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Grobbelaar C, Steenkamp V, Mabeta P. Vascular Endothelial Growth Factor Receptors in the Vascularization of Pancreatic Tumors: Implications for Prognosis and Therapy. Curr Issues Mol Biol 2025; 47:179. [PMID: 40136433 PMCID: PMC11941243 DOI: 10.3390/cimb47030179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/01/2025] [Accepted: 03/03/2025] [Indexed: 03/27/2025] Open
Abstract
In pancreatic cancer (PC), vascular endothelial growth factor (VEGF) and its primary receptor, vascular endothelial growth factor receptor (VEGFR)-2, are central drivers of angiogenesis and metastasis, with their overexpression strongly associated with poor prognosis. In some PC patients, VEGF levels correlate with disease stage, tumor burden, and survival outcomes. However, therapies targeting VEGF and VEGFR-2, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, have demonstrated limited efficacy, partly due to the emergence of resistance mechanisms. Resistance appears to stem from the activation of alternative vascularization pathways. This review explores the multifaceted roles of VEGFRs in pancreatic cancer, including VEGFR-1 and VEGFR-3. Potential strategies to improve VEGFR-targeting therapies, such as combination treatments, the development of more selective inhibitors, and the use of biomarkers, are discussed as promising approaches to enhance treatment efficacy and outcomes.
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Affiliation(s)
- Craig Grobbelaar
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0002, South Africa;
| | - Vanessa Steenkamp
- Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0002, South Africa;
| | - Peace Mabeta
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0002, South Africa;
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Marzano S, Pinto G, Di Porzio A, Amato J, Randazzo A, Amoresano A, Pagano B. Identifying G-quadruplex-interacting proteins in cancer-related gene promoters. Commun Chem 2025; 8:64. [PMID: 40025218 PMCID: PMC11873050 DOI: 10.1038/s42004-025-01462-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 02/20/2025] [Indexed: 03/04/2025] Open
Abstract
G-quadruplexes (G4s) are noncanonical DNA or RNA secondary structures involved in numerous biological processes. Their recognition by G4-related proteins (G4RPs) is essential for modulating biological pathways, particularly those associated with transcription and cancer progression. Identifying G4RPs is crucial for understanding their role in diseases like cancer, as these proteins may represent promising therapeutic targets. In this study, a proteomic-based fishing-for-partners approach was employed to identify putative interactors of G4-forming DNA sequences from the promoter regions of cancer-related genes DAP, HIF-1α, JAZF-1, and PDGF-A. A total of eighty-six G4RPs were identified, including nineteen known RNA and/or DNA G4 interactors. Notably, fourteen proteins were identified as potential interactors of all four investigated G4-forming DNA, seven of which were novel G4RPs. Direct interactions with G4s were validated for five of these proteins (AHNAK, GAPDH, HNRNP M, LMNA, and PPIA) using surface plasmon resonance experiments, which showed nanomolar binding affinities. This study not only validated known G4RPs but also led to the discovery of new G4/protein interactions, providing the basis for further investigation into their biological significance and potential implications in disease-associated pathways.
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Affiliation(s)
- Simona Marzano
- Department of Pharmacy, University of Naples Federico II, 80131, Naples, Italy
| | - Gabriella Pinto
- Department of Chemical Sciences, University of Naples Federico II, 80126, Naples, Italy
- Interuniversity Consortium "Istituto Nazionale Biostrutture e Biosistemi", 00136, Rome, Italy
| | - Anna Di Porzio
- Department of Pharmacy, University of Naples Federico II, 80131, Naples, Italy
| | - Jussara Amato
- Department of Pharmacy, University of Naples Federico II, 80131, Naples, Italy.
| | - Antonio Randazzo
- Department of Pharmacy, University of Naples Federico II, 80131, Naples, Italy
| | - Angela Amoresano
- Department of Chemical Sciences, University of Naples Federico II, 80126, Naples, Italy
- Interuniversity Consortium "Istituto Nazionale Biostrutture e Biosistemi", 00136, Rome, Italy
| | - Bruno Pagano
- Department of Pharmacy, University of Naples Federico II, 80131, Naples, Italy.
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3
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Mohamed AA, Eble MJ, Dahl E, Jonigk D, Warkentin S. Prognostic implications of HIF-1α expression in anal squamous cell carcinoma treated with intensity-modulated radiotherapy (IMRT). Clin Transl Radiat Oncol 2024; 49:100853. [PMID: 39290454 PMCID: PMC11405990 DOI: 10.1016/j.ctro.2024.100853] [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: 06/09/2024] [Revised: 08/28/2024] [Accepted: 09/01/2024] [Indexed: 09/19/2024] Open
Abstract
Background Hypoxia-inducible factor-1α (HIF-1α) is a crucial transcription factor activated under hypoxic conditions, known to regulate genes associated with tumor survival, progression, and response to therapy. This study aimed to evaluate the prognostic significance of HIF-1α expression in patients with anal squamous cell carcinoma (ASCC) undergoing chemoradiation therapy. Methods We conducted a retrospective analysis of 28 ASCC patients treated with intensity-modulated radiotherapy (IMRT) at our center from 2009 to 2022. HIF-1α expression was assessed via immunohistochemistry on formalin-fixed paraffin-embedded tissue specimens. Quantitative analysis of HIF-1α expression was performed, and its relationship with clinical outcomes, including disease-free survival (DFS), locoregional relapse-free survival (LRRFS), and overall survival (OS), was examined using Cox regression models. Furthermore, ASCC tissue specimens from 17 patients were analyzed for potential PIK3CA mutations using Sanger sequencing. Results High HIF-1α expression was significantly associated with poorer DFS (p = 0.005), LRRFS (p = 0.012), and OS (p = 0.009). HIF1α expression was marginally significantly higher in males compared to females (p = 0.056) while there was no significant difference found based on tumor stage or p16 status. However, a positive correlation was identified between BMI and HIF-1α levels (Pearson correlation r = 0.5, p = 0.0084), suggesting a link between metabolic status and tumor hypoxia. Only one patient exhibited a PIK3CA mutation, preventing a reliable assessment of its correlation with HIF-1α expression. Conclusion Our findings underscore the importance of HIF-1α as a potential biomarker for predicting survival outcomes in ASCC patients treated with chemoradiation. The association between higher BMI and increased HIF-1α expression may provide insights into the interplay between metabolic health and tumor biology in ASCC. Further studies with larger cohorts are needed to validate these findings and explore targeted therapies focusing on HIF-1α modulation.
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Affiliation(s)
- Ahmed Allam Mohamed
- Department of Radiation Oncology, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen, Bonn, Cologne and Duesseldorf (CIO ABCD), Aachen, Germany
| | - Michael J Eble
- Department of Radiation Oncology, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen, Bonn, Cologne and Duesseldorf (CIO ABCD), Aachen, Germany
| | - Edgar Dahl
- Institute of Pathology, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen, Bonn, Cologne and Duesseldorf (CIO ABCD), Aachen, Germany
| | - Danny Jonigk
- Institute of Pathology, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen, Bonn, Cologne and Duesseldorf (CIO ABCD), Aachen, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center of Lung Research (DZL), Hanover, Germany
| | - Svetlana Warkentin
- Institute of Pathology, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen, Bonn, Cologne and Duesseldorf (CIO ABCD), Aachen, Germany
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4
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Grobbelaar C, Kgomo M, Mabeta P. Angiogenesis and Pancreatic Cancer: Novel Approaches to Overcome Treatment Resistance. Curr Cancer Drug Targets 2024; 24:1116-1127. [PMID: 38299403 DOI: 10.2174/0115680096284588240105051402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/18/2023] [Accepted: 12/19/2023] [Indexed: 02/02/2024]
Abstract
Pancreatic cancer (PCa) is acknowledged as a significant contributor to global cancer- related mortality and is widely recognized as one of the most challenging malignant diseases to treat. Pancreatic ductal adenocarcinoma (PDAC), which is the most common type of PCa, is highly aggressive and is mostly incurable. The poor prognosis of this neoplasm is exacerbated by the prevalence of angiogenic molecules, which contribute to stromal stiffness and immune escape. PDAC overexpresses various proangiogenic proteins, including vascular endothelial growth factor (VEGF)-A, and the levels of these molecules correlate with poor prognosis and treatment resistance. Moreover, VEGF-targeting anti-angiogenesis treatments are associated with the onset of resistance due to the development of hypoxia, which in turn induces the production of angiogenic molecules. Furthermore, excessive angiogenesis is one of the hallmarks of the second most common form of PCa, namely, pancreatic neuroendocrine tumor (PNET). In this review, the role of angiogenesis regulators in promoting disease progression in PCa, and the impact of these molecules on resistance to gemcitabine and various therapies against PCa are discussed. Finally, the use of anti-angiogenic agents in combination with chemotherapy and other targeted therapeutic molecules is discussed as a novel solution to overcome current treatment limitations in PCa.
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Affiliation(s)
- Craig Grobbelaar
- Department of Physiology, University of Pretoria, CNR Lynnwood Road and Roper Street, Hatfield, 0028, South Africa
| | - Mpho Kgomo
- Department of Internal Medicine, Faculty of Health Sciences, University of Pretoria, 9 Bophelo Road, Arcadia, CNR Lynnwood Road and Roper Street, Hatfield, 0028, South Africa
| | - Peace Mabeta
- Department of Physiology, University of Pretoria, CNR Lynnwood Road and Roper Street, Hatfield, 0028South Africa
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Guo JS, Li JJ, Wang ZH, Liu Y, Yue YX, Li HB, Zhao XH, Sun YJ, Ding YH, Ding F, Guo DS, Wang L, Chen Y. Dual hypoxia-responsive supramolecular complex for cancer target therapy. Nat Commun 2023; 14:5634. [PMID: 37704601 PMCID: PMC10500001 DOI: 10.1038/s41467-023-41388-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 09/01/2023] [Indexed: 09/15/2023] Open
Abstract
The prognosis with pancreatic cancer is among the poorest of any human cancer. One of the important factors is the tumor hypoxia. Targeting tumor hypoxia is considered a desirable therapeutic option. However, it has not been translated into clinical success in the treatment of pancreatic cancer. With enhanced cytotoxicities against hypoxic pancreatic cancer cells, BE-43547A2 (BE) may serve as a promising template for hypoxia target strategy. Here, based on rational modification, a BE prodrug (NMP-BE) is encapsulated into sulfonated azocalix[5]arene (SAC5A) to generate a supramolecular dual hypoxia-responsive complex NMP-BE@SAC5A. Benefited from the selective load release within cancer cells, NMP-BE@SAC5A markedly suppresses tumor growth at low dose in pancreatic cancer cells xenograft murine model without developing systemic toxicity. This research presents a strategy for the modification of covalent compounds to achieve efficient delivery within tumors, a horizon for the realization of safe and reinforced hypoxia target therapy using a simple approach.
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Affiliation(s)
- Jian-Shuang Guo
- College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China
| | - Juan-Juan Li
- College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Key Laboratory of Functional Polymer Materials (Ministry of Education), Nankai University, Tianjin, 300071, China
| | - Ze-Han Wang
- College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Key Laboratory of Functional Polymer Materials (Ministry of Education), Nankai University, Tianjin, 300071, China
| | - Yang Liu
- College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China
| | - Yu-Xin Yue
- College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Key Laboratory of Functional Polymer Materials (Ministry of Education), Nankai University, Tianjin, 300071, China
| | - Hua-Bin Li
- College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Key Laboratory of Functional Polymer Materials (Ministry of Education), Nankai University, Tianjin, 300071, China
| | - Xiu-He Zhao
- College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China
| | - Yuan-Jun Sun
- College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China
| | - Ya-Hui Ding
- College of Chemistry, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China
| | - Fei Ding
- College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Key Laboratory of Functional Polymer Materials (Ministry of Education), Nankai University, Tianjin, 300071, China
| | - Dong-Sheng Guo
- College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Key Laboratory of Functional Polymer Materials (Ministry of Education), Nankai University, Tianjin, 300071, China.
| | - Liang Wang
- College of Chemistry, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China.
| | - Yue Chen
- College of Chemistry, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China
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Yoshikawa N, Yoshida K, Liu W, Matsukawa T, Hattori S, Yoshihara M, Tamauchi S, Ikeda Y, Yokoi A, Shimizu Y, Niimi K, Kajiyama H. The prognostic significance of DDIT4 in endometrial cancer. Cancer Biomark 2023:CBM220368. [PMID: 37302026 DOI: 10.3233/cbm-220368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
BACKGROUND Despite extensive research on endometrial cancer and tumor hypoxic microenvironment, there are no reports exploring the role of DDIT4 in endometrial cancer. OBJECTIVE This study aimed to elucidate the significance of DDIT4, as a prognostic biomarker for endometrial cancer by immunohistochemical staining and statistical analysis. METHODS Four endometrial cancer cells were cultured under normoxia and hypoxia, and the differentially expressed genes were examined using RNA-seq. Immunohistochemical staining for DDIT4 and HIF1A was performed in 86 patients with type II endometrial cancer treated at our hospital, and their correlation with other clinicopathological factors and the prognostic role was analyzed using statistical methods. RESULTS The expression analysis of hypoxia-inducible genes using four types of endometrial cancer cells revealed that DDIT4 was among the 28 genes that were upregulated in all cells. Based on our results of immunohistochemistry of DDIT4 expression in endometrial cancer tissues, univariate and multivariate analyses based on COX regression analysis showed that high DDIT4 expression significantly correlated to favorable prognosis in both progression-free survival and overall survival. Limited to recurrent cases, metastasis to only lymph nodes was significantly related to high DDIT4 expression, whereas metastasis to other parenchymal organs was significantly dominant in patients with low DDIT4 expression. CONCLUSIONS The expression of DDIT4 enables to predict survival and recurrence in type II endometrial cancer.
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Affiliation(s)
- Nobuhisa Yoshikawa
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kosuke Yoshida
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Wenting Liu
- Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tetsuya Matsukawa
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Satomi Hattori
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masato Yoshihara
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Satoshi Tamauchi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiki Ikeda
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akira Yokoi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yusuke Shimizu
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kaoru Niimi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Laser Capture Microdissection: A Gear for Pancreatic Cancer Research. Int J Mol Sci 2022; 23:ijms232314566. [PMID: 36498893 PMCID: PMC9741023 DOI: 10.3390/ijms232314566] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/16/2022] [Accepted: 11/19/2022] [Indexed: 11/24/2022] Open
Abstract
The advancement in molecular techniques has been attributed to the quality and significance of cancer research. Pancreatic cancer (PC) is one of the rare cancers with aggressive behavior and a high mortality rate. The asymptomatic nature of the disease until its advanced stage has resulted in late diagnosis as well as poor prognosis. The heterogeneous character of PC has complicated cancer development and progression studies. The analysis of bulk tissues of the disease was insufficient to understand the disease, hence, the introduction of the single-cell separating technique aided researchers to decipher more about the specific cell population of tumors. This review gives an overview of the Laser Capture Microdissection (LCM) technique, one of the single-cell separation methods used in PC research.
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Szarka A, Lőrincz T, Hajdinák P. Friend or Foe: The Relativity of (Anti)oxidative Agents and Pathways. Int J Mol Sci 2022; 23:ijms23095188. [PMID: 35563576 PMCID: PMC9099968 DOI: 10.3390/ijms23095188] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/04/2022] [Accepted: 05/05/2022] [Indexed: 12/17/2022] Open
Abstract
An element, iron, a process, the generation of reactive oxygen species (ROS), and a molecule, ascorbate, were chosen in our study to show their dual functions and their role in cell fate decision. Iron is a critical component of numerous proteins involved in metabolism and detoxification. On the other hand, excessive amounts of free iron in the presence of oxygen can promote the production of potentially toxic ROS. They can result in persistent oxidative stress, which in turn can lead to damage and cell death. At the same time, ROS—at strictly regulated levels—are essential to maintaining the redox homeostasis, and they are engaged in many cellular signaling pathways, so their total elimination is not expedient. Ascorbate establishes a special link between ROS generation/elimination and cell death. At low concentrations, it behaves as an excellent antioxidant and has an important role in ROS elimination. However, at high concentrations, in the presence of transition metals such as iron, it drives the generation of ROS. In the term of the dual function of these molecules and oxidative stress, ascorbate/ROS-driven cell deaths are not necessarily harmful processes—they can be live-savers too.
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Affiliation(s)
- András Szarka
- Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary; (T.L.); (P.H.)
- Biotechnology Model Laboratory, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
- Correspondence:
| | - Tamás Lőrincz
- Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary; (T.L.); (P.H.)
- Biotechnology Model Laboratory, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
| | - Péter Hajdinák
- Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary; (T.L.); (P.H.)
- Biotechnology Model Laboratory, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
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Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer. Pharmaceutics 2022; 14:pharmaceutics14040713. [PMID: 35456547 PMCID: PMC9031349 DOI: 10.3390/pharmaceutics14040713] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/17/2022] [Accepted: 03/22/2022] [Indexed: 02/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) presents as an unmet clinical challenge for drug delivery due to its unique hypoxic biology. Vinblastine-N-Oxide (CPD100) is a hypoxia-activated prodrug (HAP) that selectively converts to its parent compound, vinblastine, a potent cytotoxic agent, under oxygen gradient. The study evaluates the efficacy of microfluidics formulated liposomal CPD100 (CPD100Li) in PDAC. CPD100Li were formulated with a size of 95 nm and a polydispersity index of 0.2. CPD100Li was stable for a period of 18 months when freeze-dried at a concentration of 3.55 mg/mL. CPD100 and CPD100Li confirmed selective activation at low oxygen levels in pancreatic cancer cell lines. Moreover, in 3D spheroids, CPD100Li displayed higher penetration and disruption compared to CPD100. In patient-derived 3D organoids, CPD100Li exhibited higher cell inhibition in the organoids that displayed higher expression of hypoxia-inducible factor 1 alpha (HIF1A) compared to CPD100. In the orthotopic model, the combination of CPD100Li with gemcitabine (GEM) (standard of care for PDAC) showed higher efficacy than CPD100Li alone for a period of 90 days. In summary, the evaluation of CPD100Li in multiple cellular models provides a strong foundation for its clinical application in PDAC.
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Ravichandran R, PriyaDharshini LC, Sakthivel KM, Rasmi RR. Role and regulation of autophagy in cancer. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166400. [PMID: 35341960 DOI: 10.1016/j.bbadis.2022.166400] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 03/17/2022] [Accepted: 03/18/2022] [Indexed: 02/07/2023]
Abstract
Autophagy is an intracellular self-degradative mechanism which responds to cellular conditions like stress or starvation and plays a key role in regulating cell metabolism, energy homeostasis, starvation adaptation, development and cell death. Numerous studies have stipulated the participation of autophagy in cancer, but the role of autophagy either as tumor suppressor or tumor promoter is not clearly understood. However, mechanisms by which autophagy promotes cancer involves a diverse range of modifications of autophagy associated proteins such as ATGs, Beclin-1, mTOR, p53, KRAS etc. and autophagy pathways like mTOR, PI3K, MAPK, EGFR, HIF and NFκB. Furthermore, several researches have highlighted a context-dependent, cell type and stage-dependent regulation of autophagy in cancer. Alongside this, the interaction between tumor cells and their microenvironment including hypoxia has a great potential in modulating autophagy response in favour to substantiate cancer cell metabolism, self-proliferation and metastasis. In this review article, we highlight the mechanism of autophagy and their contribution to cancer cell proliferation and development. In addition, we discuss about tumor microenvironment interaction and their consequence on selective autophagy pathways and the involvement of autophagy in various tumor types and their therapeutic interventions concentrated on exploiting autophagy as a potential target to improve cancer therapy.
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Affiliation(s)
- Rakesh Ravichandran
- Department of Biotechnology, PSG College of Arts and Science, Civil Aerodrome Post, Coimbatore 641 014, Tamil Nadu, India
| | | | - Kunnathur Murugesan Sakthivel
- Department of Biochemistry, PSG College of Arts and Science, Civil Aerodrome Post, Coimbatore 641 014, Tamil Nadu, India
| | - Rajan Radha Rasmi
- Department of Biotechnology, PSG College of Arts and Science, Civil Aerodrome Post, Coimbatore 641 014, Tamil Nadu, India.
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Li RU, Tang K, Li Q. Pan-cancer Bioinformatics Analysis of the Double-edged Role of Hypoxia-inducible Factor 1α (HIF-1α) in Human Cancer. CANCER DIAGNOSIS & PROGNOSIS 2022; 2:263-278. [PMID: 35399173 PMCID: PMC8962818 DOI: 10.21873/cdp.10104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 01/26/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND/AIM Despite the emergence of cellular, animal, and clinical-based evidence demonstrating a link between hypoxia-inducible factor-1α (HIF-1α) and malignancy, the comprehensive assessment of HIF-1α in pan-cancer patients remains unclear, particularly regarding HIF-1α expression and its association with immune infiltration and immune checkpoint. The present study aimed to investigate the role of HIF-1α expression in various types of malignancies through bioinformatics analysis. MATERIALS AND METHODS We investigated the expression and prognostic value of HIF-1α in pan-cancer based on the TCGA (The Cancer Genome Atlas) dataset. The abundance of immune infiltration was estimated by xCell immune deconvolution methods. We investigated the relationship of HIF-1α expression with immune infiltration and immune checkpoint gene expression, with a focus on gastric adenocarcinoma (STAD) and lung squamous cell carcinoma (LUSC). RESULTS HIF-1α expression had different effects on the prognosis of various cancers. In contrast to the protective effect of HIF-1α expression in LUSC, high levels of HIF-1α expression played a detrimental role in the survival of STAD patients. There was a significant positive correlation between HIF-1α expression and immune infiltration in STAD patients, including regulatory T-cells (Tregs), T-cell CD4+ Th2, neutrophils, M1 and M2 macrophages. In addition, immune checkpoint molecules showed different HIF-1α-related profiles in various carcinomas. CONCLUSION A relatively comprehensive view of the oncogenic role of HIF-1α in various tumors based on a pan-cancer analysis is provided in this study. HIF-1α may be considered a poor prognostic biomarker for STAD and, moreover, it may be involved in regulating tumor immune infiltration.
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Affiliation(s)
- R U Li
- Department of Geriatrics, the Hengshui Harrison International Peace Hospital, Hebei, P.R. China
| | - Kang Tang
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Qian Li
- Department of Thoracic Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
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12
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Hirt CK, Booij TH, Grob L, Simmler P, Toussaint NC, Keller D, Taube D, Ludwig V, Goryachkin A, Pauli C, Lenggenhager D, Stekhoven DJ, Stirnimann CU, Endhardt K, Ringnalda F, Villiger L, Siebenhüner A, Karkampouna S, De Menna M, Beshay J, Klett H, Kruithof-de Julio M, Schüler J, Schwank G. Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label treatment. CELL GENOMICS 2022; 2:100095. [PMID: 35187519 PMCID: PMC7612395 DOI: 10.1016/j.xgen.2022.100095] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 01/27/2021] [Accepted: 01/19/2022] [Indexed: 05/22/2023]
Abstract
Pancreatic cancer (PDAC) is a highly aggressive malignancy for which the identification of novel therapies is urgently needed. Here, we establish a human PDAC organoid biobank from 31 genetically distinct lines, covering a representative range of tumor subtypes, and demonstrate that these reflect the molecular and phenotypic heterogeneity of primary PDAC tissue. We use CRISPR-Cas9 genome editing and drug screening to characterize drug-gene interactions with ARID1A and BRCA2. We find that missense- but not frameshift mutations in the PDAC driver gene ARID1A are associated with increased sensitivity to the kinase inhibitors dasatinib (p < 0.0001) and VE-821 (p < 0.0001). We conduct an automated drug-repurposing screen with 1,172 FDA-approved compounds, identifying 26 compounds that effectively kill PDAC organoids, including 19 chemotherapy drugs currently approved for other cancer types. We validate the activity of these compounds in vitro and in vivo. The in vivo validated hits include emetine and ouabain, compounds which are approved for non-cancer indications and which perturb the ability of PDAC organoids to respond to hypoxia. Our study provides proof-of-concept for advancing precision oncology and identifying candidates for drug repurposing via genome editing and drug screening in tumor organoid biobanks.
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Affiliation(s)
- Christian K. Hirt
- Institute of Molecular Health Sciences, ETH Zurich, Switzerland
- Institute of Pharmacology and Toxicology, University Zurich, Switzerland
| | - Tijmen H. Booij
- NEXUS Personalized Health Technologies, ETH Zurich, Switzerland
| | - Linda Grob
- NEXUS Personalized Health Technologies, ETH Zurich, Switzerland
- SIB Swiss Institute of Bioinformatics, Zurich, Switzerland
| | - Patrik Simmler
- Institute of Molecular Health Sciences, ETH Zurich, Switzerland
- Institute of Pharmacology and Toxicology, University Zurich, Switzerland
| | - Nora C. Toussaint
- NEXUS Personalized Health Technologies, ETH Zurich, Switzerland
- SIB Swiss Institute of Bioinformatics, Zurich, Switzerland
| | - David Keller
- NEXUS Personalized Health Technologies, ETH Zurich, Switzerland
| | - Doreen Taube
- Institute of Molecular Health Sciences, ETH Zurich, Switzerland
| | - Vanessa Ludwig
- Institute of Molecular Health Sciences, ETH Zurich, Switzerland
| | | | - Chantal Pauli
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Switzerland
| | - Daniela Lenggenhager
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Switzerland
| | - Daniel J. Stekhoven
- NEXUS Personalized Health Technologies, ETH Zurich, Switzerland
- SIB Swiss Institute of Bioinformatics, Zurich, Switzerland
| | | | - Katharina Endhardt
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Switzerland
| | - Femke Ringnalda
- Institute of Molecular Health Sciences, ETH Zurich, Switzerland
| | - Lukas Villiger
- Institute of Molecular Health Sciences, ETH Zurich, Switzerland
- Institute of Pharmacology and Toxicology, University Zurich, Switzerland
| | | | - Sofia Karkampouna
- Department for BioMedical Research, Urology Research laboratory, University Bern, Switzerland
- Department of Urology, Inselspital, Bern University Hospital, Switzerland
| | - Marta De Menna
- Department for BioMedical Research, Urology Research laboratory, University Bern, Switzerland
- Department of Urology, Inselspital, Bern University Hospital, Switzerland
| | - Janette Beshay
- Discovery Services, Oncotest, Charles River, Freiburg, Germany
| | - Hagen Klett
- Discovery Services, Oncotest, Charles River, Freiburg, Germany
| | - Marianna Kruithof-de Julio
- Department for BioMedical Research, Urology Research laboratory, University Bern, Switzerland
- Department of Urology, Inselspital, Bern University Hospital, Switzerland
| | - Julia Schüler
- Discovery Services, Oncotest, Charles River, Freiburg, Germany
| | - Gerald Schwank
- Institute of Molecular Health Sciences, ETH Zurich, Switzerland
- Institute of Pharmacology and Toxicology, University Zurich, Switzerland
- Corresponding author
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Lamptey J, Czika A, Aremu JO, Pervaz S, Adu-Gyamfi EA, Otoo A, Li F, Wang YX, Ding YB. The role of fascin in carcinogenesis and embryo implantation. Exp Cell Res 2021; 409:112885. [PMID: 34662557 DOI: 10.1016/j.yexcr.2021.112885] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 10/09/2021] [Accepted: 10/11/2021] [Indexed: 01/02/2023]
Abstract
The cytoskeleton, with its actin bundling proteins, plays crucial roles in a host of cellular function, such as cancer metastasis, antigen presentation and trophoblast migration and invasion, as a result of cytoskeletal remodeling. A key player in cytoskeletal remodeling is fascin. Upregulation of fascin induces the transition of epithelial phenotypes to mesenchymal phenotypes through complex interaction with transcription factors. Fascin expression also regulates mitochondrial F-actin to promote oxidative phosphorylation (OXPHOS) in some cancer cells. Trophoblast cells, on the other hand, exhibit similar physiological functions, involving the upregulation of genes crucial for its migration and invasion. Owing to the similar tumor-like characteristics among cancer and trophoblats, we review recent studies on fascin in relation to cancer and trophoblast cell biology; and based on existing evidence, link fascin to the establishment of the maternal-fetal interface.
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Affiliation(s)
- Jones Lamptey
- School of Basic Medicine, Chongqing Medical University, Chongqing, People's Republic of China; Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing, People's Republic of China; Kumasi Centre for Collaborative Research in Tropical Medicine, KCCR, UPO, Kumasi, Ghana.
| | - Armin Czika
- School of Basic Medicine, Chongqing Medical University, Chongqing, People's Republic of China; Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing, People's Republic of China
| | - John Ogooluwa Aremu
- Department of Human Anatomy and Histoembryology, Harbin Medical University, Harbin, People's Republic of China
| | - Sadaf Pervaz
- School of Basic Medicine, Chongqing Medical University, Chongqing, People's Republic of China; Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing, People's Republic of China
| | - Enoch Appiah Adu-Gyamfi
- School of Basic Medicine, Chongqing Medical University, Chongqing, People's Republic of China; Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing, People's Republic of China
| | - Antonia Otoo
- School of Basic Medicine, Chongqing Medical University, Chongqing, People's Republic of China; Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing, People's Republic of China
| | - Fangfang Li
- Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing, People's Republic of China
| | - Ying-Xiong Wang
- School of Basic Medicine, Chongqing Medical University, Chongqing, People's Republic of China; Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing, People's Republic of China.
| | - Yu-Bin Ding
- Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing, People's Republic of China.
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14
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Kato A, Ng S, Thangasamy A, Han H, Zhou W, Raeppel S, Fallon M, Guha S, Ammanamanchi S. A potential signaling axis between RON kinase receptor and hypoxia-inducible factor-1 alpha in pancreatic cancer. Mol Carcinog 2021; 60:734-745. [PMID: 34347914 PMCID: PMC9292374 DOI: 10.1002/mc.23339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 11/06/2022]
Abstract
The Cancer Genome Atlas (TCGA) of a pancreatic cancer cohort identified high MST1R (RON tyrosine kinase receptor) expression correlated with poor prognosis in human pancreatic cancer. RON expression is null/minimal in normal pancreas but elevates from pan-in lesions through invasive carcinomas. We report using multiple approaches RON directly regulates HIF-1α, a critical driver of genes involved in cancer cell invasion and metastasis. RON and HIF-1α are highly co-expressed in the 101 human PDAC tumors analyzed and RON expression correlated with HIF-1α expression in a subset of PDAC cell lines. knockdown of RON expression in RON positive cells blocked HIF-1α expression, whereas ectopic RON expression in RON null cells induced HIF-1α expression suggesting the direct regulation of HIF-1α by RON kinase receptor. RON regulates HIF-1α through an unreported transcriptional mechanism involving PI3 kinase-mediated AKT phosphorylation and Sp1-dependent HIF-1α promoter activity leading to increased HIF-1α mRNA expression. RON/HIF-1α modulation altered the invasive behavior of PDAC cells. A small-molecule RON kinase inhibitor decreased RON ligand, MSP-induced HIF-1α expression, and invasion of PDAC cells. Immunohistochemical analysis on RON knockdown orthotopic PDAC tumor xenograft confirmed that RON inhibition significantly blocked HIF-1α expression. RON/HIF-1α co-expression also exists in triple-negative breast cancer cells, a tumor type that also lacks molecular therapeutic targets. This is the first report describing RON/HIF-1α axis in any tumor type and is a potential novel therapeutic target.
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Affiliation(s)
- Akihisa Kato
- Department of Internal MedicineUniversity of Arizona College of Medicine‐PhoenixPhoenixArizonaUSA
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Serina Ng
- Division of Molecular MedicineTGenPhoenixArizonaUSA
| | - Amalraj Thangasamy
- Department of MedicineUniversity of Texas Health Science CenterSan AntonioTexasUSA
| | - Haiyong Han
- Division of Molecular MedicineTGenPhoenixArizonaUSA
| | - Wendi Zhou
- Department of PathologyBanner University Medical CenterPhoenixArizonaUSA
| | | | - Michael Fallon
- Department of Internal MedicineUniversity of Arizona College of Medicine‐PhoenixPhoenixArizonaUSA
| | - Sushovan Guha
- Department of Internal MedicineUniversity of Arizona College of Medicine‐PhoenixPhoenixArizonaUSA
| | - Sudhakar Ammanamanchi
- Department of Internal MedicineUniversity of Arizona College of Medicine‐PhoenixPhoenixArizonaUSA
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15
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Jain A, Bhardwaj V. Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities. World J Gastroenterol 2021; 27:6527-6550. [PMID: 34754151 PMCID: PMC8554400 DOI: 10.3748/wjg.v27.i39.6527] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/22/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Although chemotherapeutic regimens such as gemcitabine+ nab-paclitaxel and FOLFIRINOX (FOLinic acid, 5-Fluroruracil, IRINotecan, and Oxaliplatin) significantly improve patient survival, the prevalence of therapy resistance remains a major roadblock in the success of these agents. This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mechanisms has shaped clinical trials for pancreatic cancer chemotherapy. Specifically, we have discussed the metabolic alterations and DNA repair mechanisms observed in PDAC and current approaches in targeting these mechanisms. Our discussion also includes the lessons learned following the failure of immunotherapy in PDAC and current approaches underway to improve tumor's immunological response.
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Affiliation(s)
- Aditi Jain
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Vikas Bhardwaj
- Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States
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16
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AKIN DF, ILIKCI R. Mutations and expression profile of EDIL3 and correlation with HIF1A and tumor-associated carbonic anhydrases in pancreatic cancer. CLINICAL AND EXPERIMENTAL HEALTH SCIENCES 2021. [DOI: 10.33808/clinexphealthsci.756701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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17
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Xelwa N, Candy GP, Devar J, Omoshoro-Jones J, Smith M, Nweke EE. Targeting Growth Factor Signaling Pathways in Pancreatic Cancer: Towards Inhibiting Chemoresistance. Front Oncol 2021; 11:683788. [PMID: 34195085 PMCID: PMC8236623 DOI: 10.3389/fonc.2021.683788] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 05/24/2021] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer is one of the most deadly cancers, ranking amongst the top leading cause of cancer related deaths in developed countries. Features such as dense stroma microenvironment, abnormal signaling pathways, and genetic heterogeneity of the tumors contribute to its chemoresistant characteristics. Amongst these features, growth factors have been observed to play crucial roles in cancer cell survival, progression, and chemoresistance. Here we review the role of the individual growth factors in pancreatic cancer chemoresistance. Importantly, the interplay between the tumor microenvironment and chemoresistance is explored in the context of pivotal role played by growth factors. We further describe current and future potential therapeutic targeting of these factors.
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18
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Penny HL, Sieow JL, Gun SY, Lau MC, Lee B, Tan J, Phua C, Toh F, Nga Y, Yeap WH, Janela B, Kumar D, Chen H, Yeong J, Kenkel JA, Pang A, Lim D, Toh HC, Hon TLK, Johnson CI, Khameneh HJ, Mortellaro A, Engleman EG, Rotzschke O, Ginhoux F, Abastado JP, Chen J, Wong SC. Targeting Glycolysis in Macrophages Confers Protection Against Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2021; 22:6350. [PMID: 34198548 PMCID: PMC8231859 DOI: 10.3390/ijms22126350] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/28/2021] [Accepted: 06/07/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1β inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.
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Affiliation(s)
- Hweixian Leong Penny
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Je Lin Sieow
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Sin Yee Gun
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Mai Chan Lau
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Bernett Lee
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Jasmine Tan
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Cindy Phua
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Florida Toh
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Yvonne Nga
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Wei Hseun Yeap
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Baptiste Janela
- Skin Research Institute of Singapore (SRIS), 11 Mandalay Road, #17-01 Clinical Sciences Building, Singapore 308232, Singapore;
| | - Dilip Kumar
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Hao Chen
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Joe Yeong
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Justin A. Kenkel
- Department of Pathology, Stanford University School of Medicine, 3373 Hillview Ave., Palo Alto, CA 94304, USA; (J.A.K.); (E.G.E.)
| | - Angela Pang
- National University Cancer Institute Singapore, NUH Medical Centre (NUHMC) @ Levels 8-10, 5 Lower Kent Ridge Road, Singapore 119074, Singapore;
| | - Diana Lim
- Department of Pathology, National University Health System, National University Hospital, Lower Kent Ridge Road, 1 Main Building, Level 3, Singapore 119074, Singapore;
| | - Han Chong Toh
- National Cancer Centre, 11 Hospital Crescent, Singapore 169610, Singapore;
| | - Tony Lim Kiat Hon
- Division of Pathology, Singapore General Hospital, 20 College Road, Academia, Level 7, Singapore 169856, Singapore;
| | | | - Hanif Javanmard Khameneh
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Alessandra Mortellaro
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Edgar G. Engleman
- Department of Pathology, Stanford University School of Medicine, 3373 Hillview Ave., Palo Alto, CA 94304, USA; (J.A.K.); (E.G.E.)
| | - Olaf Rotzschke
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Florent Ginhoux
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Jean-Pierre Abastado
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Jinmiao Chen
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
| | - Siew Cheng Wong
- Singapore Immunology Network, A*STAR, Singapore, 8A Biomedical Grove Level 3 & 4 Immunos Building, Singapore 138648, Singapore; (J.L.S.); (S.Y.G.); (M.C.L.); (B.L.); (J.T.); (C.P.); (F.T.); (Y.N.); (W.H.Y.); (D.K.); (H.C.); (J.Y.); (H.J.K.); (A.M.); (O.R.); (F.G.); (J.-P.A.); (J.C.)
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Basu M, Chatterjee A, Chakraborty B, Chatterjee E, Ghosh S, Samadder S, Pal DK, Roy A, Chakrabarti J, Ghosh A, Panda CK. High nuclear expression of HIF1α, synergizing with inactivation of LIMD1 and VHL, portray worst prognosis among the bladder cancer patients: association with arsenic prevalence. J Cancer Res Clin Oncol 2021; 147:2309-2322. [PMID: 34080067 DOI: 10.1007/s00432-021-03661-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 05/05/2021] [Indexed: 11/25/2022]
Abstract
PURPOSE Our study was aimed to understand the importance of LIMD1-VHL-HIF1α pathway in development of bladder carcinoma (BlCa) in association with arsenic prevalence. METHODS At first, the mRNA expression pattern of the genes of this pathway (LIMD1, VHL and HIF1α) was checked in GEO datasets and in our samples. Next, genetic and epigenetic profiling of LIMD1 and VHL was done in our sample pool, validated in T24 BlCa cell line. The results were next correlated with various clinico-pathological parameters. RESULTS Differential under-expression of LIMD1 and VHL genes was found in muscle-invasive BlCa (MIBC) in comparison to non-muscle-invasive BlCa (NMIBC). However, HIF1α protein, but mRNA, was found to be overexpressed among the MIBC samples; depicting the probability of HIF1α protein stabilization. Analysis of genetic and epigenetic profiles of LIMD1 and VHL exposed a frequent promoter methylation of LIMD1 gene in MIBC samples. Further, in-depth look into the results unveiled that the high nuclear expression of HIF1α was significantly correlated with genetic alterations of LIMD1, alone or in combination with VHL. Moreover, treating the T24 cells with a de-methylating agent (5-aza-2'-deoxycytidine) re-expressed the methylated LIMD1 and VHL genes, which in turn, reduced the HIF1α protein level significantly. Additionally, patients with high arsenic content (> 112 ng/g, AsH) seemed to have recurrent promoter methylation in LIMD1, as well as co-methylation/alteration of LIMD1 and VHL gene. Lastly, high nuclear expression of HIF1α in association with co-alteration of VHL and LIMD1 showed the worst overall survival (OS) among the patients. CONCLUSION To conclude, MIBC samples portrayed higher alterations in VHL and LIMD1, thereby, stabilizing HIF1α protein and lowering the OS of patients.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Arsenic Poisoning/diagnosis
- Arsenic Poisoning/epidemiology
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Transitional Cell/diagnosis
- Carcinoma, Transitional Cell/epidemiology
- Carcinoma, Transitional Cell/genetics
- Carcinoma, Transitional Cell/pathology
- Cell Line, Tumor
- Cell Nucleus/genetics
- Cell Nucleus/metabolism
- Cell Nucleus/pathology
- Comorbidity
- DNA Methylation
- Datasets as Topic
- Female
- Gene Expression Regulation, Neoplastic
- Gene Silencing
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- LIM Domain Proteins/genetics
- LIM Domain Proteins/metabolism
- Male
- Middle Aged
- Neoplasm Invasiveness
- Prevalence
- Prognosis
- Survival Analysis
- Urinary Bladder Neoplasms/diagnosis
- Urinary Bladder Neoplasms/epidemiology
- Urinary Bladder Neoplasms/genetics
- Urinary Bladder Neoplasms/pathology
- Von Hippel-Lindau Tumor Suppressor Protein/genetics
- Von Hippel-Lindau Tumor Suppressor Protein/metabolism
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Affiliation(s)
- Mukta Basu
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37 S. P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Amvrin Chatterjee
- Department of Urology, IPGMER, SSKM, 244 A.J.C. Bose Road, Kolkata, 700020, India
| | - Balarko Chakraborty
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37 S. P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Essha Chatterjee
- National Institute of Pharmaceutical Education and Research, Kukatpally Industrial Estate, Balanagar, Hyderabad, Telangana, 500037, India
| | - Sabnam Ghosh
- Department of Life Science, Presidency University, 86/1, College Street, Kolkata, 700073, India
| | - Sudip Samadder
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37 S. P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Dilip Kumar Pal
- Department of Urology, IPGMER, SSKM, 244 A.J.C. Bose Road, Kolkata, 700020, India
| | - Anup Roy
- Nil Ratan Sarkar Medical College and Hospital, Kolkata, West Bengal, India
| | - Jayanta Chakrabarti
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37 S. P. Mukherjee Road, Kolkata, West Bengal, 700026, India
| | - Amlan Ghosh
- Department of Life Science, Presidency University, 86/1, College Street, Kolkata, 700073, India
| | - Chinmay Kumar Panda
- Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37 S. P. Mukherjee Road, Kolkata, West Bengal, 700026, India.
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HIF1α-dependent induction of the mitochondrial chaperone TRAP1 regulates bioenergetic adaptations to hypoxia. Cell Death Dis 2021; 12:434. [PMID: 33934112 PMCID: PMC8088431 DOI: 10.1038/s41419-021-03716-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 03/22/2021] [Accepted: 04/06/2021] [Indexed: 02/08/2023]
Abstract
The mitochondrial paralog of the Hsp90 chaperone family TRAP1 is often induced in tumors, but the mechanisms controlling its expression, as well as its physiological functions remain poorly understood. Here, we find that TRAP1 is highly expressed in the early stages of Zebrafish development, and its ablation delays embryogenesis while increasing mitochondrial respiration of fish larvae. TRAP1 expression is enhanced by hypoxic conditions both in developing embryos and in cancer models of Zebrafish and mammals. The TRAP1 promoter contains evolutionary conserved hypoxic responsive elements, and HIF1α stabilization increases TRAP1 levels. TRAP1 inhibition by selective compounds or by genetic knock-out maintains a high level of respiration in Zebrafish embryos after exposure to hypoxia. Our data identify TRAP1 as a primary regulator of mitochondrial bioenergetics in highly proliferating cells following reduction in oxygen tension and HIF1α stabilization.
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21
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Prion Protein of Extracellular Vesicle Regulates the Progression of Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13092144. [PMID: 33946823 PMCID: PMC8124505 DOI: 10.3390/cancers13092144] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/09/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Cellular prion protein (PrPC) are overexpressed in cancers and related to cancer proliferation, invasion, metastasis, and drug resistance. The aim of our study was to investigate the role of PrPC-expressing exosomes regulating the colorectal cancer cells (CRC) behavior and tumor progression. We confirmed the increased sphere formation, expression of cancer initiating genes, motility, and tumor growth by hypoxic exosomes. Also, PrPC-expressing exosomes induced the microenvironment of metastasis via increase of endothelial permeability and angiogenic cytokine secretion. The treatment of anti-PrPC and 5-fluorouracil decreased the tumor progression. Targeting PrPC is an effective therapeutic strategy in cancer therapy. Abstract Colorectal cancer (CRC) is one of the leading causes of cancer-related death due to its aggressive metastasis in later stages. Although there is a growing interest in the tumorigenic role of cellular prion protein (PrPC) in the process of metastasis, the precise mechanism behind the cellular communication involving prion proteins remains poorly understood. This study found that hypoxic tumor microenvironment increased the PrPC-expressing exosomes from CRC, and these exosomes regulate the CRC cell behavior and tumor progression depending on the expression of PrPC. Hypoxic exosomes from CRC cells promoted sphere formation, the expression of tumor-inducing genes, migration, invasion, and tumor growth. Furthermore, these exosomes increased endothelial permeability, migration, invasion, and angiogenic cytokine secretion. These effects were associated with PrPC expression. Application of anti-PrPC antibody with 5-fluorouracil significantly suppressed the CRC progression in a murine xenograft model. Taken together, these findings indicate that PrP-expressing exosomes secreted by hypoxic CRC cells are a key factor in the tumorigenic CRC-to-CRC and CRC-to-endothelial cell communication. Significance: These findings suggest that inhibiting PrPC in hypoxic exosomes during chemotherapy may be an effective therapeutic strategy in colorectal cancer.
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Kang G, Hu M, Ren H, Wang J, Cheng X, Li R, Yuan B, Balan Y, Bai Z, Huang H. VHH212 nanobody targeting the hypoxia-inducible factor 1α suppresses angiogenesis and potentiates gemcitabine therapy in pancreatic cancer in vivo. Cancer Biol Med 2021; 18:772-787. [PMID: 33830713 PMCID: PMC8330535 DOI: 10.20892/j.issn.2095-3941.2020.0568] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 01/14/2021] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE We aimed to develop a novel anti-HIF-1α intrabody to decrease gemcitabine resistance in pancreatic cancer patients. METHODS Surface plasmon resonance and glutathione S-transferase pull-down assays were conducted to identify the binding affinity and specificity of anti-HIF-1α VHH212 [a single-domain antibody (nanobody)]. Molecular dynamics simulation was used to determine the protein-protein interactions between hypoxia-inducible factor-1α (HIF-1α) and VHH212. The real-time polymerase chain reaction (PCR) and Western blot analyses were performed to identify the expressions of HIF-1α and VEGF-A in pancreatic ductal adenocarcinoma cell lines. The efficiency of the VHH212 nanobody in inhibiting the HIF-1 signaling pathway was measured using a dual-luciferase reporter assay. Finally, a PANC-1 xenograft model was developed to evaluate the anti-tumor efficiency of combined treatment. Immunohistochemistry analysis was conducted to detect the expressions of HIF-1α and VEGF-A in tumor tissues. RESULTS VHH212 was stably expressed in tumor cells with low cytotoxicity, high affinity, specific subcellular localization, and neutralization of HIF-1α in the cytoplasm or nucleus. The binding affinity between VHH212 and the HIF-1α PAS-B domain was 42.7 nM. Intrabody competitive inhibition of the HIF-1α heterodimer with an aryl hydrocarbon receptor nuclear translocator was used to inhibit the HIF-1/VEGF pathway in vitro. Compared with single agent gemcitabine, co-treatment with gemcitabine and a VHH212-encoding adenovirus significantly suppressed tumor growth in the xenograft model with 80.44% tumor inhibition. CONCLUSIONS We developed an anti-HIF-1α nanobody and showed the function of VHH212 in a preclinical murine model of PANC-1 pancreatic cancer. The combination of VHH212 and gemcitabine significantly inhibited tumor development. These results suggested that combined use of anti-HIF-1α nanobodies with first-line treatment may in the future be an effective treatment for pancreatic cancer.
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Affiliation(s)
- Guangbo Kang
- Department of Biochemical Engineering, School of Chemical Engineering & Technology, Tianjin University, Tianjin 300350, China
- Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
| | - Min Hu
- Department of Biochemical Engineering, School of Chemical Engineering & Technology, Tianjin University, Tianjin 300350, China
- Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
| | - He Ren
- Department of Gastroenterology, Center of Tumor Immunology and Cytotherapy, Medical Research Center of The Affiliated Hospital of Qingdao University, Qingdao 266003, China
| | - Jiewen Wang
- Department of Biochemical Engineering, School of Chemical Engineering & Technology, Tianjin University, Tianjin 300350, China
- Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
| | - Xin Cheng
- Department of Biochemical Engineering, School of Chemical Engineering & Technology, Tianjin University, Tianjin 300350, China
- Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
| | - Ruowei Li
- Department of Biochemical Engineering, School of Chemical Engineering & Technology, Tianjin University, Tianjin 300350, China
- Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
| | - Bo Yuan
- Department of Biochemical Engineering, School of Chemical Engineering & Technology, Tianjin University, Tianjin 300350, China
- Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
| | - Yasmine Balan
- Department of Chemical and Biological Engineering, University of Ottawa, Ottawa K1N 6N5, Canada
| | - Zixuan Bai
- Department of Biochemical Engineering, School of Chemical Engineering & Technology, Tianjin University, Tianjin 300350, China
- Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
| | - He Huang
- Department of Biochemical Engineering, School of Chemical Engineering & Technology, Tianjin University, Tianjin 300350, China
- Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
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Huang X, Liu Y, Wang Y, Bailey C, Zheng P, Liu Y. Dual Targeting Oncoproteins MYC and HIF1α Regresses Tumor Growth of Lung Cancer and Lymphoma. Cancers (Basel) 2021; 13:cancers13040694. [PMID: 33572152 PMCID: PMC7914643 DOI: 10.3390/cancers13040694] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/03/2021] [Accepted: 02/05/2021] [Indexed: 12/11/2022] Open
Abstract
MYC and HIF1α are among the most important oncoproteins whose pharmacologic inhibition has been challenging for the diverse mechanisms driving their abnormal expression and because of the challenge in blocking protein-DNA interactions. Surprisingly, we found that MYC and HIF1α proteins in echinomycin-treated cells were degraded through proteasome dependent pathways, respectively by the β-TrCP- or VHL-dependent mechanisms. The degradation is induced in a variety of cancer types, including those with mutations in the p53 tumor and LKB tumor suppressors and the KRAS oncogene. Consistent with inhibition of MYC and HIF1α, administration of echinomycin inhibited growth of lung adenocarcinoma xenograft and a syngeneic lymphoma model in mice. Furthermore, echinomycin efficiently induced regression of syngeneic mouse lymphoma driven by MYC over-expression. Our data demonstrated a new mechanism by which echinomycin simultaneously targets MYC and HIF1α for degradation to inhibit growth of lung cancer and lymphoma. Given the broad impact of β-TrCP or VHL in stability of oncogenic proteins, echinomycin may emerge as a non-PROTAC (proteolysis targeting chimera) degrader of oncogenic proteins.
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Affiliation(s)
- Xiaohu Huang
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Correspondence: (X.H.); (Y.L.)
| | - Yan Liu
- Division of Immunotherapy, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USA; (Y.L.); (Y.W.); (C.B.); (P.Z.)
| | - Yin Wang
- Division of Immunotherapy, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USA; (Y.L.); (Y.W.); (C.B.); (P.Z.)
| | - Christopher Bailey
- Division of Immunotherapy, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USA; (Y.L.); (Y.W.); (C.B.); (P.Z.)
| | - Pan Zheng
- Division of Immunotherapy, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USA; (Y.L.); (Y.W.); (C.B.); (P.Z.)
- Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USA
- OncoImmune, Inc., Rockville, MD 20850, USA
| | - Yang Liu
- Division of Immunotherapy, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USA; (Y.L.); (Y.W.); (C.B.); (P.Z.)
- Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USA
- OncoImmune, Inc., Rockville, MD 20850, USA
- Correspondence: (X.H.); (Y.L.)
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Stellate Cells Aid Growth-Permissive Metabolic Reprogramming and Promote Gemcitabine Chemoresistance in Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13040601. [PMID: 33546284 PMCID: PMC7913350 DOI: 10.3390/cancers13040601] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/04/2021] [Accepted: 01/29/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary The great majority, more than 90%, of patients with pancreatic ductal adenocarcinoma (PDAC) die within less than five years after detection of the disease, despite recent treatment advances. The poor prognosis is related to late diagnosis, aggressive disease progression, and tumor resistance to conventional chemotherapy. PDAC tumor tissue is characterized by dense fibrosis and poor nutrient availability. A large portion of the tumor is made up of stromal fibroblasts, the pancreatic stellate cells (PSCs), which are known to contribute to tumor progression in several ways. PSCs have been shown to act as an alternate energy source, induce drug resistance, and inhibit drug availability in tumor cells, however, the underlying exact molecular mechanisms remain unknown. In this literature review, we discuss recent available knowledge about the contributions of PSCs to the overall progression of PDAC via changes in tumor metabolism and how this is linked to therapy resistance. Abstract Pancreatic ductal adenocarcinoma (PDAC), also known as pancreatic cancer (PC), is characterized by an overall poor prognosis and a five-year survival that is less than 10%. Characteristic features of the tumor are the presence of a prominent desmoplastic stromal response, an altered metabolism, and profound resistance to cancer drugs including gemcitabine, the backbone of PDAC chemotherapy. The pancreatic stellate cells (PSCs) constitute the major cellular component of PDAC stroma. PSCs are essential for extracellular matrix assembly and form a supportive niche for tumor growth. Various cytokines and growth factors induce activation of PSCs through autocrine and paracrine mechanisms, which in turn promote overall tumor growth and metastasis and induce chemoresistance. To maintain growth and survival in the nutrient-poor, hypoxic environment of PDAC, tumor cells fulfill their high energy demands via several unconventional ways, a process generally referred to as metabolic reprogramming. Accumulating evidence indicates that activated PSCs not only contribute to the therapy-resistant phenotype of PDAC but also act as a nutrient supplier for the tumor cells. However, the precise molecular links between metabolic reprogramming and an acquired therapy resistance in PDAC remain elusive. This review highlights recent findings indicating the importance of PSCs in aiding growth-permissive metabolic reprogramming and gemcitabine chemoresistance in PDAC.
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Abstract
Background: Early diagnosis in pancreatic cancer is key for improving prognosis. Hypoxia plays a critical role in tumor progression. Thus, an evaluation of associations between pancreatic tumor progression and markers of hypoxia is needed. Methods: We assessed the expression of hypoxia-inducible factors (HIF-1α and HIF-2α) by immuno-histochemical staining from 29 subjects with the following: pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), neuroendocrine tumor (NET), and pancreatic ductal adenocarcinoma (PDAC) and compared it to the expression in non-tumor samples. Results: Expression of HIF-1α increased significantly from PanIN (3.01 ± 0.17) to IPMN (7.63 ± 0.18), NET (9.10 ± 0.23) and PDAC samples (11.06 ± 0.15, p < 0.0001). Similar findings were observed for HIF-2α (p < 0.0001)}. A strong correlation between HIF-1α and HIF-2α expression was demonstrated (R2 = 0.8408, p < 0.0001). Conclusions: This data suggest that HIF-1α and HIF-2α may play a role in the progression from PanIN through PDAC. Further studies are necessary to confirm these findings and determine the effect of HIFs abrogation on tumor progression that can lead to novel therapies.
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Shah VM, Sheppard BC, Sears RC, Alani AW. Hypoxia: Friend or Foe for drug delivery in Pancreatic Cancer. Cancer Lett 2020; 492:63-70. [PMID: 32822815 DOI: 10.1016/j.canlet.2020.07.041] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/24/2020] [Accepted: 07/30/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid tumors with an overall five-year survival rate of that has only just reached 10%. The tumor microenvironment of PDAC is characterized by desmoplasia, which consist of dense stroma of fibroblasts and inflammatory cells, resulting in a hypoxic environment due to limited oxygen diffusion through the tumor. Hypoxia contributes to the aggressive tumor biology by promoting tumor progression, malignancy, and promoting resistance to conventional and targeted therapeutic agents. In depth research in the area has identified that hypoxia modulates the tumor biology through hypoxia inducible factors (HIFs), which not only are the key determinant of pancreatic malignancy but also an important target for therapy. In this review, we summarize the recent advances in understanding hypoxia driven phenotypes, which are responsible for the highly aggressive and metastatic characteristics of pancreatic cancer, and how hypoxia can be exploited as a target for drug delivery.
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Affiliation(s)
- Vidhi M Shah
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University/OHSU, 2730 SW Moody Ave., Portland, OR, 97201, USA; Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 S. W. Sam Jackson Park Rd., Portland, OR, 97239, USA
| | - Brett C Sheppard
- Department of Surgery, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 S.W Sam Jackson Park Road, Portland, OR, 97239, USA; OHSU Knight Cancer Institute at Oregon Health & Science University, Portland, OR, 97239, USA
| | - Rosalie C Sears
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 S.W Sam Jackson Park Road, Portland, OR, 97239, USA; Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 S. W. Sam Jackson Park Rd., Portland, OR, 97239, USA; OHSU Knight Cancer Institute at Oregon Health & Science University, Portland, OR, 97239, USA
| | - Adam Wg Alani
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University/OHSU, 2730 SW Moody Ave., Portland, OR, 97201, USA; OHSU Knight Cancer Institute at Oregon Health & Science University, Portland, OR, 97239, USA; Department of Biomedical Engineering, School of Medicine at Oregon Health & Science University, Portland, OR, 97239, USA.
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Guan JT, Li XX, Peng DW, Zhang WM, Qu J, Lu F, D'Amato RJ, Chi ZL. MicroRNA-18a-5p Administration Suppresses Retinal Neovascularization by Targeting FGF1 and HIF1A. Front Pharmacol 2020; 11:276. [PMID: 32210827 PMCID: PMC7076186 DOI: 10.3389/fphar.2020.00276] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 02/26/2020] [Indexed: 12/17/2022] Open
Abstract
Pathologic ocular neovascularization commonly results in visual impairment or even blindness in numerous fundus diseases, including proliferative diabetic retinopathy (PDR), retinopathy of prematurity (ROP), and age-related macular degeneration (AMD). MicroRNAs regulate angiogenesis through modulating target genes and disease progression, making them a new class of targets for drug discovery. In this study, we investigated the potential role of miR-18a-5p in retinal neovascularization using a mouse model of oxygen-induced proliferative retinopathy (OIR). We found that miR-18a-5p was highly expressed in the retina of pups as well as retinal endothelial cells, and was consistently down-regulated during retinal development. On the other hand, miR-18a-5p was increased significantly during pathologic neovascularization in the retinas of OIR mice. Moreover, intravitreal administration of miRNA mimic, agomiR-18a-5p, significantly suppressed retinal neovascularization in OIR models. Accordingly, agomir-18a-5p markedly suppressed human retinal microvascular endothelial cell (HRMEC) function including proliferation, migration, and tube formation ability. Additionally, we demonstrated that miR-18a-5p directly down-regulated known vascular growth factors, fibroblast growth factor 1 (FGF1) and hypoxia-inducible factor 1-alpha (HIF1A), as the target genes. In conclusion, miR-18a-5p may be a useful drug target for pathologic ocular neovascularization.
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Affiliation(s)
- Ji-Tian Guan
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xin-Xin Li
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China
| | - De-Wei Peng
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wen-Meng Zhang
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jia Qu
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fan Lu
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China.,International Joint Research Center for Regenerative Medicine and Neurogenetics, Wenzhou Medical University, Wenzhou, China
| | - Robert J D'Amato
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Boston, MA, United States.,Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
| | - Zai-Long Chi
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China.,International Joint Research Center for Regenerative Medicine and Neurogenetics, Wenzhou Medical University, Wenzhou, China
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Wu LF, Xu GP, Zhao Q, Zhou LJ, Wang D, Chen WX. The association between hypoxia inducible factor 1 subunit alpha gene rs2057482 polymorphism and cancer risk: a meta-analysis. BMC Cancer 2019; 19:1123. [PMID: 31744467 PMCID: PMC6862742 DOI: 10.1186/s12885-019-6329-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023] Open
Abstract
Background The rs2057482 polymorphism in the hypoxia inducible factor 1 subunit alpha (HIF1A) gene has been reported to be associated with a risk of several types of cancer, but this association has not yet been definitively confirmed. We performed this meta-analysis to determine whether rs2057482 is associated with overall cancer risk. Methods The PubMed, Embase, and Web of Science databases were searched for the potential studies about the association between the rs2057482 and cancer risk. The data of genotype frequencies in cases with cancer and controls were extracted from the selected studies. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated to determine the strength of the associations. Results The meta-analysis showed an association between the rs2057482 polymorphism and overall cancer risk. However, a stratified analysis of ethnicity did not show any significant association between rs2057482 and cancer risk in the Asian population. Conclusions The rs2057482 polymorphism was associated with decreased overall cancer risk, based on the currently available studies. However, this conclusion needs verification by further well-designed epidemiology studies that examine different cancer types and more subjects.
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Affiliation(s)
- Li-Fang Wu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Gui-Ping Xu
- Transfusion Department, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qing Zhao
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Li-Jing Zhou
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Ding Wang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Wei-Xian Chen
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
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Mok L, Kim Y, Lee S, Choi S, Lee S, Jang JY, Park T. HisCoM-PAGE: Hierarchical Structural Component Models for Pathway Analysis of Gene Expression Data. Genes (Basel) 2019; 10:E931. [PMID: 31739607 PMCID: PMC6896173 DOI: 10.3390/genes10110931] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/06/2019] [Accepted: 11/07/2019] [Indexed: 01/10/2023] Open
Abstract
Although there have been several analyses for identifying cancer-associated pathways, based on gene expression data, most of these are based on single pathway analyses, and thus do not consider correlations between pathways. In this paper, we propose a hierarchical structural component model for pathway analysis of gene expression data (HisCoM-PAGE), which accounts for the hierarchical structure of genes and pathways, as well as the correlations among pathways. Specifically, HisCoM-PAGE focuses on the survival phenotype and identifies its associated pathways. Moreover, its application to real biological data analysis of pancreatic cancer data demonstrated that HisCoM-PAGE could successfully identify pathways associated with pancreatic cancer prognosis. Simulation studies comparing the performance of HisCoM-PAGE with other competing methods such as Gene Set Enrichment Analysis (GSEA), Global Test, and Wald-type Test showed HisCoM-PAGE to have the highest power to detect causal pathways in most simulation scenarios.
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Affiliation(s)
- Lydia Mok
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, Korea
| | - Yongkang Kim
- Department of Statistics, Seoul National University, Seoul 08826, Korea
| | - Sungyoung Lee
- Center for Precision Medicine, Seoul National University Hospital, Seoul 03080, Korea
| | - Sungkyoung Choi
- Department of Applied Mathematics, Hanyang University (ERICA), Ansan 15588, Korea
| | - Seungyeoun Lee
- Department of Mathematics and Statistics, Sejong University, Seoul 05006, Korea
| | - Jin-Young Jang
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Taesung Park
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, Korea
- Department of Statistics, Seoul National University, Seoul 08826, Korea
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Jing X, Yang F, Shao C, Wei K, Xie M, Shen H, Shu Y. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer 2019; 18:157. [PMID: 31711497 PMCID: PMC6844052 DOI: 10.1186/s12943-019-1089-9] [Citation(s) in RCA: 1239] [Impact Index Per Article: 206.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 10/18/2019] [Indexed: 02/06/2023] Open
Abstract
AIM Clinical resistance is a complex phenomenon in major human cancers involving multifactorial mechanisms, and hypoxia is one of the key components that affect the cellular expression program and lead to therapy resistance. The present study aimed to summarize the role of hypoxia in cancer therapy by regulating the tumor microenvironment (TME) and to highlight the potential of hypoxia-targeted therapy. METHODS Relevant published studies were retrieved from PubMed, Web of Science, and Embase using keywords such as hypoxia, cancer therapy, resistance, TME, cancer, apoptosis, DNA damage, autophagy, p53, and other similar terms. RESULTS Recent studies have shown that hypoxia is associated with poor prognosis in patients by regulating the TME. It confers resistance to conventional therapies through a number of signaling pathways in apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux. CONCLUSION Hypoxia targeting might be relevant to overcome hypoxia-associated resistance in cancer treatment.
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Affiliation(s)
- Xinming Jing
- Department of Oncology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China.,Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fengming Yang
- Department of Oncology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China.,Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chuchu Shao
- Department of Oncology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China.,Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ke Wei
- Department of Thoracic surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mengyan Xie
- Department of Oncology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China.,Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hua Shen
- Department of Oncology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China. .,Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Yongqian Shu
- Department of Oncology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China. .,Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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31
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Maruggi M, Layng FI, Lemos R, Garcia G, James BP, Sevilla M, Soldevilla F, Baaten BJ, de Jong PR, Koh MY, Powis G. Absence of HIF1A Leads to Glycogen Accumulation and an Inflammatory Response That Enables Pancreatic Tumor Growth. Cancer Res 2019; 79:5839-5848. [PMID: 31585939 DOI: 10.1158/0008-5472.can-18-2994] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 05/15/2019] [Accepted: 09/25/2019] [Indexed: 12/20/2022]
Abstract
Cancer cells respond to hypoxia by upregulating the hypoxia-inducible factor 1α (HIF1A) transcription factor, which drives survival mechanisms that include metabolic adaptation and induction of angiogenesis by VEGF. Pancreatic tumors are poorly vascularized and severely hypoxic. To study the angiogenic role of HIF1A, and specifically probe whether tumors are able to use alternative pathways in its absence, we created a xenograft mouse tumor model of pancreatic cancer lacking HIF1A. After an initial delay of about 30 days, the HIF1A-deficient tumors grew as rapidly as the wild-type tumors and had similar vascularization. These changes were maintained in subsequent passages of tumor xenografts in vivo and in cell lines ex vivo. There were many cancer cells with a "clear-cell" phenotype in the HIF1A-deficient tumors; this was the result of accumulation of glycogen. Single-cell RNA sequencing (scRNA-seq) of the tumors identified hypoxic cancer cells with inhibited glycogen breakdown, which promoted glycogen accumulation and the secretion of inflammatory cytokines, including interleukins 1β (IL1B) and 8 (IL8). scRNA-seq of the mouse tumor stroma showed enrichment of two subsets of myeloid dendritic cells (cDC), cDC1 and cDC2, that secreted proangiogenic cytokines. These results suggest that glycogen accumulation associated with a clear-cell phenotype in hypoxic cancer cells lacking HIF1A can initiate an alternate pathway of cytokine and DC-driven angiogenesis. Inhibiting glycogen accumulation may provide a treatment for cancers with the clear-cell phenotype. SIGNIFICANCE: These findings establish a novel mechanism by which tumors support angiogenesis in an HIF1α-independent manner.
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Affiliation(s)
- Marco Maruggi
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Fabiana Izidro Layng
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Robert Lemos
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Guillermina Garcia
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Brian P James
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Monica Sevilla
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Ferran Soldevilla
- Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Bas J Baaten
- Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Petrus R de Jong
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California
| | - Mei Yee Koh
- Department of Pharmacology, University of Utah, Salt Lake City, Utah
| | - Garth Powis
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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32
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Patton MC, Zubair H, Khan MA, Singh S, Singh AP. Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival. J Cell Biochem 2019; 121:828-839. [PMID: 31407387 DOI: 10.1002/jcb.29328] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 07/15/2019] [Indexed: 12/17/2022]
Abstract
Pancreatic tumors are highly desmoplastic and poorly-vascularized, and therefore must develop adaptive mechanisms to sustain their survival under hypoxic condition. Extracellular vesicles (EV) play vital roles in pancreatic tumor pathobiology by facilitating intercellular communication. Here we studied the effect of hypoxia on the release of EVs and examined their role in adaptive survival of pancreatic cancer (PC) cells. Hypoxia promoted the release of EV in PC cell lines, MiaPaCa and AsPC1, wherein former exhibited a far greater induction. Moreover, a time-dependent, measurable and significant increase was recorded for small EV (SEV) in both the cell lines with only minimal induction observed for medium (MEV) and large EVs (LEV). Similarly, noticeable changes in size distribution of SEV were also recorded with a shift toward smaller average size under extreme hypoxia. Thrombospondin (apoptotic bodies marker) was exclusively detected on LEVs, while Arf6 (microvesicles marker) was mostly present on MEV with some expression in LEV as well. However, CD9 and CD63 (exosome markers) were expressed in both SEV and MEVs with a decreased expression recorded under hypoxia. Among all subfractions, SEV was the most bioactive in promoting the survival of hypoxic PC cells and hypoxia-inducible factor-1α stabilization was involved in heightened EV release under hypoxia and for their potency to promote hypoxic cell survival. Altogether, our findings provide a novel mechanism for the adaptive hypoxic survival of PC cells and should serve as the basis for future investigations on broader functional implications of EV.
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Affiliation(s)
- Mary C Patton
- Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama
| | - Haseeb Zubair
- Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama
| | - Mohammad Aslam Khan
- Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama
| | - Seema Singh
- Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama
| | - Ajay P Singh
- Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama
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Adamska A, Domenichini A, Capone E, Damiani V, Akkaya BG, Linton KJ, Di Sebastiano P, Chen X, Keeton AB, Ramirez-Alcantara V, Maxuitenko Y, Piazza GA, De Laurenzi V, Sala G, Falasca M. Pharmacological inhibition of ABCC3 slows tumour progression in animal models of pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:312. [PMID: 31378204 PMCID: PMC6681491 DOI: 10.1186/s13046-019-1308-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 07/02/2019] [Indexed: 12/20/2022]
Abstract
Background Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive and lethal disease, lacking effective therapeutic approaches. Available therapies only marginally prolong patient survival and are frequently coupled with severe adverse events. It is therefore pivotal to investigate novel and safe pharmacological approaches. We have recently identified the ABC transporter, ABCC3, whose expression is dependent on mutation of TP53, as a novel target in PDAC. ABCC3-mediated regulation of PDAC cell proliferation and tumour growth in vivo was demonstrated and was shown to be conferred by upregulation of STAT3 signalling and regulation of apoptosis. Methods To verify the potential of ABCC3 as a pharmacological target, a small molecule inhibitor of ABCC3, referred to here as MCI-715, was designed. In vitro assays were performed to assess the effects of ABCC3 inhibition on anchorage-dependent and anchorage-independent PDAC cell growth. The impact of ABCC3 inhibition on specific signalling pathways was verified by Western blotting. The potential of targeting ABCC3 with MCI-715 to counteract PDAC progression was additionally tested in several animal models of PDAC, including xenograft mouse models and transgenic mouse model of PDAC. Results Using both mouse models and human cell lines of PDAC, we show that the pharmacological inhibition of ABCC3 significantly decreased PDAC cell proliferation and clonal expansion in vitro and in vivo, remarkably slowing tumour growth in mice xenografts and patient-derived xenografts and increasing the survival rate in a transgenic mouse model. Furthermore, we show that stromal cells in pancreatic tumours, which actively participate in PDAC progression, are enriched for ABCC3, and that its inhibition may contribute to stroma reprogramming. Conclusions Our results indicate that ABCC3 inhibition with MCI-715 demonstrated strong antitumor activity and is well tolerated, which leads us to conclude that ABCC3 inhibition is a novel and promising therapeutic strategy for a considerable cohort of patients with pancreatic cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1308-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Aleksandra Adamska
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia
| | - Alice Domenichini
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia
| | - Emily Capone
- Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, 66100, Chieti, Italy
| | - Verena Damiani
- Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, 66100, Chieti, Italy
| | - Begum Gokcen Akkaya
- Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, Newark Street, London, E1 2AT, UK
| | - Kenneth J Linton
- Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, Newark Street, London, E1 2AT, UK
| | - Pierluigi Di Sebastiano
- Department of Surgery, Unit of Surgical Oncology, SS. Annunziata Hospital, G. D'Annunzio University, I-66100, Chieti, Italy
| | - Xi Chen
- Drug Discovery Research Center, USA Health Mitchell Cancer Institute, Mobile, AL, USA
| | - Adam B Keeton
- Drug Discovery Research Center, USA Health Mitchell Cancer Institute, Mobile, AL, USA
| | | | - Yulia Maxuitenko
- Drug Discovery Research Center, USA Health Mitchell Cancer Institute, Mobile, AL, USA
| | - Gary A Piazza
- Drug Discovery Research Center, USA Health Mitchell Cancer Institute, Mobile, AL, USA
| | - Vincenzo De Laurenzi
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia.,Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, 66100, Chieti, Italy
| | - Gianluca Sala
- Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, 66100, Chieti, Italy
| | - Marco Falasca
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, 6102, Australia. .,Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, Newark Street, London, E1 2AT, UK.
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ABCC3 is a novel target for the treatment of pancreatic cancer. Adv Biol Regul 2019; 73:100634. [PMID: 31053501 DOI: 10.1016/j.jbior.2019.04.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 04/23/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023]
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a very aggressive disease, lacking effective therapeutic approaches and leaving PDAC patients with a poor prognosis. The life expectancy of PDAC patients has not experienced a significant change in the last few decades with a five-year survival rate of only 8%. To address this unmet need, novel pharmacological targets must be identified for clinical intervention. ATP Binding Cassette (ABC) transporters are frequently overexpressed in different cancer types and represent one of the major mechanisms responsible for chemoresistance. However, a more direct role for ABC transporters in tumorigenesis has not been widely investigated. Here, we show that ABCC3 (ABC Subfamily C Member 3; previously known as MRP3) is overexpressed in PDAC cell lines and also in clinical samples. We demonstrate that ABCC3 expression is regulated by mutant p53 via miR-34 and that the transporter drives PDAC progression via transport of the bioactive lipid lysophosphatidylinositol (LPI). Disruption of ABCC3 function either by genetic knockdown reduces pancreatic cancer cell growth in vitro and in vivo. Mechanistically, we demonstrate that knockdown of ABCC3 reduce cell proliferation by inhibition of STAT3 and HIF1α signalling pathways, previously been shown to be key regulators of PDAC progression. Collectively, our results identify ABCC3 as a novel and promising target in PDAC therapy.
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35
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Hashimoto Y, Ishida M, Ryota H, Yamamoto T, Kosaka H, Hirooka S, Yamaki S, Kotsuka M, Matsui Y, Yanagimoto H, Tsuta K, Satoi S. Adipophilin expression is an indicator of poor prognosis in patients with pancreatic ductal adenocarcinoma: An immunohistochemical analysis. Pancreatology 2019; 19:443-448. [PMID: 30879968 DOI: 10.1016/j.pan.2019.03.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 02/21/2019] [Accepted: 03/06/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Adipophilin is a lipid droplet-associated protein, and its expression has been correlated with aggressive clinical behavior in some types of carcinomas, though its role in pancreatic ductal adenocarcinoma (PDAC) has not been clarified. This study aimed to evaluate the role of adipophilin in PDAC. METHODS By immunohistochemical staining using tissue microarrays, we analyzed the expression profiles of adipophilin in 181 consecutive PDAC patients who underwent macroscopic margin-negative resection from January 2008 to December 2015. Overall survival (OS) and recurrence-free survival (RFS) were compared based on adipophilin expression, and the risk factors for OS, RFS, and early recurrence (within 6 months) were analyzed. RESULTS Of the 181 evaluated patients, 51 (28.2%) were positive for adipophilin expression. A histopathological grade of 3 (p = 0.0012), higher CA19-9 level (p = 0.0016), and R1 status (p = 0.028) were significantly associated with adipophilin-positive patients who had significantly poor OS and RFS compared to those associated with adipophilin-negative patients (p = 0.0007 and p = 0.0022, respectively). They also showed a significantly higher incidence of early recurrence (p = 0.030), based on multivariate analyses. CONCLUSIONS Adipophilin is a potential independent prognostic marker for PDAC.
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Affiliation(s)
- Yuki Hashimoto
- Department of Surgery, Kansai Medical University, Osaka, Japan
| | - Mitsuaki Ishida
- Department of Pathology and Clinical Laboratory, Kansai Medical University, Osaka, Japan.
| | - Hironori Ryota
- Department of Surgery, Kansai Medical University, Osaka, Japan
| | | | - Hisashi Kosaka
- Department of Surgery, Kansai Medical University, Osaka, Japan
| | - Satoshi Hirooka
- Department of Surgery, Kansai Medical University, Osaka, Japan
| | - So Yamaki
- Department of Surgery, Kansai Medical University, Osaka, Japan
| | - Masaya Kotsuka
- Department of Surgery, Kansai Medical University, Osaka, Japan
| | - Yoichi Matsui
- Department of Surgery, Kansai Medical University, Osaka, Japan
| | | | - Koji Tsuta
- Department of Pathology and Clinical Laboratory, Kansai Medical University, Osaka, Japan
| | - Sohei Satoi
- Department of Surgery, Kansai Medical University, Osaka, Japan
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Salinas-Vera YM, Marchat LA, Gallardo-Rincón D, Ruiz-García E, Astudillo-De La Vega H, Echavarría-Zepeda R, López-Camarillo C. AngiomiRs: MicroRNAs driving angiogenesis in cancer (Review). Int J Mol Med 2019; 43:657-670. [PMID: 30483765 DOI: 10.3892/ijmm.2018.4003] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 10/22/2018] [Indexed: 01/13/2023] Open
Abstract
Angiogenesis is an important hallmark of cancer serving a key role in tumor growth and metastasis. Therefore, tumor angiogenesis has become an attractive target for development of novel drug therapies. An increased amount of anti‑angiogenic compounds is currently in preclinical and clinical development for personalized therapies. However, resistance to current angiogenesis inhibitors is emerging, indicating that there is a need to identify novel anti‑angiogenic agents. In the last decade, the field of microRNA biology has exploded revealing unsuspected functions in tumor angiogenesis. These small non‑coding RNAs, which have been dubbed as angiomiRs, may target regulatory molecules driving angiogenesis, such as cytokines, metalloproteinases and growth factors, including vascular endothelial growth factor, platelet‑derived growth factor, fibroblast growth factor, epidermal growth factor, hypoxia inducible factor‑1, as well as mitogen‑activated protein kinase, phosphoinositide 3‑kinase and transforming growth factor signaling pathways. The present review discusses the current progress towards understanding the functions of miRNAs in tumor angiogenesis regulation in diverse types of human cancer. Furthermore, the potential clinical application of angiomiRs towards anti‑angiogenic tumor therapy was explored.
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Affiliation(s)
- Yarely M Salinas-Vera
- Posgrado en Ciencias Genomicas, Universidad Autonoma de la Ciudad de Mexico, Ciudad de Mexico 03100, Mexico
| | - Laurence A Marchat
- Programa en Biomedicina Molecular y Red de Biotecnologia, Instituto Politecnico Nacional, Ciudad de Mexico 07320, Mexico
| | - Dolores Gallardo-Rincón
- Laboratorio de Medicina Translacional, Instituto Nacional de Cancerología, Ciudad de Mexico 14080, Mexico
| | - Erika Ruiz-García
- Laboratorio de Medicina Translacional, Instituto Nacional de Cancerología, Ciudad de Mexico 14080, Mexico
| | - Horacio Astudillo-De La Vega
- Laboratorio de Investigacion Translacional en Cáncer y Terapia Celular, Hospital de Oncologia, Centro Médico Nacional Siglo XXI, Ciudad de Mexico 06720, Mexico
| | | | - César López-Camarillo
- Posgrado en Ciencias Genomicas, Universidad Autonoma de la Ciudad de Mexico, Ciudad de Mexico 03100, Mexico
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Chen BB, Tien YW, Chang MC, Cheng MF, Chang YT, Yang SH, Wu CH, Kuo TC, Shih IL, Yen RF, Shih TTF. Multiparametric PET/MR imaging biomarkers are associated with overall survival in patients with pancreatic cancer. Eur J Nucl Med Mol Imaging 2018; 45:1205-1217. [PMID: 29476229 DOI: 10.1007/s00259-018-3960-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 01/22/2018] [Indexed: 12/11/2022]
Abstract
PURPOSE To correlate the overall survival (OS) with the imaging biomarkers of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), diffusion-weighted imaging (DWI), magnetic resonance spectroscopy, and glucose metabolic activity derived from integrated fluorine 18 fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI in patients with pancreatic cancer. METHODS This prospective study was approved by the institutional review board and informed consent was obtained from all participants. Sixty-three consecutive patients (mean age, 62.7 ± 12 y; men/women, 40/23) with pancreatic cancer underwent PET/MRI before treatment. The imaging biomarkers were comprised of DCE-MRI parameters (peak, IAUC 60 , K trans , k ep , v e ), the minimum apparent diffusion coefficient (ADCmin), choline level, standardized uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) of the tumors. The relationships between these imaging biomarkers with OS were evaluated with the Kaplan-Meier and Cox proportional hazard models. RESULTS Seventeen (27%) patients received curative surgery, with the median follow-up duration being 638 days. Univariate analysis showed that patients at a low TNM stage (≦3, P = 0.041), high peak (P = 0.006), high ADCmin (P = 0.002) and low TLG (P = 0.01) had better OS. Moreover, high TLG/peak ratio was associated with poor OS (P = 0.016). Multivariate analysis indicated that ADCmin (P = 0.011) and TLG/peak ratio (P = 0.006) were independent predictors of OS after adjustment for age, gender, tumor size, and TNM stage. The TLG/peak ratio was an independent predictor of OS in a subgroup of patients who did not receive curative surgery (P = 0.013). CONCLUSION The flow-metabolism mismatch reflected by the TLG/peak ratio may better predict OS than other imaging biomarkers from PET/MRI in pancreatic cancer patients.
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Affiliation(s)
- Bang-Bin Chen
- Department of Medical Imaging and Radiology, National Taiwan University College of Medicine and Hospital, No 7, Chung-Shan South Rd, Taipei, 10016, Taiwan
| | - Yu-Wen Tien
- Department of Surgery, National Taiwan University College of Medicine and Hospital, No 7, Chung-Shan South Rd, Taipei, 10016, Taiwan
| | - Ming-Chu Chang
- Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No 7, Chung-Shan South Rd, Taipei, 10016, Taiwan
| | - Mei-Fang Cheng
- Department of Nuclear Medicine and Radiology, National Taiwan University College of Medicine and Hospital, No 7, Chung-Shan South Rd, Taipei, 10016, Taiwan
| | - Yu-Ting Chang
- Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No 7, Chung-Shan South Rd, Taipei, 10016, Taiwan
| | - Shih-Hung Yang
- Department of Oncology, National Taiwan University College of Medicine and Hospital, No 7, Chung-Shan South Rd, Taipei, 10016, Taiwan
| | - Chih-Horng Wu
- Department of Medical Imaging and Radiology, National Taiwan University College of Medicine and Hospital, No 7, Chung-Shan South Rd, Taipei, 10016, Taiwan
| | - Ting-Chun Kuo
- Department of Surgery, National Taiwan University College of Medicine and Hospital, No 7, Chung-Shan South Rd, Taipei, 10016, Taiwan
| | - I-Lun Shih
- Department of Medical Imaging and Radiology, National Taiwan University College of Medicine and Hospital, No 7, Chung-Shan South Rd, Taipei, 10016, Taiwan
| | - Ruoh-Fang Yen
- Department of Nuclear Medicine and Radiology, National Taiwan University College of Medicine and Hospital, No 7, Chung-Shan South Rd, Taipei, 10016, Taiwan
| | - Tiffany Ting-Fang Shih
- Department of Medical Imaging and Radiology, National Taiwan University College of Medicine and Hospital, No 7, Chung-Shan South Rd, Taipei, 10016, Taiwan.
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Zhu S, Deng S, He C, Liu M, Chen H, Zeng Z, Zhong J, Ye Z, Deng S, Wu H, Wang C, Zhao G. Reciprocal loop of hypoxia-inducible factor-1α (HIF-1α) and metastasis-associated protein 2 (MTA2) contributes to the progression of pancreatic carcinoma by suppressing E-cadherin transcription. J Pathol 2018; 245:349-360. [PMID: 29708271 DOI: 10.1002/path.5089] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 03/17/2018] [Accepted: 04/20/2018] [Indexed: 12/15/2022]
Abstract
Metastasis-associated protein 2 (MTA2) is overexpressed in certain malignancies, and plays important roles in tumour metastasis and progression. The present study highlights the function of MTA2 in pancreatic carcinoma through its role as a deacetylator of hypoxia-inducible factor-1α (HIF-1α) and a cotranscriptional factor for E-cadherin expression. We found that overexpression of MTA2 promoted, and knockdown of MTA2 inhibited, the invasion and proliferation of pancreatic carcinoma cells both in vitro and in xenograft models in vivo. We also found that MTA2 is transcriptionally upregulated by HIF-1α through a hypoxia response element (HRE) of the MTA2 promoter in response to hypoxia. Reciprocally, MTA2 deacetylates HIF-1α and enhances its stability through interacting with histone deacetylase 1 (HDAC1). Consequently, HIF-1α recruits MTA2 and HDAC1 to the HRE of the E-cadherin promoter, by which E-cadherin transcription is repressed. In agreement with these experimental results, MTA2 is positively associated with HIF-1α, but inversely correlated with E-cadherin, in pancreatic carcinoma samples. Moreover, data from The Cancer Genome Atlas on 172 pancreatic carcinomas indicate an association between high expression of MTA2 and short overall survival. Taken together, our study identifies MTA2 as a critical hub and potential therapeutic target to inhibit the progression and metastasis of pancreatic carcinoma. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Shuai Zhu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Shijiang Deng
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Chi He
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Mingliang Liu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Hengyu Chen
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Zhu Zeng
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Jianxin Zhong
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Zeng Ye
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Shichang Deng
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Chunyou Wang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Gang Zhao
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
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39
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Biancur DE, Kimmelman AC. The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance. Biochim Biophys Acta Rev Cancer 2018; 1870:67-75. [PMID: 29702208 DOI: 10.1016/j.bbcan.2018.04.011] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 04/20/2018] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer that is highly refractory to the current standards of care. The difficulty in treating this disease is due to a number of different factors, including altered metabolism. In PDA, the metabolic rewiring favors anabolic reactions which supply the cancer cell with necessary cellular building blocks for unconstrained growth. Furthermore, PDA cells display high levels of basal autophagy and macropinocytosis. KRAS is the driving oncogene in PDA and many of the metabolic changes are downstream of its activation. Together, these unique pathways for nutrient utilization and acquisition result in metabolic plasticity enabling cells to rapidly adapt to nutrient and oxygen fluctuations. This remarkable adaptability has been implicated as a cause of the intense therapeutic resistance. In this review, we discuss metabolic pathways in PDA tumors and highlight how they contribute to the pathogenesis and treatment of the disease.
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Affiliation(s)
- Douglas E Biancur
- Perlmutter Cancer Center, Department of Radiation Oncology, NYU Medical School, New York 10016, NY, United States
| | - Alec C Kimmelman
- Perlmutter Cancer Center, Department of Radiation Oncology, NYU Medical School, New York 10016, NY, United States.
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40
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Jones RB, Dorsett KA, Hjelmeland AB, Bellis SL. The ST6Gal-I sialyltransferase protects tumor cells against hypoxia by enhancing HIF-1α signaling. J Biol Chem 2018; 293:5659-5667. [PMID: 29475939 PMCID: PMC5900773 DOI: 10.1074/jbc.ra117.001194] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 02/15/2018] [Indexed: 02/05/2023] Open
Abstract
Aberrant cell surface glycosylation is prevalent in tumor cells, and there is ample evidence that glycans have functional roles in carcinogenesis. Nonetheless, many molecular details remain unclear. Tumor cells frequently exhibit increased α2-6 sialylation on N-glycans, a modification that is added by the ST6Gal-I sialyltransferase, and emerging evidence suggests that ST6Gal-I-mediated sialylation promotes the survival of tumor cells exposed to various cell stressors. Here we report that ST6Gal-I protects cancer cells from hypoxic stress. It is well known that hypoxia-inducible factor 1α (HIF-1α) is stabilized in hypoxic cells, and, in turn, HIF-1α directs the transcription of genes important for cell survival. To investigate a putative role for ST6Gal-I in the hypoxic response, we examined HIF-1α accumulation in ovarian and pancreatic cancer cells in ST6Gal-I overexpression or knockdown experiments. We found that ST6Gal-I activity augmented HIF-1α accumulation in cells grown in a hypoxic environment or treated with two chemical hypoxia mimetics, deferoxamine and dimethyloxalylglycine. Correspondingly, hypoxic cells with high ST6Gal-I expression had increased mRNA levels of HIF-1α transcriptional targets, including the glucose transporter genes GLUT1 and GLUT3 and the glycolytic enzyme gene PDHK1 Interestingly, high ST6Gal-I-expressing cells also had an increased pool of HIF-1α mRNA, suggesting that ST6Gal-I may influence HIF-1α expression. Finally, cells grown in hypoxia for several weeks displayed enriched ST6Gal-I expression, consistent with a pro-survival function. Taken together, these findings unravel a glycosylation-dependent mechanism that facilitates tumor cell adaptation to a hypoxic milieu.
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MESH Headings
- Antigens, CD/biosynthesis
- Antigens, CD/genetics
- Cell Line, Tumor
- Cell Survival/genetics
- Female
- Gene Expression Regulation, Enzymologic
- Gene Expression Regulation, Neoplastic
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Ovarian Neoplasms/genetics
- Ovarian Neoplasms/metabolism
- Ovarian Neoplasms/pathology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- RNA, Neoplasm/biosynthesis
- RNA, Neoplasm/genetics
- Sialyltransferases/biosynthesis
- Sialyltransferases/genetics
- Signal Transduction
- Tumor Hypoxia
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Affiliation(s)
- Robert B Jones
- From the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294
| | - Kaitlyn A Dorsett
- From the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294
| | - Anita B Hjelmeland
- From the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294
| | - Susan L Bellis
- From the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294
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41
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Bauer AS, Nazarov PV, Giese NA, Beghelli S, Heller A, Greenhalf W, Costello E, Muller A, Bier M, Strobel O, Hackert T, Vallar L, Scarpa A, Büchler MW, Neoptolemos JP, Kreis S, Hoheisel JD. Transcriptional variations in the wider peritumoral tissue environment of pancreatic cancer. Int J Cancer 2018; 142:1010-1021. [PMID: 28983920 PMCID: PMC5813190 DOI: 10.1002/ijc.31087] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 08/10/2017] [Accepted: 08/30/2017] [Indexed: 01/23/2023]
Abstract
Transcriptional profiling was performed on 452 RNA preparations isolated from various types of pancreatic tissue from tumour patients and healthy donors, with a particular focus on peritumoral samples. Pancreatic ductal adenocarcinomas (PDAC) and cystic tumours were most different in these non-tumorous tissues surrounding them, whereas the actual tumours exhibited rather similar transcript patterns. The environment of cystic tumours was transcriptionally nearly identical to normal pancreas tissue. In contrast, the tissue around PDAC behaved a lot like the tumour, indicating some kind of field defect, while showing far less molecular resemblance to both chronic pancreatitis and healthy tissue. This suggests that the major pathogenic difference between cystic and ductal tumours may be due to their cellular environment rather than the few variations between the tumours. Lack of correlation between DNA methylation and transcript levels makes it unlikely that the observed field defect in the peritumoral tissue of PDAC is controlled to a large extent by such epigenetic regulation. Functionally, a strikingly large number of autophagy-related transcripts was changed in both PDAC and its peritumoral tissue, but not in other pancreatic tumours. A transcription signature of 15 autophagy-related genes was established that permits a prognosis of survival with high accuracy and indicates the role of autophagy in tumour biology.
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Affiliation(s)
- Andrea S. Bauer
- Division of Functional Genome AnalysisGerman Cancer Research Centre (DKFZ)HeidelbergGermany
| | - Petr V. Nazarov
- Genomics and Proteomics Research Unit, Luxembourg Institute of HealthLuxembourg CityLuxembourg
| | - Nathalia A. Giese
- Department of General SurgeryUniversity Hospital HeidelbergHeidelbergGermany
| | - Stefania Beghelli
- Department of Pathology and DiagnosticsUniversità di VeronaVeronaItaly
| | - Anette Heller
- Department of General SurgeryUniversity Hospital HeidelbergHeidelbergGermany
| | - William Greenhalf
- National Institute for Health Research, Pancreas Biomedical Research Unit and the Liverpool Experimental Cancer Medicine CentreLiverpoolUnited Kingdom
| | - Eithne Costello
- National Institute for Health Research, Pancreas Biomedical Research Unit and the Liverpool Experimental Cancer Medicine CentreLiverpoolUnited Kingdom
| | - Arnaud Muller
- Genomics and Proteomics Research Unit, Luxembourg Institute of HealthLuxembourg CityLuxembourg
| | - Melanie Bier
- Division of Functional Genome AnalysisGerman Cancer Research Centre (DKFZ)HeidelbergGermany
| | - Oliver Strobel
- Department of General SurgeryUniversity Hospital HeidelbergHeidelbergGermany
| | - Thilo Hackert
- Department of General SurgeryUniversity Hospital HeidelbergHeidelbergGermany
| | - Laurent Vallar
- Genomics and Proteomics Research Unit, Luxembourg Institute of HealthLuxembourg CityLuxembourg
| | - Aldo Scarpa
- Department of Pathology and DiagnosticsUniversità di VeronaVeronaItaly
| | - Markus W. Büchler
- Department of General SurgeryUniversity Hospital HeidelbergHeidelbergGermany
| | - John P. Neoptolemos
- National Institute for Health Research, Pancreas Biomedical Research Unit and the Liverpool Experimental Cancer Medicine CentreLiverpoolUnited Kingdom
| | - Stephanie Kreis
- Life Sciences Research Unit, University of LuxembourgLuxembourg CityLuxembourg
| | - Jörg D. Hoheisel
- Division of Functional Genome AnalysisGerman Cancer Research Centre (DKFZ)HeidelbergGermany
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42
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Pharmacologic ascorbate (P-AscH -) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma. Clin Exp Metastasis 2018; 35:37-51. [PMID: 29396728 DOI: 10.1007/s10585-018-9876-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 01/31/2018] [Indexed: 12/24/2022]
Abstract
HIF-1α is a transcriptional regulator that functions in the adaptation of cells to hypoxic conditions; it strongly impacts the prognosis of patients with cancer. High-dose, intravenous, pharmacological ascorbate (P-AscH-), induces cytotoxicity and oxidative stress selectively in cancer cells by acting as a pro-drug for the delivery of hydrogen peroxide (H2O2); early clinical data suggest improved survival and inhibition of metastasis in patients being actively treated with P-AscH-. Previous studies have demonstrated that activation of HIF-1α is necessary for P-AscH- sensitivity. We hypothesized that pancreatic cancer (PDAC) progression and metastasis could be be targeted by P-AscH- via H2O2-mediated inhibition of HIF-1α stabilization. Our study demonstrates an oxygen- and prolyl hydroxylase-independent regulation of HIF-1α by P-AscH-. Additionally, P-AscH- decreased VEGF secretion in a dose-dependent manner that was reversible with catalase, consistent with an H2O2-mediated mechanism. Pharmacological and genetic manipulations of HIF-1α did not alter P-AscH--induced cytotoxicity. In vivo, P-AscH- inhibited tumor growth and VEGF expression. We conclude that P-AscH- suppresses the levels of HIF-1α protein in hypoxic conditions through a post-translational mechanism. These findings suggest potential new therapies specifically designed to inhibit the mechanisms that drive metastases as a part of PDAC treatment.
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43
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HIF-1 maintains a functional relationship between pancreatic cancer cells and stromal fibroblasts by upregulating expression and secretion of Sonic hedgehog. Oncotarget 2018. [PMID: 29535824 PMCID: PMC5828220 DOI: 10.18632/oncotarget.24156] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Hypoxic and stroma-rich microenvironments, characteristic features of pancreatic cancers, are strongly associated with a poor prognosis. However, whether and how hypoxia increases stromal compartments remain largely unknown. Here, we investigated the potential importance of a master regulator of the cellular adaptive response to hypoxia, hypoxia-inducible factor-1 (HIF-1), in the formation of stroma-rich microenvironments of pancreatic tumors. We found that pancreatic cancer cells secreted more Sonic hedgehog protein (SHH) under hypoxia by upregulating its expression and efficiency of secretion in a HIF-1-dependent manner. Recombinant SHH, which was confirmed to activate the hedgehog signaling pathway, accelerated the growth of fibroblasts in a dose-dependent manner. The SHH protein secreted from pancreatic cancer cells under hypoxic conditions promoted the growth of fibroblasts by stimulating their Sonic hedgehog signaling pathway. These results suggest that the increased secretion of SHH by HIF-1 is potentially responsible for the formation of detrimental and stroma-rich microenvironments in pancreatic cancers, therefore providing a rational basis to target it in cancer therapy.
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44
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Phanstiel O. An overview of polyamine metabolism in pancreatic ductal adenocarcinoma. Int J Cancer 2017; 142:1968-1976. [PMID: 29134652 DOI: 10.1002/ijc.31155] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 10/19/2017] [Accepted: 11/06/2017] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest major cancers, with a five year survival rate of less than 8%. With current therapies only giving rise to modest life extension, new approaches are desperately needed. Even though targeting polyamine metabolism is a proven anticancer strategy, there are no reports, which thoroughly survey the literature describing the role of polyamine biosynthesis and transport in PDAC. This review seeks to fill this void by describing what is currently known about polyamine metabolism in PDAC and identifies new targets and opportunities to treat this disease. Due to the pleiotropic effects that polyamines play in cells, this review covers diverse areas ranging from polyamine metabolism (biosynthesis, catabolism and transport), as well as the potential role of polyamines in desmoplasia, autophagy and immune privilege. Understanding these diverse roles provides the opportunity to design new therapies to treat this deadly cancer via polyamine depletion.
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Affiliation(s)
- Otto Phanstiel
- Department of Medical Education, College of Medicine, University of Central Florida, Orlando, FL
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45
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Lee J, Lee J, Yun JH, Choi C, Cho S, Kim SJ, Kim JH. Autocrine DUSP28 signaling mediates pancreatic cancer malignancy via regulation of PDGF-A. Sci Rep 2017; 7:12760. [PMID: 28986588 PMCID: PMC5630619 DOI: 10.1038/s41598-017-13023-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 09/15/2017] [Indexed: 01/17/2023] Open
Abstract
Pancreatic cancer remains one of the most deadly cancers with a grave prognosis. Despite continuous efforts to improve remedial values, limited progress has been made. We have reported that dual specificity phosphatase 28 (DUSP28) has a critical role of chemo-resistance and migration in pancreatic cancers. However, its mechanism remains unclear. Here, we further clarify the function of DUSP28 in pancreatic cancers. Analysis using a public microarray database and in vitro assay indicated a critical role of platelet derived growth factor A (PDGF-A) in pancreatic cancer malignancy. PDGF-A was positively regulated by DUSP28 expression at the mRNA and protein levels. Enhanced DUSP28 sensitized pancreatic cancer cells to exogenous PDGF-A treatment in migration, invasion, and proliferation. Transfection with siRNA targeting DUSP28 blunted the influence of administered PDGF-A by inhibition of phosphorylation of FAK, ERK1/2, and p38 signalling pathways. In addition, DUSP28 and PDGF-A formed an acquired autonomous autocrine-signaling pathway. Furthermore, targeting DUSP28 inhibited the tumor growth and migratory features through the blockade of PDGF-A expression and intracellular signaling in vivo. Our results establish novel insight into DUSP28 and PDGF-A related autonomous signaling pathway in pancreatic cancer.
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Affiliation(s)
- Jungwhoi Lee
- Department of biotechnology, College of Applied Life Science, SARI, Jeju National University, Jeju-do, 63243, Republic of Korea.
| | - Jungsul Lee
- Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, Republic of Korea
| | - Jeong Hun Yun
- Department of biotechnology, College of Applied Life Science, SARI, Jeju National University, Jeju-do, 63243, Republic of Korea
| | - Chulhee Choi
- Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, Republic of Korea
| | - Sayeon Cho
- College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Seung Jun Kim
- Division of Strategic Research Planning and Assessment, Korea Research Institute of Bioscience & Biotechnology, Daejeon, 34141, Republic of Korea
| | - Jae Hoon Kim
- Department of biotechnology, College of Applied Life Science, SARI, Jeju National University, Jeju-do, 63243, Republic of Korea.
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46
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Xia YJ, Jiang XT, Jiang SB, He XJ, Luo JG, Liu ZC, Wang L, Tao HQ, Chen JZ. PHD3 affects gastric cancer progression by negatively regulating HIF1A. Mol Med Rep 2017; 16:6882-6889. [PMID: 28901473 DOI: 10.3892/mmr.2017.7455] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 03/14/2017] [Indexed: 11/05/2022] Open
Abstract
Prolyl hydroxylase 3 (PHD3) is widely accepted as a tumor suppressor; however, the expression of PHD3 in various cancer types remains controversial. The present study aimed to investigate the association between PHD3 expression and the clinicopathological features of gastric cancer using reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry. The effects of PHD3 in gastric cancer cell lines were assessed using western blot analysis and transwell migration assays. The present results revealed that PHD3 expression was increased in adjacent non‑cancerous tissue compared with in gastric cancer tissue, and PHD3 overexpression was correlated with the presence of well‑differentiated cancer cells, early cancer stage classification and the absence of lymph node metastasis. In vitro experiments demonstrated that PHD3 may act as a negative regulator of hypoxia‑inducible factor‑1α and vascular endothelial growth factor, both of which participate in tumor angiogenesis. In conclusion, the present results suggested that PHD3 may act as a tumor suppressor in gastric cancer. Therefore, the targeted regulation of PHD3 may have potential as a novel therapeutic approach for the treatment of patients with gastric cancer.
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Affiliation(s)
- Ying-Jie Xia
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
| | - Xiao-Ting Jiang
- Key Laboratory of Gastroenterology of Zhejiang, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Shi-Bin Jiang
- Key Laboratory of Gastroenterology of Zhejiang, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Xu-Jun He
- Key Laboratory of Gastroenterology of Zhejiang, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Jun-Gang Luo
- Key Laboratory of Gastroenterology of Zhejiang, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Zheng-Chuang Liu
- Key Laboratory of Gastroenterology of Zhejiang, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Liang Wang
- Department of Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
| | - Hou-Quan Tao
- Key Laboratory of Gastroenterology of Zhejiang, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Jian-Zhong Chen
- Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
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47
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New M, Van Acker T, Long JS, Sakamaki JI, Ryan KM, Tooze SA. Molecular Pathways Controlling Autophagy in Pancreatic Cancer. Front Oncol 2017; 7:28. [PMID: 28316954 PMCID: PMC5334363 DOI: 10.3389/fonc.2017.00028] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 02/15/2017] [Indexed: 12/19/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancer types where the 5-year survival rate shows no improvement. Despite conflicting evidence, the majority of data points to an essential role for autophagy in PDAC growth and survival, in particular constitutively activated autophagy, can provide crucial fuel to PDAC tumor cells in their nutrient-deprived environment. Autophagy, which is required for cell homeostasis, can both suppress and promote tumorigenesis and tumor survival in a context-dependent manner. Protein by protein, the mystery of how PDAC abuses the cell's homeostasis system for its malignant growth has recently begun to be unraveled. In this review, we focus on how autophagy is responsible for growth and development of PDAC tumors and where autophagy and the mechanisms controlling it fit into PDAC metabolism. Understanding the range of pathways controlling autophagy and their interplay in PDAC could open the way for new therapeutic avenues.
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Affiliation(s)
- Maria New
- Molecular Cell Biology of Autophagy Laboratory, The Francis Crick Institute, London, UK
| | - Tim Van Acker
- Molecular Cell Biology of Autophagy Laboratory, The Francis Crick Institute, London, UK
| | - Jaclyn S. Long
- Tumour Cell Death Laboratory, Cancer Research UK Beatson Institute, Glasgow, UK
| | - Jun-ichi Sakamaki
- Tumour Cell Death Laboratory, Cancer Research UK Beatson Institute, Glasgow, UK
| | - Kevin M. Ryan
- Tumour Cell Death Laboratory, Cancer Research UK Beatson Institute, Glasgow, UK
| | - Sharon A. Tooze
- Molecular Cell Biology of Autophagy Laboratory, The Francis Crick Institute, London, UK
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48
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Zhang D, Lei J, Ma J, Chen X, Sheng L, Jiang Z, Nan L, Xu Q, Duan W, Wang Z, Li X, Wu Z, Wu E, Ma Q, Huo X. β2-adrenogenic signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1α. Oncotarget 2017; 7:17760-72. [PMID: 26497365 PMCID: PMC4951248 DOI: 10.18632/oncotarget.5677] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 10/06/2015] [Indexed: 12/20/2022] Open
Abstract
Cigarette smoking is a risk factor for pancreatic cancer. It is suggested that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, mediates the carcinogenic action of cigarette smoking by promoting cancer growth. In the present study, we show that smoking, HIF-1α expression and β2-adrenogenic receptor (β2-AR) expression are negatively correlated with the overall survival of pancreatic cancer patients. Moreover, HIF-1α expression and β2-AR expression are positively correlated with smoking status, different histological differentiation and among the tumor node metastasis (TNM) stages in pancreatic cancer patients. NNK increases HIF-1α expression in pancreatic cancer in vitro and in vivo. Furthermore, knockdown of HIF-1α and ICI118, 551 (a β2-AR selective antagonist) abrogates NNK-induced pancreatic cancer proliferation and invasion in vitro and inhibits NNK-induced pancreatic cancer growth in vivo. However, using CoCl2 (a HIF-1α stabilizing agent which decreases HIF-1α degradation under normoxia conditions) reverses ICI118, 551 induced effects under NNK exposure. Thus, our data indicate that β2-AR signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1α. Taken together, β2-AR signaling and HIF-1α may represent promising therapeutic targets for preventing smoking induced pancreatic cancer progression.
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Affiliation(s)
- Dong Zhang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Jianjun Lei
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Jiguang Ma
- Department of Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Xin Chen
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Liang Sheng
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Zhengdong Jiang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Ligang Nan
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Qinhong Xu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Wanxing Duan
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Xuqi Li
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Erxi Wu
- Department of Neurosurgery, Baylor Scott and White Health, Temple, TX, 76508, USA
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Xiongwei Huo
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
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Erkan M, Kurtoglu M, Kleeff J. The role of hypoxia in pancreatic cancer: a potential therapeutic target? Expert Rev Gastroenterol Hepatol 2016; 10:301-16. [PMID: 26560854 DOI: 10.1586/17474124.2016.1117386] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
One of the key factors that correlates with poor survival of patients with pancreatic cancer is the extent of hypoxic areas within the tumor tissue. The adaptation of pancreatic cancer cells to limited oxygen delivery promotes the induction of an invasive and treatment-resistant phenotype, triggering metastases at an early stage of tumor development, which resist in most cases adjuvant therapies following tumor resection. In this article, the authors summarize the evidence demonstrating the significance of hypoxia in pancreatic cancer pathogenesis and discuss the possible hypoxia-induced mechanisms underlying its aggressive nature. We then conclude with promising strategies that target hypoxia-adapted pancreatic cancer cells.
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Affiliation(s)
- Mert Erkan
- a Department of Surgery , Koç University School of Medicine , Istanbul , Turkey
| | - Metin Kurtoglu
- b Department of Oncology , Koç University School of Medicine , Istanbul , Turkey
| | - Jorg Kleeff
- c Department of Surgery , The Royal Liverpool and Broadgreen University Hospitals , Liverpool , UK.,d Department of General-, Visceral- and Pediatric Surgery , University Hospital Düsseldorf, Heinrich Heine University Düsseldorf , Düsseldorf , Germany
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Moschovis D, Bamias G, Delladetsima I. Mucins in neoplasms of pancreas, ampulla of Vater and biliary system. World J Gastrointest Oncol 2016; 8:725-734. [PMID: 27795812 PMCID: PMC5064050 DOI: 10.4251/wjgo.v8.i10.725] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 07/19/2016] [Accepted: 08/15/2016] [Indexed: 02/05/2023] Open
Abstract
Tumors of the pancreas, the ampulla of Vater, and the extrahepatic and intrahepatic bile ducts have significant histological similarities due to the common embryonic origin of the pancreatobiliary system. This obviates the need for discovery of biomarkers with diagnostic and prognostic value for these tumors. Mucins, especially MUC-1, -2, -4 and -5AC, are important candidates for developing into such reliable biomarkers. Increased expression of MUC1 occurs in pancreatic ductal adenocarcinomas and is associated with increased degrees of dysplasia in pancreatic intraepithelial neoplasia (PanIN). Positive expression of MUC2 in intraductal papillary mucinus neoplasms (IPMN) of the intestinal type indicates high potential progression to invasive carcinoma with de novo expression of MUC1, while absence of MUC2 expression in IPMNs of gastric type implies low potential to malignant evolution. De novo MUC4 expression correlates to the severity of dysplasia in PanIN and is associated with a poor prognosis in patients with pancreatic ductal adenocarcinomas. In biliary intraepithelial neoplasia (BilIN), increased expression of MUC1 is associated with higher degrees of dysplasia. Intrahepatic cholangiocarcinomas (ICC) are characterized by increased expression of all glycoforms of MUC1. Positive MUC2 expression in intraductal papillary neoplasm of the bile ducts (IPNB) of the intestinal type indicates high malignant potential with de novo expression of MUC1 in the invasive element. Absent MUC2 expression in any degree of BilIN may prove useful in differentiating them from IPNB. De novo expression of MUC4 is associated with poor prognosis in patients with ICC or carcinoma of the extrahepatic bile ducts (EHBDC). High de novo expression of MUC5AC is found in all degrees of BilIN and all types of IPNB and ICC. The MUC5AC is useful in the detection of neoplastic lesions of the bile duct at an early stage. Increased expression of mucin MUC1 in carcinoma of the ampulla of Vater associated with unfavorable behavior of the tumor, such as lymph node metastasis, infiltration of the pancreas and duodenum, advanced TNM classification and worse prognosis. Patients with intra-ampullary papillary-tubular neoplasm (IAPN) of the pancreatobiliary immunophenotype did not show MUC2, while those of the intestinal immunophenotype are MUC2 positive. The expression of MUC4 is associated with poor prognosis in patients with carcinoma of the ampulla of Vater favoring metastasis and making them resistant to apoptosis. Moreover, it appears that MUC4 positivity correlates with recurrence of the tumor. Expression of MUC5AC is associated with the invasive potential of the tumor.
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