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1
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Fatima N, Fatima H, Ahmad S, Hashmi MATS, Sheikh N. Understanding the role of Hedgehog signaling pathway and gut dysbiosis in fueling liver cancer. Mol Biol Rep 2025; 52:411. [PMID: 40261446 DOI: 10.1007/s11033-025-10504-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 04/09/2025] [Indexed: 04/24/2025]
Abstract
Liver cancer is one of the most prevalent types of cancer worldwide with less than 20% of patients surviving in the past half a decade. Several molecular pathways have been uncovered that may lead to the development of liver cancer but more recently the Hedgehog pathway (HH) and its interactions with the gut microbiota has emerged as an underlying cause of the development of liver cancer. Gut-liver axis is vital to maintaining homeostasis. The HH pathway controls cellular differentiation, proliferation, and apoptosis evasions, its abnormal activation can lead to uncontrolled proliferation of liver cancer stem cells. Additionally, the intricate interplay between HH signaling and the gut microbiota introduces a novel dimension. Recent investigations suggest that potential modulation of HH activity by gut microbiota influence HCC progression. This review explores a crosstalk between HH signaling and the gut microbiota, uncovering intricate mechanisms by which it fuels liver cancer development. This interplay provides insights into gut dysbiosis, HCC etiology and potential therapeutic avenues, highlighting the cooperative role of HH signaling and gut microbiota in shaping the overall HCC landscape.
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Affiliation(s)
- Naz Fatima
- Department of Zoology, Faculty of Science and Technology, University of Central Punjab, Lahore, Pakistan.
- Department of Internal Medicine & Gastroenterology, University of Michigan, Ann Arbor, 48109, USA.
| | - Hooriya Fatima
- Institute of Zoology, University of Punjab (Quaid-i-Azam Campus), Lahore, 54590, Pakistan
| | - Sadia Ahmad
- Institute of Zoology, University of Punjab (Quaid-i-Azam Campus), Lahore, 54590, Pakistan
| | | | - Nadeem Sheikh
- Institute of Zoology, University of Punjab (Quaid-i-Azam Campus), Lahore, 54590, Pakistan
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2
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Mitranovici MI, Caravia LG, Moraru L, Pușcașiu L. Targeting Cancer Stemness Using Nanotechnology in a Holistic Approach: A Narrative Review. Pharmaceutics 2025; 17:277. [PMID: 40142941 PMCID: PMC11945010 DOI: 10.3390/pharmaceutics17030277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 01/20/2025] [Accepted: 02/18/2025] [Indexed: 03/28/2025] Open
Abstract
Increasing evidence shows that a very small population of cancer stem cells (CSCs) is responsible for cancer recurrence, drug resistance, and metastasis. CSCs usually reside in hypoxic tumor regions and are characterized by high tumorigenicity. Their inaccessible nature allows them to avoid the effects of conventional treatments such as chemotherapy, radiotherapy, and surgery. In addition, conventional chemo- and radiotherapy is potentially toxic and could help CSCs to spread and survive. New therapeutic targets against CSCs are sought, including different signaling pathways and distinct cell surface markers. Recent advances in nanotechnology have provided hope for the development of new therapeutic avenues to eradicate CSCs. In this review, we present newly discovered nanoparticles that can be co-loaded with an apoptosis-inducing agent or differentiation-inducing agent, with high stability, cellular penetration, and drug release. We also summarize the molecular characteristics of CSCs and the signaling pathways responsible for their survival and maintenance. Controlled drug release targeting CSCs aims to reduce stemness-related drug resistance, suppress tumor growth, and prevent tumor relapse and metastases.
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Affiliation(s)
- Melinda-Ildiko Mitranovici
- Department of Anatomy, Faculty of Medicine, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania;
| | - Laura Georgiana Caravia
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Liviu Moraru
- Department of Anatomy, Faculty of Medicine, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania;
| | - Lucian Pușcașiu
- Department of Anatomy, Faculty of Medicine, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology, 540142 Targu Mures, Romania;
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3
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Zheng J, Wang S, Xia L, Sun Z, Chan KM, Bernards R, Qin W, Chen J, Xia Q, Jin H. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther 2025; 10:35. [PMID: 39915447 PMCID: PMC11802921 DOI: 10.1038/s41392-024-02075-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/18/2024] [Accepted: 11/14/2024] [Indexed: 02/09/2025] Open
Abstract
Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.
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Affiliation(s)
- Jiaojiao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Siying Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, PR China
| | - René Bernards
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, PR China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Haojie Jin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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4
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Kim JH, Dareowolabi BO, Thiruvengadam R, Moon EY. Application of Nanotechnology and Phytochemicals in Anticancer Therapy. Pharmaceutics 2024; 16:1169. [PMID: 39339205 PMCID: PMC11435124 DOI: 10.3390/pharmaceutics16091169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/22/2024] [Accepted: 08/31/2024] [Indexed: 09/30/2024] Open
Abstract
Cancer is well recognized as a leading cause of mortality. Although surgery tends to be the primary treatment option for many solid cancers, cancer surgery is still a risk factor for metastatic diseases and recurrence. For this reason, a variety of medications has been adopted for the postsurgical care of patients with cancer. However, conventional medicines have shown major challenges such as drug resistance, a high level of drug toxicity, and different drug responses, due to tumor heterogeneity. Nanotechnology-based therapeutic formulations could effectively overcome the challenges faced by conventional treatment methods. In particular, the combined use of nanomedicine with natural phytochemicals can enhance tumor targeting and increase the efficacy of anticancer agents with better solubility and bioavailability and reduced side effects. However, there is limited evidence in relation to the application of phytochemicals in cancer treatment, particularly focusing on nanotechnology. Therefore, in this review, first, we introduce the drug carriers used in advanced nanotechnology and their strengths and limitations. Second, we provide an update on well-studied nanotechnology-based anticancer therapies related to the carcinogenesis process, including signaling pathways related to transforming growth factor-β (TGF-β), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3 kinase (PI3K), Wnt, poly(ADP-ribose) polymerase (PARP), Notch, and Hedgehog (HH). Third, we introduce approved nanomedicines currently available for anticancer therapy. Fourth, we discuss the potential roles of natural phytochemicals as anticancer drugs. Fifth, we also discuss the synergistic effect of nanocarriers and phytochemicals in anticancer therapy.
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Affiliation(s)
- Jin Hee Kim
- Department of Integrative Bioscience & Biotechnology, Sejong University, Seoul 05006, Republic of Korea; (B.O.D.); (E.-Y.M.)
| | - Boluwatife Olamide Dareowolabi
- Department of Integrative Bioscience & Biotechnology, Sejong University, Seoul 05006, Republic of Korea; (B.O.D.); (E.-Y.M.)
| | - Rekha Thiruvengadam
- Center for Global Health Research, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha Medical College, Saveetha University, Chennai 600077, India;
| | - Eun-Yi Moon
- Department of Integrative Bioscience & Biotechnology, Sejong University, Seoul 05006, Republic of Korea; (B.O.D.); (E.-Y.M.)
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5
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Fernandes Q, Therachiyil L, Khan AQ, Bedhiafi T, Korashy HM, Bhat AA, Uddin S. Shrinking the battlefield in cancer therapy: Nanotechnology against cancer stem cells. Eur J Pharm Sci 2023; 191:106586. [PMID: 37729956 DOI: 10.1016/j.ejps.2023.106586] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 09/07/2023] [Accepted: 09/18/2023] [Indexed: 09/22/2023]
Abstract
Cancer remains one of the leading causes of mortality worldwide, presenting a significant healthcare challenge owing to the limited efficacy of current treatments. The application of nanotechnology in cancer treatment leverages the unique optical, magnetic, and electrical attributes of nanomaterials to engineer innovative, targeted therapies. Specifically, manipulating nanomaterials allows for enhanced drug loading efficiency, improved bioavailability, and targeted delivery systems, reducing the non-specific cytotoxic effects characteristic of conventional chemotherapies. Furthermore, recent advances in nanotechnology have demonstrated encouraging results in specifically targeting CSCs, a key development considering the role of these cells in disease recurrence and resistance to treatment. Despite these breakthroughs, the clinical approval rates of nano-drugs have not kept pace with research advances, pointing to existing obstacles that must be addressed. In conclusion, nanotechnology presents a novel, powerful tool in the fight against cancer, particularly in targeting the elusive and treatment-resistant CSCs. This comprehensive review delves into the intricacies of nanotherapy, explicitly targeting cancer stem cells, their markers, and associated signaling pathways.
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Affiliation(s)
- Queenie Fernandes
- College of Medicine, Qatar University, Doha, Qatar; Translational Cancer Research Facility, Hamad Medical Corporation, National Center for Cancer Care and Research, PO. Box 3050, Doha, Qatar
| | - Lubna Therachiyil
- Academic Health System, Hamad Medical Corporation, Translational Research Institute, Doha 3050, Qatar; Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha 2713, Qatar
| | - Abdul Q Khan
- Academic Health System, Hamad Medical Corporation, Translational Research Institute, Doha 3050, Qatar
| | - Takwa Bedhiafi
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha 2713, Qatar
| | - Hesham M Korashy
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha 2713, Qatar
| | - Ajaz A Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Shahab Uddin
- College of Medicine, Qatar University, Doha, Qatar; Academic Health System, Hamad Medical Corporation, Dermatology Institute, Doha 3050, Qatar; Laboratory of Animal Research Center, Qatar University, Doha 2713, Qatar; Department of Biosciences, Integral University, Lucknow, Uttar Pradesh 22602, India.
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6
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Bagka M, Choi H, Héritier M, Schwaemmle H, Pasquer QTL, Braun SMG, Scapozza L, Wu Y, Hoogendoorn S. Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1. Nat Commun 2023; 14:3893. [PMID: 37393376 PMCID: PMC10314895 DOI: 10.1038/s41467-023-39657-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 06/22/2023] [Indexed: 07/03/2023] Open
Abstract
Target deconvolution of small molecule hits from phenotypic screens presents a major challenge. Many screens have been conducted to find inhibitors for the Hedgehog signaling pathway - a developmental pathway with many implications in health and disease - yielding many hits but only few identified cellular targets. We here present a strategy for target identification based on Proteolysis-Targeting Chimeras (PROTACs), combined with label-free quantitative proteomics. We develop a PROTAC based on Hedgehog Pathway Inhibitor-1 (HPI-1), a phenotypic screen hit with unknown cellular target. Using this Hedgehog Pathway PROTAC (HPP) we identify and validate BET bromodomains as the cellular targets of HPI-1. Furthermore, we find that HPP-9 is a long-acting Hedgehog pathway inhibitor through prolonged BET bromodomain degradation. Collectively, we provide a powerful PROTAC-based approach for target deconvolution, that answers the longstanding question of the cellular target of HPI-1 and yields a PROTAC that acts on the Hedgehog pathway.
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Affiliation(s)
- Meropi Bagka
- Department of Organic Chemistry, Faculty of Sciences, University of Geneva, Geneva, Switzerland
| | - Hyeonyi Choi
- Department of Organic Chemistry, Faculty of Sciences, University of Geneva, Geneva, Switzerland
| | - Margaux Héritier
- School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland
| | - Hanna Schwaemmle
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Quentin T L Pasquer
- Department of Organic Chemistry, Faculty of Sciences, University of Geneva, Geneva, Switzerland
| | - Simon M G Braun
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Leonardo Scapozza
- School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland
| | - Yibo Wu
- Chemical Biology Mass Spectrometry Platform (CHEMBIOMS), Faculty of Sciences, University of Geneva, Geneva, Switzerland
| | - Sascha Hoogendoorn
- Department of Organic Chemistry, Faculty of Sciences, University of Geneva, Geneva, Switzerland.
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7
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Yue M, Guo T, Nie DY, Zhu YX, Lin M. Advances of nanotechnology applied to cancer stem cells. World J Stem Cells 2023; 15:514-529. [PMID: 37424953 PMCID: PMC10324502 DOI: 10.4252/wjsc.v15.i6.514] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/01/2023] [Accepted: 04/18/2023] [Indexed: 06/26/2023] Open
Abstract
Cancer stem cells (CSCs) are a small proportion of the cells that exist in cancer tissues. They are considered to be the culprit of tumor genesis, development, drug resistance, metastasis and recurrence because of their self-renewal, proliferation, and differentiation potential. The elimination of CSCs is thus the key to cure cancer, and targeting CSCs provides a new method for tumor treatment. Due to the advantages of controlled sustained release, targeting and high biocompatibility, a variety of nanomaterials are used in the diagnosis and treatments targeting CSCs and promote the recognition and removal of tumor cells and CSCs. This article mainly reviews the research progress of nanotechnology in sorting CSCs and nanodrug delivery systems targeting CSCs. Furthermore, we identify the problems and future research directions of nanotechnology in CSC therapy. We hope that this review will provide guidance for the design of nanotechnology as a drug carrier so that it can be used in clinic for cancer therapy as soon as possible.
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Affiliation(s)
- Miao Yue
- Clinical Laboratory, Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu Province, China
| | - Ting Guo
- Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, Jiangsu Province, China
| | - Deng-Yun Nie
- Clinical Laboratory, Nanjing University of Chinese Medicine, Taizhou 225300, Jiangsu Province, China
| | - Yin-Xing Zhu
- Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, Jiangsu Province, China
| | - Mei Lin
- Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, Jiangsu Province, China.
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8
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Chai JY, Sugumar V, Alshawsh MA, Wong WF, Arya A, Chong PP, Looi CY. The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis. Biomedicines 2021; 9:1188. [PMID: 34572373 PMCID: PMC8466551 DOI: 10.3390/biomedicines9091188] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/29/2021] [Accepted: 09/01/2021] [Indexed: 12/22/2022] Open
Abstract
The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved among mammals, with crucial roles in regulating embryonic development as well as in cancer initiation and progression. The GLI transcription factors (GLI1, GLI2, and GLI3) are effectors of the Hh pathway and are regulated via Smoothened (SMO)-dependent and SMO-independent mechanisms. The SMO-dependent route involves the common Hh-PTCH-SMO axis, and mutations or transcriptional and epigenetic dysregulation at these levels lead to the constitutive activation of GLI transcription factors. Conversely, the SMO-independent route involves the SMO bypass regulation of GLI transcription factors by external signaling pathways and their interacting proteins or by epigenetic and transcriptional regulation of GLI transcription factors expression. Both routes of GLI activation, when dysregulated, have been heavily implicated in tumorigenesis of many known cancers, making them important targets for cancer treatment. Hence, this review describes the various SMO-dependent and SMO-independent routes of GLI regulation in the tumorigenesis of multiple cancers in order to provide a holistic view of the paradigms of hedgehog signaling networks involving GLI regulation. An in-depth understanding of the complex interplay between GLI and various signaling elements could help inspire new therapeutic breakthroughs for the treatment of Hh-GLI-dependent cancers in the future. Lastly, we have presented an up-to-date summary of the latest findings concerning the use of Hh inhibitors in clinical developmental studies and discussed the challenges, perspectives, and possible directions regarding the use of SMO/GLI inhibitors in clinical settings.
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Affiliation(s)
- Jian Yi Chai
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia; (J.Y.C.); (P.P.C.)
| | - Vaisnevee Sugumar
- School of Medicine, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia;
| | | | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia;
| | - Aditya Arya
- School of Biosciences, Faculty of Science, Building 184, The University of Melbourne, Melbourne, VIC 3010, Australia;
| | - Pei Pei Chong
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia; (J.Y.C.); (P.P.C.)
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia
| | - Chung Yeng Looi
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia; (J.Y.C.); (P.P.C.)
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health & Medical Sciences, Taylor’s University, 1 Jalan Taylors, Subang Jaya 47500, Malaysia
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9
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Zarębska I, Gzil A, Durślewicz J, Jaworski D, Antosik P, Ahmadi N, Smolińska-Świtała M, Grzanka D, Szylberg Ł. The clinical, prognostic and therapeutic significance of liver cancer stem cells and their markers. Clin Res Hepatol Gastroenterol 2021; 45:101664. [PMID: 33667731 DOI: 10.1016/j.clinre.2021.101664] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 09/24/2020] [Accepted: 02/17/2021] [Indexed: 02/04/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of death among cancers. The poor prognosis of HCC might be caused by a population of cancer stem cells (CSC). CSC have similar characteristics to normal stem cells and are responsible for cancer recurrence, chemoresistance, radioresistance and metastasis. Liver cancer stem cells (LCSC) are identified via specific surface markers, such as CD44, CD90, CD133, and EpCAM (CD326). Recent studies suggested a complex interaction between mentioned LCSC markers and clinical features of HCC. A high expression of CSC is correlated with a negative prognostic factor after surgical resection of HCC and is connected with more aggressive tumor behavior. Moreover, LCSC might be responsible for increasing resistance to sorafenib, a kinase inhibitor drug. A reduction in the LCSC population may be crucial to successful advanced HCC therapy.
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Affiliation(s)
- Izabela Zarębska
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland.
| | - Arkadiusz Gzil
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Justyna Durślewicz
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Damian Jaworski
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Paulina Antosik
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Navid Ahmadi
- Chair and Department of Oncologic Pathology and Prophylactics, Greater Poland Cancer Center, Poznan University of Medical Sciences, Poland
| | - Marta Smolińska-Świtała
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Łukasz Szylberg
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland; Department of Pathomorphology, Military Clinical Hospital, Bydgoszcz, Poland; Department of Tumor Pathology and Pathomorphology, Oncology Center, Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
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10
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Javed Z, Javed Iqbal M, Rasheed A, Sadia H, Raza S, Irshad A, Koch W, Kukula-Koch W, Głowniak-Lipa A, Cho WC, Sharifi-Rad J. Regulation of Hedgehog Signaling by miRNAs and Nanoformulations: A Possible Therapeutic Solution for Colorectal Cancer. Front Oncol 2021; 10:607607. [PMID: 33489917 PMCID: PMC7817854 DOI: 10.3389/fonc.2020.607607] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022] Open
Abstract
Hedgehog (Hh) signaling aberrations trigger differentiation and proliferation in colorectal cancer (CRC). However, the current approaches which inhibit this vital cellular pathway provoke some side effects. Therefore, it is necessary to look for new therapeutic options. MicroRNAs are small molecules that modulate expression of the target genes and can be utilized as a potential therapeutic option for CRC. On the other hand, nanoformulations have been implemented in the treatment of plethora of diseases. Owing to their excessive bioavailability, limited cytotoxicity and high specificity, nanoparticles may be considered as an alternative drug delivery platform for the Hh signaling mediated CRC. This article reviews the Hh signaling and its involvement in CRC with focus on miRNAs, nanoformulations as potential diagnostic/prognostic and therapeutics for CRC.
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Affiliation(s)
- Zeeshan Javed
- Office for Research Innovation and Commercialization, Lahore Garrison University, Lahore, Pakistan
| | - Muhammad Javed Iqbal
- Department of Biotechnology, Faculty of Sciences, University of Sialkot, Sialkot, Pakistan
| | - Amna Rasheed
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Haleema Sadia
- Department of Biotechnology, Balochistan University of Information Technology, Engineering and Management Sciences, Quetta, Pakistan
| | - Shahid Raza
- Office for Research Innovation and Commercialization, Lahore Garrison University, Lahore, Pakistan
| | - Asma Irshad
- Department of Life Sciences, University of Management and Technology, Lahore, Pakistan
| | - Wojciech Koch
- Chair and Department of Food and Nutrition, Medical University of Lublin, Lublin, Poland
| | | | - Anna Głowniak-Lipa
- Department of Cosmetology, University of Information Technology and Management in Rzeszów, Rzeszów, Poland
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador
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11
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The Role of Smoothened in Cancer. Int J Mol Sci 2020; 21:ijms21186863. [PMID: 32962123 PMCID: PMC7555769 DOI: 10.3390/ijms21186863] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/13/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023] Open
Abstract
Smoothened (SMO) belongs to the Hedgehog (HH) signaling pathway, which regulates cell growth, migration, invasion and stem cells in cancer. The HH signaling pathway includes both canonical and noncanonical pathways. The canonical HH pathway functions through major HH molecules such as HH ligands, PTCH, SMO and GLI, whereas the noncanonical HH pathway involves the activation of SMO or GLI through other pathways. The role of SMO has been discussed in different types of cancer, including breast, liver, pancreatic and colon cancers. SMO expression correlates with tumor size, invasiveness, metastasis and recurrence. In addition, SMO inhibitors can suppress cancer formation, reduce the proliferation of cancer cells, trigger apoptosis and suppress cancer stem cell activity. A better understanding of the role of SMO in cancer could contribute to the development of novel therapeutic approaches.
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Dzobo K, Senthebane DA, Ganz C, Thomford NE, Wonkam A, Dandara C. Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review. Cells 2020; 9:E1896. [PMID: 32823711 PMCID: PMC7464860 DOI: 10.3390/cells9081896] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/04/2020] [Accepted: 08/11/2020] [Indexed: 12/24/2022] Open
Abstract
Despite great strides being achieved in improving cancer patients' outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance culminating in relapse continues to be associated with fatal disease. The cancer stem cell theory posits that tumors are driven by specialized cancer cells called cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterized in many cancers with data illustrating that CSCs display great abilities to self-renew, resist therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of several survival signaling pathways and increased immune evasion as well as DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we revisit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.
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Affiliation(s)
- Kevin Dzobo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory, Cape Town 7925, South Africa; (D.A.S.); (C.G.)
- Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Dimakatso Alice Senthebane
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory, Cape Town 7925, South Africa; (D.A.S.); (C.G.)
- Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Chelene Ganz
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory, Cape Town 7925, South Africa; (D.A.S.); (C.G.)
- Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Nicholas Ekow Thomford
- Division of Human Genetics, Department of Pathology and Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa; (N.E.T.); (A.W.); (C.D.)
- Department of Medical Biochemistry, School of Medical Sciences, College of Health Sciences, University of Cape Coast, PMB, Cape Coast, Ghana
| | - Ambroise Wonkam
- Division of Human Genetics, Department of Pathology and Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa; (N.E.T.); (A.W.); (C.D.)
| | - Collet Dandara
- Division of Human Genetics, Department of Pathology and Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa; (N.E.T.); (A.W.); (C.D.)
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Gu Y, Zheng X, Ji J. Liver cancer stem cells as a hierarchical society: yes or no? Acta Biochim Biophys Sin (Shanghai) 2020; 52:723-735. [PMID: 32490517 DOI: 10.1093/abbs/gmaa050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer stem cells (CSCs) are cells possessing abilities of self-renewal, differentiation, and tumorigenicity in NOD/SCID mice. Based on this definition, multiple cell surface markers (such as CD24, CD133, CD90, and EpCAM) as well as chemical methods are discovered to enrich liver CSCs in the recent decade. Accumulated studies have revealed molecular signatures and signaling pathways involved in regulating different liver CSCs. Among liver CSCs positive for different markers, some molecular features and regulatory pathways are commonly shared, while some are only unique in certain CSC populations. These studies imply that liver CSCs exhibit diverse heterogeneity, while a functional relationship also exists. The aim of this review is to revisit the society of liver CSCs and summarize the common or unique molecular features of known liver CSCs. We hope to call for attention of researchers on the relationship of the liver CSC subgroups and to provide clues on the hierarchical structure of the liver CSC society.
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Affiliation(s)
- Yuanzhuo Gu
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Xin Zheng
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Junfang Ji
- MOE Key Laboratory of Biosystems Homeostasis and Protection, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
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14
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Valcourt DM, Dang MN, Wang J, Day ES. Nanoparticles for Manipulation of the Developmental Wnt, Hedgehog, and Notch Signaling Pathways in Cancer. Ann Biomed Eng 2020; 48:1864-1884. [PMID: 31686312 PMCID: PMC7196499 DOI: 10.1007/s10439-019-02399-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 10/30/2019] [Indexed: 02/07/2023]
Abstract
The Wnt, Hedgehog, and Notch signaling pathways play a crucial role in early development and the maintenance of adult tissues. When dysregulated, these developmental signaling pathways can drive the formation and progression of cancer by facilitating cell survival, proliferation, and stem-like behavior. While this makes these pathways promising targets for therapeutic intervention, their pharmacological inhibition has been challenging due to the substantial complexity that exists within each pathway and the complicated crosstalk that occurs between the pathways. Recently, several small molecule inhibitors, ribonucleic acid (RNA) molecules, and antagonistic antibodies have been developed that can suppress these signaling pathways in vitro, but many of them face systemic delivery challenges. Nanoparticle-based delivery vehicles can overcome these challenges to enhance the performance and anti-cancer effects of these therapeutic molecules. This review summarizes the mechanisms by which the Wnt, Hedgehog, and Notch signaling pathways contribute to cancer growth, and discusses various nanoparticle formulations that have been developed to deliver small molecules, RNAs, and antibodies to cancer cells to inhibit these signaling pathways and halt tumor progression. This review also outlines some of the challenges that these nanocarriers must overcome to achieve therapeutic efficacy and clinical translation.
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Affiliation(s)
- D M Valcourt
- Department of Biomedical Engineering, University of Delaware, 161 Colburn Lab, Newark, DE, 19716, USA
| | - M N Dang
- Department of Biomedical Engineering, University of Delaware, 161 Colburn Lab, Newark, DE, 19716, USA
| | - J Wang
- Department of Biomedical Engineering, University of Delaware, 161 Colburn Lab, Newark, DE, 19716, USA
| | - E S Day
- Department of Biomedical Engineering, University of Delaware, 161 Colburn Lab, Newark, DE, 19716, USA.
- Department of Materials Science & Engineering, University of Delaware, 201 DuPont Hall, Newark, DE, 19716, USA.
- Helen F. Graham Cancer Center & Research Institute, 4701 Ogletown Stanton Road, Newark, DE, 19713, USA.
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Vanderburgh JP, Kwakwa KA, Werfel TA, Merkel AR, Gupta MK, Johnson RW, Guelcher SA, Duvall CL, Rhoades JA. Systemic delivery of a Gli inhibitor via polymeric nanocarriers inhibits tumor-induced bone disease. J Control Release 2019; 311-312:257-272. [PMID: 31494183 DOI: 10.1016/j.jconrel.2019.08.038] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 08/22/2019] [Accepted: 08/31/2019] [Indexed: 12/22/2022]
Abstract
Solid tumors frequently metastasize to bone and induce bone destruction leading to severe pain, fractures, and other skeletal-related events (SREs). Osteoclast inhibitors such as bisphosphonates delay SREs but do not prevent skeletal complications or improve overall survival. Because bisphosphonates can cause adverse side effects and are contraindicated for some patients, we sought an alternative therapy to reduce tumor-associated bone destruction. Our previous studies identified the transcription factor Gli2 as a key regulator of parathyroid hormone-related protein (PTHrP), which is produced by bone metastatic tumor cells to promote osteoclast-mediated bone destruction. In this study, we tested the treatment effect of a Gli antagonist GANT58, which inhibits Gli2 nuclear translocation and PTHrP expression in tumor cells. In initial testing, GANT58 did not have efficacy in vivo due to its low water solubility and poor bioavailability. We therefore developed a micellar nanoparticle (NP) to encapsulate and colloidally stabilize GANT58, providing a fully aqueous, intravenously injectable formulation based on the polymer poly(propylene sulfide)135-b-poly[(oligoethylene glycol)9 methyl ether acrylate]17 (PPS135-b-POEGA17). POEGA forms the hydrophilic NP surface while PPS forms the hydrophobic NP core that sequesters GANT58. In response to reactive oxygen species (ROS), PPS becomes hydrophilic and degrades to enable drug release. In an intratibial model of breast cancer bone metastasis, treatment with GANT58-NPs decreased bone lesion area by 49% (p<.01) and lesion number by 38% (p<.05) and resulted in a 2.5-fold increase in trabecular bone volume (p<.001). Similar results were observed in intracardiac and intratibial models of breast and lung cancer bone metastasis, respectively. Importantly, GANT58-NPs reduced tumor cell proliferation but did not alter mesenchymal stem cell proliferation or osteoblast mineralization in vitro, nor was there evidence of cytotoxicity after repeated in vivo treatment. Thus, inhibition of Gli2 using GANT58-NPs is a potential therapy to reduce bone destruction that should be considered for further testing and development toward clinical translation.
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Affiliation(s)
- Joseph P Vanderburgh
- Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA
| | - Kristin A Kwakwa
- Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA
| | - Thomas A Werfel
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - Alyssa R Merkel
- Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Mukesh K Gupta
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - Rachelle W Johnson
- Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Scott A Guelcher
- Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN 37235, USA; Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Craig L Duvall
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - Julie A Rhoades
- Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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Asghari F, Khademi R, Esmaeili Ranjbar F, Veisi Malekshahi Z, Faridi Majidi R. Application of Nanotechnology in Targeting of Cancer Stem Cells: A Review. Int J Stem Cells 2019; 12:227-239. [PMID: 31242721 PMCID: PMC6657943 DOI: 10.15283/ijsc19006] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 03/15/2019] [Accepted: 04/07/2019] [Indexed: 12/13/2022] Open
Abstract
Cancer is increasingly apparent as a systems-level, network happening. The central tendency of malignant alteration can be described as a two-phase procedure, where an initial increase of network plasticity is followed by reducing plasticity at late stages of tumor improvement. Cancer stem cells (CSCs) are cancer cells that take characteristics associated with normal stem cells. Cancer therapy has been based on the concept that most of the cancer cells have a similar ability to separate metastasise and kill the host. In this review, we addressed the use of nanotechnology in the treatment of cancer stem cells.
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Affiliation(s)
- Fatemeh Asghari
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Rahele Khademi
- International affairs, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Faezeh Esmaeili Ranjbar
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ziba Veisi Malekshahi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Faridi Majidi
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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17
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Nanoparticles in dermatologic surgery. J Am Acad Dermatol 2019; 83:1144-1149. [PMID: 30991121 DOI: 10.1016/j.jaad.2019.04.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 03/22/2019] [Accepted: 04/10/2019] [Indexed: 11/23/2022]
Abstract
Nanotechnology is an emerging branch of science that involves the engineering of functional systems on the nanoscale (1-100 nm). Nanotechnology has been used in biomedical and therapeutic agents with the aim of providing novel treatment solutions where small molecule size may be beneficial for modulation of biologic function. Recent investigation in nanomedicine has become increasingly important to cutaneous pathophysiology, such as functional designs directed towards skin cancers and wound healing. This review outlines the application of nanoparticles relevant to dermatologic surgery.
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18
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Taniguchi H, Suzuki Y, Natori Y. The Evolving Landscape of Cancer Stem Cells and Ways to Overcome Cancer Heterogeneity. Cancers (Basel) 2019; 11:cancers11040532. [PMID: 31013960 PMCID: PMC6520864 DOI: 10.3390/cancers11040532] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 04/02/2019] [Accepted: 04/04/2019] [Indexed: 12/18/2022] Open
Abstract
Cancer stem cells (CSCs) with therapeutic resistance and plasticity can be found in various types of tumors and are recognized as attractive targets for treatments. As CSCs are derived from tissue stem or progenitor cells, and/or dedifferentiated mature cells, their signal transduction pathways are critical in the regulation of CSCs; chronic inflammation causes the accumulation of genetic mutations and aberrant epigenetic changes in these cells, potentially leading to the production of CSCs. However, the nature of CSCs appears to be stronger than the treatments of the past. To improve the treatments targeting CSCs, it is important to inhibit several molecules on the signaling cascades in CSCs simultaneously, and to overcome cancer heterogeneity caused by the plasticity. To select suitable target molecules for CSCs, we have to explore the landscape of CSCs from the perspective of cancer stemness and signaling systems, based on the curated databases of cancer-related genes. We have been studying the integration of a broad range of knowledge and experiences from cancer biology, and also from other interdisciplinary basic sciences. In this review, we have introduced the concept of developing novel strategies targeting CSCs.
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Affiliation(s)
- Hiroaki Taniguchi
- The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-0071, Japan.
- Clinical and Translational Research Center Keio University Hospital, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
| | - Yasunori Suzuki
- Clinical and Translational Research Center Keio University Hospital, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
| | - Yukikazu Natori
- BioThinkTank Co. Ltd. 4-10-1-E1706 Minatomirai, Nishi-ku Yokohama, Kanagawa 220-0012, Japan.
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19
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Delivering Combination Chemotherapies and Targeting Oncogenic Pathways via Polymeric Drug Delivery Systems. Polymers (Basel) 2019; 11:polym11040630. [PMID: 30959799 PMCID: PMC6523645 DOI: 10.3390/polym11040630] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 03/22/2019] [Accepted: 03/24/2019] [Indexed: 12/24/2022] Open
Abstract
The side-effects associated with chemotherapy necessitates better delivery of chemotherapeutics to the tumor. Nanoparticles can load higher amounts of drug and improve delivery to tumors, increasing the efficacy of treatment. Polymeric nanoparticles, in particular, have been used extensively for chemotherapeutic delivery. This review describes the efforts made to deliver combination chemotherapies and inhibit oncogenic pathways using polymeric drug delivery systems. Combinations of chemotherapeutics with other drugs or small interfering RNA (siRNA) combinations have been summarized. Special attention is given to the delivery of drug combinations that involve either paclitaxel or doxorubicin, two popular chemotherapeutics in clinic. Attempts to inhibit specific pathways for oncotherapy have also been described. These include inhibition of oncogenic pathways (including those involving HER2, EGFR, MAPK, PI3K/Akt, STAT3, and HIF-1α), augmentation of apoptosis by inhibiting anti-apoptosis proteins (Bcl-2, Bcl-xL, and survivin), and targeting dysregulated pathways such as Wnt/β-catenin and Hedgehog.
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20
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Turdo A, Veschi V, Gaggianesi M, Chinnici A, Bianca P, Todaro M, Stassi G. Meeting the Challenge of Targeting Cancer Stem Cells. Front Cell Dev Biol 2019; 7:16. [PMID: 30834247 PMCID: PMC6387961 DOI: 10.3389/fcell.2019.00016] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 02/01/2019] [Indexed: 12/18/2022] Open
Abstract
Notwithstanding cancer patients benefit from a plethora of therapeutic alternatives, drug resistance remains a critical hurdle. Indeed, the high mortality rate is associated with metastatic disease, which is mostly incurable due to the refractoriness of metastatic cells to current treatments. Increasing data demonstrate that tumors contain a small subpopulation of cancer stem cells (CSCs) able to establish primary tumor and metastasis. CSCs are endowed with multiple treatment resistance capabilities comprising a highly efficient DNA damage repair machinery, the activation of survival pathways, enhanced cellular plasticity, immune evasion and the adaptation to a hostile microenvironment. Due to the presence of distinct cell populations within a tumor, cancer research has to face the major challenge of targeting the intra-tumoral as well as inter-tumoral heterogeneity. Thus, targeting molecular drivers operating in CSCs, in combination with standard treatments, may improve cancer patients’ outcomes, yielding long-lasting responses. Here, we report a comprehensive overview on the most significant therapeutic advances that have changed the known paradigms of cancer treatment with a particular emphasis on newly developed compounds that selectively affect the CSC population. Specifically, we are focusing on innovative therapeutic approaches including differentiation therapy, anti-angiogenic compounds, immunotherapy and inhibition of epigenetic enzymes and microenvironmental cues.
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Affiliation(s)
- Alice Turdo
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Veronica Veschi
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Miriam Gaggianesi
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Aurora Chinnici
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Paola Bianca
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Matilde Todaro
- Department of PROMISE, University of Palermo, Palermo, Italy
| | - Giorgio Stassi
- Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
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21
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Fu P, Hu B, Ma X, Yang Z, Yu M, Sun H, Huang A, Zhang X, Wang J, Hu Z, Zhou C, Tang W, Ning R, Xu Y, Zhou J. New insight into BIRC3: A novel prognostic indicator and a potential therapeutic target for liver cancer. J Cell Biochem 2018; 120:6035-6045. [PMID: 30368883 DOI: 10.1002/jcb.27890] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 09/21/2018] [Indexed: 12/25/2022]
Affiliation(s)
- Pei‐Yao Fu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
| | - Bo Hu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
| | - Xiao‐Lu Ma
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
- Laboratory Medicine Department Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
| | - Zhang‐Fu Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
| | - Min‐Cheng Yu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
| | - Hai‐Xiang Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
| | - Ao Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
| | - Xin Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
| | - Jian Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
| | - Zhi‐Qiang Hu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
| | - Chen‐Hao Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
| | - Wei‐Guo Tang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
| | - Ren Ning
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
| | - Yang Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital of Fudan University Shanghai China
- Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai China
- State Key Laboratory of Genetic Engineering Fudan University Shanghai China
- Shanghai Key Laboratory of Organ Transplantation Zhongshan Hospital, Fudan University Shanghai China
- Institute of Biomedical Sciences, Fudan University Shanghai China
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Glioma-Associated Oncogene Homolog Inhibitors Have the Potential of Suppressing Cancer Stem Cells of Breast Cancer. Int J Mol Sci 2018; 19:ijms19051375. [PMID: 29734730 PMCID: PMC5983844 DOI: 10.3390/ijms19051375] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 04/25/2018] [Accepted: 05/02/2018] [Indexed: 01/07/2023] Open
Abstract
Overexpression of Sonic Hedgehog signaling (Shh) pathway molecules is associated with invasiveness and recurrence in breast carcinoma. Therefore, inhibition of the Shh pathway downstream molecule Glioma-associated Oncogene Homolog (Gli) was investigated for its ability to reduce progression and invasiveness of patient-derived breast cancer cells and cell lines. Human primary breast cancer T2 cells with high expression of Shh signaling pathway molecules were compared with breast cancer line MDA-MB-231 cells. The therapeutic effects of Gli inhibitors were examined in terms of the cell proliferation, apoptosis, cancer stem cells, cell migration and gene expression. Blockade of the Shh signaling pathway could reduce cell proliferation and migration only in MDA-MB-231 cells. Hh pathway inhibitor-1 (HPI-1) increased the percentages of late apoptotic cells in MDA-MB-231 cells and early apoptotic cells in T2 cells. It reduced Bcl2 expression for cell proliferation and increased Bim expression for apoptosis. In addition, Gli inhibitor HPI-1 decreased significantly the percentages of cancer stem cells in T2 cells. HPI-1 worked more effectively than GANT-58 against breast carcinoma cells. In conclusion, HPI-1 could inhibit cell proliferation, reduce cell invasion and decrease cancer stem cell population in breast cancer cells. To target Gli-1 could be a potential strategy to suppress breast cancer stem cells.
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Peng WT, Sun WY, Li XR, Sun JC, Du JJ, Wei W. Emerging Roles of G Protein-Coupled Receptors in Hepatocellular Carcinoma. Int J Mol Sci 2018; 19:ijms19051366. [PMID: 29734668 PMCID: PMC5983678 DOI: 10.3390/ijms19051366] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 04/24/2018] [Accepted: 04/26/2018] [Indexed: 12/13/2022] Open
Abstract
Among a great variety of cell surface receptors, the largest superfamily is G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain receptors. GPCRs can modulate diverse signal-transduction pathways through G protein-dependent or independent pathways which involve β-arrestins, G protein receptor kinases (GRKs), ion channels, or Src kinases under physiological and pathological conditions. Recent studies have revealed the crucial role of GPCRs in the tumorigenesis and the development of cancer metastasis. We will sum up the functions of GPCRs—particularly those coupled to chemokines, prostaglandin, lysophosphatidic acid, endothelin, catecholamine, and angiotensin—in the proliferation, invasion, metastasis, and angiogenesis of hepatoma cells and the development of hepatocellular carcinoma (HCC) in this review. We also highlight the potential avenues of GPCR-based therapeutics for HCC.
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Affiliation(s)
- Wen-Ting Peng
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Wu-Yi Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Xin-Ran Li
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Jia-Chang Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Jia-Jia Du
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
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Zhang J, Wang L, Li H, Zhou J, Feng Z, Xu Y, Chen X, Liu H, Jin H, Yang J, Yang Y, Chen G, Wang G. Partial hepatectomy promotes implanted mouse hepatic tumor growth by activating hedgehog signaling. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:2920-2930. [PMID: 31938417 PMCID: PMC6958302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 03/25/2018] [Indexed: 06/10/2023]
Abstract
OBJECTIVE To investigate the role hedgehog signaling (Hh) in the growth of implanted hepatic tumors after partial hepatectomy (PH) in mice. METHODS H22 cells were implanted to the scapula of 2 BALB/c (nu/nu) nude mice and tumor developed in 2 weeks. 40 nude mice were randomized into 4 groups: non-hepatectomy group (Sham operation group), 30% hepatectomy group, 70% hepatectomy group, and 70% hepatectomy with cyclopamine (Hh inhibitor). The hepatectomy model of nude mice was established. After hepatectomy, the tumor tissues incised from the scapula were implanted to the rest of the livers of the 4 groups. After 2 weeks, the tumor formation rates and the volumes of the implanted tumors were compared. Hh related proteins and downstream cytokine VEGF were tested by Western blot and Immunohistochemistry. All the data were analyzed to explore the role of Hh in the growth of tumor after PH. RESULTS The volumes of the implanted tumors after liver resection were significantly higher in the 70% PH group than those in 0% and 30% PH groups; meanwhile, we also found that expression of the Hh ligand Indian Hh, its downstream transcription factor protein Gli-1, and its target VEGF were remarkably increased after PH, especially in the 70% PH group. Additionally, applying the Hh inhibitor cyclopamine to mice that underwent 70% PH significantly inhibited the growth of implanted tumors. CONCLUSIONS The Hh signaling pathway was activated after PH and promoted liver regeneration. The growth of implanted hepatic tumors was also accelerated after PH via paracrine signaling.
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Affiliation(s)
- Junbin Zhang
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, Guangdong Province, PR China
- Guangdong Provincial Key Laboratory of Liver Disease ResearchGuangzhou, Guangdong Province, PR China
| | - Li Wang
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, Guangdong Province, PR China
- Guangdong Provincial Key Laboratory of Liver Disease ResearchGuangzhou, Guangdong Province, PR China
| | - Hui Li
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, Guangdong Province, PR China
- Guangdong Provincial Key Laboratory of Liver Disease ResearchGuangzhou, Guangdong Province, PR China
| | - Jing Zhou
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, Guangdong Province, PR China
| | - Zhiying Feng
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, Guangdong Province, PR China
| | - Yichun Xu
- Department of Orthopedics, The Third Affiliated Hospital of Sun Yat-sen University, Lingnan HospitalGuangzhou, Guangdong Province, PR China
| | - Xiaolong Chen
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, Guangdong Province, PR China
- Guangdong Provincial Key Laboratory of Liver Disease ResearchGuangzhou, Guangdong Province, PR China
| | - Huilin Liu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, Guangdong Province, PR China
- Guangdong Provincial Key Laboratory of Liver Disease ResearchGuangzhou, Guangdong Province, PR China
| | - Hai Jin
- Department of Medical Ultrasonics, Guangzhou First People’s Hospital, The Second Affiliated Hospital of South China University of TechnologyGuangzhou, Guangdong Province, PR China
| | - Jianxu Yang
- Department of Intensive Care Unit, Henan Provincial People’s HospitalZhengzhou, Henan Province, PR China
| | - Yang Yang
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, Guangdong Province, PR China
- Guangdong Provincial Key Laboratory of Liver Disease ResearchGuangzhou, Guangdong Province, PR China
| | - Guihua Chen
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, Guangdong Province, PR China
- Guangdong Provincial Key Laboratory of Liver Disease ResearchGuangzhou, Guangdong Province, PR China
| | - Genshu Wang
- Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, Guangdong Province, PR China
- Guangdong Provincial Key Laboratory of Liver Disease ResearchGuangzhou, Guangdong Province, PR China
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Da Silva CG, Peters GJ, Ossendorp F, Cruz LJ. The potential of multi-compound nanoparticles to bypass drug resistance in cancer. Cancer Chemother Pharmacol 2017; 80:881-894. [PMID: 28887666 PMCID: PMC5676819 DOI: 10.1007/s00280-017-3427-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 08/29/2017] [Indexed: 01/28/2023]
Abstract
PURPOSE The therapeutic efficacy of conventional chemotherapy against several solid tumors is generally limited and this is often due to the development of resistance or poor delivery of the drugs to the tumor. Mechanisms of resistance may vary between cancer types. However, with current development of genetic analyses, imaging, and novel delivery systems, we may be able to characterize and bypass resistance, e.g., by inhibition of the right target at the tumor site. Therefore, combined drug treatments, where one drug will revert or obstruct the development of resistance and the other will concurrently kill the cancer cell, are rational solutions. However, drug exposure of one drug will defer greatly from the other due to their physicochemical properties. In this sense, multi-compound nanoparticles are an excellent modality to equalize drug exposure, i.e., one common physicochemical profile. In this review, we will discuss novel approaches that employ nanoparticle technology that addresses specific mechanisms of resistance in cancer. METHODS The PubMed literature was consulted and reviewed. RESULTS Nanoparticle technology is emerging as a dexterous solution that may address several forms of resistance in cancer. For instance, we discuss advances that address mechanisms of resistance with multi-compound nanoparticles which co-deliver chemotherapeutics with an anti-resistance agent. Promising anti-resistance agents are (1) targeted in vivo gene silencing methods aimed to disrupt key resistance gene expression or (2) protein kinase inhibitors to disrupt key resistance pathways or (3) efflux pumps inhibitors to limit drug cellular efflux.
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Affiliation(s)
- C G Da Silva
- Translational Nanobiomaterials and Imaging, Department of Radiology, Bldg.1, C2-187h, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Godefridus J Peters
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - Ferry Ossendorp
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands
| | - Luis J Cruz
- Translational Nanobiomaterials and Imaging, Department of Radiology, Bldg.1, C2-187h, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
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Pharmacological targeting of GLI1 inhibits proliferation, tumor emboli formation and in vivo tumor growth of inflammatory breast cancer cells. Cancer Lett 2017; 411:136-149. [PMID: 28965853 DOI: 10.1016/j.canlet.2017.09.033] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 09/15/2017] [Accepted: 09/21/2017] [Indexed: 01/01/2023]
Abstract
Activation of the Hedgehog (Hh) pathway effector GLI1 is linked to tumorigenesis and invasiveness in a number of cancers, with targeting of GLI1 by small molecule antagonists shown to be effective. We profiled a collection of GLI antagonists possessing distinct mechanisms of action for efficacy in phenotypic models of inflammatory and non-inflammatory breast cancer (IBC and non-IBC) that we showed expressed varying levels of Hh pathway mediators. Compounds GANT61, HPI-1, and JK184 decreased cell proliferation, inhibited GLI1 mRNA expression and decreased the number of colonies formed in TN-IBC (SUM149) and TNBC (MDA-MB-231 and SUM159) cell lines. In addition, GANT61 and JK184 significantly down-regulated GLI1 targets that regulate cell cycle (cyclin D and E) and apoptosis (Bcl2). GANT61 reduced SUM149 spheroid growth and emboli formation, and in orthotopic SUM149 tumor models significantly decreased tumor growth. We successfully utilized phenotypic profiling to identify a subset of GLI1 antagonists that were prioritized for testing in in vivo models. Our results indicated that GLI1 activation in TN-IBC as in TNBC, plays a vital role in promoting cell proliferation, motility, tumor growth, and formation of tumor emboli.
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Miao Y, Zhang H, Pan Y, Ren J, Ye M, Xia F, Huang R, Lin Z, Jiang S, Zhang Y, Songyang Z, Zhang Y. Single-walled carbon nanotube: One specific inhibitor of cancer stem cells in osteosarcoma upon downregulation of the TGFβ1 signaling. Biomaterials 2017; 149:29-40. [PMID: 28988062 DOI: 10.1016/j.biomaterials.2017.09.032] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 09/11/2017] [Accepted: 09/25/2017] [Indexed: 02/06/2023]
Abstract
Cancer stem cells (CSCs) are believed to have a critical role in tumorigenesis, metastasis, therapeutic resistance or recurrence. Therefore, strategies designed to specifically target and eliminate CSCs have become one of the most promising and desirable ways for tumor treatment. Osteosarcoma stem cells (OSCs), the CSCs in osteosarcoma (OS), are critically associated with OS progression. Here, we show that single-walled carbon nanotubes (SWCNTs), including unmodified SWCNT (SWCNT-Raw) and SWCNT-COOH, have the ability to specifically inhibit the process of TGFβ1-induced OS cells dedifferentiation, prevent the stem cell phenotypes acquisition in OS cells and reduce the OSC viability under conditions which mimic the OS microenvironment. Concurrently, SWCNT treatment significantly down-regulates the expression of OSC markers in OS, and markedly reduces the tumor microvessel density and tumor growth. Furthermore, we found that SWCNT could suppress the TGFβ1-induced activation of TGFβ type I receptor and downstream signaling, which are key for the OSC formation and maintenance. Our results reveal an unexpected function of SWCNT in negative modulation of OSCs, and provide significant implications for the potential CSCs-targeted therapeutic applications of SWCNT.
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Affiliation(s)
- Yanyan Miao
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Haixia Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Yubin Pan
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Jian Ren
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Miaoman Ye
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Fangfang Xia
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Rui Huang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Zhuoheng Lin
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Shuai Jiang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Ya Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Zhou Songyang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China.
| | - Yan Zhang
- Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China.
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Qin W, Huang G, Chen Z, Zhang Y. Nanomaterials in Targeting Cancer Stem Cells for Cancer Therapy. Front Pharmacol 2017; 8:1. [PMID: 28149278 PMCID: PMC5241315 DOI: 10.3389/fphar.2017.00001] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Accepted: 01/03/2017] [Indexed: 12/25/2022] Open
Abstract
Cancer stem cells (CSCs) have been identified in almost all cancers and give rise to metastases and can also act as a reservoir of cancer cells that may cause a relapse after surgery, radiation, or chemotherapy. Thus they are obvious targets in therapeutic approaches and also a great challenge in cancer treatment. The threat presented by CSCs lies in their unlimited proliferative ability and multidrug resistance. These findings have necessitated an effective novel strategy to target CSCs for cancer treatment. Nanomaterials are on the route to providing novel methods in cancer therapies. Although, there have been a large number of excellent work in the field of targeted cancer therapy, it remains an open question how nanomaterials can meet future demands for targeting and eradicating of CSCs. In this review, we summarized recent and highlighted future prospects for targeting CSCs for cancer therapies by using a variety of nanomaterials.
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Affiliation(s)
- Weiwei Qin
- Institute of Medical Instrument and Application, School of Pharmaceutical Sciences, Sun Yat-Sen University Guangzhou, China
| | - Guan Huang
- Institute of Medical Instrument and Application, School of Pharmaceutical Sciences, Sun Yat-Sen University Guangzhou, China
| | - Zuanguang Chen
- Institute of Medical Instrument and Application, School of Pharmaceutical Sciences, Sun Yat-Sen University Guangzhou, China
| | - Yuanqing Zhang
- Institute of Medical Instrument and Application, School of Pharmaceutical Sciences, Sun Yat-Sen University Guangzhou, China
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29
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Wang A, Qu L, Wang L. At the crossroads of cancer stem cells and targeted therapy resistance. Cancer Lett 2017; 385:87-96. [DOI: 10.1016/j.canlet.2016.10.039] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 10/24/2016] [Accepted: 10/25/2016] [Indexed: 02/07/2023]
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Garcia-Mazas C, Csaba N, Garcia-Fuentes M. Biomaterials to suppress cancer stem cells and disrupt their tumoral niche. Int J Pharm 2016; 523:490-505. [PMID: 27940172 DOI: 10.1016/j.ijpharm.2016.12.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 12/02/2016] [Accepted: 12/07/2016] [Indexed: 01/04/2023]
Abstract
Lack of improvement in the treatment options of several types of cancer can largely be attributed to the presence of a subpopulation of cancer cells with stem cell signatures and to the tumoral niche that supports and protects these cells. This review analyses the main strategies that specifically modulate or suppress cancer stem cells (CSCs) and the tumoral niche (TN), focusing on the role of biomaterials (i.e. implants, nanomedicines, etc.) in these therapies. In the case of CSCs, we discuss differentiation therapies and the disruption of critical cellular signaling networks. For the TN, we analyze diverse strategies to modulate tumor hypervascularization and hypoxia, tumor extracellular matrix, and the inflammatory and tumor immunosuppressive environment. Due to their capacity to control drug disposition and integrate diverse functionalities, biomaterial-based therapies can provide important benefits in these strategies. We illustrate this by providing case studies where biomaterial-based therapies either show CSC suppression and TN disruption or improved delivery of major modulators of these features. Finally, we discuss the future of these technologies in the framework of these emerging therapeutic concepts.
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Affiliation(s)
- Carla Garcia-Mazas
- Center for Research in Molecular Medicine and Chronic Diseases (CIMUS) and Dept. of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, 15782 Campus Vida, Santiago de Compostela, Spain
| | - Noemi Csaba
- Center for Research in Molecular Medicine and Chronic Diseases (CIMUS) and Dept. of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, 15782 Campus Vida, Santiago de Compostela, Spain
| | - Marcos Garcia-Fuentes
- Center for Research in Molecular Medicine and Chronic Diseases (CIMUS) and Dept. of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, 15782 Campus Vida, Santiago de Compostela, Spain.
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31
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Intraperitoneal 188Re-Liposome delivery switches ovarian cancer metabolism from glycolysis to oxidative phosphorylation and effectively controls ovarian tumour growth in mice. Radiother Oncol 2016; 119:282-90. [DOI: 10.1016/j.radonc.2016.02.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Revised: 12/24/2015] [Accepted: 02/01/2016] [Indexed: 01/02/2023]
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Nai QY, Wei MX, Xu W. Regulatory mechanisms and therapeutic targeting of liver cancer stem cells. Shijie Huaren Xiaohua Zazhi 2016; 24:1198-1205. [DOI: 10.11569/wcjd.v24.i8.1198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
As cancer stem cells have been confirmed in many human solid tumors, hepatocellular carcinoma has been considered a stem cell disease. The existence of liver cancer stem cells in liver cancer has been a research hotspot recently. Cancer stem cell theory believes that tumorigenesis, development, metastasis, recurrence and drug resistance are closely associated with cancer stem cells. Therefore, the isolation and identification of liver cancer stem cells play a very important role in early prevention, early diagnosis, effective therapy and improving prognosis of liver cancer. This paper summarizes the origin, surface molecular markers, signal transduction and regulation of liver cancer stem cells, and discusses the therapies targeting liver cancer stem cells.
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Borah A, Raveendran S, Rochani A, Maekawa T, Kumar DS. Targeting self-renewal pathways in cancer stem cells: clinical implications for cancer therapy. Oncogenesis 2015; 4:e177. [PMID: 26619402 PMCID: PMC4670961 DOI: 10.1038/oncsis.2015.35] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 09/10/2015] [Accepted: 09/22/2015] [Indexed: 12/21/2022] Open
Abstract
Extensive cancer research in the past few decades has identified the existence of a rare subpopulation of stem cells in the grove of cancer cells. These cells are known as the cancer stem cells marked by the presence of surface biomarkers, multi-drug resistance pumps and deregulated self-renewal pathways (SRPs). They have a crucial role in provoking cancer cells leading to tumorigenesis and its progressive metastasis. Cancer stem cells (CSCs) are much alike to normal stem cells in their self-renewal mechanisms. However, deregulations in the SRPs are seen in CSCs, making them resistant to conventional chemotherapeutic agents resulting in the tumor recurrence. Current treatment strategies in cancer fail to detect and differentiate the CSCs from their non-tumorigenic progenies owing to absence of specific biomarkers. Now, it has become imperative to understand complex functional biology of CSCs, especially the signaling pathways to design improved treatment strategies to target them. It is hopeful that the SRPs in CSCs offer a promising target to alter their survival strategies and impede their tumorigenic potential. However, there are many perils associated with the direct targeting method by conventional therapeutic agents such as off targets, poor bioavailability and poor cellular distribution. Recent evidences have shown an increased use of small molecule antagonists directly to target these SRPs may lead to severe side-effects. An alternative to solve these issues could be an appropriate nanoformulation. Nanoformulations of these molecules could provide an added advantage for the selective targeting of the pathways especially Hedgehog, Wnt, Notch and B-cell-specific moloney murine leukemia virus integration site 1 in the CSCs while sparing the normal stem cells. Hence, to achieve this goal a complete understanding of the molecular pathways corroborate with the use of holistic nanosystem (nanomaterial inhibition molecule) could possibly be an encouraging direction for future cancer therapy.
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Affiliation(s)
- A Borah
- Bio Nano Electronics Research Center, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Saitama, Japan
| | - S Raveendran
- Bio Nano Electronics Research Center, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Saitama, Japan
| | - A Rochani
- Bio Nano Electronics Research Center, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Saitama, Japan
| | - T Maekawa
- Bio Nano Electronics Research Center, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Saitama, Japan
| | - D S Kumar
- Bio Nano Electronics Research Center, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Saitama, Japan
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Justilien V, Fields AP. Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells. Clin Cancer Res 2015; 21:505-13. [PMID: 25646180 DOI: 10.1158/1078-0432.ccr-14-0507] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The Hedgehog (Hh) signaling pathway is critical for embryonic development. In adult tissues, Hh signaling is relatively quiescent with the exception of roles in tissue maintenance and repair. Aberrant activation of Hh signaling is implicated in multiple aspects of transformation, including the maintenance of the cancer stem cell (CSC) phenotype. Preclinical studies indicate that CSCs from many tumor types are sensitive to Hh pathway inhibition and that Hh-targeted therapeutics block many aspects of transformation attributed to CSCs, including drug resistance, relapse, and metastasis. However, to date, Hh inhibitors, specifically those targeting Smoothened [such as vismodegib, BMS-833923, saridegib (IPI-926), sonidegib/erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506, and TAK-441], have demonstrated good efficacy as monotherapy in patients with basal cell carcinoma and medulloblastoma, but have shown limited activity in other tumor types. This lack of success is likely due to many factors, including a lack of patient stratification in early trials, cross-talk between Hh and other oncogenic signaling pathways that can modulate therapeutic response, and a limited knowledge of Hh pathway activation mechanisms in CSCs from most tumor types. Here, we discuss Hh signaling mechanisms in the context of human cancer, particularly in the maintenance of the CSC phenotype, and consider new therapeutic strategies that hold the potential to expand considerably the scope and therapeutic efficacy of Hh-directed anticancer therapy.
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Affiliation(s)
- Verline Justilien
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida
| | - Alan P Fields
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida.
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Abstract
Cancer stem cells (CSCs) have been shown to be markedly resistant to conventional cancer treatments such as chemotherapy and radiation therapy. Therefore, therapeutic strategies that selectively target CSCs will ultimately lead to better cancer treatments. Currently, accessible conventional therapeutic agents mainly eliminate the bulk tumor but do not eliminate CSCs. Therefore, the discovery and improvement of CSC-targeting therapeutic agents are necessary. Nanoparticles effectively inhibit multiple types of CSCs by targeting specific signaling pathways (Wnt/β-catenin, Notch, transforming growth factor-β, and hedgehog signaling) and/or specific markers (aldehyde dehydrogenases, CD44, CD90, and CD133) critically involved in CSC function and maintenance. In this review article, we summarized a number of findings to provide current information about their therapeutic potential of nanoparticles in various cancer cell types and CSCs.
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Affiliation(s)
- In-Sun Hong
- Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea ; Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Republic of Korea
| | - Gyu-Beom Jang
- Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea ; Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Republic of Korea
| | - Hwa-Yong Lee
- The Faculty of Liberal Arts, Jungwon University, Chungbuk, Republic of Korea
| | - Jeong-Seok Nam
- Laboratory of Tumor Suppressor, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea ; Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Republic of Korea
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36
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Targeting GLI factors to inhibit the Hedgehog pathway. Trends Pharmacol Sci 2015; 36:547-58. [DOI: 10.1016/j.tips.2015.05.006] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/14/2015] [Accepted: 05/15/2015] [Indexed: 12/17/2022]
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Tsai CL, Hsu FM, Tzen KY, Liu WL, Cheng AL, Cheng JCH. Sonic Hedgehog inhibition as a strategy to augment radiosensitivity of hepatocellular carcinoma. J Gastroenterol Hepatol 2015; 30:1317-24. [PMID: 25682950 DOI: 10.1111/jgh.12931] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/05/2015] [Indexed: 01/10/2023]
Abstract
BACKGROUND AND AIM Sonic Hedgehog (SHH) is a regulator in tumorigenesis of hepatocellular carcinoma (HCC). This study aimed to determine whether radiation-induced SHH signaling occurs in HCC and whether SHH inhibitor acts as a radiosensitizer. METHODS The in vitro effects of combining SHH ligand (recombinant human SHH) or inhibitor (cyclopamine) with irradiation were evaluated in the human HCC cell lines, Huh-7 and PLC/PRF/5, and murine cell line BNL. Cell survival and apoptosis were measured using a colony formation assay, annexin-V staining, and poly (ADP-ribose) polymerase activation. Western blotting and immunofluorescence staining were used to detect protein expression. The in vivo response to radiotherapy and/or cyclopamine was tested in BALB/c mice bearing an orthotopic allogeneic tumor. RESULTS Treatment of HCC cells with irradiation and SHH ligand had a protective effect on clonogenic cell survival. Treatment with irradiation and cyclopamine was a more potent inhibitor of cell proliferation than either modality alone. The antiproliferative activity of cyclopamine was attributable to apoptosis induction. Radiation dose-dependently upregulated the expression of Gli-1 (a transcription factor induced by SHH), and this effect was observed mainly in the nucleus. When combined with cyclopamine, irradiation inhibited Gli-1 and increased DNA double-strand breakage. Radiotherapy increased SHH and Gli-1 expression in allogeneic tumor. When compared with radiotherapy alone, cyclopamine with radiotherapy reduced the mean tumor size of orthotopic tumors by 67% (P < 0.05). CONCLUSION Combining an SHH inhibitor with radiotherapy may enhance HCC cell and orthotopic tumor radiosensitivity.
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Affiliation(s)
- Chiao-Ling Tsai
- Division of Radiation Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Feng-Ming Hsu
- Division of Radiation Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Kai-Yuan Tzen
- Department of Nuclear Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Molecular Imaging Center, National Taiwan University, Taipei, Taiwan
| | - Wei-Lin Liu
- Division of Radiation Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Ann-Lii Cheng
- Division of Medical Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jason Chia-Hsien Cheng
- Division of Radiation Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
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Digging a hole under Hedgehog: downstream inhibition as an emerging anticancer strategy. Biochim Biophys Acta Rev Cancer 2015; 1856:62-72. [PMID: 26080084 DOI: 10.1016/j.bbcan.2015.06.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/04/2015] [Accepted: 06/11/2015] [Indexed: 12/25/2022]
Abstract
Hedgehog signaling is a key regulator of development and stem cell fate and its aberrant activation is a leading cause of a number of tumors. Activating germline or somatic mutations of genes encoding Hh pathway components are found in Basal Cell Carcinoma (BCC) and Medulloblastoma (MB). Ligand-dependent Hedgehog hyperactivation, due to autocrine or paracrine mechanisms, is also observed in a large number of malignancies of the breast, colon, skin, bladder, pancreas and other tissues. The key tumorigenic role of Hedgehog has prompted effort aimed at identifying inhibitors of this signaling. To date, only the antagonists of the membrane transducer Smo have been approved for therapy or are under clinical trials in patients with BCC and MB linked to Ptch or Smo mutations. Despite the good initial response, patients treated with Smo antagonists have eventually developed resistance due to the occurrence of compensating mechanisms. Furthermore, Smo antagonists are not effective in tumors where the Hedgehog hyperactivation is due to mutations of pathway components downstream of Smo, or in case of non-canonical, Smo-independent activation of the Gli transcription factors. For all these reasons, the research of Hh inhibitors acting downstream of Smo is becoming an area of intensive investigation. In this review we illustrate the progresses made in the identification of effective Hedgehog inhibitors and their application in cancer, with a special emphasis on the newly identified downstream inhibitors. We describe in detail the Gli inhibitors and illustrate their mode of action and applications in experimental and/or clinical settings.
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Wang P, Song W, Li H, Wang C, Shi B, Guo W, Zhong L. Association between donor and recipient smoothened gene polymorphisms and the risk of hepatocellular carcinoma recurrence following orthotopic liver transplantation in a Han Chinese population. Tumour Biol 2015; 36:7807-15. [PMID: 25944162 DOI: 10.1007/s13277-015-3370-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 03/24/2015] [Indexed: 01/20/2023] Open
Abstract
Hepatocellular carcinoma (HCC) recurrence after orthotopic liver transplantation (OLT) is potential cause for the poor outcome. Smoothened (SMO) gene has been considered associating with HCC and HCC recurrence, but its association with HCC recurrence after OLT is not clear yet. In this study, we aim at evaluating the association between donor and recipient SMO gene polymorphisms and HCC recurrence after OLT. A total of 76 patients with HCC who had undergone OLT from July 2007 to August 2012 were included. A single nucleotide polymorphism (SNP), SMO rs3824, located at the 3'UTR region, was genotyped and analyzed in both donor and recipient. We demonstrated that recipient rs3824 polymorphism was significantly associated with HCC recurrence following OLT. In multivariate logistic regression analysis, TNM stage (p = 0.001), recipient SMO rs3824 genotype (CG vs. CC/GG p = 0.001), and histologic grade (p = 0.019) were identified as independent risk factors of HCC recurrence. Recurrence-free survival (RFS) and overall survival (OS) were significantly higher in the recipient CC/GG group than in the CG group (p = 0.003 and p = 0.011, respectively). Cox proportional hazards modeling revealed that TNM stage, recipient SMO rs3824 genotype, pre-OLT serum AFP level, and histologic grade were independent factors (p < 0.05) for patients' clinical outcomes. In conclusion, recipient SMO rs3824 polymorphism is associated with an increased risk of HCC recurrence following OLT and has a potential clinical value for the prognosis of HCC patients treated with OLT.
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MESH Headings
- Adult
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/therapy
- Carcinoma, Hepatocellular/virology
- China/epidemiology
- DNA, Neoplasm/analysis
- DNA, Neoplasm/genetics
- Female
- Follow-Up Studies
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/mortality
- Liver Neoplasms/therapy
- Liver Neoplasms/virology
- Liver Transplantation/adverse effects
- Male
- Middle Aged
- Neoplasm Invasiveness
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/etiology
- Neoplasm Recurrence, Local/mortality
- Neoplasm Staging
- Polymorphism, Genetic/genetics
- Prognosis
- Receptors, G-Protein-Coupled/genetics
- Risk Factors
- Smoothened Receptor
- Survival Rate
- Tissue Donors
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Affiliation(s)
- Pusen Wang
- Department of General Surgery, Affiliated First People's Hospital, Shanghai Jiao Tong University, 100 Haining Road, Shanghai, 200080, China
| | - Weiyong Song
- Department of General Surgery, The First People's Hospital of Yongkang City, Yongkang City, Zhejiang Province, 321300, China
| | - Hao Li
- Department of General Surgery, Affiliated First People's Hospital, Shanghai Jiao Tong University, 100 Haining Road, Shanghai, 200080, China
| | - Cunguang Wang
- Department of General Surgery, Affiliated First People's Hospital, Shanghai Jiao Tong University, 100 Haining Road, Shanghai, 200080, China
| | - Baojie Shi
- Department of General Surgery, Affiliated First People's Hospital, Shanghai Jiao Tong University, 100 Haining Road, Shanghai, 200080, China
| | - Wenzhi Guo
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation, The first Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
| | - Lin Zhong
- Department of General Surgery, Affiliated First People's Hospital, Shanghai Jiao Tong University, 100 Haining Road, Shanghai, 200080, China.
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Malhi S, Gu X. Nanocarrier-mediated drugs targeting cancer stem cells: an emerging delivery approach. Expert Opin Drug Deliv 2015; 12:1177-201. [PMID: 25601619 DOI: 10.1517/17425247.2015.998648] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Cancer stem cells (CSCs) play an important role in the development of drug resistance, metastasis and recurrence. Current conventional therapies do not commonly target CSCs. Nanocarrier-based delivery systems targeting cancer cells have entered a new era of treatment, where specific targeting to CSCs may offer superior outcomes to efficient cancer therapies. AREAS COVERED This review discusses the involvement of CSCs in tumor progression and relevant mechanisms associated with CSCs resistance to conventional chemo- and radio-therapies. It highlights CSCs-targeted strategies that are either under evaluation or could be explored in the near future, with a focus on various nanocarrier-based delivery systems of drugs and nucleic acids to CSCs. Novel nanocarriers targeting CSCs are presented in a cancer-specific way to provide a current perspective on anti-CSCs therapeutics. EXPERT OPINION The field of CSCs-targeted therapeutics is still emerging with a few small molecules and macromolecules currently proving efficacy in clinical trials. However considering the complexities of CSCs and existing delivery difficulties in conventional anticancer therapies, CSC-specific delivery systems would face tremendous technical and clinical challenges. Nanocarrier-based approaches have demonstrated significant potential in specific drug delivery and targeting; their success in CSCs-targeted drug delivery would not only significantly enhance anticancer treatment but also address current difficulties associated with cancer resistance, metastasis and recurrence.
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Affiliation(s)
- Sarandeep Malhi
- University of Manitoba, College of Pharmacy, Faculty of Health Sciences , 750 McDermot Avenue Winnipeg, MB R3E 0H5 , Canada
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Daige CL, Wiggins JF, Priddy L, Nelligan-Davis T, Zhao J, Brown D. Systemic delivery of a miR34a mimic as a potential therapeutic for liver cancer. Mol Cancer Ther 2014; 13:2352-60. [PMID: 25053820 DOI: 10.1158/1535-7163.mct-14-0209] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
miR34a is a tumor-suppressor miRNA that functions within the p53 pathway to regulate cell-cycle progression and apoptosis. With apparent roles in metastasis and cancer stem cell development, miR34a provides an interesting opportunity for therapeutic development. A mimic of miR34a was complexed with an amphoteric liposomal formulation and tested in two different orthotopic models of liver cancer. Systemic dosing of the formulated miR34a mimic increased the levels of miR34a in tumors by approximately 1,000-fold and caused statistically significant decreases in the mRNA levels of several miR34a targets. The administration of the formulated miR34a mimic caused significant tumor growth inhibition in both models of liver cancer, and tumor regression was observed in more than one third of the animals. The antitumor activity was observed in the absence of any immunostimulatory effects or dose-limiting toxicities. Accumulation of the formulated miR34a mimic was also noted in the spleen, lung, and kidney, suggesting the potential for therapeutic use in other cancers.
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Affiliation(s)
| | | | | | | | - Jane Zhao
- Mirna Therapeutics, Inc., Austin, Texas
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42
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Drug delivery nanoparticles in skin cancers. BIOMED RESEARCH INTERNATIONAL 2014; 2014:895986. [PMID: 25101298 PMCID: PMC4102061 DOI: 10.1155/2014/895986] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 04/28/2014] [Indexed: 12/17/2022]
Abstract
Nanotechnology involves the engineering of functional systems at nanoscale, thus being attractive for disciplines ranging from materials science to biomedicine. One of the most active research areas of the nanotechnology is nanomedicine, which applies nanotechnology to highly specific medical interventions for prevention, diagnosis, and treatment of diseases, including cancer disease. Over the past two decades, the rapid developments in nanotechnology have allowed the incorporation of multiple therapeutic, sensing, and targeting agents into nanoparticles, for detection, prevention, and treatment of cancer diseases. Nanoparticles offer many advantages as drug carrier systems since they can improve the solubility of poorly water-soluble drugs, modify pharmacokinetics, increase drug half-life by reducing immunogenicity, improve bioavailability, and diminish drug metabolism. They can also enable a tunable release of therapeutic compounds and the simultaneous delivery of two or more drugs for combination therapy. In this review, we discuss the recent advances in the use of different types of nanoparticles for systemic and topical drug delivery in the treatment of skin cancer. In particular, the progress in the treatment with nanocarriers of basal cell carcinoma, squamous cell carcinoma, and melanoma has been reported.
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Atwood SX, Whitson RJ, Oro AE. Advanced treatment for basal cell carcinomas. Cold Spring Harb Perspect Med 2014; 4:a013581. [PMID: 24985127 DOI: 10.1101/cshperspect.a013581] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Basal cell carcinomas (BCCs) are very common epithelial cancers that depend on the Hedgehog pathway for tumor growth. Traditional therapies such as surgical excision are effective for most patients with sporadic BCC; however, better treatment options are needed for cosmetically sensitive or advanced and metastatic BCC. The first approved Hedgehog antagonist targeting the membrane receptor Smoothened, vismodegib, shows remarkable effectiveness on both syndromic and nonsyndromic BCCs. However, drug-resistant tumors frequently develop, illustrating the need for the development of next-generation Hedgehog antagonists targeting pathway components downstream from Smoothened. In this article, we will summarize available BCC treatment options and discuss the development of next-generation antagonists.
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Affiliation(s)
- Scott X Atwood
- Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305
| | - Ramon J Whitson
- Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305
| | - Anthony E Oro
- Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305
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Abstract
The Hedgehog (Hh) pathway is a developmental signaling pathway involved in numerous developmental processes, including determination of cell fate, patterning, proliferation, survival, and differentiation. While this pathway is silenced in most adult tissues, aberrant activation of it has been documented in a variety of malignancies. In cancers such as basal cell carcinoma (BCC), ligand-independent mechanisms lead to constitutive Hh pathway activation through mutations in components of the pathway, including patched-1 (PTCH1) or smoothened (SMO). On the contrary, numerous other solid and hematologic tumors have been shown to harbor ligand-dependent activation of the Hh pathway by autocrine or paracrine mechanisms. Given that aberrant Hh pathway signaling has been seen in a number of malignancies, this pathway has been an attractive target for drug development. While the best-characterized approach is to target the SMO receptor, other rational approaches for inhibiting the Hh pathway include inhibiting downstream components or directly binding Hh ligands. In January of 2012, vismodegib, a SMO antagonist, became the first agent to target the Hh pathway to receive approval by the United States Food and Drug Administration (FDA) after this agent showed remarkable activity in phase I and II trials for the treatment of BCC. Despite promising preclinical studies with Hh pathway inhibitors in other malignancies that have suggested a potential role for these agents, attempts to translate this potential to clinical benefit has been disappointing. Future efforts will require further careful interpretation and analysis to determine the potential determinants and predictors of efficacy. Currently, several phase I and II trials evaluating Hh inhibitors in a variety of tumor settings are underway.
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Affiliation(s)
- Joshua M Ruch
- Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA
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Pinter M, Sieghart W, Schmid M, Dauser B, Prager G, Dienes HP, Trauner M, Peck-Radosavljevic M. Hedgehog inhibition reduces angiogenesis by downregulation of tumoral VEGF-A expression in hepatocellular carcinoma. United European Gastroenterol J 2014; 1:265-75. [PMID: 24917971 DOI: 10.1177/2050640613496605] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Accepted: 06/12/2013] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Dysregulation and activation of Hedgehog (Hh) signalling may contribute to tumorigenesis, angiogenesis, and metastatic seeding in several solid tumours. OBJECTIVE We investigated the impact of Hh inhibition on tumour growth and angiogenesis using in-vitro and in-vivo models of hepatocellular carcinoma (HCC). METHODS The effect of the Hh pathway inhibitor GDC-0449 on tumour growth was investigated using an orthotopic rat model. Effects on angiogenesis were determined by immunohistochemical staining of von Willebrand factor antigen and by assessing the mRNA expression of several angiogenic factors. In vitro, HCC cell lines were treated with GDC-0449 and evaluated for viability and expression of vascular endothelial growth factor (VEGF). Endothelial cells were evaluated for viability, migration, and tube formation. RESULTS In the orthotopic HCC model, GDC-0449 significantly decreased tumoral VEGF expression which was accompanied by a significant reduction of microvessel density and tumour growth. In HCC cells, GDC-0449 had no effect on cell growth but significantly reduced target gene regulation and VEGF expression while having no direct effect on endothelial cell viability, migration, and tube formation. CONCLUSIONS Hh inhibition with GDC-0449 downregulates tumoral VEGF production in vitro and reduces tumoral VEGF expression, angiogenesis, and tumour growth in an orthotopic HCC model.
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Banerjee U, Hadden MK. Recent advances in the design of Hedgehog pathway inhibitors for the treatment of malignancies. Expert Opin Drug Discov 2014; 9:751-71. [PMID: 24850423 DOI: 10.1517/17460441.2014.920817] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
INTRODUCTION The Hedgehog (Hh) signaling pathway is known to be dysregulated in several forms of cancer. Hence, specifically targeting this signaling cascade is a valid and promising strategy for successful therapeutic intervention. Several components within the Hh pathway have been proven to be druggable; however, challenges in the discovery and development process for small molecules targeting this pathway have been identified. AREAS COVERED This review details both the current state and future potential of Hh pathway inhibitors as anticancer chemotherapeutics that target a variety of human malignancies. EXPERT OPINION The initial development of Hh pathway inhibitors focused on small-molecule antagonists of Smoothened, a transmembrane protein that is a key regulator of pathway signaling. More recently, efforts to identify and develop inhibitors of pathway signaling that function through alternate mechanisms have been increasing. However, none of these have advanced into clinical trials. Further, early evidence suggesting the broad application of Hh pathway inhibitors as a monotherapy in a wide range of human cancers has not been validated. The potential for Hh pathway inhibitors as combination therapy has demonstrated promising preclinical results. However, more research to identify rational drug combinations to fully explore the potential of this anticancer drug class is warranted.
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Affiliation(s)
- Upasana Banerjee
- University of Connecticut, Department of Pharmaceutical Sciences , 69 N Eagleville Rd, Unit 3092, Storrs, CT 06269-3092 , USA +1 860 486 8446 ;
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Nanomedicine: The Promise and Challenges in Cancer Chemotherapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 811:207-33. [DOI: 10.1007/978-94-017-8739-0_11] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Abstract
PURPOSE In the treatment of rhabdomyosarcoma (RMS), invasion and metastasis remain the most critical determinants of resectability and survival. The objective of this study was to determine whether Hedgehog (Hh) signaling plays a role in the invasion of RMS. METHODS Two kinds of specific Hh signaling inhibitors, cyclopamine and forskolin, were used to suppress activated Hh signals in three RMS cell lines. The effects of the Hh signaling inhibitors on tumor cell invasion and motility were investigated using Matrigel invasion assays and wound closure assays, respectively. RESULTS The number of invaded cells counted in six random microscopic fields in the Matrigel chambers was significantly decreased by both cyclopamine and forskolin in every RMS cell line. Furthermore, the wound closure assays revealed that a blockade of the Hh signaling pathway by the Hh inhibitors strongly impairs RMS cell motility, as visualized by the delayed closure of the gaps generated in the cultured cell monolayers of the three RMS cell lines. CONCLUSIONS Both the invasive capacity and motility of RMS cells are significantly suppressed by Hh signaling inhibitors, demonstrating that the Hh pathway plays an important role in the invasion of RMS. Hh inhibitors may provide a new paradigm for the treatment of RMS.
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Affiliation(s)
- Takaharu Oue
- Division of Pediatric Surgery, Department of Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan,
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Zhao Y, Alakhova DY, Kabanov AV. Can nanomedicines kill cancer stem cells? Adv Drug Deliv Rev 2013; 65:1763-83. [PMID: 24120657 DOI: 10.1016/j.addr.2013.09.016] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 09/30/2013] [Accepted: 09/30/2013] [Indexed: 12/12/2022]
Abstract
Most tumors are heterogeneous and many cancers contain small population of highly tumorigenic and intrinsically drug resistant cancer stem cells (CSCs). Like normal stem cell, CSCs have the ability to self-renew and differentiate to other tumor cell types. They are believed to be a source for drug resistance, tumor recurrence and metastasis. CSCs often overexpress drug efflux transporters, spend most of their time in non-dividing G0 cell cycle state, and therefore, can escape the conventional chemotherapies. Thus, targeting CSCs is essential for developing novel therapies to prevent cancer relapse and emerging of drug resistance. Nanocarrier-based therapeutic agents (nanomedicines) have been used to achieve longer circulation times, better stability and bioavailability over current therapeutics. Recently, some groups have successfully applied nanomedicines to target CSCs to eliminate the tumor and prevent its recurrence. These approaches include 1) delivery of therapeutic agents (small molecules, siRNA, antibodies) that affect embryonic signaling pathways implicated in self-renewal and differentiation in CSCs, 2) inhibiting drug efflux transporters in an attempt to sensitize CSCs to therapy, 3) targeting metabolism in CSCs through nanoformulated chemicals and field-responsive magnetic nanoparticles and carbon nanotubes, and 4) disruption of multiple pathways in drug resistant cells using combination of chemotherapeutic drugs with amphiphilic Pluronic block copolymers. Despite clear progress of these studies the challenges of targeting CSCs by nanomedicines still exist and leave plenty of room for improvement and development. This review summarizes biological processes that are related to CSCs, overviews the current state of anti-CSCs therapies, and discusses state-of-the-art nanomedicine approaches developed to kill CSCs.
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Merchant JL, Saqui-Salces M. Inhibition of Hedgehog signaling in the gastrointestinal tract: targeting the cancer microenvironment. Cancer Treat Rev 2013; 40:12-21. [PMID: 24007940 DOI: 10.1016/j.ctrv.2013.08.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Revised: 08/02/2013] [Accepted: 08/06/2013] [Indexed: 02/08/2023]
Abstract
This review summarizes emerging information regarding the Hedgehog (Hh) signaling pathway during neoplastic transformation in the gastrointestinal tract. Although there is a role for the well-established canonical pathway in which Hedgehog ligands interact with their receptor Patched, there is sufficient evidence that downstream components of the Hh pathway, e.g., Gli1, are hijacked by non-Hh signaling pathways to promote the conversion of the epithelium to dysplasia and carcinoma. We review the canonical pathway and involvement of primary cilia, and then focus on current evidence for Hh signaling in luminal bowel cancers as well as accessory organs, i.e., liver, pancreas and biliary ducts. We conclude that targeting the Hh pathway with small molecules, nutriceuticals and other mechanisms will likely require a combination of inhibitors that target Gli transcription factors in addition to canonical modulators such as Smoothened.
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Affiliation(s)
- Juanita L Merchant
- Departments of Internal Medicine and Molecular and Integrative Physiology, Division of Gastroenterology, University of Michigan, United States.
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