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Hu ZY, Ding D, Song Y, Deng YF, Zhang CM, Yu T. Molecular mechanism of pancreatic ductal adenocarcinoma: The heterogeneity of cancer-associated fibroblasts and key signaling pathways. World J Clin Oncol 2025; 16:97007. [PMID: 39995552 PMCID: PMC11686552 DOI: 10.5306/wjco.v16.i2.97007] [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] [Received: 05/20/2024] [Revised: 10/04/2024] [Accepted: 11/04/2024] [Indexed: 12/11/2024] Open
Abstract
Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis, leading to a notably low five-year survival rate. This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers, such as mutations in CDKN2A, KRAS, SMAD4, and TP53, along with the influence of cancer-associated fibroblasts (CAFs) on disease progression. In particular, we focused on the pivotal roles of signaling pathways such as the transforming growth factor-β and Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies. This study provides new scientific perspectives on pancreatic cancer treatment, especially in the development of precision medicine and targeted therapeutic strategies, and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens. Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.
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Affiliation(s)
- Zhong-Yuan Hu
- First School of Clinical Medicine, Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China
| | - Ding Ding
- First School of Clinical Medicine, Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China
| | - Yu Song
- College of Acupuncture and Massage, Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China
| | - Ya-Feng Deng
- Graduate School, Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, China
| | - Cheng-Ming Zhang
- Digestive Department I, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi’an 710000, Shaanxi Province, China
| | - Tao Yu
- Digestive Department I, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xi’an 710000, Shaanxi Province, China
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2
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Hunt HL, Goncalves BG, Biggs MA, Rico MI, Murray ME, Lebedenko CG, Banerjee IA. Design and investigation of interactions of novel peptide conjugates of purine and pyrimidine derivatives with EGFR and its mutant T790M/L858R: an in silico and laboratory study. Mol Divers 2024; 28:3683-3711. [PMID: 38240950 DOI: 10.1007/s11030-023-10772-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 11/17/2023] [Indexed: 12/21/2024]
Abstract
Peptide-based therapeutics have been gaining attention due to their ability to actively target tumor cells. Additionally, several varieties of nucleotide derivatives have been developed to reduce cell proliferation and induce apoptosis of tumor cells. In this work, we have developed novel peptide conjugates with newly designed purine analogs and pyrimidine derivatives and explored the binding interactions with the kinase domain of wild-type EGFR and its mutant EGFR [L858R/ T790M] which are known to be over-expressed in tumor cells. The peptides explored included WNWKV (derived from sea cucumber) and LARFFS, which in previous work was predicted to bind to Domain I of EGFR. Computational studies conducted to explore binding interactions include molecular docking studies, molecular dynamics simulations and MMGBSA to investigate the binding abilities and stability of the complexes. The results indicate that conjugation enhanced binding capabilities, particularly for the WNWKV conjugates. MMGBSA analysis revealed nearly twofold higher binding toward the T790M/L858R double mutant receptor. Several conjugates were shown to have strong and stable binding with both wild-type and mutant EGFR. As a proof of concept, we synthesized pyrimidine conjugates with both peptides and determined the KD values using SPR analysis. The results corroborated with the computational analyses. Additionally, cell viability and apoptosis studies with lung cancer cells expressing the wild-type and double mutant proteins revealed that the WNWKV conjugate showed greater potency than the LARFFS conjugate, while LARFFS peptide alone showed poor binding to the kinase domain. Thus, we have designed peptide conjugates that show potential for further laboratory studies for developing therapeutics for targeting the EGFR receptor and its mutant T790M/L858R.
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Affiliation(s)
- Hannah L Hunt
- Department of Chemistry, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USA
| | - Beatriz G Goncalves
- Department of Chemistry, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USA
| | - Mary A Biggs
- Department of Chemistry, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USA
| | - Mia I Rico
- Department of Chemistry, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USA
| | - Molly E Murray
- Department of Chemistry, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USA
| | - Charlotta G Lebedenko
- Department of Chemistry, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USA
| | - Ipsita A Banerjee
- Department of Chemistry, Fordham University, 441 East Fordham Road, Bronx, NY, 10458, USA.
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3
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Basar E, Mead H, Shum B, Rauter I, Ay C, Skaletz-Rorowski A, Brockmeyer NH. Biological Barriers for Drug Delivery and Development of Innovative Therapeutic Approaches in HIV, Pancreatic Cancer, and Hemophilia A/B. Pharmaceutics 2024; 16:1207. [PMID: 39339243 PMCID: PMC11435036 DOI: 10.3390/pharmaceutics16091207] [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: 07/26/2024] [Revised: 09/06/2024] [Accepted: 09/07/2024] [Indexed: 09/30/2024] Open
Abstract
Biological barriers remain a major obstacle for the development of innovative therapeutics. Depending on a disease's pathophysiology, the involved tissues, cell populations, and cellular components, drugs often have to overcome several biological barriers to reach their target cells and become effective in a specific cellular compartment. Human biological barriers are incredibly diverse and include multiple layers of protection and obstruction. Importantly, biological barriers are not only found at the organ/tissue level, but also include cellular structures such as the outer plasma membrane, the endolysosomal machinery, and the nuclear envelope. Nowadays, clinicians have access to a broad arsenal of therapeutics ranging from chemically synthesized small molecules, biologicals including recombinant proteins (such as monoclonal antibodies and hormones), nucleic-acid-based therapeutics, and antibody-drug conjugates (ADCs), to modern viral-vector-mediated gene therapy. In the past decade, the therapeutic landscape has been changing rapidly, giving rise to a multitude of innovative therapy approaches. In 2018, the FDA approval of patisiran paved the way for small interfering RNAs (siRNAs) to become a novel class of nucleic-acid-based therapeutics, which-upon effective drug delivery to their target cells-allow to elegantly regulate the post-transcriptional gene expression. The recent approvals of valoctocogene roxaparvovec and etranacogene dezaparvovec for the treatment of hemophilia A and B, respectively, mark the breakthrough of viral-vector-based gene therapy as a new tool to cure disease. A multitude of highly innovative medicines and drug delivery methods including mRNA-based cancer vaccines and exosome-targeted therapy is on the verge of entering the market and changing the treatment landscape for a broad range of conditions. In this review, we provide insights into three different disease entities, which are clinically, scientifically, and socioeconomically impactful and have given rise to many technological advancements: acquired immunodeficiency syndrome (AIDS) as a predominant infectious disease, pancreatic carcinoma as one of the most lethal solid cancers, and hemophilia A/B as a hereditary genetic disorder. Our primary objective is to highlight the overarching principles of biological barriers that can be identified across different disease areas. Our second goal is to showcase which therapeutic approaches designed to cross disease-specific biological barriers have been promising in effectively treating disease. In this context, we will exemplify how the right selection of the drug category and delivery vehicle, mode of administration, and therapeutic target(s) can help overcome various biological barriers to prevent, treat, and cure disease.
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Affiliation(s)
- Emre Basar
- WIR—Walk In Ruhr, Center for Sexual Health & Medicine, Department of Dermatology, Venerology and Allergology, Ruhr-University Bochum, 44787 Bochum, Germany;
| | | | - Bennett Shum
- GenePath LLC, Sydney, NSW 2067, Australia
- EMBL Australia Node in Single Molecule Science, School of Medical Sciences, University of NSW, Sydney, NSW 2052, Australia
| | | | - Cihan Ay
- Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria
| | - Adriane Skaletz-Rorowski
- WIR—Walk In Ruhr, Center for Sexual Health & Medicine, Department of Dermatology, Venerology and Allergology, Ruhr-University Bochum, 44787 Bochum, Germany;
| | - Norbert H. Brockmeyer
- WIR—Walk In Ruhr, Center for Sexual Health & Medicine, Department of Dermatology, Venerology and Allergology, Ruhr-University Bochum, 44787 Bochum, Germany;
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4
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Do CTP, Prochnau JY, Dominguez A, Wang P, Rao MK. The Road Ahead in Pancreatic Cancer: Emerging Trends and Therapeutic Prospects. Biomedicines 2024; 12:1979. [PMID: 39335494 PMCID: PMC11428787 DOI: 10.3390/biomedicines12091979] [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: 08/01/2024] [Revised: 08/15/2024] [Accepted: 08/21/2024] [Indexed: 09/30/2024] Open
Abstract
This review explores the challenges and emerging trends in pancreatic cancer therapy. In particular, we focus on the tumor microenvironment and the potential of immunotherapy for pancreatic cancer. Pancreatic ductal adenocarcinoma, characterized by its dense stromal architecture, presents unique challenges for effective treatment. Recent advancements have emphasized the role of the tumor microenvironment in therapeutic resistance and disease progression. We discuss novel strategies targeting the desmoplastic barrier and immunosuppressive cells to enhance immune cell infiltration and activation. Recent clinical trials, particularly those involving novel immunotherapeutic agents and tumor vaccines, are examined to understand their efficacy and limitations. Our analysis reveals that combining immunotherapy with chemotherapy, radiation therapy, or drugs targeting epigenetic processes shows promise, improving overall survival rates and response to treatment. For instance, trials utilizing checkpoint inhibitors in combination with standard chemotherapies have extended disease-free survival by up to 6 months compared to chemotherapy alone. Importantly, vaccines targeting specific tumor neoantigens have shown the potential to increase patient survival. However, these approaches also face significant challenges, including overcoming the immunosuppressive tumor microenvironment and enhancing the delivery and efficacy of therapeutic agents. By providing an overview of both the promising results and the obstacles encountered, this review aims to highlight ongoing efforts to refine immunotherapy approaches for better patient outcomes.
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Affiliation(s)
- Chris T P Do
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Jack Y Prochnau
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Angel Dominguez
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Pei Wang
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Manjeet K Rao
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
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5
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Martinez S, Wu S, Geuenich M, Malik A, Weber R, Woo T, Zhang A, Jang GH, Dervovic D, Al-Zahrani KN, Tsai R, Fodil N, Gros P, Gallinger S, Neely GG, Notta F, Sendoel A, Campbell K, Elling U, Schramek D. In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer. Nat Commun 2024; 15:5266. [PMID: 38902237 PMCID: PMC11189927 DOI: 10.1038/s41467-024-49450-3] [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: 12/06/2022] [Accepted: 06/05/2024] [Indexed: 06/22/2024] Open
Abstract
Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, which revealed USP15 and SCAF1 as pancreatic tumor suppressors. Mechanistically, we find that USP15 functions in a haploinsufficient manner and that loss of USP15 or SCAF1 leads to reduced inflammatory TNFα, TGF-β and IL6 responses and increased sensitivity to PARP inhibition and Gemcitabine. Furthermore, we find that loss of SCAF1 leads to the formation of a truncated, inactive USP15 isoform at the expense of full-length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 alterations are observed in 31% of pancreatic cancer patients. Our results highlight the utility of in vivo CRISPR screens to integrate human cancer genomics and mouse modeling for the discovery of cancer driver genes with potential prognostic and therapeutic implications.
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Affiliation(s)
- Sebastien Martinez
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Shifei Wu
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Michael Geuenich
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Ahmad Malik
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Ramona Weber
- Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland
| | - Tristan Woo
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Amy Zhang
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Gun Ho Jang
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Dzana Dervovic
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Khalid N Al-Zahrani
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Ricky Tsai
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Nassima Fodil
- Department of Biochemistry, Dahdaleh Institute of Genomic Medicine, McGill University, Montreal, QC, Canada
| | - Philippe Gros
- Department of Biochemistry, Dahdaleh Institute of Genomic Medicine, McGill University, Montreal, QC, Canada
| | - Steven Gallinger
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - G Gregory Neely
- Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre, and School of Life and Environmental Sciences, The University of Sydney, Camperdown, NSW 2006, Australia
| | - Faiyaz Notta
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Ataman Sendoel
- Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland
| | - Kieran Campbell
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Ulrich Elling
- Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Dr. Bohr-Gasse 3, Vienna BioCenter (VBC), 1030, Vienna, Austria
| | - Daniel Schramek
- Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
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6
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Nishio Y, Kato K, Oishi H, Takahashi Y, Saitoh S. MYCN in human development and diseases. Front Oncol 2024; 14:1417607. [PMID: 38884091 PMCID: PMC11176553 DOI: 10.3389/fonc.2024.1417607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 05/15/2024] [Indexed: 06/18/2024] Open
Abstract
Somatic mutations in MYCN have been identified across various tumors, playing pivotal roles in tumorigenesis, tumor progression, and unfavorable prognoses. Despite its established notoriety as an oncogenic driver, there is a growing interest in exploring the involvement of MYCN in human development. While MYCN variants have traditionally been associated with Feingold syndrome type 1, recent discoveries highlight gain-of-function variants, specifically p.(Thr58Met) and p.(Pro60Leu), as the cause for megalencephaly-polydactyly syndrome. The elucidation of cellular and murine analytical data from both loss-of-function (Feingold syndrome model) and gain-of-function models (megalencephaly-polydactyly syndrome model) is significantly contributing to a comprehensive understanding of the physiological role of MYCN in human development and pathogenesis. This review discusses the MYCN's functional implications for human development by reviewing the clinical characteristics of these distinct syndromes, Feingold syndrome, and megalencephaly-polydactyly syndrome, providing valuable insights into the understanding of pathophysiological backgrounds of other syndromes associated with the MYCN pathway and the overall comprehension of MYCN's role in human development.
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Affiliation(s)
- Yosuke Nishio
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Kohji Kato
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
| | - Hisashi Oishi
- Department of Comparative and Experimental Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yoshiyuki Takahashi
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shinji Saitoh
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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7
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Wu D, Wang Q, Yan S, Sun X, Qin Y, Yuan M, Wang NY, Huang XT. Extended survival with metastatic pancreatic cancer under fruquintinib treatment after failed chemotherapy: Two case reports. World J Clin Cases 2024; 12:1296-1304. [PMID: 38524525 PMCID: PMC10955531 DOI: 10.12998/wjcc.v12.i7.1296] [Citation(s) in RCA: 1] [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: 10/08/2023] [Revised: 01/02/2024] [Accepted: 02/05/2024] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND Pancreatic cancer is a highly malignant disease. After decades of treatment progress, the current five-year survival rate for patients is still less than 10%. For later-line treatment, the treatment options are even more limited. Anti-angiogenic drugs can improve progression-free survival in patients with advanced pancreatic cancer. Preclinical data show that fruquintinib might improve the prognosis of advanced pancreatic cancer by targeting angiogenesis and lymphopoiesis, improving the abnormal vascular structure, and modulating the tumour immune microenvironment. CASE SUMMARY We present two cases of third-line fruquintinib monotherapy that brought an extraprolonged progress-free survival (PFS) of 10 months. Patient 1 took adjuvant gemcitabine-based and first-line nab-paclitaxel-based chemotherapy and then used local radiotherapy combined with programmed cell death 1 receptor (PD-1). Each line lasted approximately 7 months. Moreover, the patient took third-line fruquintinib, which was followed by stable disease for 10 months, during which no additional adverse effect was observed. The patient later refused to take fruquintinib due to difficulty urinating and lower abdominal pain after the coronavirus disease 2019 (COVID-19) infection. The patient died in February 2023. Patient 2 also took two prior lines of chemotherapy and then local radiotherapy combined with S-1. After confirmed disease progression, the patient experienced a continuous partial response after using fruquintinib monotherapy in the third line. After the patient had COVID-19 in December 2022, fruquintinib was discontinued. The patient died in January 2023 due to disease progression. CONCLUSION Both cases achieved a PFS benefit from later-line single-agent fruquintinib therapy. With its better safety profile, fruquintinib may be worth exploring and studying in more depth as a later-line treatment for pancreatic cancer patients.
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Affiliation(s)
- Dan Wu
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Qiong Wang
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Shuai Yan
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Xia Sun
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Ya Qin
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Ming Yuan
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Nan-Yao Wang
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
| | - Xian-Ting Huang
- Department of Oncology, Jiangyin People's Hospital, Wuxi 214400, Jiangsu Province, China
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8
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Pramanik N, Gupta A, Ghanwatkar Y, Mahato RI. Recent advances in drug delivery and targeting for the treatment of pancreatic cancer. J Control Release 2024; 366:231-260. [PMID: 38171473 PMCID: PMC10922996 DOI: 10.1016/j.jconrel.2023.12.053] [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: 09/17/2023] [Revised: 11/24/2023] [Accepted: 12/29/2023] [Indexed: 01/05/2024]
Abstract
Despite significant treatment efforts, pancreatic ductal adenocarcinoma (PDAC), the deadliest solid tumor, is still incurable in the preclinical stages due to multifacet stroma, dense desmoplasia, and immune regression. Additionally, tumor heterogeneity and metabolic changes are linked to low grade clinical translational outcomes, which has prompted the investigation of the mechanisms underlying chemoresistance and the creation of effective treatment approaches by selectively targeting genetic pathways. Since targeting upstream molecules in first-line oncogenic signaling pathways typically has little clinical impact, downstream signaling pathways have instead been targeted in both preclinical and clinical studies. In this review, we discuss how the complexity of various tumor microenvironment (TME) components and the oncogenic signaling pathways that they are connected to actively contribute to the development and spread of PDAC, as well as the ways that recent therapeutic approaches have been targeted to restore it. We also illustrate how many endogenous stimuli-responsive linker-based nanocarriers have recently been developed for the specific targeting of distinct oncogenes and their downstream signaling cascades as well as their ongoing clinical trials. We also discuss the present challenges, prospects, and difficulties in the development of first-line oncogene-targeting medicines for the treatment of pancreatic cancer patients.
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Affiliation(s)
- Nilkamal Pramanik
- Department of Pharmaceutical Sciences, the University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Aditya Gupta
- Department of Pharmaceutical Sciences, the University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Yashwardhan Ghanwatkar
- Department of Pharmaceutical Sciences, the University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, the University of Nebraska Medical Center, Omaha, NE 68198, USA.
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9
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Dirks ML, McDougal OM. Pharmacology of Veratrum californicum Alkaloids as Hedgehog Pathway Antagonists. Pharmaceuticals (Basel) 2024; 17:123. [PMID: 38256956 PMCID: PMC10821092 DOI: 10.3390/ph17010123] [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: 11/21/2023] [Revised: 01/10/2024] [Accepted: 01/15/2024] [Indexed: 01/24/2024] Open
Abstract
Veratrum californicum contains steroidal alkaloids that function as inhibitors of hedgehog (Hh) signaling, a pathway involved in the growth and differentiation of cells and normal tissue development. This same Hh pathway is abnormally active for cell proliferation in more than 20 types of cancer. In this current study, alkaloids have been extracted from the root and rhizome of V. californicum, followed by their separation into five fractions using high performance liquid chromatography. Mass spectrometry was used to identify the presence of twenty-five alkaloids, nine more than are commonly cited in literature reports, and the Bruker Compass Data Analysis software was used to predict the molecular formula for every detected alkaloid. The Gli activity of the raw extract and each fraction were compared to 0.1 µM cyclopamine, and fractions 1, 2, and 4 showed increased bioactivity through suppression of the Hh signaling pathway. Fractions 2 and 4 had enhanced bioactivity, but fraction 1 was most effective in inhibiting Hh signaling. The composition of fraction 1 consisted of veratrosine, cycloposine, and potential isomers of each.
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Affiliation(s)
- Madison L. Dirks
- Biomolecular Sciences Graduate Programs, Boise State University, Boise, ID 83725, USA;
| | - Owen M. McDougal
- Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, USA
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10
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Mia MAR, Dey D, Sakib MR, Biswas MY, Prottay AAS, Paul N, Rimti FH, Abdullah Y, Biswas P, Iftehimul M, Paul P, Sarkar C, El-Nashar HAS, El-Shazly M, Islam MT. The efficacy of natural bioactive compounds against prostate cancer: Molecular targets and synergistic activities. Phytother Res 2023; 37:5724-5754. [PMID: 37786304 DOI: 10.1002/ptr.8017] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 08/17/2023] [Accepted: 09/05/2023] [Indexed: 10/04/2023]
Abstract
Globally, prostate cancer (PCa) is regarded as a challenging health issue, and the number of PCa patients continues to rise despite the availability of effective treatments in recent decades. The current therapy with chemotherapeutic drugs has been largely ineffective due to multidrug resistance and the conventional treatment has restricted drug accessibility to malignant tissues, necessitating a higher dosage resulting in increased cytotoxicity. Plant-derived bioactive compounds have recently attracted a great deal of attention in the field of PCa treatment due to their potent effects on several molecular targets and synergistic effects with anti-PCa drugs. This review emphasizes the molecular mechanism of phytochemicals on PCa cells, the synergistic effects of compound-drug interactions, and stem cell targeting for PCa treatment. Some potential compounds, such as curcumin, phenethyl-isothiocyanate, fisetin, baicalein, berberine, lutein, and many others, exert an anti-PCa effect via inhibiting proliferation, metastasis, cell cycle progression, and normal apoptosis pathways. In addition, multiple studies have demonstrated that the isolated natural compounds: d-limonene, paeonol, lanreotide, artesunate, and bicalutamide have potential synergistic effects. Further, a significant number of natural compounds effectively target PCa stem cells. However, further high-quality studies are needed to firmly establish the clinical efficacy of these phytochemicals against PCa.
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Affiliation(s)
- Md Abdur Rashid Mia
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Dipta Dey
- Department of Biochemistry and Molecular Biology, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Musfiqur Rahman Sakib
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Md Yeaman Biswas
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology (JUST), Jashore, Bangladesh
| | - Abdullah Al Shamsh Prottay
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Niloy Paul
- Department of Biochemistry and Molecular Biology, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Fahmida Hoque Rimti
- Bachelor of Medicine and Surgery, Chittagong Medical College, Chawkbazar, Bangladesh
| | - Yusuf Abdullah
- Department of Biochemistry and Molecular Biology, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Partha Biswas
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology (JUST), Jashore, Bangladesh
| | - Md Iftehimul
- Department of Fisheries and Marine Bioscience, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Priyanka Paul
- Department of Biochemistry and Molecular Biology, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Chandan Sarkar
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Heba A S El-Nashar
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Mohamed El-Shazly
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Muhammad Torequl Islam
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
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11
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Puente-Cobacho B, Varela-López A, Quiles JL, Vera-Ramirez L. Involvement of redox signalling in tumour cell dormancy and metastasis. Cancer Metastasis Rev 2023; 42:49-85. [PMID: 36701089 PMCID: PMC10014738 DOI: 10.1007/s10555-022-10077-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 12/27/2022] [Indexed: 01/27/2023]
Abstract
Decades of research on oncogene-driven carcinogenesis and gene-expression regulatory networks only started to unveil the complexity of tumour cellular and molecular biology. This knowledge has been successfully implemented in the clinical practice to treat primary tumours. In contrast, much less progress has been made in the development of new therapies against metastasis, which are the main cause of cancer-related deaths. More recently, the role of epigenetic and microenviromental factors has been shown to play a key role in tumour progression. Free radicals are known to communicate the intracellular and extracellular compartments, acting as second messengers and exerting a decisive modulatory effect on tumour cell signalling. Depending on the cellular and molecular context, as well as the intracellular concentration of free radicals and the activation status of the antioxidant system of the cell, the signalling equilibrium can be tilted either towards tumour cell survival and progression or cell death. In this regard, recent advances in tumour cell biology and metastasis indicate that redox signalling is at the base of many cell-intrinsic and microenvironmental mechanisms that control disseminated tumour cell fate and metastasis. In this manuscript, we will review the current knowledge about redox signalling along the different phases of the metastatic cascade, including tumour cell dormancy, making emphasis on metabolism and the establishment of supportive microenvironmental connections, from a redox perspective.
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Affiliation(s)
- Beatriz Puente-Cobacho
- Department of Genomic Medicine, GENYO, Centre for Genomics and Oncology, Pfizer-University of Granada and Andalusian Regional Government, PTS, Granada, Spain
| | - Alfonso Varela-López
- Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Center, University of Granada, Granada, Spain
| | - José L Quiles
- Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Center, University of Granada, Granada, Spain
| | - Laura Vera-Ramirez
- Department of Genomic Medicine, GENYO, Centre for Genomics and Oncology, Pfizer-University of Granada and Andalusian Regional Government, PTS, Granada, Spain. .,Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Center, University of Granada, Granada, Spain.
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12
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Ali M, Wani SUD, Salahuddin M, S.N. M, K M, Dey T, Zargar MI, Singh J. Recent advance of herbal medicines in cancer- a molecular approach. Heliyon 2023; 9:e13684. [PMID: 36865478 PMCID: PMC9971193 DOI: 10.1016/j.heliyon.2023.e13684] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 02/01/2023] [Accepted: 02/07/2023] [Indexed: 02/16/2023] Open
Abstract
Bioactive compounds are crucial for an extensive range of therapeutic uses, and some exhibit anticancer activity. Scientists advocate that phytochemicals modulate autophagy and apoptosis, involved in the underlying pathobiology of cancer development and regulation. The pharmacological aiming of the autophagy-apoptosis signaling pathway using phytocompounds hence offers an auspicious method that is complementary to conventional cancer chemotherapy. The current review aims to explore the molecular level of the autophagic-apoptotic pathway to know its implication in the pathobiology of cancer and explore the essential cellular process as a druggable anticancer target and therapeutic emergence of naturally derived phytocompound-based anticancer agents. The data in the review were collected from scientific databases such as Google search, Web of Science, PubMed, Scopus, Medline, and Clinical Trials. With a broad outlook, we investigated their cutting-edge scientifically revealed and/or searched pharmacologic effects, a novel mechanism of action, and molecular signaling pathway of phytochemicals in cancer therapy. In this review, the evidence is focused on molecular pharmacology, specifically caspase, Nrf2, NF-kB, autophagic-apoptotic pathway, and several mechanisms to understand their role in cancer biology.
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Affiliation(s)
- Mohammad Ali
- Department of Pharmacy Practice, East Point College of Pharmacy, Bangalore, 560049, India
| | - Shahid Ud Din Wani
- Department of Pharmaceutical Sciences, School of Applied Sciences and Technology, University of Kashmir, Srinagar, 190006, India
| | - Md Salahuddin
- Department of Pharmaceutical Chemistry, Al-Ameen College of Pharmacy, Bangalore, 560027, India
| | - Manjula S.N.
- Department of Pharmacology, JSS College of Pharmacy Mysuru, JSS Academy of Higher Education and Research, Mysuru, 570004, India
| | - Mruthunjaya K
- Department of Pharmacognosy, JSS College of Pharmacy Mysuru, JSS Academy of Higher Education and Research, Mysuru, 570004, India
| | - Tathagata Dey
- Department of Pharmaceutical Chemistry, East Point College of Pharmacy, Bangalore, 560049, India
| | - Mohammed Iqbal Zargar
- Department of Pharmaceutical Sciences, School of Applied Sciences and Technology, University of Kashmir, Srinagar, 190006, India
| | - Jagadeesh Singh
- Department of Pharmacognosy, East Point College of Pharmacy, Bangalore, 560049, India
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13
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Lahmar Z, Ahmed E, Fort A, Vachier I, Bourdin A, Bergougnoux A. Hedgehog pathway and its inhibitors in chronic obstructive pulmonary disease (COPD). Pharmacol Ther 2022; 240:108295. [PMID: 36191777 DOI: 10.1016/j.pharmthera.2022.108295] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 08/22/2022] [Accepted: 09/28/2022] [Indexed: 11/05/2022]
Abstract
COPD affects millions of people and is now ranked as the third leading cause of death worldwide. This largely untreatable chronic airway disease results in irreversible destruction of lung architecture. The small lung hypothesis is now supported by epidemiological, physiological and clinical studies. Accordingly, the early and severe COPD phenotype carries the most dreadful prognosis and finds its roots during lung growth. Pathophysiological mechanisms remain poorly understood and implicate individual susceptibility (genetics), a large part of environmental factors (viral infections, tobacco consumption, air pollution) and the combined effects of those triggers on gene expression. Genetic susceptibility is most likely involved as the disease is severe and starts early in life. The latter observation led to the identification of Mendelian inheritance via disease-causing variants of SERPINA1 - known as the basis for alpha-1 anti-trypsin deficiency, and TERT. In the last two decades multiple genome wide association studies (GWAS) identified many single nucleotide polymorphisms (SNPs) associated with COPD. High significance SNPs are located in 4q31 near HHIP which encodes an evolutionarily highly conserved physiological inhibitor of the Hedgehog signaling pathway (HH). HHIP is critical to several in utero developmental lung processes. It is also implicated in homeostasis, injury response, epithelial-mesenchymal transition and tumor resistance to apoptosis. A few studies have reported decreased HHIP RNA and protein levels in human adult COPD lungs. HHIP+/- murine models led to emphysema. HH pathway inhibitors, such as vismodegib and sonidegib, are already validated in oncology, whereas other drugs have evidenced in vitro effects. Targeting the Hedgehog pathway could lead to a new therapeutic avenue in COPD. In this review, we focused on the early and severe COPD phenotype and the small lung hypothesis by exploring genetic susceptibility traits that are potentially treatable, thus summarizing promising therapeutics for the future.
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Affiliation(s)
- Z Lahmar
- Department of Respiratory Diseases, CHU de Montpellier, Montpellier, France
| | - E Ahmed
- Department of Respiratory Diseases, CHU de Montpellier, Montpellier, France; PhyMedExp, Univ Montpellier, Inserm U1046, CNRS UMR 9214, Montpellier, France
| | - A Fort
- PhyMedExp, Univ Montpellier, Inserm U1046, CNRS UMR 9214, Montpellier, France
| | - I Vachier
- Department of Respiratory Diseases, CHU de Montpellier, Montpellier, France; PhyMedExp, Univ Montpellier, Inserm U1046, CNRS UMR 9214, Montpellier, France
| | - A Bourdin
- Department of Respiratory Diseases, CHU de Montpellier, Montpellier, France; PhyMedExp, Univ Montpellier, Inserm U1046, CNRS UMR 9214, Montpellier, France
| | - A Bergougnoux
- PhyMedExp, Univ Montpellier, Inserm U1046, CNRS UMR 9214, Montpellier, France; Laboratoire de Génétique Moléculaire et de Cytogénomique, CHU de Montpellier, Montpellier, France.
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14
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Gelat B, Rathaur P, Malaviya P, Patel B, Trivedi K, Johar K, Gelat R. The intervention of epithelial-mesenchymal transition in homeostasis of human retinal pigment epithelial cells: a review. J Histotechnol 2022; 45:148-160. [DOI: 10.1080/01478885.2022.2137665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Brijesh Gelat
- Department of Zoology, BMTC and Human Genetics, School of Sciences, Gujarat University, Ahmedabad, India
| | - Pooja Rathaur
- Department of Cell and Molecular Biology, Iladevi Cataract and IOL Research Centre, Ahmedabad, Gujarat, India
| | - Pooja Malaviya
- Department of Cell and Molecular Biology, Iladevi Cataract and IOL Research Centre, Ahmedabad, Gujarat, India
| | - Binita Patel
- Department of Life Science, School of Sciences, Gujarat University, Ahmedabad, India
| | - Krupali Trivedi
- Department of Zoology, BMTC and Human Genetics, School of Sciences, Gujarat University, Ahmedabad, India
| | - Kaid Johar
- Department of Zoology, BMTC and Human Genetics, School of Sciences, Gujarat University, Ahmedabad, India
| | - Rahul Gelat
- Institute of Teaching and Research in Ayurveda (ITRA), Gujarat Ayurved University, Jamnagar, India
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15
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Nicheperovich A, Townsend-Nicholson A. Towards Precision Oncology: The Role of Smoothened and Its Variants in Cancer. J Pers Med 2022; 12:jpm12101648. [PMID: 36294790 PMCID: PMC9605185 DOI: 10.3390/jpm12101648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 09/28/2022] [Accepted: 09/29/2022] [Indexed: 11/07/2022] Open
Abstract
The G protein-coupled receptor Smoothened (Smo) is a central signal transducer of the Hedgehog (Hh) pathway which has been linked to diverse forms of tumours. Stimulated by advancements in structural and functional characterisation, the Smo receptor has been recognised as an important therapeutic target in Hh-driven cancers, and several Smo inhibitors have now been approved for cancer therapy. This receptor is also known to be an oncoprotein itself and its gain-of-function variants have been associated with skin, brain, and liver cancers. According to the COSMIC database, oncogenic mutations of Smo have been identified in various other tumours, although their oncogenic effect remains unknown in these tissues. Drug resistance is a common challenge in cancer therapies targeting Smo, and data analysis shows that healthy individuals also harbour resistance mutations. Based on the importance of Smo in cancer progression and the high incidence of resistance towards Smo inhibitors, this review suggests that detection of Smo variants through tumour profiling could lead to increased precision and improved outcomes of anti-cancer treatments.
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16
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Jiang J. Hedgehog signaling mechanism and role in cancer. Semin Cancer Biol 2022; 85:107-122. [PMID: 33836254 PMCID: PMC8492792 DOI: 10.1016/j.semcancer.2021.04.003] [Citation(s) in RCA: 103] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/25/2021] [Accepted: 04/02/2021] [Indexed: 12/12/2022]
Abstract
Cell-cell communication through evolutionarily conserved signaling pathways governs embryonic development and adult tissue homeostasis. Deregulation of these signaling pathways has been implicated in a wide range of human diseases including cancer. One such pathway is the Hedgehog (Hh) pathway, which was originally discovered in Drosophila and later found to play a fundamental role in human development and diseases. Abnormal Hh pathway activation is a major driver of basal cell carcinomas (BCC) and medulloblastoma. Hh exerts it biological influence through a largely conserved signal transduction pathway from the activation of the GPCR family transmembrane protein Smoothened (Smo) to the conversion of latent Zn-finger transcription factors Gli/Ci proteins from their repressor (GliR/CiR) to activator (GliA/CiA) forms. Studies from model organisms and human patients have provided deep insight into the Hh signal transduction mechanisms, revealed roles of Hh signaling in a wide range of human cancers, and suggested multiple strategies for targeting this pathway in cancer treatment.
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Affiliation(s)
- Jin Jiang
- Department of Molecular Biology and Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA.
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17
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Modulation of Hedgehog Signaling for the Treatment of Basal Cell Carcinoma and the Development of Preclinical Models. Biomedicines 2022; 10:biomedicines10102376. [PMID: 36289637 PMCID: PMC9598418 DOI: 10.3390/biomedicines10102376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/17/2022] [Accepted: 09/20/2022] [Indexed: 11/17/2022] Open
Abstract
Basal Cell Carcinoma (BCC) is the most commonly diagnosed cancer worldwide. While the survivability of BCC is high, many patients are excluded from clinically available treatments due to health risks or personal choice. Further, patients with advanced or metastatic disease have severely limited treatment options. The dysregulation of the Hedgehog (Hh) signaling cascade drives onset and progression of BCC. As such, the modulation of this pathway has driven advancements in BCC research. In this review, we focus firstly on inhibitors that target the Hh pathway as chemotherapeutics against BCC. Two therapies targeting Hh signaling have been made clinically available for BCC patients, but these treatments suffer from limited initial efficacy and a high rate of chemoresistant tumor recurrence. Herein, we describe more recent developments of chemical scaffolds that have been designed to hopefully improve upon the available therapeutics. We secondly discuss the history and recent efforts involving modulation of the Hh genome as a method of producing in vivo models of BCC for preclinical research. While there are many advancements left to be made towards improving patient outcomes with BCC, it is clear that targeting the Hh pathway will remain at the forefront of research efforts in designing more effective chemotherapeutics as well as relevant preclinical models.
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18
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Pancreatic ductal adenocarcinoma: tumor microenvironment and problems in the development of novel therapeutic strategies. Clin Exp Med 2022:10.1007/s10238-022-00886-1. [DOI: 10.1007/s10238-022-00886-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/30/2022] [Indexed: 12/19/2022]
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19
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Raja Arul GL, Toruner MD, Gatenby RA, Carr RM. Ecoevolutionary biology of pancreatic ductal adenocarcinoma. Pancreatology 2022; 22:730-740. [PMID: 35821188 DOI: 10.1016/j.pan.2022.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 06/01/2022] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, is an aggressive disease predicted to be the 2nd cause of cancer mortality in the US by 2040. While first-line therapy has improved, 5-year overall survival has only increased from 5 to ∼10%, and surgical resection is only available for ∼20% of patients as most present with advanced disease, which is invariably lethal. PDAC has well-established highly recurrent mutations in four driver genes including KRAS, TP53, CDKN2A, and SMAD4. Unfortunately, these genetic drivers are not currently therapeutically actionable. Despite extensive sequencing efforts, few additional significantly recurrent and druggable drivers have been identified. In the absence of targetable mutations, chemotherapy remains the mainstay of treatment for most patients. Further, the role of the above driver mutations on PDAC initiation and early development is well-established. However, these mutations alone cannot account for PDAC heterogeneity nor discern early from advanced disease. Taken together, management of PDAC is an example highlighting the shortcomings of the current precision medicine paradigm. PDAC, like other malignancies, represents an ecoevolutionary process. Better understanding the disease through this lens can facilitate the development of novel therapeutic strategies to better control and cure PDAC. This review aims to integrate the current understanding of PDAC pathobiology into an ecoevolutionary framework.
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Affiliation(s)
| | - Merih D Toruner
- Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Robert A Gatenby
- Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Ryan M Carr
- Department of Oncology, Mayo Clinic, Rochester, MN, USA.
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20
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Min M, Song T, Sun M, Wang T, Tan J, Zhang J. Dhh signaling pathway regulates reconstruction of seminiferous tubule-like structure. Reprod Biol 2022; 22:100684. [PMID: 35987158 DOI: 10.1016/j.repbio.2022.100684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 07/05/2022] [Accepted: 08/08/2022] [Indexed: 10/15/2022]
Abstract
The reconstruction of a tubule-like structure in vitro has provided a promising system to analyze factors that drive morphogenesis and the underlying mechanisms. In this study, we took advantage of the inhibitor cyclopamine and a smoothened agonist to detect the role of the Dhh signaling pathway in the reconstructed tubule-like structure. Sertoli cells did not show polarity, rounded peritubular myoid cells and scattered Leydig cells were observed, combined with less laminin and lower proliferation of Leydig, peritubular myoid, germ, and Sertoli cells. However, in the presence of SAG, elongated peritubular myoid cells gathered at the bottom of polarized Sertoli cells, and most of the Leydig cells gathered at the outer part of the elongated peritubular myoid cells. Moreover, SAG promoted the secretion of laminin, assisting in the formation of the basal membrane and promoting the proliferation of Leydig, peritubular myoid, and germ cells. The level of Gli1 was significantly downregulated when treated with cyclopamine, whereas it was significantly upregulated when treated with SAG. These results indicate that the Dhh signaling pathway regulates the reconstruction of tubule-like structures by regulating the expression of Gli1.
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Affiliation(s)
- Ming Min
- Department of Immunology, Zunyi Medical University, Zunyi, China; Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China; Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, China; People's Hospital of Qingbaijiang District, Qingbaijiang, 61300 Chengdu, China
| | - Tao Song
- Department of Immunology, Zunyi Medical University, Zunyi, China; Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China; Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, China
| | - Mengdi Sun
- Department of Immunology, Zunyi Medical University, Zunyi, China; Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China; Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, China
| | - Tingting Wang
- Department of Immunology, Zunyi Medical University, Zunyi, China; Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China; Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, China
| | - Jun Tan
- Department of Histology and Embryology, Zunyi Medical University, Zunyi 563000, China.
| | - Jidong Zhang
- Department of Immunology, Zunyi Medical University, Zunyi, China; Special Key Laboratory of Gene Detection & Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China; Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, China.
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21
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Quatannens D, Verhoeven Y, Van Dam P, Lardon F, Prenen H, Roeyen G, Peeters M, Smits ELJ, Van Audenaerde J. Targeting hedgehog signaling in pancreatic ductal adenocarcinoma. Pharmacol Ther 2022; 236:108107. [PMID: 34999181 DOI: 10.1016/j.pharmthera.2022.108107] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/27/2021] [Accepted: 01/03/2022] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer related death. The urgent need for effective therapies is highlighted by the lack of adequate targeting. In PDAC, hedgehog (Hh) signaling is known to be aberrantly activated, which prompted the pathway as a possible target for effective treatment for PDAC patients. Unfortunately, specific targeting of upstream molecules within the Hh signaling pathway failed to bring clinical benefit. This led to the ongoing debate on Hh targeting as a therapeutic treatment for PDAC patients. Additionally, concurrent non-canonical activation routes also result in translocation of Gli transcription factors into the nucleus. Therefore, different downstream targets of the Hh signaling pathway were identified and evaluated in preclinical and clinical research. In this review we summarize the variety of Hh signaling antagonists in different preclinical models of PDAC. Furthermore, we discuss published and ongoing clinical trials that evaluated Hh antagonists and point out the current hurdles and future perspectives in the light of redesigning Hh-targeting therapies for the treatment of PDAC patients.
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Affiliation(s)
- Delphine Quatannens
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Yannick Verhoeven
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Peter Van Dam
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Unit of Gynecologic Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Filip Lardon
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Hans Prenen
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Geert Roeyen
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Hepatobiliary Transplantation and Endocrine Surgery, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Marc Peeters
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Evelien L J Smits
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Jonas Van Audenaerde
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
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22
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Xiang ML, Hu BY, Qi ZH, Wang XN, Xie TZ, Wang ZJ, Ma DY, Zeng Q, Luo XD. Chemistry and bioactivities of natural steroidal alkaloids. NATURAL PRODUCTS AND BIOPROSPECTING 2022; 12:23. [PMID: 35701630 PMCID: PMC9198197 DOI: 10.1007/s13659-022-00345-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 04/12/2022] [Indexed: 05/11/2023]
Abstract
Steroidal alkaloids possess the basic steroidal skeleton with a nitrogen atom in rings or side chains incorporated as an integral part of the molecule. They have demonstrated a wide range of biological activities, and some of them have even been developed as therapeutic drugs, such as abiraterone acetate (Zytiga®), a blockbuster drug, which has been used for the treatment of prostate cancer. Structurally diverse natural steroidal alkaloids present a wide spectrum of biological activities, which are attractive for natural product chemistry and medicinal chemistry communities. This review comprehensively covers the structural classification, isolation and various biological activities of 697 natural steroidal alkaloids discovered from 1926 to October 2021, with 363 references being cited.
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Affiliation(s)
- Mei-Ling Xiang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, People's Republic of China
| | - Bin-Yuan Hu
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, People's Republic of China
| | - Zi-Heng Qi
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, People's Republic of China
| | - Xiao-Na Wang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, People's Republic of China
| | - Tian-Zhen Xie
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, People's Republic of China
| | - Zhao-Jie Wang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, People's Republic of China
| | - Dan-Yu Ma
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, People's Republic of China
| | - Qi Zeng
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, People's Republic of China
| | - Xiao-Dong Luo
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, People's Republic of China.
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China.
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23
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Koltai T, Reshkin SJ, Carvalho TMA, Di Molfetta D, Greco MR, Alfarouk KO, Cardone RA. Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review. Cancers (Basel) 2022; 14:2486. [PMID: 35626089 PMCID: PMC9139729 DOI: 10.3390/cancers14102486] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.
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Affiliation(s)
| | - Stephan Joel Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
| | - Khalid Omer Alfarouk
- Zamzam Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Alfarouk Biomedical Research LLC, Temple Terrace, FL 33617, USA
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (D.D.M.); (M.R.G.); (R.A.C.)
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24
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Nam A, Song WJ, An JH, Rebhun RB, Youn HY, Seo KW. Expression of the hedgehog signaling pathway and the effect of inhibition at the level of Smoothened in canine osteosarcoma cell lines. Vet Comp Oncol 2022; 20:778-787. [PMID: 35521940 DOI: 10.1111/vco.12828] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 04/12/2022] [Accepted: 05/03/2022] [Indexed: 11/27/2022]
Abstract
Osteosarcoma (OSA) is the most common malignant bone cancer in dogs. Canine and human OSA share several features, including tumor environments, response to traditional treatment, and several molecular pathways. Hedgehog (Hh) signaling is known to contribute to tumorigenesis and progression of various cancers, including human OSA. This study aimed to identify the role of the Hh signaling pathway in canine OSA cell lines, including Abrams, D17, and Moresco, focusing on the signal transducer Smoothened (SMO). mRNA and protein levels of Hh pathway components, including SHH, IHH, SMO, and PTCH1, were aberrant in all examined OSA cell lines compared with canine osteoblast cells. The SMO inhibitor cyclopamine significantly decreased cell viability and colony-forming ability in the canine OSA cell lines in a dose-dependent manner. Moresco cells, which expressed the highest level of SMO protein, were the most sensitive to the anticancer effect of cyclopamine among the three canine OSA cell lines tested. Hh downstream target gene and protein expression in canine OSA cell lines were downregulated after cyclopamine treatment. In addition, cyclopamine significantly increased apoptotic cell death in Abrams and Moresco cells. The findings that Hh/SMO is activated in canine OSA cell lines and cyclopamine suppresses OSA cell survival via inhibition of SMO suggest that the Hh/SMO signaling pathway might be a novel therapeutic target for canine OSA. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Aryung Nam
- Department of Veterinary Internal Medicine, Konkuk University Veterinary Medical Teaching Hospital, Seoul, South Korea
| | - Woo-Jin Song
- Department of Veterinary Internal Medicine, College of Veterinary Medicine and Research Institute of Veterinary Science, Jeju National University, Jeju, South Korea
| | - Ju-Hyun An
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Robert B Rebhun
- Department of Surgical and Radiological Sciences, University of California Davis, School of Veterinary Medicine, Davis, California, United States of America
| | - Hwa-Young Youn
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Kyoung-Won Seo
- Laboratory of Veterinary Internal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
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25
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Rahi S, Mehan S. Understanding Abnormal SMO-SHH Signaling in Autism Spectrum Disorder: Potential Drug Target and Therapeutic Goals. Cell Mol Neurobiol 2022; 42:931-953. [PMID: 33206287 PMCID: PMC11441210 DOI: 10.1007/s10571-020-01010-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 11/12/2020] [Indexed: 12/13/2022]
Abstract
Autism is a multifactorial neurodevelopmental condition; it demonstrates some main characteristics, such as impaired social relationships and increased repetitive behavior. The initiation of autism spectrum disorder is mostly triggered during brain development by the deregulation of signaling pathways. Sonic hedgehog (SHH) signaling is one such mechanism that influences neurogenesis and neural processes during the development of the central nervous system. SMO-SHH signaling is also an important part of a broad variety of neurological processes, including neuronal cell differentiation, proliferation, and survival. Dysregulation of SMO-SHH signaling leads to many physiological changes that lead to neurological disorders such as ASD and contribute to cognitive decline. The aberrant downregulation of SMO-SHH signals contributes to the proteolytic cleavage of GLI (glioma-associated homolog) into GLI3 (repressor), which increases oxidative stress, neuronal excitotoxicity, neuroinflammation, and apoptosis by suppressing target gene expression. We outlined in this review that SMO-SHH deregulation plays a crucial role in the pathogenesis of autism and addresses the current status of SMO-SHH pathway modulators. Additionally, a greater understanding of the SHH signaling pathway is an effort to improve successful treatment for autism and other neurological disorders.
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Affiliation(s)
- Saloni Rahi
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Sidharth Mehan
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India.
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26
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Winter K, Dzieniecka M, Strzelczyk J, Wągrowska-Danilewicz M, Danilewicz M, Zatorski H, Małecka-Wojciesko E. Hedgehog Signaling Pathway Proteins in Prognosis of Pancreatic Ductal Adenocarcinoma and Its Differentiation From Chronic Pancreatitis. Pancreas 2022; 51:219-227. [PMID: 35584378 DOI: 10.1097/mpa.0000000000002001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES The Hedgehog signaling pathway (Hh) probably plays a role in development and progression of pancreatic ductal adenocarcinoma (PDAC). METHODS In our study, 114 patients (83 with PDAC and 31 with chronic pancreatitis [CP]) after pancreatic surgery were enrolled. The immunoexpression of Sonic hedgehog (Shh), Smoothened (Smo), and Glioblastoma transcription factor 1 (Gli1) and Ki-67 were detected in tissue specimens. RESULTS Mean (standard deviation) immunoexpression of all Hh pathway molecules was significantly higher in PDAC than in CP patients: Shh, 2.24 (0.57) versus 1.17 (0.25) (P < 0.01); Smo, 2.62 (0.34) versus 1.21 (0.23) (P < 0.01); and Gli1, 1.74 (0.74) versus 1.15 (0.72) (P < 0.01). Patients with a lower expression level (z score <0) of Shh and Ki-67 have longer overall survival when compared with z score >0 (15.97 vs 8.53 months [P = 0.0087] and 15.20 vs 5.53 months [P = 0.0004], respectively). In addition, Shh sensitivity in PDAC detection was 84.3%; specificity, 93.5%; positive predictive value, 97.2%; and negative predictive value, 69%. CONCLUSIONS Our results suggest the prognostic role of the Hh pathway in PDAC and a role in the differential diagnosis with CP.
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Affiliation(s)
- Katarzyna Winter
- From the Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
| | | | | | | | - Marian Danilewicz
- Nephropathology, Division of Morphometry, Medical University of Lodz, Lodz, Poland
| | - Hubert Zatorski
- From the Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
| | - Ewa Małecka-Wojciesko
- From the Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
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27
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Tang X, Sui X, Weng L, Liu Y. SNAIL1: Linking Tumor Metastasis to Immune Evasion. Front Immunol 2021; 12:724200. [PMID: 34917071 PMCID: PMC8669501 DOI: 10.3389/fimmu.2021.724200] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
The transcription factor Snail1, a key inducer of epithelial-mesenchymal transition (EMT), plays a critical role in tumor metastasis. Its stability is strictly controlled by multiple intracellular signal transduction pathways and the ubiquitin-proteasome system (UPS). Increasing evidence indicates that methylation and acetylation of Snail1 also affects tumor metastasis. More importantly, Snail1 is involved in tumor immunosuppression by inducing chemokines and immunosuppressive cells into the tumor microenvironment (TME). In addition, some immune checkpoints potentiate Snail1 expression, such as programmed death ligand 1 (PD-L1) and T cell immunoglobulin 3 (TIM-3). This mini review highlights the pathways and molecules involved in maintenance of Snail1 level and the significance of Snail1 in tumor immune evasion. Due to the crucial role of EMT in tumor metastasis and tumor immunosuppression, comprehensive understanding of Snail1 function may contribute to the development of novel therapeutics for cancer.
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Affiliation(s)
- Xiaolong Tang
- Department of Laboratory Medicine, Binzhou Medical University, Binzhou, China
| | - Xue Sui
- Department of Laboratory Medicine, Binzhou Medical University, Binzhou, China
| | - Liang Weng
- Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Molecular Radiation Oncology Hunan Province, Xiangya Hospital, Central South University, Changsha, China.,Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Xiangya Hospital, Central South University, Changsha, China.,Hunan Provincial Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South University, Changsha, China.,Institute of Gerontological Cancer Research, National Clinical Research Center for Gerontology, Changsha, China.,Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha, China
| | - Yongshuo Liu
- Department of Clinical Laboratory, Binzhou Medical University Hospital, Binzhou, China.,Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
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28
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Patel TN, Dhanyamraju PK. Role of aberrant Sonic hedgehog signaling pathway in cancers and developmental anomalies. J Biomed Res 2021; 36:1-9. [PMID: 34963676 PMCID: PMC8894283 DOI: 10.7555/jbr.35.20210139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Development is a sophisticated process maintained by various signal transduction pathways, including the Hedgehog (Hh) pathway. Several important functions are executed by the Hh signaling cascade such as organogenesis, tissue regeneration, and tissue homeostasis, among various others. Considering the multiple functions carried out by this pathway, any mutation causing aberrant Hh signaling may lead to myriad developmental abnormalities besides cancers. In the present review article, we explored a wide range of diseases caused by aberrant Hh signaling, including developmental defects and cancers. Finally, we concluded this mini-review with various treatment strategies for Hh-induced diseases.
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Affiliation(s)
- Trupti N Patel
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore Campus, Vellore, Tamil Nadu 632014, India
| | - Pavan Kumar Dhanyamraju
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA.,Penn State Cancer Institute, Hershey, PA 17033, USA
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29
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Cao W, Li Y, Sun H, Yang C, Zhu J, Xie C, Li X, Wu J, Geng S, Wang L, Sun L, Geng G, Han H, Zhong C. Apatinib Suppresses Gastric Cancer Stem Cells Properties by Inhibiting the Sonic Hedgehog Pathway. Front Cell Dev Biol 2021; 9:679806. [PMID: 34350176 PMCID: PMC8326764 DOI: 10.3389/fcell.2021.679806] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 06/28/2021] [Indexed: 12/15/2022] Open
Abstract
The presence of gastric cancer stem cells (GCSCs) marks the onset of gastric carcinoma. The sonic hedgehog (SHH) pathway plays a vital role in the maintenance of GCSC characteristics. Apatinib has been approved in China for advanced gastric cancer (GC) treatment. However, whether apatinib can target GCSCs and affect the SHH pathway remains unclear. The present study aimed to investigate the underlying mechanism of apatinib’s antitumor effects on GC. The expression levels of GCSC markers and number of CD133+ cells were significantly elevated in the sphere-forming cells. Apatinib effectively suppressed GCSC traits by inhibiting tumorsphere formation and cell proliferation, suppressing GCSC markers expression and CD133+ cell number, and inducing apoptosis. Apatinib downregulated the activation of the SHH pathway; while upregulation of the SHH pathway attenuated the inhibitory effects of apatinib on GCSCs. Moreover, apatinib treatment significantly delayed tumor growth and inhibited GCSC characteristics in the xenograft model. Our data suggested that apatinib exhibited inhibitory effects on GCSCs by suppressing SHH pathway both in vitro and in vivo, thus providing new insights into the therapeutic application of apatinib in GCSC suppression and advanced gastric cancer treatment.
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Affiliation(s)
- Wanshuang Cao
- Cancer Research Division, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yuan Li
- Department of Clinical Nutrition, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Hongliang Sun
- Department of Urology, Taikang Xianlin Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Chenying Yang
- Cancer Research Division, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jianyun Zhu
- Suzhou Digestive Diseases and Nutrition Research Center, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Chunfeng Xie
- Cancer Research Division, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xiaoting Li
- Cancer Research Division, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jieshu Wu
- Cancer Research Division, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Shanshan Geng
- Cancer Research Division, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Lu Wang
- Jiangsu Hengrui Medicine Co., Ltd., Lianyungang, China
| | - Liangfei Sun
- Jiangsu Hengrui Medicine Co., Ltd., Lianyungang, China
| | - Guozhu Geng
- Jiangsu Hengrui Medicine Co., Ltd., Lianyungang, China
| | - Hongyu Han
- State Key Laboratory of Oncology in South China, Department of Clinical Nutrition, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Caiyun Zhong
- Cancer Research Division, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
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30
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Xie C, Lin PJ, Hao J. Eggmanone Effectively Overcomes Prostate Cancer Cell Chemoresistance. Biomedicines 2021; 9:biomedicines9050538. [PMID: 34066000 PMCID: PMC8151738 DOI: 10.3390/biomedicines9050538] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/23/2021] [Accepted: 05/10/2021] [Indexed: 12/24/2022] Open
Abstract
Prostate cancer chemoresistance is a major therapeutic problem, and the underlying mechanism is not well understood and effective therapies to overcome this problem are not available. Phosphodiesterase-4 (PDE4), a main intracellular enzyme for cAMP hydrolysis, has been previously shown to involve in the early chemo-sensitive prostate cancer cell proliferation and progression, but its role in the more-advanced chemo-resistant prostate cancer is completely unknown. Here we found that the expression of PDE4 subtype, PDE4D, is highly elevated in the chemo-resistant prostate cancer cells (DU145-TxR and PC3-TxR) in comparison to the chemo-sensitive prostate cancer cells (DU145 and PC3). Inhibition of PDE4D with a potent and selective PDED4 inhibitor, Eggmanone, effectively decreases the invasion and proliferation as well as induces cell death of the chemo-resistant prostate cancer cells (DU145-TxR and PC3-TxR). These results were confirmed by siRNA knockdown of PDE4D. We and colleagues previously reported that Eggmanone can effectively blocked sonic Hedgehog signaling via PDE4D inhibition, and here our study suggests that that Eggmanone downregulated proliferation of the chemo-resistant prostate cancer cells via sonic Hedgehog signaling. In addition, Eggmanone treatment dose-dependently increases docetaxel cytotoxicity to DU145-TxR and PC3-TxR. As cancer stem cells (CSCs) are known to be implicated in cancer chemoresistance, we further examined Eggmanone impacts on CSC-like properties in the chemo-resistant prostate cancer cells. Our study shows that Eggmanone effectively down-regulates the expression of CSCs’ marker genes Nanog and ABC sub-family G member 2 (ABCG2) and attenuates sphere formation in DU145-TxR and PC3-TxR cells. In summary, our work shows that Eggmanone effectively overcomes the chemoresistance of prostate cancer cells presumably through sonic Hedgehog signaling and targeting CSCs, suggesting that Eggmanone may serve as a novel agent for chemo-resistant prostate cancer.
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Affiliation(s)
- Chen Xie
- College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, USA;
| | - Pen-Jen Lin
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA;
| | - Jijun Hao
- College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, USA;
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA;
- Correspondence: ; Tel.: +1-(909)-469-8686; Fax: +1-909-469-5635
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31
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Al-Share B, Hammad N, Diab M. Pancreatic adenocarcinoma: molecular drivers and the role of targeted therapy. Cancer Metastasis Rev 2021; 40:355-371. [PMID: 33398620 DOI: 10.1007/s10555-020-09948-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/15/2020] [Indexed: 01/05/2023]
Abstract
Prognosis from pancreatic ductal adenocarcinoma (PDAC) continues to be poor despite the many efforts channeled to improve its management. Although the mainstay treatment is still traditional chemotherapy, recent advances highlighted a promising potential for targeted therapy in the management of this disease. Those advances emphasize the significance of timely genomic profiling of tumor tissue as well as germline testing of patients to identify potential markers of targeted therapy. While targeted therapy is reserved for a relatively small subset of patients with PDAC, ongoing research is uncovering additional markers, and targeted agents, that will hopefully translate to better outcomes for patients.
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Affiliation(s)
- Bayan Al-Share
- Department of Oncology, Wayne State University, Karmanos Cancer Institute, Detroit, MI, USA
| | - Nour Hammad
- Department of Oncology, Ascension Providence Hospital and Medical Center/Michigan State University/Collage of Human Medicine, Southfield, MI, USA
| | - Maria Diab
- Department of Oncology, Emory University, Atlanta, GA, USA.
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32
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Jasim KA, Waheed IF, Topps M, Gesquiere AJ. Multifunctional system for combined chemodynamic–photodynamic therapy employing the endothelin axis based on conjugated polymer nanoparticles. Polym Chem 2021. [DOI: 10.1039/d1py00964h] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Most nanomedicines that attack tumors by Reactive Oxygen Species (ROS) based on lipid peroxidation mechanisms require external activation to work.
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Affiliation(s)
- Khalaf A. Jasim
- Department of Chemistry, College of Science, Tikrit University, Tikrit 34001, Iraq
| | - Ibrahim F. Waheed
- Department of Chemistry, College of Science, Tikrit University, Tikrit 34001, Iraq
| | - Martin Topps
- NanoScience Technology Center, University of Central Florida, Orlando, FL 32826, USA
- Department of Chemistry, University of Central Florida, Orlando, FL 32826, USA
| | - Andre J. Gesquiere
- NanoScience Technology Center, University of Central Florida, Orlando, FL 32826, USA
- Department of Chemistry, University of Central Florida, Orlando, FL 32826, USA
- Department of Materials Science and Engineering, University of Central Florida, Orlando, FL 32826, USA
- The College of Optics and Photonics (CREOL), University of Central Florida, Orlando, FL 32826, USA
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33
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Giuntini G, Monaci S, Cau Y, Mori M, Naldini A, Carraro F. Inhibition of Melanoma Cell Migration and Invasion Targeting the Hypoxic Tumor Associated CAXII. Cancers (Basel) 2020; 12:E3018. [PMID: 33080820 PMCID: PMC7602957 DOI: 10.3390/cancers12103018] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/09/2020] [Accepted: 10/14/2020] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Intratumoral hypoxia contributes to cancer progression and poor prognosis. Carbonic anhydrases IX (CAIX) and XII (CAXII) play pivotal roles in tumor cell adaptation and survival, as aberrant Hedgehog (Hh) pathway does. In malignant melanoma both features have been investigated for years, but they have not been correlated before and/or identified as a potential pharmacological target. Here, for the first time, we demonstrated that malignant melanoma cell motility was impaired by targeting CAXII via either CAs inhibitors or through the inhibition of the Hh pathway. METHODS We tested cell motility in three melanoma cell lines (WM-35, SK-MEL28, and A375), with different invasiveness capabilities. To this end we performed a scratch assay in the presence of the smoothened (SMO) antagonist cyclopamine (cyclo) or CAs inhibitors under normoxia or hypoxia. Then, we analyzed the invasiveness potential in the cell lines which were more affected by cyclo and CAs inhibitors (SK-MEL28 and A375). Western blot was employed to assess the expression of the hypoxia inducible factor 1α, CAXII, and FAK phosphorylation. Immunofluorescence staining was performed to verify the blockade of CAXII expression. RESULTS Hh inhibition reduced melanoma cell migration and CAXII expression under both normoxic and hypoxic conditions. Interestingly, basal CAXII expression was higher in the two more aggressive melanoma cell lines. Finally, a direct CAXII blockade impaired melanoma cell migration and invasion under hypoxia. This was associated with a decrease of FAK phosphorylation and metalloprotease activities. CONCLUSIONS CAXII may be used as a target for melanoma treatment not only through its direct inhibition, but also through Hh blockade.
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Affiliation(s)
- Gaia Giuntini
- Department of Molecular and Developmental Medicine, Cellular and Molecular Physiology Unit, University of Siena, 53100 Siena, Italy; (G.G.); (S.M.); (A.N.)
| | - Sara Monaci
- Department of Molecular and Developmental Medicine, Cellular and Molecular Physiology Unit, University of Siena, 53100 Siena, Italy; (G.G.); (S.M.); (A.N.)
| | - Ylenia Cau
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (Y.C.); (M.M.)
| | - Mattia Mori
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (Y.C.); (M.M.)
| | - Antonella Naldini
- Department of Molecular and Developmental Medicine, Cellular and Molecular Physiology Unit, University of Siena, 53100 Siena, Italy; (G.G.); (S.M.); (A.N.)
| | - Fabio Carraro
- Department of Medical Biotechnologies, Cellular and Molecular Physiology Unit, University of Siena, 53100 Siena, Italy
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34
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Jiang B, Zhou L, Lu J, Wang Y, Liu C, You L, Guo J. Stroma-Targeting Therapy in Pancreatic Cancer: One Coin With Two Sides? Front Oncol 2020; 10:576399. [PMID: 33178608 PMCID: PMC7593693 DOI: 10.3389/fonc.2020.576399] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 09/25/2020] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with one of the worst prognoses worldwide and has an overall 5-year survival rate of only 9%. Although chemotherapy is the recommended treatment for patients with advanced PDAC, its efficacy is not satisfactory. The dense dysplastic stroma of PDAC is a major obstacle to the delivery of chemotherapy drugs and plays an important role in the progression of PDAC. Therefore, stroma-targeting therapy is considered a potential treatment strategy to improve the efficacy of chemotherapy and patient survival. While several preclinical studies have shown encouraging results, the anti-tumor potential of the PDAC stroma has also been revealed, and the extreme depletion might promote tumor progression and undermine patient survival. Therefore, achieving a balance between stromal abundance and depletion might be the further of stroma-targeting therapy. This review summarized the current progress of stroma-targeting therapy in PDAC and discussed the double-edged sword of its therapeutic effects.
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Affiliation(s)
- Bolun Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li Zhou
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Lu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yizhi Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chengxi Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Junchao Guo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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35
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Booker BE, Steg AD, Kovac S, Landen CN, Amm HM. The use of hedgehog antagonists in cancer therapy: a comparison of clinical outcomes and gene expression analyses. Cancer Biol Ther 2020; 21:873-883. [PMID: 32914706 DOI: 10.1080/15384047.2020.1806640] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hedgehog (HH) signaling, a critical developmental pathway, has been implicated in cancer initiation and progression. With vismodegib and sonidegib having been approved for clinical use, increasing numbers of HH inhibitors alone and in combination with chemotherapies are in clinical trials. Here we highlight the clinical research on HH antagonists and the genetics of response to these compounds in human cancers. Selectivity of HH inhibitors, determined by decreased pathway transcriptional activity, has been demonstrated in many clinical trials. Patients with advanced/metastatic basal cell carcinoma have benefited the most, whereas HH antagonists did little to improve survival rates in other cancers. Correlation between clinical response and HH gene expression vary among different cancer types. Predicting response and resistance to HH inhibitors presents a challenge and continues to remain an important area of research. New approaches combine standard of care chemotherapies and molecularly targeted therapies to increase the clinical utility of HH inhibitors.
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Affiliation(s)
- Burthia E Booker
- Oral and Maxillofacial Surgery, University of Alabama at Birmingham , Birmingham, AL, USA
| | - Adam D Steg
- McWhorter School of Pharmacy, Samford University , Birmingham, AL, USA
| | - Stefan Kovac
- McWhorter School of Pharmacy, Samford University , Birmingham, AL, USA
| | - Charles N Landen
- Department of Obstetrics and Gynecology, University of Virginia , Charlottesville, VA, USA
| | - Hope M Amm
- Oral and Maxillofacial Surgery, University of Alabama at Birmingham , Birmingham, AL, USA
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36
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Ho WJ, Jaffee EM. Disrupting a converging metabolic target turns up the immunologic-heat in pancreatic tumors. J Clin Invest 2020; 130:71-73. [PMID: 31793910 DOI: 10.1172/jci133685] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Pancreatic ductal adenocarcinomas (PDACs) are classically immunologically cold tumors that have failed to demonstrate a significant response to immunotherapeutic strategies. This feature is attributed to both the immunosuppressive tumor microenvironment (TME) and limited immune cell access due to the surrounding stromal barrier, a histological hallmark of PDACs. In this issue of the JCI, Sharma et al. employ a broad glutamine antagonist, 6-diazo-5-oxo-l-norleucine (DON), to target a metabolic program that underlies both PDAC growth and hyaluronan production. Their findings describe an approach to converting the PDAC TME into a hot TME, thereby empowering immunotherapeutic strategies such as anti-PD1 therapy.
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Affiliation(s)
- Won Jin Ho
- Sidney Kimmel Comprehensive Cancer Center.,Bloomberg-Kimmel Institute for Cancer Immunotherapy
| | - Elizabeth M Jaffee
- Sidney Kimmel Comprehensive Cancer Center.,Bloomberg-Kimmel Institute for Cancer Immunotherapy.,Pancreatic Cancer Precision Medicine Program.,Department of Pathology, and.,Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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37
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Roife D, Sarcar B, Fleming JB. Stellate Cells in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1263:67-84. [PMID: 32588324 DOI: 10.1007/978-3-030-44518-8_6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
As tumor microenvironments share many of the same qualities as chronic wounds, attention is turning to the wound-repair cells that support the growth of cancerous cells. Stellate cells are star-shaped cells that were first discovered in the perisinusoidal spaces in the liver and have been found to support wound healing by the secretion of growth factors and extracellular matrix. They have since been also found to serve a similar function in the pancreas. In both organs, the wound-healing process may become dysregulated and lead to pathological fibrosis (also known as cirrhosis in the liver). In recent years there has been increasing attention paid to the role of these cells in tumor formation and progression. They may be a factor in initiating the first steps of carcinogenesis such as with liver cirrhosis and hepatocellular carcinoma and also contribute to continued tumor growth, invasion, metastasis, evasion of the immune system, and resistance to chemotherapy, in cancers of both the liver and pancreas. In this chapter we aim to review the structure and function of hepatic and pancreatic stellate cells and their contributions to the tumor microenvironment in their respective cancers and also discuss potential new targets for cancer therapy based on our new understanding of these vital components of the tumor stroma.
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Affiliation(s)
- David Roife
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA.,Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Bhaswati Sarcar
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Jason B Fleming
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
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38
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Wuputra K, Ku CC, Wu DC, Lin YC, Saito S, Yokoyama KK. Prevention of tumor risk associated with the reprogramming of human pluripotent stem cells. J Exp Clin Cancer Res 2020; 39:100. [PMID: 32493501 PMCID: PMC7268627 DOI: 10.1186/s13046-020-01584-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 04/22/2020] [Indexed: 02/07/2023] Open
Abstract
Human pluripotent embryonic stem cells have two special features: self-renewal and pluripotency. It is important to understand the properties of pluripotent stem cells and reprogrammed stem cells. One of the major problems is the risk of reprogrammed stem cells developing into tumors. To understand the process of differentiation through which stem cells develop into cancer cells, investigators have attempted to identify the key factors that generate tumors in humans. The most effective method for the prevention of tumorigenesis is the exclusion of cancer cells during cell reprogramming. The risk of cancer formation is dependent on mutations of oncogenes and tumor suppressor genes during the conversion of stem cells to cancer cells and on the environmental effects of pluripotent stem cells. Dissecting the processes of epigenetic regulation and chromatin regulation may be helpful for achieving correct cell reprogramming without inducing tumor formation and for developing new drugs for cancer treatment. This review focuses on the risk of tumor formation by human pluripotent stem cells, and on the possible treatment options if it occurs. Potential new techniques that target epigenetic processes and chromatin regulation provide opportunities for human cancer modeling and clinical applications of regenerative medicine.
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Affiliation(s)
- Kenly Wuputra
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Chia-Chen Ku
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Deng-Chyang Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Ying-Chu Lin
- School of Dentistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Shigeo Saito
- Waseda University Research Institute for Science and Engineering, Shinjuku, Tokyo, 162-8480, Japan.
- Saito Laboratory of Cell Technology Institute, Yaita, Tochigi, 329-1571, Japan.
| | - Kazunari K Yokoyama
- Graduate Institute of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., San-Ming District, Kaohsiung, 807, Taiwan.
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
- Waseda University Research Institute for Science and Engineering, Shinjuku, Tokyo, 162-8480, Japan.
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Aaliyari-Serej Z, Ebrahimi A, Barazvan B, Ebrahimi-Kalan A, Hajiasgharzadeh K, Kazemi T, Baradaran B. Recent Advances in Targeting of Breast Cancer Stem Cells Based on Biological Concepts and Drug Delivery System Modification. Adv Pharm Bull 2020; 10:338-349. [PMID: 32665892 PMCID: PMC7335982 DOI: 10.34172/apb.2020.042] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Revised: 12/03/2019] [Accepted: 12/05/2019] [Indexed: 02/06/2023] Open
Abstract
Breast cancer with various biological diversity known as the common reason of death in the world and despite progress in novel therapeutic approaches, it faced with failure and recurrence in general. Recent clinical and preclinical statistics support cancer stem cells (CSCs) hypothesis and its similarities with normal stem cells. Evaluation of related paper conclude in significance finding in the further characterization of CSCs biology such as surface biomarkers, microenvironment regulatory molecules, cell signaling pathways, cell to cell transition and drug efflux pumps to overcome multidrug resistance and effective therapy. Emerging novel data indicate biological concepts in the base of unsuccessful treatment. A powerful understanding of the cell signaling pathways in cancer and CSCs topics can be led us to define and control treatment problems in cancer. More recently nano medicine based on drug delivery system modification and new implications on combinatorial therapy have been used to treat breast cancer effectively. The aim of this review is focus on CSCs as a potential target of cancer therapy, to overcome the limitation and problems of current therapeutic strategies in cancer.
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Affiliation(s)
- Zeynab Aaliyari-Serej
- Department of Applied Cell Sciences, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ayyub Ebrahimi
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Halic Uuniversity, Istanbul, Turkey
| | - Balal Barazvan
- Department of Basic Sciences, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Abbas Ebrahimi-Kalan
- Department of Neurosciences and Cognition, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Tohid Kazemi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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40
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Čermák V, Dostál V, Jelínek M, Libusová L, Kovář J, Rösel D, Brábek J. Microtubule-targeting agents and their impact on cancer treatment. Eur J Cell Biol 2020; 99:151075. [PMID: 32414588 DOI: 10.1016/j.ejcb.2020.151075] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 02/25/2020] [Accepted: 03/17/2020] [Indexed: 02/07/2023] Open
Abstract
Microtubule-targeting agents (MTAs) constitute a diverse group of chemical compounds that bind to microtubules and affect their properties and function. Disruption of microtubules induces various cellular responses often leading to cell cycle arrest or cell death, the most common effect of MTAs. MTAs have found a plethora of practical applications in weed control, as fungicides and antiparasitics, and particularly in cancer treatment. Here we summarize the current knowledge of MTAs, the mechanisms of action and their role in cancer treatment. We further outline the potential use of MTAs in anti-metastatic therapy based on inhibition of cancer cell migration and invasiveness. The two main problems associated with cancer therapy by MTAs are high systemic toxicity and development of resistance. Toxic side effects of MTAs can be, at least partly, eliminated by conjugation of the drugs with various carriers. Moreover, some of the novel MTAs overcome the resistance mediated by both multidrug resistance transporters as well as overexpression of specific β-tubulin types. In anti-metastatic therapy, MTAs should be combined with other drugs to target all modes of cancer cell invasion.
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Affiliation(s)
- Vladimír Čermák
- Department of Cell Biology, Charles University, Viničná 7, 12843 Prague, Czech Republic; Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (BIOCEV), Průmyslová 595, 25242 Vestec u Prahy, Czech Republic
| | - Vojtěch Dostál
- Department of Cell Biology, Charles University, Viničná 7, 12843 Prague, Czech Republic
| | - Michael Jelínek
- Department of Biochemistry, Cell and Molecular Biology & Center for Research of Diabetes, Metabolism, and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Lenka Libusová
- Department of Cell Biology, Charles University, Viničná 7, 12843 Prague, Czech Republic
| | - Jan Kovář
- Department of Biochemistry, Cell and Molecular Biology & Center for Research of Diabetes, Metabolism, and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Daniel Rösel
- Department of Cell Biology, Charles University, Viničná 7, 12843 Prague, Czech Republic; Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (BIOCEV), Průmyslová 595, 25242 Vestec u Prahy, Czech Republic
| | - Jan Brábek
- Department of Cell Biology, Charles University, Viničná 7, 12843 Prague, Czech Republic; Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (BIOCEV), Průmyslová 595, 25242 Vestec u Prahy, Czech Republic.
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41
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Zhao H, Mu X, Zhang X, You Q. Lung Cancer Inhibition by Betulinic Acid Nanoparticles via Adenosine 5'-Triphosphate (ATP)-Binding Cassette Transporter G1 Gene Downregulation. Med Sci Monit 2020; 26:e922092. [PMID: 32277808 PMCID: PMC7169437 DOI: 10.12659/msm.922092] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Despite scientific advancement in radiotherapy and chemotherapy, the 5-year survival rate of lung cancer patients is around 15%. The present study explored the anticancer potential of betulinic acid nanoparticles against lung cancer cells. MATERIAL AND METHODS The proliferative changes in lung cancer cells by betulinic acid nanoparticles were measured by MTT assay. Cell cycle analysis was performed by flow cytometry using propidium iodide stain. Transwell and wound healing assay were used for determination of HKULC2 cell metastatic potential. RESULTS The betulinic acid nanoparticle treatment significantly (P<0.05) reduced proliferation of HKULC2, H1299, and H23 cells. The proliferation of HKULC2, H1299, and H23 cells was reduced to 33%, 28% and 24%, respectively on treatment with 10 µM of betulinic acid nanoparticles. The results from flow cytometry showed that betulinic acid nanoparticle exposure lead to cell cycle arrest in G1 phase in HKULC2 cells. Treatment with betulinic acid nanoparticles markedly decreased migration potential of HKULC2 cells. The invasive ability of HKULC2 cells was also suppressed markedly on exposure to betulinic acid nanoparticles. Western blotting of HKULC2 cells showed that betulinic acid nanoparticles promoted the expression of p21 and p53 and downregulated CD133, ALDH, BCL2, MCL1, and c-Myc expression. Betulinic acid nanoparticles reduced the expression of ABCG1 protein markedly. CONCLUSIONS The present study demonstrated that betulinic acid nanoparticles inhibit proliferation, metastatic ability, and arrest cell cycle in lung cancer cells through downregulation of ABCG1 oncogene expression. Therefore, betulinic acid nanoparticles may be used as therapeutic agent for the treatment of lung cancer.
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Affiliation(s)
- Hao Zhao
- Department of Thoracic Surgery, The Second Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Xiaoyan Mu
- Department of Traumatic Orthopaedic Brotherhood of Surgical, The Second Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Xiaopeng Zhang
- Supply Room, The Second Hospital of Shandong University, Jinan, Shandong, China (mainland)
| | - Qingyong You
- Department of Thoracic Surgery, The Second Hospital of Shandong University, Jinan, Shandong, China (mainland)
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42
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Pothula SP, Pirola RC, Wilson JS, Apte MV. Pancreatic stellate cells: Aiding and abetting pancreatic cancer progression. Pancreatology 2020; 20:409-418. [PMID: 31928917 DOI: 10.1016/j.pan.2020.01.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 12/09/2019] [Accepted: 01/06/2020] [Indexed: 12/11/2022]
Abstract
Tumour-stromal interactions have now been acknowledged to play a major role in pancreatic cancer (PC) progression. The abundant collagenous stroma is produced by a specific cell type in the pancreas-the pancreatic stellate cell (PSC). Pancreatic stellate cells (PSCs) are a unique resident cell type of pancreas and with a critical role in both healthy and diseased pancreas. Accumulating evidence indicates that PSCs interact closely with cancer cells as well as with other cell types of the stroma such as immune cells, endothelial cells and neuronal cells, to set up a growth permissive microenvironment for pancreatic tumours, which facilitates local tumour growth as well as distant metastasis. Consequently, recent work in the field has focused on the development of novel therapeutic approaches targeting the stroma to inhibit PC progression. Such a multi-pronged approach targeting both tumour and stromal elements of PC has been successfully applied in pre-clinical settings. The challenge now is to translate the pre-clinical findings into the clinical setting to achieve better outcomes for pancreatic cancer patients.
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Affiliation(s)
- Srinivasa P Pothula
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, and the Ingham Institute for Applied Medical Research, Liverpool, Australia
| | - Romano C Pirola
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, and the Ingham Institute for Applied Medical Research, Liverpool, Australia
| | - Jeremy S Wilson
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, and the Ingham Institute for Applied Medical Research, Liverpool, Australia
| | - Minoti V Apte
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, and the Ingham Institute for Applied Medical Research, Liverpool, Australia.
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43
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Bradney MJ, Venis SM, Yang Y, Konieczny SF, Han B. A Biomimetic Tumor Model of Heterogeneous Invasion in Pancreatic Ductal Adenocarcinoma. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2020; 16:e1905500. [PMID: 31997571 PMCID: PMC7069790 DOI: 10.1002/smll.201905500] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 12/13/2019] [Indexed: 05/21/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a complex, heterogeneous, and genetically unstable disease. Its tumor microenvironment (TME) is complicated by heterogeneous cancer cell populations and strong desmoplastic stroma. This complex and heterogeneous environment makes it challenging to discover and validate unique therapeutic targets. Reliable and relevant in vitro PDAC tumor models can significantly advance the understanding of the PDAC TME and may enable the discovery and validation of novel drug targets. In this study, an engineered tumor model is developed to mimic the PDAC TME. This biomimetic model, named ductal tumor-microenvironment-on-chip (dT-MOC), permits analysis and experimentation on the epithelial-mesenchymal transition (EMT) and local invasion with intratumoral heterogeneity. This dT-MOC is a microfluidic platform where a duct of murine genetically engineered pancreatic cancer cells is embedded within a collagen matrix. The cancer cells used carry two of the three mutations of KRAS, CDKN2A, and TP53, which are key driver mutations of human PDAC. The intratumoral heterogeneity is mimicked by co-culturing these cancer cells. Using the dT-MOC model, heterogeneous invasion characteristics, and response to transforming growth factor-beta1 are studied. A mechanism of EMT and local invasion caused by the interaction between heterogeneous cancer cell populations is proposed.
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Affiliation(s)
- Michael J Bradney
- School of Mechanical Engineering, Purdue University, West Lafayette, IN, 47907, USA
| | - Stephanie M Venis
- School of Mechanical Engineering, Purdue University, West Lafayette, IN, 47907, USA
| | - Yi Yang
- Department of Biological Science, Purdue University, West Lafayette, IN, 47907, USA
| | - Stephen F Konieczny
- Department of Biological Science, Purdue University, West Lafayette, IN, 47907, USA
| | - Bumsoo Han
- School of Mechanical Engineering, Purdue University, West Lafayette, IN, 47907, USA
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44
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Quaglio D, Infante P, Di Marcotullio L, Botta B, Mori M. Hedgehog signaling pathway inhibitors: an updated patent review (2015-present). Expert Opin Ther Pat 2020; 30:235-250. [PMID: 32070165 DOI: 10.1080/13543776.2020.1730327] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Hedgehog (Hh) signaling plays a pivotal role in tissue development and stemness, and its deregulation is found in many different tumors. Several efforts have been devoted to discovery of Hh inhibitors, including three drugs approved by the Food and Drug Administration (FDA), targeting the upstream receptor smoothened (SMO). However, SMO mutations or SMO-independent Hh pathway activation raise the need for novel Hh inhibitors.Areas covered: This review describes Hh inhibitors with anticancer potential patented in the period 2015-present.Expert opinion: Despite the initial enthusiasm in SMO antagonists, drug-resistant mutations, and SMO-independent Hh activation limited their clinical application. A growing number of therapeutic strategies are currently focusing on downstream Hh effectors (i.e. glioma-associate oncogenes (GLI) proteins) or other signaling pathways related to Hh, in addition to drug repositioning. Given the heterogenic nature of cancers, a terrific clinical impact is expected by multi-targeting approaches able to modulate simultaneously SMO and GLI, and/or additional targets that act as regulators of Hh signaling. It is expected that these alternative strategies might be investigated in clinical trials in the next years against a wide variety of tumor types, and that they provide improved outcomes compared to current SMO antagonists or other single-agent anticancer drugs.
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Affiliation(s)
- Deborah Quaglio
- Department of Chemistry and Technology of Drugs, Department of Excellence 2018-2022, Sapienza University of Rome, Rome, Italy
| | - Paola Infante
- Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
| | - Lucia Di Marcotullio
- Department of Molecular Medicine, Department of Excellence 2018-2022, Sapienza University of Rome, Rome, Italy.,Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Bruno Botta
- Department of Chemistry and Technology of Drugs, Department of Excellence 2018-2022, Sapienza University of Rome, Rome, Italy
| | - Mattia Mori
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy
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45
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De Jesus-Acosta A, Sugar EA, O'Dwyer PJ, Ramanathan RK, Von Hoff DD, Rasheed Z, Zheng L, Begum A, Anders R, Maitra A, McAllister F, Rajeshkumar NV, Yabuuchi S, de Wilde RF, Batukbhai B, Sahin I, Laheru DA. Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma. Br J Cancer 2020; 122:498-505. [PMID: 31857726 PMCID: PMC7029016 DOI: 10.1038/s41416-019-0683-3] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 11/12/2019] [Accepted: 11/28/2019] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling. METHODS Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib). RESULTS Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37-6.97) and 9.79 months (95% CI: 7.85-10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment. CONCLUSIONS Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01088815.
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Affiliation(s)
- Ana De Jesus-Acosta
- Department of Medical Oncology, Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, USA.
| | - Elizabeth A Sugar
- Department of Biostatistics, the Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Peter J O'Dwyer
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Ramesh K Ramanathan
- Honor Health Research Institute & Translational Genomics Research Institute, Scottsdale, AZ, USA
| | - Daniel D Von Hoff
- Honor Health Research Institute & Translational Genomics Research Institute, Scottsdale, AZ, USA
| | - Zeshaan Rasheed
- Department of Medical Oncology, Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, USA
| | - Lei Zheng
- Department of Medical Oncology, Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, USA
| | - Asma Begum
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Robert Anders
- Departments of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Anirban Maitra
- Departments of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Florencia McAllister
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - N V Rajeshkumar
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Roeland F de Wilde
- Departments of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Bhavina Batukbhai
- Department of Medical Oncology, Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, USA
| | - Ismet Sahin
- Department of Engineering, Texas Southern University, Houston, TX, USA
| | - Daniel A Laheru
- Department of Medical Oncology, Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD, USA
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46
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Jeng KS, Chang CF, Lin SS. Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments. Int J Mol Sci 2020; 21:ijms21030758. [PMID: 31979397 PMCID: PMC7037908 DOI: 10.3390/ijms21030758] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 01/20/2020] [Accepted: 01/20/2020] [Indexed: 02/07/2023] Open
Abstract
During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, proliferation, and maintenance. Moreover, aberrant activation of SHH signaling occurs in cancers of the skin, brain, liver, gallbladder, pancreas, stomach, colon, breast, lung, prostate, and hematological malignancies. Recent studies have shown that the tumor microenvironment or stroma could affect tumor development and metastasis. One hypothesis has been proposed, claiming that the pancreatic epithelia secretes SHH that is essential in establishing and regulating the pancreatic tumor microenvironment in promoting cancer progression. The SHH signaling pathway is also activated in the cancer stem cells (CSC) of several neoplasms. The self-renewal of CSC is regulated by the SHH/Smoothened receptor (SMO)/Glioma-associated oncogene homolog I (GLI) signaling pathway. Combined use of SHH signaling inhibitors and chemotherapy/radiation therapy/immunotherapy is therefore key in targeting CSCs.
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Kasten BB, Ferrone S, Zinn KR, Buchsbaum DJ. B7-H3-targeted Radioimmunotherapy of Human Cancer. Curr Med Chem 2020; 27:4016-4038. [PMID: 30836909 PMCID: PMC8668195 DOI: 10.2174/0929867326666190228120908] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 01/28/2019] [Accepted: 01/28/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND Targeted Radioimmunotherapy (RIT) is an attractive approach to selectively localize therapeutic radionuclides to malignant cells within primary and metastatic tumors while sparing normal tissues from the effects of radiation. Many human malignancies express B7-H3 on the tumor cell surface, while expression on the majority of normal tissues is limited, presenting B7-H3 as a candidate target for RIT. This review provides an overview of the general principles of targeted RIT and discusses publications that have used radiolabeled B7-H3-targeted antibodies for RIT of cancer in preclinical or clinical studies. METHODS Databases including PubMed, Scopus, and Google Scholar were searched for publications through June 2018 using a combination of terms including "B7-H3", "radioimmunotherapy", "targeted", "radiotherapy", and "cancer". After screening search results for relevancy, ten publications were included for discussion. RESULTS B7-H3-targeted RIT studies to date range from antibody development and assessment of novel Radioimmunoconjugates (RICs) in animal models of human cancer to phase II/III trials in humans. The majority of clinical studies have used B7-H3-targeted RICs for intra- compartment RIT of central nervous system malignancies. The results of these studies have indicated high tolerability and favorable efficacy outcomes, supporting further assessment of B7-H3-targeted RIT in larger trials. Preclinical B7-H3-targeted RIT studies have also shown encouraging therapeutic outcomes in a variety of solid malignancies. CONCLUSION B7-H3-targeted RIT studies over the last 15 years have demonstrated feasibility for clinical development and support future assessment in a broader array of human malignancies. Future directions worthy of exploration include strategies that combine B7-H3- targeted RIT with chemotherapy or immunotherapy.
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Affiliation(s)
- Benjamin B. Kasten
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A
| | - Kurt R. Zinn
- Institute for Quantitative Health Science and Engineering, Department of Radiology, Michigan State University, East Lansing, Michigan, U.S.A
| | - Donald J. Buchsbaum
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A
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Gupta PK, Dharanivasan G, Misra R, Gupta S, Verma RS. Nanomedicine in Cancer Stem Cell Therapy. Nanobiomedicine (Rij) 2020. [DOI: 10.1007/978-981-32-9898-9_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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Ni F, Tang H, Wang C, Zhang H, Zheng C, Zhang N, Chen B, Sun L. Baohuoside I Inhibits the Proliferation of Pancreatic Cancer Cells via mTOR/S6K1-Caspases/Bcl2/Bax Apoptotic Signaling. Cancer Manag Res 2019; 11:10609-10621. [PMID: 31908533 PMCID: PMC6927568 DOI: 10.2147/cmar.s228926] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 12/06/2019] [Indexed: 12/12/2022] Open
Abstract
Background Although the incidence of pancreatic cancer has increased markedly, the 5-year survival rate for this disease is considerably low compared with other types of cancer. Moreover, the mortality rate of pancreatic cancer is similar to its incidence rate. Current therapeutic agents exhibit a lack of specificity for pancreatic cancer. Baohuoside I is traditionally used to treat orgasmic disorder and inflammation. However, its role in pancreatic cancer is unknown. Objective To explore the effects of Baohuoside I on pancreatic cancer and to study the potential-related molecular mechanism. Materials and methods In the present study, the antineoplastic effect of Baohuoside I was investigated with regard to pancreatic cancer via colony formation, transwell and migration assay. The energy metabolism changes of pancreatic cancer were tested by flow cytometry analysis and oxidative phosphorylation and glycolysis assay. The target signaling members were analyzed by Western blot. Results Baohuoside I inhibited the cell growth of pancreatic cancer cells. In addition, it affected intracellular energy metabolism to induce cancer cell apoptosis via the mTOR/S6K1 and the caspase/Bcl2/Bax signaling pathways. Conclusion The present data provide further insight into the development of novel drugs against pancreatic cancer.
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Affiliation(s)
- Fubiao Ni
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Hengjie Tang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Cheng Wang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Hewei Zhang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Chenlei Zheng
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Ning Zhang
- First School of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Bicheng Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
| | - Linxiao Sun
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China
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Takabatake K, Shimo T, Murakami J, Anqi C, Kawai H, Yoshida S, Wathone Oo M, Haruka O, Sukegawa S, Tsujigiwa H, Nakano K, Nagatsuka H. The Role of Sonic Hedgehog Signaling in the Tumor Microenvironment of Oral Squamous Cell Carcinoma. Int J Mol Sci 2019; 20:ijms20225779. [PMID: 31744214 PMCID: PMC6888610 DOI: 10.3390/ijms20225779] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/11/2019] [Accepted: 11/15/2019] [Indexed: 01/08/2023] Open
Abstract
Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of SHH expression appear to correlate with cancer progression. However, the role of SHH in the tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC) is still unclear. No studies have compared the expression of SHH in different subtypes of OSCC and focused on the relationship between the tumor parenchyma and stroma. In this study, we analyzed SHH and expression of its receptor, Patched-1 (PTCH), in the TME of different subtypes of OSCC. Fifteen endophytic-type cases (ED type) and 15 exophytic-type cases (EX type) of OSCC were used. H&E staining, immunohistochemistry (IHC), double IHC, and double-fluorescent IHC were performed on these samples. ED-type parenchyma more strongly expressed both SHH and PTCH than EX-type parenchyma. In OSCC stroma, CD31-positive cancer blood vessels, CD68- and CD11b-positive macrophages, and α-smooth muscle actin-positive cancer-associated fibroblasts partially expressed PTCH. On the other hand, in EX-type stroma, almost no double-positive cells were observed. These results suggest that autocrine effects of SHH induce cancer invasion, and paracrine effects of SHH govern parenchyma-stromal interactions of OSCC. The role of the SHH pathway is to promote growth and invasion.
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Affiliation(s)
- Kiyofumi Takabatake
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
- Correspondence: ; Tel.: +81-086-235-6651
| | - Tsuyoshi Shimo
- Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido 0610293, Japan;
| | - Jun Murakami
- Department of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan;
| | - Chang Anqi
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
- Department of Anatomy, Basic Medical Science College, Harbin Medical University, Harbin 150081, China
| | - Hotaka Kawai
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
| | - Saori Yoshida
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
| | - May Wathone Oo
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
| | - Omori Haruka
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
| | - Shintaro Sukegawa
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
- Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, Kagawa 7608557, Japan
| | - Hidetsugu Tsujigiwa
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
- Department of Life Science, Faculty of Science, Okayama University of Science, Okayama 7000005, Japan
| | - Keisuke Nakano
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
| | - Hitoshi Nagatsuka
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008525, Japan (H.K.); (S.Y.); (M.W.O.); (O.H.); (S.S.); (H.T.); (K.N.); (H.N.)
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