mitochondrial membrane potential; cleavage of poly (ADP-ribose) polymerase and caspases-3, 8 and 9 as well as down-regulation of anti-apoptotic proteins including Mcl-1 and X-IAP. Multiplex analysis of phosphorylation of diverse components of signalling cascades revealed that HF induced changes in P38MAPK activation; increased phosphorylation of c-jun, c-jun NH(2)-terminal kinase (JNK), p53 and Hsp-27. Importantly, HF triggered synergistic cytotoxicity in combination with lenalidomide, melphalan, dexamethasone, and doxorubicin. Taken together, these preclinical studies provide the preclinical framework for future clinical studies of HF in MM.
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Affiliation(s)
- Merav Leiba
- Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02115, USA
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Ansari D, Chen BC, Dong L, Zhou MT, Andersson R. Pancreatic cancer: translational research aspects and clinical implications. World J Gastroenterol 2012; 18:1417-1424. [PMID: 22509073 PMCID: PMC3319937 DOI: 10.3748/wjg.v18.i13.1417] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Revised: 12/29/2011] [Accepted: 01/18/2012] [Indexed: 02/06/2023] Open
Abstract
Despite improvements in surgical techniques and adjuvant chemotherapy, the overall mortality rates in pancreatic cancer have generally remained relatively unchanged and the 5-year survival rate is actually below 2%. This paper will address the importance of achieving an early diagnosis and identifying markers for prognosis and response to therapy such as genes, proteins, microRNAs or epigenetic modifications. However, there are still major hurdles when translating investigational biomarkers into routine clinical practice. Furthermore, novel ways of secondary screening in high-risk individuals, such as artificial neural networks and modern imaging, will be discussed. Drug resistance is ubiquitous in pancreatic cancer. Several mechanisms of drug resistance have already been revealed, including human equilibrative nucleoside transporter-1 status, multidrug resistance proteins, aberrant signaling pathways, microRNAs, stromal influence, epithelial-mesenchymal transition-type cells and recently the presence of cancer stem cells/cancer-initiating cells. These factors must be considered when developing more customized types of intervention ("personalized medicine"). In the future, multifunctional nanoparticles that combine a specific targeting agent, an imaging probe, a cell-penetrating agent, a biocompatible polymer and an anti-cancer drug may become valuable for the management of patients with pancreatic cancer.
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Interventions that induce modifications in the tumor microenvironment. Cancer Radiother 2011; 15:376-82. [PMID: 21571567 DOI: 10.1016/j.canrad.2011.01.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2010] [Accepted: 01/15/2011] [Indexed: 02/06/2023]
Abstract
Non-surgical cancer therapeutic strategies have focused primarily on direct killing of cancer cells by chemotherapy and/or radiation therapy. However, it is becoming increasingly clear that the efficacy of these therapies can be significantly influenced by the tumor microenvironment. The microenvironment poses both obstacles and opportunities for new therapeutic interventions. New developments in this area are the topic of this review.
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Dunér S, Lopatko Lindman J, Ansari D, Gundewar C, Andersson R. Pancreatic cancer: the role of pancreatic stellate cells in tumor progression. Pancreatology 2011; 10:673-681. [PMID: 21242706 DOI: 10.1159/000320711] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma is an aggressive and highly lethal disease frequently characterized by a dense stromal or desmoplastic response. Accumulating evidence exists that tumor desmoplasia plays a central role in disease progression and that e.g. activated pancreatic stellate cells (PSCs) are responsible for the excess matrix production. The mechanisms underlying the tumor versus stroma interplay are complex. Pancreatic cancer cells release mitogenic and fibrogenic stimulants, such as transforming growth factor β(1), platelet-derived growth factor (PDGF), sonic hedgehog, galectin 3, endothelin 1 and serine protease inhibitor nexin 2, all of which may promote the activated PSC phenotype. Stellate cells in turn secrete various factors, including PDGF, stromal-derived factor 1, epidermal growth factor, insulin-like growth factor 1, fibroblast growth factor, secreted protein acidic and rich in cysteine, matrix metalloproteinases, small leucine-rich proteoglycans, periostin and collagen type I that mediate effects on tumor growth, invasion, metastasis and resistance to chemotherapy. This review intends to shed light on the mechanisms by which PSCs in the stroma influence pancreatic cancer development. The increased understanding of this interaction will be of potential value in designing new modalities of targeted therapy. and IAP.
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Affiliation(s)
- Siri Dunér
- Department of Surgery, Clinical Sciences Lund, Lund University and Lund University Hospital, Lund, Sweden
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Har-Shai Y, Mettanes I, Zilberstein Y, Genin O, Spector I, Pines M. Keloid histopathology after intralesional cryosurgery treatment. J Eur Acad Dermatol Venereol 2010; 25:1027-36. [DOI: 10.1111/j.1468-3083.2010.03911.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Mathison A, Liebl A, Bharucha J, Mukhopadhyay D, Lomberk G, Shah V, Urrutia R. Pancreatic stellate cell models for transcriptional studies of desmoplasia-associated genes. Pancreatology 2010. [PMID: 20847583 DOI: 10.1159/000320540] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Pancreatic stellate cells are emerging as key players in pathophysiopathological processes underlying the development of pancreatic disease, including pancreatitis and cancer. The cells are scarce in the pancreas making their isolation time and resource use consuming. METHODS Therefore, with the ultimate goal of facilitating mechanistic studies, here we report the isolation, characterization, and immortalization of stellate cell lines from rat and mouse origin. RESULTS These cell lines display morphological and molecular markers as well as non-tumorigenic characteristics similar to the frequently used hepatic counterparts. In addition, we have tested their robustness as a model for transcriptional regulatory studies. We find that these cells respond well to TGFβ signaling by triggering a distinct cascade of gene expression, some genes overlap with the TGFβ response of LX2 cells. These cells express several key chromatin proteins and epigenetic regulators involved in the regulation of gene expression, including co-repressors such as Sin3A (short-term repression), HP1 (long-term repression), as well as CBP/p300 (activation). Furthermore, these cells are well suited for Gal4-based transcriptional activation and repression assays. CONCLUSIONS The cell model reported here may therefore help fuel investigations in the field of signaling, transcription, and perhaps other studies on similarly exciting cellular processes. and IAP.
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Affiliation(s)
- Angela Mathison
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minn, USA
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