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Juhász P, Méhes G. Tumor Hypoxia: How Conventional Histology Is Reshaped in Breast Carcinoma. Int J Mol Sci 2025; 26:4423. [PMID: 40362659 PMCID: PMC12072647 DOI: 10.3390/ijms26094423] [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: 03/18/2025] [Revised: 04/28/2025] [Accepted: 05/05/2025] [Indexed: 05/15/2025] Open
Abstract
Intratumoral hypoxia is common in any form of malignancy initializing focal necrosis or tumor cell adaptation. Hypoxia inducible factor-1-driven reprogramming favors the loss of tumor cell proliferation (quiescence) and partial cellular reversion, induces stemness and/or mesenchymal-like features in the exposed tumor areas. The characteristic hypoxia-driven tumor cell phenotype is principally directed to reduce energy consumption and to enhance survival, but the gained features also contribute to growth advantage and induce the reorganization of the microenvironment and protective mechanisms against external stress. The hypoxia-induced phenotypic changes are at least in part reflected by conventional morphology in breast carcinoma. Intratumoral variability of classical morphological signs, such as the growth pattern, the histological grade, cell proliferation, necrosis, microcalcification, angiogenesis, and the immune cell infiltration is also related with the co-existence of hypoxic areas. Thus, a deeper understanding of hypoxia-activated mechanisms is required. The current paper aims to summarize the major tissue factors involved in the response to hypoxia and their potential contribution to the breast carcinoma phenotype.
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Affiliation(s)
| | - Gábor Méhes
- Department of Pathology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary;
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Sharma R, Yadav J, Bhat SA, Musayev A, Myrzagulova S, Sharma D, Padha N, Saini M, Tuli HS, Singh T. Emerging Trends in Neuroblastoma Diagnosis, Therapeutics, and Research. Mol Neurobiol 2025; 62:6423-6466. [PMID: 39804528 DOI: 10.1007/s12035-024-04680-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 12/20/2024] [Indexed: 03/29/2025]
Abstract
This review explores the current understanding and recent advancements in neuroblastoma, one of the most common extracranial solid pediatric cancers, accounting for ~ 15% of childhood cancer-related mortality. The hallmarks of NBL, including angiogenesis, metastasis, apoptosis resistance, cell cycle dysregulation, drug resistance, and responses to hypoxia and ROS, underscore its complex biology. The tumor microenvironment's significance in disease progression is acknowledged in this study, along with the pivotal role of cancer stem cells in sustaining tumor growth and heterogeneity. A number of molecular signatures are being studied in order to better understand the disease, with many of them serving as targets for the development of new therapeutics. This includes inhibitor therapies for NBL patients, which notably concentrate on ALK signaling, MDM2, PI3K/Akt/mTOR, Wnt, and RAS-MAPK pathways, along with regulators of epigenetic mechanisms. Additionally, this study offers an extensive understanding of the molecular therapies used, such as monoclonal antibodies and CAR-T therapy, focused on both preclinical and clinical studies. Radiation therapy's evolving role and the promise of stem cell transplantation-mediated interventions underscore the dynamic landscape of NBL treatment. This study has also emphasized the recent progress in the field of diagnosis, encompassing the adoption of artificial intelligence and liquid biopsy as a non-intrusive approach for early detection and ongoing monitoring of NBL. Furthermore, the integration of innovative treatment approaches such as CRISPR-Cas9, and cancer stem cell therapy has also been emphasized in this review.
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Affiliation(s)
- Rishabh Sharma
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Amity Stem Cell Institute, Amity Medical School, Amity University, Haryana, 122412, India
| | - Jaya Yadav
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Amity Stem Cell Institute, Amity Medical School, Amity University, Haryana, 122412, India
| | - Sajad Ahmad Bhat
- Asfendiyarov Kazakh National Medical University, Almaty, 050000, Kazakhstan
- Department of Biochemistry, NIMS University, Rajasthan, Jaipur, 303121, India
| | - Abdugani Musayev
- Asfendiyarov Kazakh National Medical University, Almaty, 050000, Kazakhstan
| | | | - Deepika Sharma
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
| | - Nipun Padha
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Department of Zoology, Cluster University of Jammu, Jammu, 180001, India
| | - Manju Saini
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
- Amity Stem Cell Institute, Amity Medical School, Amity University, Haryana, 122412, India
| | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, Haryana, 133207, India
| | - Tejveer Singh
- Translational Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India.
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, (INMAS-DRDO), New Delhi, Delhi, 110054, India.
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Bonaventure A, Simpson J, Kane E, Roman E. Maternal illnesses during pregnancy and the risk of childhood cancer: A medical-record based analysis (UKCCS). Int J Cancer 2025; 156:920-929. [PMID: 39535336 DOI: 10.1002/ijc.35166] [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: 03/27/2024] [Revised: 07/22/2024] [Accepted: 08/06/2024] [Indexed: 11/16/2024]
Abstract
Often relying on mother's recollections of past events, the possible relationship between maternal illness in pregnancy and risk of malignancy in their offspring has long been a focus of research. Free from recall bias, this study of childhood cancer (0-14 years) examined these associations using data abstracted from mothers' primary-care (1623 cases, 2521 controls) and obstetric (2721 cases, 5169 controls) records. Maternal infections and other illnesses in pregnancy were examined for any possible associations with childhood leukaemia, lymphoma, CNS or embryonal tumours using pooled information from the two medical record sources (2885 cases and 5499 controls), accounting for potential confounders. Maternal anaemia was associated with childhood acute myeloid leukaemia (AML) (odds ratio, OR = 2.07, 95%CI [1.40-3.08]). Anaemia during pregnancy was also recorded more frequently in the notes of mothers of children with medulloblastoma, retinoblastoma and embryonal rhabdomyosarcoma: ORs 2.36 [1.36-4.11], 1.83 [1.01-3.33] and 2.91 [1.64-5.16] respectively. Other associations included urinary tract infections (UTIs) and non-Hodgkin lymphoma (NHL); preeclampsia and NHL; and polyhydramnios with both AML and NHL. No evidence was found to suggest that influenza during pregnancy impacted on childhood leukaemia risk. In conclusion, our findings are supportive of an association between maternal anaemia in pregnancy and childhood AML, and maternal anaemia and embryonal tumours; underscoring the need for further research exploring the potential causes and roles of iron and vitamin deficiencies. Due to small numbers and lack of corroborative evidence, the associations observed for UTIs, preeclampsia, and polyhydramnios must be treated cautiously.
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Affiliation(s)
- Audrey Bonaventure
- Epidemiology of Childhood and Adolescent Cancer (EPICEA) Team, Center for Research in Epidemiology and StatisticS (CRESS), Université Paris Cité, Université Sorbonne Paris Nord, INSERM, INRAE, Villejuif, France
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK
| | - Jill Simpson
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK
| | - Eleanor Kane
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK
| | - Eve Roman
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK
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Zhang S, Peng S. Copper-Based biomaterials for anti-tumor therapy: Recent advances and perspectives. Acta Biomater 2025; 193:107-127. [PMID: 39800096 DOI: 10.1016/j.actbio.2025.01.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 01/03/2025] [Accepted: 01/09/2025] [Indexed: 01/15/2025]
Abstract
Copper, an essential trace element, is integral to numerous metabolic pathways across biological systems. In recent years, copper-based biomaterials have garnered significant interest due to their superior biocompatibility and multifaceted functionalities, particularly in the treatment of malignancies such as sarcomas and cancers. On the one hand, these copper-based materials serve as efficient carriers for a range of therapeutic agents, including chemotherapeutic drugs, small molecule inhibitors, and antibodies, allowing them for precise delivery and controlled release triggered by specific modifications and stimuli. On the other hand, they can induce cell death through mechanisms such as ferroptosis, cuproptosis, apoptosis, and pyroptosis, or inhibit the proliferation and invasion of cancer cells via their outstanding properties. Furthermore, advanced design approaches enable these materials to support tumor imaging and immune activation. Despite this progress, the full scope of their functional capabilities remains to be fully elucidated. This review provides an overview of the anti-tumor functions, underlying mechanisms, and design strategies of copper-based biomaterials, along with their advantages and limitations. The aim is to provide insights into the design, study, and development of novel multifunctional biomaterials, with the ultimate goal of accelerating the clinical application of copper-based nanomaterials in cancer therapy. STATEMENT OF SIGNIFICANCE: This study explores the groundbreaking potential of copper-based biomaterials in cancer therapy, uniquely combining biocompatibility with diverse therapeutic mechanisms such as targeted drug delivery and inhibition of cancer cells through specific cell death pathways. By enhancing tumor imaging and immune activation, copper-based nanomaterials have opened new avenues for cancer treatment. This review examines these multifunctional biomaterials, highlighting their advantages and current limitations while addressing gaps in existing research. The findings aim to accelerate clinical applications of these materials in the field of oncology, providing valuable insights for the design of next-generation copper-based therapies. Therefore, this work is highly relevant to researchers and practitioners focused on innovative cancer treatments.
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Affiliation(s)
- Shufang Zhang
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education of Xiangya Hospital and School of Basic Medical Science, Central South University, Changsha, Hunan 410013, China; Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Shuping Peng
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education of Xiangya Hospital and School of Basic Medical Science, Central South University, Changsha, Hunan 410013, China; Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
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Ye J, Jiang H, Tiche S, He C, Liu J, Bian F, Jedoui M, Forgo B, Islam MT, Zhao M, Emengo P, He B, Li Y, Li A, Truong A, Ho J, Simmermaker C, Yang Y, Zhou MN, Hu Z, Svensson K, Cuthbertson D, Hazard F, Xing L, Shimada H, Chiu B. Restoring Mitochondrial Quantity and Quality to Reverse Warburg Effect and Drive Tumor Differentiation. RESEARCH SQUARE 2024:rs.3.rs-5494402. [PMID: 39711563 PMCID: PMC11661309 DOI: 10.21203/rs.3.rs-5494402/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors, and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the TCA cycle and switching substrate preference from glutamine to glucose. These effects were reversed by ETC inhibitors or in ρ0 cells lacking mtDNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing analysis of the orthotopic xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, which could potentially significantly improve patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.
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Liang J, Zhou X, Lin Y, Yin H, Liu Y, Xie Z, Lin H, Wu T, Zhang X, Tan Z, Cheng Z, Yin W, Guo Z, Chen W. Prospective study on the association between 36 human blood cell traits and pan-cancer outcomes: a mendelian randomization analysis. BMC Cancer 2024; 24:1442. [PMID: 39578790 PMCID: PMC11583664 DOI: 10.1186/s12885-024-13133-5] [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: 07/17/2024] [Accepted: 10/30/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Research on the link between blood cell traits and cancer risk has gained significant attention. Traditional epidemiological and cell biology studies, have identified correlations between blood traits and cancer risks. These findings are important as they suggest potential risk factors and biological mechanisms. However, these studies often can't confirm causality, pointing to the need for further investigation to understand these relationships better. METHODS Mendelian randomization (MR), utilizing single-nucleotide polymorphisms as instrumental variables, was employed to investigate blood cell trait causal effects on cancer risk. Thirty-six blood cell traits were analyzed, and their impact on 28 major cancer outcomes was assessed using data from the FinnGen cohort, with eight major cancer outcomes and 22 cancer subsets. Furthermore, 1,008 MR analyses were conducted, incorporating sensitivity analyses (weighted median, MR-Egger, and MR-PRESSO) to address potential pleiotropy and heterogeneity. RESULTS The analysis (data from 173,480 individuals primarily of European descent) revealed significant results. An increase in eosinophil count was associated with a reduced risk of colorectal malignancies (OR = 0.7702 per 1 SD higher level, 95% CI = 0.6852 to 0.8658; P = 1.22E-05). Similarly, an increase in total eosinophil and basophil count was linked to a decreased risk of colorectal malignancies (OR = 0.7798 per 1 SD higher level, 95% CI = 0.6904 to 0.8808; P = 6.30E-05). Elevated hematocrit (HCT) levels were associated with a reduced risk of ovarian cancer (OR = 0.5857 per 1 SD higher level, 95% CI = 0.4443 to 0.7721; P = 1.47E-04). No significant heterogeneity or horizontal pleiotropy was observed. CONCLUSIONS Our study highlights the complex and context-dependent roles of blood cell traits in cancers.
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Affiliation(s)
- Jinghao Liang
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, 510120, China
| | - Xinyi Zhou
- Second Clinical Medical College, Guangdong Medical University, Dongguan, 523000, China
| | - Yijian Lin
- Second Clinical Medical College, Guangdong Medical University, Dongguan, 523000, China
| | - Hongming Yin
- Second Clinical Medical College, Guangdong Medical University, Dongguan, 523000, China
| | - Yuanqing Liu
- Second Clinical Medical College, Guangdong Medical University, Dongguan, 523000, China
| | - Zixian Xie
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, 510120, China
| | - Hongmiao Lin
- The Sixth School of Clinical Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511500, China
| | - Tongtong Wu
- Second Clinical Medical College, Guangdong Medical University, Dongguan, 523000, China
| | - Xinrong Zhang
- Second Clinical Medical College, Guangdong Medical University, Dongguan, 523000, China
| | - Zhaofeng Tan
- The Sixth School of Clinical Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511500, China
| | - Ziqiu Cheng
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, 510120, China
| | - Weiqiang Yin
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, 510120, China
| | - Zhihua Guo
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, 510120, China.
| | - Wenzhe Chen
- The Sixth School of Clinical Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, 511500, China.
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Xu E, Huang Z, Zhu K, Hu J, Ma X, Wang Y, Zhu J, Zhang C. PDGFRB promotes dedifferentiation and pulmonary metastasis through rearrangement of cytoskeleton under hypoxic microenvironment in osteosarcoma. Cell Signal 2024; 125:111501. [PMID: 39505287 DOI: 10.1016/j.cellsig.2024.111501] [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: 04/08/2024] [Revised: 10/15/2024] [Accepted: 10/30/2024] [Indexed: 11/08/2024]
Abstract
BACKGROUND Osteosarcoma (OS) cells commonly suffer from hypoxia and dedifferentiation, resulting in poor prognosis. We plan to identify the role of hypoxia on dedifferentiation and the associated cellular signaling. METHODS We performed sphere formation assays and determined spheroid cells as dedifferentiated cells by detecting stem cell-like markers. RNAi assay was used to explore the relationship between hypoxia inducible factor 1 subunit alpha (HIF1A) and platelet derived growth factor receptor beta (PDGFRB). We obtained PDGFRB knockdown and overexpression cells through lentiviral infection experiments and detected the expression of PDGFRB, p-PDGFRB, focal adhesion kinase (FAK), p-FAK, phosphorylated myosin light chain 2 (p-MLC2), and ras homolog family member A (RhoA) in each group. The effects of PDGFRB on cytoskeleton rearrangement and cell adhesion were explored by immunocytochemistry. Wound-healing experiments, transwell assays, and animal trials were employed to investigate the effect of PDGFRB on OS cell metastasis both in vitro and in vivo. RESULTS Dedifferentiated OS cells were found to exhibit high expression of HIF1A and PDGFRB, and HIF1A upregulated PDGFRB, subsequently activated RhoA, and increased the phosphorylation of MLC2. PDGFRB also enhanced the phosphorylation of FAK. The OS cell morphology and vinculin distribution were altered by PDGFRB. PDGFRB promoted cell dedifferentiation and had a significant impact on the migration and invasion abilities of OS cells in vitro. In addition, PDGFRB increased pulmonary metastasis of OS cells in vivo. CONCLUSION Our results demonstrated that HIF1A up-regulated PDGFRB under hypoxic conditions, and PDGFRB regulated the actin cytoskeleton, a process likely linked to the activation of RhoA and the phosphorylation of, thereby promoting OS dedifferentiation and pulmonary metastasis.
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Affiliation(s)
- Enjie Xu
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Zhen Huang
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Kunpeng Zhu
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Jianping Hu
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Xiaolong Ma
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Yongjie Wang
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Jiazhuang Zhu
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Chunlin Zhang
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China.
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Moratilla A, Martín D, Cadenas-Martín M, Stokking M, Quesada MA, Arnalich F, De Miguel MP. Hypoxia Increases the Efficiencies of Cellular Reprogramming and Oncogenic Transformation in Human Blood Cell Subpopulations In Vitro and In Vivo. Cells 2024; 13:971. [PMID: 38891103 PMCID: PMC11172288 DOI: 10.3390/cells13110971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 05/31/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024] Open
Abstract
Patients with chronic hypoxia show a higher tumor incidence; however, no primary common cause has been recognized. Given the similarities between cellular reprogramming and oncogenic transformation, we directly compared these processes in human cells subjected to hypoxia. Mouse embryonic fibroblasts were employed as controls to compare transfection and reprogramming efficiency; human adipose-derived mesenchymal stem cells were employed as controls in human cells. Easily obtainable human peripheral blood mononuclear cells (PBMCs) were chosen to establish a standard protocol to compare cell reprogramming (into induced pluripotent stem cells (iPSCs)) and oncogenic focus formation efficiency. Cell reprogramming was achieved for all three cell types, generating actual pluripotent cells capable for differentiating into the three germ layers. The efficiencies of the cell reprogramming and oncogenic transformation were similar. Hypoxia slightly increased the reprogramming efficiency in all the cell types but with no statistical significance for PBMCs. Various PBMC types can respond to hypoxia differently; lymphocytes and monocytes were, therefore, reprogrammed separately, finding a significant difference between normoxia and hypoxia in monocytes in vitro. These differences were then searched for in vivo. The iPSCs and oncogenic foci were generated from healthy volunteers and patients with chronic obstructive pulmonary disease (COPD). Although higher iPSC generation efficiency in the patients with COPD was found for lymphocytes, this increase was not statistically significant for oncogenic foci. Remarkably, a higher statistically significant efficiency in COPD monocytes was demonstrated for both processes, suggesting that physiological hypoxia exerts an effect on cell reprogramming and oncogenic transformation in vivo in at least some cell types.
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Affiliation(s)
- Adrián Moratilla
- Cell Engineering Laboratory, La Paz University Hospital Health Research Institute, IdiPAZ, 28046 Madrid, Spain; (A.M.); (D.M.); (M.C.-M.); (M.S.)
| | - Diana Martín
- Cell Engineering Laboratory, La Paz University Hospital Health Research Institute, IdiPAZ, 28046 Madrid, Spain; (A.M.); (D.M.); (M.C.-M.); (M.S.)
| | - Marta Cadenas-Martín
- Cell Engineering Laboratory, La Paz University Hospital Health Research Institute, IdiPAZ, 28046 Madrid, Spain; (A.M.); (D.M.); (M.C.-M.); (M.S.)
| | - Martha Stokking
- Cell Engineering Laboratory, La Paz University Hospital Health Research Institute, IdiPAZ, 28046 Madrid, Spain; (A.M.); (D.M.); (M.C.-M.); (M.S.)
| | - Maria Angustias Quesada
- Internal Medicine Service, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain; (M.A.Q.); (F.A.)
| | - Francisco Arnalich
- Internal Medicine Service, La Paz University Hospital, IdiPAZ, 28046 Madrid, Spain; (M.A.Q.); (F.A.)
| | - Maria P. De Miguel
- Cell Engineering Laboratory, La Paz University Hospital Health Research Institute, IdiPAZ, 28046 Madrid, Spain; (A.M.); (D.M.); (M.C.-M.); (M.S.)
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Profir M, Roşu OA, Creţoiu SM, Gaspar BS. Friend or Foe: Exploring the Relationship between the Gut Microbiota and the Pathogenesis and Treatment of Digestive Cancers. Microorganisms 2024; 12:955. [PMID: 38792785 PMCID: PMC11124004 DOI: 10.3390/microorganisms12050955] [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: 03/11/2024] [Revised: 04/25/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
Digestive cancers are among the leading causes of cancer death in the world. However, the mechanisms of cancer development and progression are not fully understood. Accumulating evidence in recent years pointing to the bidirectional interactions between gut dysbiosis and the development of a specific type of gastrointestinal cancer is shedding light on the importance of this "unseen organ"-the microbiota. This review focuses on the local role of the gut microbiota imbalance in different digestive tract organs and annexes related to the carcinogenic mechanisms. Microbiota modulation, either by probiotic administration or by dietary changes, plays an important role in the future therapies of various digestive cancers.
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Affiliation(s)
- Monica Profir
- Department of Oncology, Elias University Emergency Hospital, 011461 Bucharest, Romania; (M.P.); (O.A.R.)
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Oana Alexandra Roşu
- Department of Oncology, Elias University Emergency Hospital, 011461 Bucharest, Romania; (M.P.); (O.A.R.)
| | - Sanda Maria Creţoiu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Bogdan Severus Gaspar
- Surgery Clinic, Emergency Clinical Hospital of Bucharest, 014461 Bucharest, Romania;
- Department of Surgery, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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10
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Kato T, Sakurai M, Watanabe K, Mizukami Y, Nakagawa T, Baba K, Mizuno T, Igase M. Identification of hypoxia-induced metabolism-associated genes in canine tumours. Vet Comp Oncol 2024. [PMID: 38712488 DOI: 10.1111/vco.12979] [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: 02/16/2024] [Revised: 04/09/2024] [Accepted: 04/22/2024] [Indexed: 05/08/2024]
Abstract
Canine tumours including urothelial carcinoma, lung adenocarcinoma, mammary gland tumour, squamous cell carcinoma, and melanoma have been identified as causes of death, but effective therapies are limited due to insufficient knowledge of the molecular mechanisms involved. Within the tumour microenvironment, hypoxia activates hypoxia-inducible factor 1α (HIF1α) in tumour cells. High HIF1α expression correlates with enhanced glycolysis and poorer outcomes in human cancers. However, the molecular mechanisms underlying hypoxic tumour cells remain elusive in dogs. In our study, we investigated upregulated genes in a canine malignant melanoma cell line during hypoxia using RNA-sequencing analysis. Glycolysis and HIF1 signalling pathways were upregulated in hypoxic melanoma cells. HIF1α knockout melanoma cells revealed that the glycolysis marker MCT4 is regulated by HIF1α activation. Hypoxia induces high lactate secretion due to enhanced glycolysis in canine melanoma cells. Furthermore, we examined monocarboxylate transporter 4 (MCT4) expression in malignant melanoma and eight other types of canine tumour tissues using immunohistochemistry (IHC). Membrane-localized MCT4 protein was mostly detected in urothelial carcinoma and lung adenocarcinoma rather than malignant melanoma. We conclude that canine MCT4 protein plays a role in lactic acid efflux from glycolytic cells and may serve as a marker for hypoxia and glycolysis in canine tumours. These findings could inform future therapeutic strategies targeting MCT4.
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Affiliation(s)
- Taiki Kato
- Laboratory of Molecular Diagnostics and Therapeutics, The United Graduate School of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Masashi Sakurai
- Laboratory of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Kenji Watanabe
- Institute of Gene Research, Science Research Center, Yamaguchi University, Ube, Japan
| | - Yoichi Mizukami
- Institute of Gene Research, Science Research Center, Yamaguchi University, Ube, Japan
| | - Takayuki Nakagawa
- Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Kenji Baba
- Laboratory of Veterinary Internal Medicine, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Takuya Mizuno
- Laboratory of Molecular Diagnostics and Therapeutics, The United Graduate School of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
- Research Institute for Cell Design Medical Science, Yamaguchi University, Ube, Japan
| | - Masaya Igase
- Laboratory of Molecular Diagnostics and Therapeutics, The United Graduate School of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
- Research Institute for Cell Design Medical Science, Yamaguchi University, Ube, Japan
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11
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Stocker M, Blancke Soares A, Liebsch G, Meier RJ, Canis M, Gires O, Haubner F. Quantification of oxygen consumption in head and neck cancer using fluorescent sensor foil technology. Front Oncol 2024; 14:1002798. [PMID: 38390268 PMCID: PMC10882065 DOI: 10.3389/fonc.2024.1002798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 01/22/2024] [Indexed: 02/24/2024] Open
Abstract
Introduction Head and neck squamous cell carcinoma (HNSCC) patients suffer from frequent local recurrences that negatively impact on prognosis. Hence, distinguishing tumor and normal tissue is of clinical importance as it may improve the detection of residual tumor tissue in surgical resection margins and during imaging-based surgery planning. Differences in O2 consumption (OC) can be used to this aim, as they provide options for improved surgical, image-guided approaches. Methods In the present study, the potential of a fluorescent sensor foil-based technology to quantify OC in HNSCC was evaluated in an in vitro 3D model and in situ in patients. Results In vitro measurements of OC using hypopharyngeal and esophageal cell lines allowed a specific detection of tumor cell spheroids embedded together with cancer-associated fibroblasts in type I collagen extracellular matrix down to a diameter of 440 µm. Pre-surgery in situ measurements were conducted with a handheld recording device and sensor foils with an oxygen permeable membrane and immobilized O2-reactive fluorescent dyes. Lateral tongue carcinoma and carcinoma of the floor of the mouth were chosen for analysis owing to their facilitated accessibility. OC was evaluated over a time span of 60 seconds and was significantly higher in tumor tissue compared to healthy mucosa in the vicinity of the tumor. Discussion Hence, OC quantification using fluorescent sensor foil-based technology is a relevant parameter for the differentiation of tumor tissue of the head and neck region and may support surgery planning.
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Affiliation(s)
- Magdalena Stocker
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Ludwig Maximilians University (LMU) Munich, Munich, Germany
| | - Alexandra Blancke Soares
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Ludwig Maximilians University (LMU) Munich, Munich, Germany
| | - Gregor Liebsch
- PreSens Precision Sensing GmbH, Imaging Solutions, Regensburg, Germany
| | - Robert J Meier
- PreSens Precision Sensing GmbH, Imaging Solutions, Regensburg, Germany
| | - Martin Canis
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Ludwig Maximilians University (LMU) Munich, Munich, Germany
| | - Olivier Gires
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Ludwig Maximilians University (LMU) Munich, Munich, Germany
| | - Frank Haubner
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Ludwig Maximilians University (LMU) Munich, Munich, Germany
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12
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Jiang H, Tiche SJ, He CJ, Jedoui M, Forgo B, Zhao M, He B, Li Y, Li AM, Truong AT, Ho J, Simmermaker C, Yang Y, Zhou MN, Hu Z, Cuthbertson DJ, Svensson KJ, Hazard FK, Shimada H, Chiu B, Ye J. Mitochondrial uncoupler and retinoic acid synergistically induce differentiation and inhibit proliferation in neuroblastoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.22.576741. [PMID: 38328117 PMCID: PMC10849550 DOI: 10.1101/2024.01.22.576741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Neuroblastoma is a leading cause of death in childhood cancer cases. Unlike adult malignancies, which typically develop from aged cells through accumulated damage and mutagenesis, neuroblastoma originates from neural crest cells with disrupted differentiation. This distinct feature provides novel therapeutic opportunities beyond conventional cytotoxic methods. Previously, we reported that the mitochondrial uncoupler NEN (niclosamide ethanolamine) activated mitochondria respiration to reprogram the epigenome, promoting neuronal differentiation. In the current study, we further combine NEN with retinoic acid (RA) to promote neural differentiation both in vitro and in vivo. The treatment increased the expression of RA signaling and neuron differentiation-related genes, resulting in a global shift in the transcriptome towards a more favorable prognosis. Overall, these results suggest that the combination of a mitochondrial uncoupler and the differentiation agent RA is a promising therapeutic strategy for neuroblastoma.
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Affiliation(s)
- Haowen Jiang
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | | | - Clifford JiaJun He
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Mohamed Jedoui
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Balint Forgo
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Meng Zhao
- Department of Pathology, Stanford University, Stanford, CA, USA
- Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Bo He
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Yang Li
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Albert M. Li
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | | | - Jestine Ho
- Agilent Technologies, Inc., Santa Clara, CA, USA
| | | | - Yanan Yang
- Agilent Technologies, Inc., Santa Clara, CA, USA
| | - Meng-Ning Zhou
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Zhen Hu
- Olivia Consulting Service, Redwood City, CA, USA
| | | | - Katrin J. Svensson
- Department of Pathology, Stanford University, Stanford, CA, USA
- Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | | | | | - Bill Chiu
- Department of Surgery, Stanford University, Stanford, CA, USA
| | - Jiangbin Ye
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
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13
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Mi S, Cai S, Xue M, Wu W. HIF-1α/METTL1/m 7G axis is involved in CRC response to hypoxia. Biochem Biophys Res Commun 2024; 693:149385. [PMID: 38118310 DOI: 10.1016/j.bbrc.2023.149385] [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: 09/25/2023] [Revised: 12/04/2023] [Accepted: 12/12/2023] [Indexed: 12/22/2023]
Abstract
BACKGROUND In recent years, many studies have confirmed that hypoxia and hypoxia inducible factor (HIF)-1α drive the development of colorectal cancer (CRC). HIF-1α also modulates epitranscriptomic remodeling to regulate cancer development. However, the mechanism by which RNA methylation is altered under hypoxic conditions and the underlying regulatory mechanisms in CRC remain unclear. METHODS Here, seven common types of modifications of mRNA and tRNA were quantitated using liquid chromatography-tandem mass spectrometry. To validate the robustness of the profiling data, modifications that were consistently altered across the three CRC cell lines under hypoxia were validated via dot blot analysis. Then, 10 enzymes that could regulate the abundance of three RNA modifications in tRNA were measured in CRC cells after hypoxia treatment using quantitative real-time polymerase chain reaction. Furthermore, the regulatory role of HIF-1α in the expression of methyltransferase 1 (METTL1) under hypoxic conditions was confirmed using METTL1 promoter activity assays and HIF-1α small interfering RNA (siRNA). The binding capacity of HIF-1α to each hypoxia response element (HRE) in the promoter of METTL1 was investigated by performing Chromatin immunoprecipitation assay (ChIP). RESULTS Abundance of RNA modifications was altered more consistently and significantly in tRNA than in mRNA under hypoxic conditions. In addition, the abundance of N7-methyleguanosine (m7G) modification in tRNA decreased significantly under hypoxic conditions. As a methyltransferase of the m7G modification in tRNA, the expression of METTL1 mRNA was drastically downregulated under hypoxic conditions. Mechanistically, suppression of HIF-1α by siRNA upregulated the METTL1 promoter activity. Furthermore, ChIP showed that HIF-1α could bind with an HRE in the promoter region of METTL1, indicating that METTL1 is a direct target of HIF-1α in CRC cells under hypoxic conditions. CONCLUSIONS Our study revealed that the abundance of the m7G modification in tRNA was drastically reduced in CRC cells dependent on the HIF-1α-mediated inhibition of METTL1 transcription under hypoxic conditions.
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Affiliation(s)
- Shuyi Mi
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Shangwen Cai
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Meng Xue
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; Institute of Gastroenterology, Zhejiang University, Hangzhou, China.
| | - Weiquan Wu
- Cancer Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
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14
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Reeder BJ. Insights into the function of cytoglobin. Biochem Soc Trans 2023; 51:1907-1919. [PMID: 37721133 PMCID: PMC10657185 DOI: 10.1042/bst20230081] [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: 07/31/2023] [Revised: 09/11/2023] [Accepted: 09/12/2023] [Indexed: 09/19/2023]
Abstract
Since its discovery in 2001, the function of cytoglobin has remained elusive. Through extensive in vitro and in vivo research, a range of potential physiological and pathological mechanisms has emerged for this multifunctional member of the hemoglobin family. Currently, over 200 research publications have examined different aspects of cytoglobin structure, redox chemistry and potential roles in cell signalling pathways. This research is wide ranging, but common themes have emerged throughout the research. This review examines the current structural, biochemical and in vivo knowledge of cytoglobin published over the past two decades. Radical scavenging, nitric oxide homeostasis, lipid binding and oxidation and the role of an intramolecular disulfide bond on the redox chemistry are examined, together with aspects and roles for Cygb in cancer progression and liver fibrosis.
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Affiliation(s)
- Brandon J Reeder
- School of Life Sciences, University of Essex, Wivenhoe Park, Colchester, Essex, U.K
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15
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Koukourakis IM, Platoni K, Kouloulias V, Arelaki S, Zygogianni A. Prostate Cancer Stem Cells: Biology and Treatment Implications. Int J Mol Sci 2023; 24:14890. [PMID: 37834336 PMCID: PMC10573523 DOI: 10.3390/ijms241914890] [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: 09/06/2023] [Revised: 09/30/2023] [Accepted: 10/01/2023] [Indexed: 10/15/2023] Open
Abstract
Stem cells differentiate into mature organ/tissue-specific cells at a steady pace under normal conditions, but their growth can be accelerated during the process of tissue healing or in the context of certain diseases. It is postulated that the proliferation and growth of carcinomas are sustained by the presence of a vital cellular compartment resembling stem cells residing in normal tissues: 'stem-like cancer cells' or cancer stem cells (CSCs). Mutations in prostate stem cells can lead to the formation of prostate cancer. Prostate CSCs (PCSCs) have been identified and partially characterized. These express surface markers include CD44, CD133, integrin α2β1, and pluripotency factors like OCT4, NANOG, and SOX2. Several signaling pathways are also over-activated, including Notch, PTEN/Akt/PI3K, RAS-RAF-MEK-ERK and HH. Moreover, PCSCs appear to induce resistance to radiotherapy and chemotherapy, while their presence has been linked to aggressive cancer behavior and higher relapse rates. The development of treatment policies to target PCSCs in tumors is appealing as radiotherapy and chemotherapy, through cancer cell killing, trigger tumor repopulation via activated stem cells. Thus, blocking this reactive stem cell mobilization may facilitate a positive outcome through cytotoxic treatment.
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Affiliation(s)
- Ioannis M. Koukourakis
- Radiation Oncology Unit, 1st Department of Radiology, Aretaieion Hospital, School of Medicine, National and Kapodistrian University of Athens (NKUOA), 11528 Athens, Greece; (I.M.K.); (A.Z.)
| | - Kalliopi Platoni
- Medical Physics Unit, 2nd Department of Radiology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens (NKUOA), 12462 Athens, Greece
| | - Vassilis Kouloulias
- Radiation Oncology Unit, 2nd Department of Radiology, School of Medicine, National and Kapodistrian University of Athens (NKUOA), 12462 Athens, Greece;
| | - Stella Arelaki
- Translational Functional Cancer Genomics, National Center for Tumor Diseases, German Cancer Research Center, 69120 Heidelberg, Germany;
| | - Anna Zygogianni
- Radiation Oncology Unit, 1st Department of Radiology, Aretaieion Hospital, School of Medicine, National and Kapodistrian University of Athens (NKUOA), 11528 Athens, Greece; (I.M.K.); (A.Z.)
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16
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Strowd R, Ellingson B, Raymond C, Yao J, Wen PY, Ahluwalia M, Piotrowski A, Desai A, Clarke JL, Lieberman FS, Desideri S, Nabors LB, Ye X, Grossman S. Activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrence of glioblastoma. J Neurooncol 2023; 165:101-112. [PMID: 37864646 PMCID: PMC10863646 DOI: 10.1007/s11060-023-04456-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 09/19/2023] [Indexed: 10/23/2023]
Abstract
INTRODUCTION Hypoxia inducible factor 2-alpha (HIF2α) mediates cellular responses to hypoxia and is over-expressed in glioblastoma (GBM). PT2385 is an oral HIF2α inhibitor with in vivo activity against GBM. METHODS A two-stage single-arm open-label phase II study of adults with GBM at first recurrence following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (ORR = complete response + partial response, CR + PR); secondary outcomes were safety, overall survival (OS), and progression free survival (PFS). Exploratory objectives included pharmacokinetics (day 15 Cmin), pharmacodynamics (erythropoietin, vascular endothelial growth factor), and pH-weighted amine- chemical exchange saturation transfer (CEST) MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤ 1 ORR. RESULTS Of the 24 enrolled patients, median age was 62.1 (38.7-76.7) years, median KPS 80, MGMT promoter was methylated in 46% of tumors. PT2385 was well tolerated. Grade ≥ 3 drug-related adverse events were hypoxia (n = 2), hyponatremia (2), lymphopenia (1), anemia (1), and hyperglycemia (1). No objective radiographic responses were observed; median PFS was 1.8 months (95% CI 1.6-2.5) and OS was 7.7 months (95% CI 4.9-12.6). Drug exposure varied widely and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, p = 0.009). Baseline acidity by pH-weighted CEST MRI correlated significantly with treatment duration (R2 = 0.49, p = 0.017). Non-enhancing infiltrative disease with high acidity gave rise to recurrence. CONCLUSIONS PT2385 monotherapy had limited activity in first recurrent GBM. Drug exposure was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic lesions on CEST imaging. A second-generation HIF2α inhibitor is being studied.
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Affiliation(s)
- Roy Strowd
- Wake Forest University School of Medicine, 1 Medical Center Boulevard, Winston Salem, NC, 27104, USA.
| | | | | | - Jingwen Yao
- University of California Los Angeles, Los Angeles, CA, USA
| | | | | | | | - Arati Desai
- University of Pennsylvania, Philadelphia, PA, USA
| | | | | | | | - L Burt Nabors
- University of Alabama at Birmingham, Birmingham, AL, USA
| | - Xiaobu Ye
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, USA
| | - Stuart Grossman
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, USA
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Littleflower AB, Antony GR, Parambil ST, Subhadradevi L. Metabolic Phenotype Intricacies on Altered Glucose Metabolism of Breast Cancer Cells upon Glut-1 Inhibition and Mimic Hypoxia In Vitro. Appl Biochem Biotechnol 2023; 195:5838-5854. [PMID: 36708494 DOI: 10.1007/s12010-023-04373-5] [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] [Accepted: 01/10/2023] [Indexed: 01/29/2023]
Abstract
Breast cancer is the frequently diagnosed cancer and the leading cancer death among women. The growing tumour of the breast is composed of both normoxic and hypoxic cells, and the heterogeneity of tumour affects the targeted treatment strategies against breast cancer. The functional and therapeutic status of the Warburg effect is mostly recognized, and the genes involved in glycolysis have become a target for anticancer therapeutic strategies. Glut-1 is essential for basal glucose uptake among the glucose transporters and could act as a potential target for anticancer therapy. In the present study, we explored the alteration in the metabolic phenotype of SKBR-3 cells, representing HER-2 overexpressed breast cancer cell line, with Glut-1 inhibition by a synthetic small molecule inhibitor WZB117 in the presence or absence of cobalt chloride (CoCl2) induced biochemical hypoxia in vitro. We found that WZB117 and CoCl2 in combination could inhibit metabolic phenotype characteristics such as glucose uptake, cell migration, lactate and ATP production in SKBR-3 cells. Also, Glut-1 inhibition induced apoptosis and cell cycle arrest at the G0-G1 phase even under CoCl2-induced mimic hypoxia. Our findings suggest that Glut-1 inhibition by WZB117 could overcome the protective effect of CoCl2 mimic hypoxia by regulating glycolysis and altering the metabolic phenotype of breast cancer cells. The considering excellent efficacy and minimal toxicity suggest that WZB117 may be a promising anticancer drug to the current therapies.
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Affiliation(s)
- Ajeesh Babu Littleflower
- Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala-695011, India
| | - Gisha Rose Antony
- Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala-695011, India
| | - Sulfath Thottungal Parambil
- Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala-695011, India
| | - Lakshmi Subhadradevi
- Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala-695011, India.
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18
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Abdel-Aziz AK. Advances in acute myeloid leukemia differentiation therapy: A critical review. Biochem Pharmacol 2023; 215:115709. [PMID: 37506924 DOI: 10.1016/j.bcp.2023.115709] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/22/2023] [Accepted: 07/25/2023] [Indexed: 07/30/2023]
Abstract
Acute myeloid leukemia (AML) is characterized by impaired differentiation and indefinite proliferation of abnormal myeloid progenitors. Although differentiating agents were deemed to revolutionize AML therapy, most treated non-APL AML patients are refractory or relapse. According to cancer stem cell model, leukemia-initiating cells are the root cause of relapse given their unidirectional potential to generate differentiated AML blasts. Nonetheless, accumulating evidences emphasize the de-differentiation plasticity and leukemogenic potential of mature AML blasts and the frailty of targeting leukemic stem cells per se. This review critically discusses the potential and challenges of (lessons learnt from) conventional and novel differentiating agents in AML therapy. Although differentiating agents might hold promise, they should be exploited within the context of a rationale combination regimen eradicating all maturation/differentiation states of AML cells. The results of the routinely used immunophenotypic markers and/or morphological analyses of differentiation should be carefully interpreted given their propensity to underestimate AML burden.
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Affiliation(s)
- Amal Kamal Abdel-Aziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt; Smart Health Initiative, Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Saudia Arabia.
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19
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De Zio S, Becconi M, Soldà A, Malferrari M, Lesch A, Rapino S. Glucose micro-biosensor for scanning electrochemical microscopy characterization of cellular metabolism in hypoxic microenvironments. Bioelectrochemistry 2023; 150:108343. [PMID: 36608371 DOI: 10.1016/j.bioelechem.2022.108343] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
Mapping of the metabolic activity of tumor tissues represents a fundamental approach to better identify the tumor type, elucidate metastatic mechanisms and support the development of targeted cancer therapies. The spatially resolved quantification of Warburg effect key metabolites, such as glucose and lactate, is essential. Miniaturized electrochemical biosensors scanned over cancer cells and tumor tissue to visualize the metabolic characteristics of a tumor is attractive but very challenging due to the limited oxygen availability in the hypoxic environments of tumors that impedes the reliable applicability of glucose oxidase-based glucose micro-biosensors. Herein, the development and application of a new glucose micro-biosensor is presented that can be reliably operated under hypoxic conditions. The micro-biosensor is fabricated in a one-step synthesis by entrapping during the electrochemically driven growth of a polymeric matrix on a platinum microelectrode glucose oxidase and a catalytically active Prussian blue type aggregate and mediator. The as-obtained functionalization improves significantly the sensitivity of the developed micro-biosensor for glucose detection under hypoxic conditions compared to normoxic conditions. By using the micro-biosensor as non-invasive sensing probe in Scanning Electrochemical Microscopy (SECM), the glucose uptake by a breast metastatic adenocarcinoma cell line, with an epithelial morphology, is measured.
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Affiliation(s)
- Simona De Zio
- Department of Chemistry "Giacomo Ciamician", University of Bologna, Via F. Selmi 2, 40126 Bologna, Italy
| | - Maila Becconi
- Department of Chemistry "Giacomo Ciamician", University of Bologna, Via F. Selmi 2, 40126 Bologna, Italy
| | - Alice Soldà
- Department of Chemistry "Giacomo Ciamician", University of Bologna, Via F. Selmi 2, 40126 Bologna, Italy
| | - Marco Malferrari
- Department of Chemistry "Giacomo Ciamician", University of Bologna, Via F. Selmi 2, 40126 Bologna, Italy
| | - Andreas Lesch
- Department of Industrial Chemistry "Toso Montanari", University of Bologna, Viale del Risorgimento 4, 40136 Bologna, Italy
| | - Stefania Rapino
- Department of Chemistry "Giacomo Ciamician", University of Bologna, Via F. Selmi 2, 40126 Bologna, Italy.
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20
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Spatio-temporal modelling of phenotypic heterogeneity in tumour tissues and its impact on radiotherapy treatment. J Theor Biol 2023; 556:111248. [PMID: 36150537 DOI: 10.1016/j.jtbi.2022.111248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 08/02/2022] [Accepted: 08/17/2022] [Indexed: 11/20/2022]
Abstract
We present a mathematical model that describes how tumour heterogeneity evolves in a tissue slice that is oxygenated by a single blood vessel. Phenotype is identified with the stemness level of a cell and determines its proliferative capacity, apoptosis propensity and response to treatment. Our study is based on numerical bifurcation analysis and dynamical simulations of a system of coupled, non-local (in phenotypic "space") partial differential equations that link the phenotypic evolution of the tumour cells to local tissue oxygen levels. In our formulation, we consider a 1D geometry where oxygen is supplied by a blood vessel located on the domain boundary and consumed by the tumour cells as it diffuses through the tissue. For biologically relevant parameter values, the system exhibits multiple steady states; in particular, depending on the initial conditions, the tumour is either eliminated ("tumour-extinction") or it persists ("tumour-invasion"). We conclude by using the model to investigate tumour responses to radiotherapy, and focus on identifying radiotherapy strategies which can eliminate the tumour. Numerical simulations reveal how phenotypic heterogeneity evolves during treatment and highlight the critical role of tissue oxygen levels on the efficacy of radiation protocols that are commonly used in the clinic.
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21
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Li J, Sun B, Li Y, Li S, Wang J, Zhu Y, Lu H. Correlation analysis between shear-wave elastography and pathological profiles in breast cancer. Breast Cancer Res Treat 2023; 197:269-276. [PMID: 36374375 DOI: 10.1007/s10549-022-06804-z] [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: 09/14/2022] [Accepted: 11/03/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE To explore the correlation between shear-wave elastography (SWE) parameters and pathological profiles of invasive breast cancer. METHODS A total of 197 invasive breast cancers undergoing preoperative SWE and primary surgical treatment were included. Maximum elastic modulus (Emax), mean elastic modulus (Emean), and elastic modulus standard deviation (Esd) were calculated by SWE. Pathological profile was gold standard according to postoperative pathology. The relationship between SWE parameters and pathological factors were analyzed using univariate and multivariate analysis. RESULTS In univariate analysis, large cancers showed significantly higher Emax, Emean and Esd (all P < 0.001). Emax and Esd in the group of histological grade III were higher than those in the group of grade I (both P < 0.05). Invasive lobular carcinomas (ILC) showed higher Emean than invasive ductal carcinoma (IDC) (P < 0.001). Lymphovascular invasion (LVI) group showed higher Emax values than negative group (P < 0.05). Emax, Emean and Esd of the Ki-67 positive group presented higher values than negative group (all P < 0.05). Androgen receptor (AR) positive lesions had lower Esd than AR negative lesions (P < 0.05). In multivariate analysis, invasive size independently influenced Emax (P < 0.001). Invasive size and pathological type both independently influenced Emean (both P < 0.001). Invasive size and AR status were both independently influenced Esd (both P < 0.05). CONCLUSION SWE parameters correlated with pathological profiles of invasive breast cancer.In particular, AR positive group showed significantly low Esd than negative group.
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Affiliation(s)
- Junnan Li
- Department of Breast Imaging, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Bo Sun
- The Second Department of Breast Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Yanbo Li
- Department of Breast Imaging, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Shuang Li
- Department of Bone and Tissue Oncology, Tianjin Hospital, Tianjin University, Tianjin, China
| | - Jiahui Wang
- Department of Breast Imaging, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Ying Zhu
- Department of Breast Imaging, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Hong Lu
- Department of Breast Imaging, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China. .,Tianjin Medical University Cancer Institute and Hospital, West Huan-Hu Rd, Ti Yuan Bei, Hexi District, Tianjin, 300060, People's Republic of China.
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22
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Zebrowitz E, Aslanukov A, Kajikawa T, Bedelbaeva K, Bollinger S, Zhang Y, Sarfatti D, Cheng J, Messersmith PB, Hajishengallis G, Heber-Katz E. Prolyl-hydroxylase inhibitor-induced regeneration of alveolar bone and soft tissue in a mouse model of periodontitis through metabolic reprogramming. FRONTIERS IN DENTAL MEDICINE 2022; 3:992722. [PMID: 37641630 PMCID: PMC10462383 DOI: 10.3389/fdmed.2022.992722] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/31/2023] Open
Abstract
Bone injuries and fractures reliably heal through a process of regeneration with restoration to original structure and function when the gap between adjacent sides of a fracture site is small. However, when there is significant volumetric loss of bone, bone regeneration usually does not occur. In the present studies, we explore a particular case of volumetric bone loss in a mouse model of human periodontal disease (PD) in which alveolar bone surrounding teeth is permanently lost and not replaced. This model employs the placement a ligature around the upper second molar for 10 days leading to inflammation and bone breakdown and faithfully replicates the bacterially-induced inflammatory etiology of human PD to induce bone degeneration. After ligature removal, mice are treated with a timed-release formulation of a small molecule inhibitor of prolylhydroxylases (PHDi; 1,4-DPCA) previously shown to induce epimorphic regeneration of soft tissue in non-regenerating mice. This PHDi induces high expression of HIF-1α and is able to shift the metabolic state from OXPHOS to aerobic glycolysis, an energetic state used by stem cells and embryonic tissue. This regenerative response was completely blocked by siHIF1a. In these studies, we show that timed-release 1,4-DPCA rapidly and completely restores PD-affected bone and soft tissue with normal anatomic fidelity and with increased stem cell markers due to site-specific stem cell migration and/or de-differentiation of local tissue, periodontal ligament (PDL) cell proliferation, and increased vascularization. In-vitro studies using gingival tissue show that 1,4-DPCA indeed induces de-differentiation and the expression of stem cell markers but does not exclude the role of migrating stem cells. Evidence of metabolic reprogramming is seen by the expression of not only HIF-1a, its gene targets, and resultant de-differentiation markers, but also the metabolic genes Glut-1, Gapdh, Pdk1, Pgk1 and Ldh-a in jaw periodontal tissue.
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Affiliation(s)
- Elan Zebrowitz
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, United States of America
- Current address: New York Medical College, 40 Sunshine Cottage Rd, Valhalla New York, United States of America
| | - Azamat Aslanukov
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, United States of America
| | - Tetsuhiro Kajikawa
- University of Pennsylvania School of Dental Medicine, Department of Basic and Translational Sciences, Philadelphia, Pennsylvania, United States of America
| | - Kamila Bedelbaeva
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, United States of America
| | - Sam Bollinger
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, United States of America
- Current address: Cancer Biology Graduate Group, Stanford, California, United States of America
| | - Yong Zhang
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, United States of America
- Current address: Rockland Immunochemicals, Inc., Limerick, Pennsylvania, United States of America
| | - David Sarfatti
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, United States of America
| | - Jing Cheng
- Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America
- Current address: Alcon Laboratories, 11460 Johns Creek Pkwy, Duluth, Georgia, United States of America
| | - Phillip B. Messersmith
- Department of Bioengineering and Materials Science and Engineering, UC Berkeley, Berkeley California, United States of America
- Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America
| | - George Hajishengallis
- University of Pennsylvania School of Dental Medicine, Department of Basic and Translational Sciences, Philadelphia, Pennsylvania, United States of America
| | - Ellen Heber-Katz
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, United States of America
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23
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Gomez RL, Ibragimova S, Ramachandran R, Philpott A, Ali FR. Tumoral heterogeneity in neuroblastoma. Biochim Biophys Acta Rev Cancer 2022; 1877:188805. [PMID: 36162542 DOI: 10.1016/j.bbcan.2022.188805] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 08/28/2022] [Accepted: 09/17/2022] [Indexed: 10/31/2022]
Abstract
Neuroblastoma is a solid, neuroendocrine tumor with divergent clinical behavior ranging from asymptomatic to fatal. The diverse clinical presentations of neuroblastoma are directly linked to the high intra- and inter-tumoral heterogeneity it presents. This heterogeneity is strongly associated with therapeutic resistance and continuous relapses, often leading to fatal outcomes. The development of successful risk assessment and tailored treatment strategies lies in evaluating the extent of heterogeneity via the accurate genetic and epigenetic profiling of distinct cell subpopulations present in the tumor. Recent studies have focused on understanding the molecular mechanisms that drive tumoral heterogeneity in pursuing better therapeutic and diagnostic approaches. This review describes the cellular, genetic, and epigenetic aspects of neuroblastoma heterogeneity. In addition, we summarize the recent findings on three crucial factors that can lead to heterogeneity in solid tumors: the inherent diversity of the progenitor cells, the presence of cancer stem cells, and the influence of the tumor microenvironment.
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Affiliation(s)
- Roshna Lawrence Gomez
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, United Arab Emirates
| | - Shakhzada Ibragimova
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, United Arab Emirates
| | - Revathy Ramachandran
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, United Arab Emirates
| | - Anna Philpott
- Department of Oncology, University of Cambridge, Cambridge, United Kingdom; Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Center, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Fahad R Ali
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, United Arab Emirates.
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24
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Du Y, Han J, Jin F, Du Y. Recent Strategies to Address Hypoxic Tumor Environments in Photodynamic Therapy. Pharmaceutics 2022; 14:pharmaceutics14091763. [PMID: 36145513 PMCID: PMC9505114 DOI: 10.3390/pharmaceutics14091763] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/15/2022] [Accepted: 08/22/2022] [Indexed: 12/02/2022] Open
Abstract
Photodynamic therapy (PDT) has become a promising method of cancer treatment due to its unique properties, such as noninvasiveness and low toxicity. The efficacy of PDT is, however, significantly reduced by the hypoxia tumor environments, because PDT involves the generation of reactive oxygen species (ROS), which requires the great consumption of oxygen. Moreover, the consumption of oxygen caused by PDT would further exacerbate the hypoxia condition, which leads to angiogenesis, invasion of tumors to other parts, and metastasis. Therefore, many research studies have been conducted to design nanoplatforms that can alleviate tumor hypoxia and enhance PDT. Herein, the recent progress on strategies for overcoming tumor hypoxia is reviewed, including the direct transport of oxygen to the tumor site by O2 carriers, the in situ generation of oxygen by decomposition of oxygen-containing compounds, reduced O2 consumption, as well as the regulation of tumor microenvironments. Limitations and future perspectives of these technologies to improve PDT are also discussed.
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25
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Safa AR. Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:850-872. [PMID: 36627897 PMCID: PMC9771762 DOI: 10.20517/cdr.2022.20] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 05/10/2022] [Accepted: 05/26/2022] [Indexed: 01/13/2023]
Abstract
Resistance to anticancer agents and apoptosis results in cancer relapse and is associated with cancer mortality. Substantial data have provided convincing evidence establishing that human cancers emerge from cancer stem cells (CSCs), which display self-renewal and are resistant to anticancer drugs, radiation, and apoptosis, and express enhanced epithelial to mesenchymal progression. CSCs represent a heterogeneous tumor cell population and lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, their close relationship with the tumor microenvironment creates greater complexity in developing novel treatment strategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCs in various cancers. These include enhanced expression of ATP-binding cassette membrane transporters, activation of various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrant DNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency of mitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP [cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein], Bcl-2 family members, inhibitors of apoptosis proteins, and PI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that are unresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate CSCs. Several studies have identified promising strategies to target CSCs. These emerging strategies may help target CSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.
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Affiliation(s)
- Ahmad R. Safa
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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26
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Seki T, Saida Y, Kishimoto S, Lee J, Otowa Y, Yamamoto K, Chandramouli GV, Devasahayam N, Mitchell JB, Krishna MC, Brender JR. PEGPH20, a PEGylated human hyaluronidase, induces radiosensitization by reoxygenation in pancreatic cancer xenografts. A molecular imaging study. Neoplasia 2022; 30:100793. [PMID: 35523073 PMCID: PMC9079680 DOI: 10.1016/j.neo.2022.100793] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 11/14/2022]
Abstract
PURPOSE PEGylated human hyaluronidase (PEGPH20) enzymatically depletes hyaluronan, an important component of the extracellular matrix, increasing the delivery of therapeutic molecules. Combinations of chemotherapy and PEGPH20, however, have been unsuccessful in Phase III clinical trials. We hypothesize that by increasing tumor oxygenation by improving vascular patency and perfusion, PEGPH20 will also act as a radiosensitization agent. EXPERIMENTAL DESIGN The effect of PEGPH20 on radiation treatment was analyzed with respect to tumor growth, survival time, p02, local blood volume, and the perfusion/permeability of blood vessels in a human pancreatic adenocarcinoma BxPC3 mouse model overexpressing hyaluronan synthase 3 (HAS3). RESULTS Mice overexpressing HAS3 developed fast growing, radiation resistant tumors that became rapidly more hypoxic as time progressed. Treatment with PEGPH20 increased survival times when used in combination with radiation therapy, significantly more than either radiation therapy or PEGPH20 alone. In mice that overexpressed HAS3, EPR imaging showed an increase in local pO2 that could be linked to increases in perfusion/permeability and local blood volume immediately after PEGPH20 treatment. Hyperpolarized [1-13C] pyruvate suggested PEGPH20 caused a metabolic shift towards decreased glycolytic flux. These effects were confined to the mice overexpressing HAS3 - no effect of PEGPH20 on survival, radiation treatment, or pO2 was seen in wild type BxPC3 tumors. CONCLUSIONS PEGPH20 may be useful for radiosensitization of pancreatic cancer but only in the subset of tumors with substantial hyaluronan accumulation. The response of the treatment may potentially be monitored by non-invasive imaging of the hemodynamic and metabolic changes in the tumor microenvironment.
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Affiliation(s)
- Tomohiro Seki
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States; Josai University, Faculty of Pharmaceutical Sciences, Sakado, Japan
| | - Yu Saida
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States; Department of Respiratory Medicine and Infectious Diseases, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Shun Kishimoto
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
| | - Jisook Lee
- Halozyme Therapeutics, San Diego, California, United States
| | - Yasunori Otowa
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
| | - Kazutoshi Yamamoto
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
| | - Gadisetti Vr Chandramouli
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
| | - Nallathamby Devasahayam
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
| | - James B Mitchell
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
| | - Murali C Krishna
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
| | - Jeffery R Brender
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States.
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27
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Kciuk M, Gielecińska A, Mujwar S, Mojzych M, Marciniak B, Drozda R, Kontek R. Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies. J Enzyme Inhib Med Chem 2022; 37:1278-1298. [PMID: 35506234 PMCID: PMC9090362 DOI: 10.1080/14756366.2022.2052868] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Carbonic anhydrases IX and CAXII (CAIX/CAXII) are transmembrane zinc metalloproteins that catalyze a very basic but crucial physiological reaction: the conversion of carbon dioxide into bicarbonate with a release of the proton. CA, especially CAIX and CAXII isoforms gained the attention of many researchers interested in anticancer drug design due to pivotal functions of enzymes in the cancer cell metastasis and response to hypoxia, and their expression restricted to malignant cells. This offers an opportunity to develop new targeted therapies with fewer side effects. Continuous efforts led to the discovery of a series of diverse compounds with the most abundant sulphonamide derivatives. Here we review current knowledge considering small molecule and antibody-based targeting of CAIX/CAXII in cancer.
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Affiliation(s)
- Mateusz Kciuk
- Department of Molecular Biotechnology and Genetics, Laboratory of Cytogenetics, University of Lodz, Lodz, Poland.,Doctoral School of Exact and Natural Sciences, University of Lodz, Lodz, Poland
| | - Adrianna Gielecińska
- Department of Molecular Biotechnology and Genetics, Laboratory of Cytogenetics, University of Lodz, Lodz, Poland
| | - Somdutt Mujwar
- Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Mariusz Mojzych
- Department of Chemistry, Siedlce University of Natural Sciences and Humanities, Siedlce, Poland
| | - Beata Marciniak
- Department of Molecular Biotechnology and Genetics, Laboratory of Cytogenetics, University of Lodz, Lodz, Poland
| | - Rafał Drozda
- Department of Gastrointestinal Endoscopy, Wl. Bieganski Hospital, Lodz, Poland
| | - Renata Kontek
- Department of Molecular Biotechnology and Genetics, Laboratory of Cytogenetics, University of Lodz, Lodz, Poland
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28
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Marchus CR, Knudson JA, Morrison AE, Strawn IK, Hartman AJ, Shrestha D, Pancheri NM, Glasgow I, Schiele NR. Low-cost, open-source cell culture chamber for regulating physiologic oxygen levels. HARDWAREX 2022; 11:e00253. [PMID: 35509920 PMCID: PMC9058583 DOI: 10.1016/j.ohx.2021.e00253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 06/14/2023]
Abstract
The physiological oxygen levels for several mammalian cell types in vivo are considered to be hypoxic (low oxygen tension), but the vast majority of in vitro mammalian cell culture is conducted at atmospheric oxygen levels of around 21%. In order to understand the impact of low oxygen environments on cells, oxygen levels need to be regulated during in vitro culture. Two common methods for simulating a hypoxic environment are through the regulation of gas composition or chemical induction. Chemically mimicking hypoxia can have adverse effects such as reducing cell viability, making oxygen regulation in cell culture chambers crucial for long-term culture. However, oxygen-regulating cell culture incubators and commercial hypoxia chambers may not always be a viable option due to cost and limited customization. Other low-cost chambers have been developed, but they tend to lack control systems or are fairly small scale. Thus, the objective of this project was to design and develop a low-cost, open-source, controllable, and reproducible hypoxia chamber that can fit inside a standard cell culture incubator. This design allows for the control of O2 between 1 and 21%, while maintaining CO2 levels at 5%, as well as monitoring of temperature, pressure, and relative humidity. Testing showed our hypoxia chamber was able to maintain CO2 levels at 5% and hypoxic O2 levels at 1% and 5% for long-term cell culture. This simple and easy-to-manufacture design uses off the shelf components, and the total material cost was $832.47 (USD).
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Affiliation(s)
- Colin R.N. Marchus
- University of Idaho, Department of Chemical & Biological Engineering, Moscow, ID, United States
| | - Jacob A. Knudson
- University of Idaho, Department of Chemical & Biological Engineering, Moscow, ID, United States
| | - Alexandra E. Morrison
- University of Idaho, Department of Electrical and Computer Engineering, Moscow, ID, United States
| | - Isabell K. Strawn
- University of Idaho, Department of Chemical & Biological Engineering, Moscow, ID, United States
| | - Andrew J. Hartman
- University of Idaho, Department of Electrical and Computer Engineering, Moscow, ID, United States
| | - Dev Shrestha
- University of Idaho, Department of Chemical & Biological Engineering, Moscow, ID, United States
| | - Nicholas M. Pancheri
- University of Idaho, Department of Chemical & Biological Engineering, Moscow, ID, United States
| | - Ian Glasgow
- University of Idaho, Department of Mechanical Engineering, Moscow, ID, United States
| | - Nathan R. Schiele
- University of Idaho, Department of Chemical & Biological Engineering, Moscow, ID, United States
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29
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Filippi L, Pini A, Cammalleri M, Bagnoli P, Dal Monte M. β3-Adrenoceptor, a novel player in the round-trip from neonatal diseases to cancer: Suggestive clues from embryo. Med Res Rev 2021; 42:1179-1201. [PMID: 34967048 PMCID: PMC9303287 DOI: 10.1002/med.21874] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 09/29/2021] [Accepted: 12/15/2021] [Indexed: 01/19/2023]
Abstract
The role of the β-adrenoceptors (β-ARs) in hypoxia-driven diseases has gained visibility after the demonstration that propranolol promotes the regression of infantile hemangiomas and ameliorates the signs of retinopathy of prematurity (ROP). Besides the role of β2-ARs, preclinical studies in ROP have also revealed that β3-ARs are upregulated by hypoxia and that they are possibly involved in retinal angiogenesis. In a sort of figurative round trip, peculiarities typical of ROP, where hypoxia drives retinal neovascularization, have been then translated to cancer, a disease equally characterized by hypoxia-driven angiogenesis. In this step, investigating the role of β3-ARs has taken advantage of the assumption that cancer growth uses a set of strategies in common with embryo development. The possibility that hypoxic induction of β3-ARs may represent one of the mechanisms through which primarily embryo (and then cancer, as an astute imitator) adapts to grow in an otherwise hostile environment, has grown evidence. In both cancer and embryo, β3-ARs exert similar functions by exploiting a metabolic shift known as the Warburg effect, by acquiring resistance against xenobiotics, and by inducing a local immune tolerance. An additional potential role of β3-AR as a marker of stemness has been suggested by the finding that its antagonism induces cancer cell differentiation evoking that β3-ARs may help cancer to grow in a nonhospital environment, a strategy also exploited by embryos. From cancer, the round trip goes back to neonatal diseases for which new possible interpretative keys and potential pharmacological perspectives have been suggested.
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Affiliation(s)
- Luca Filippi
- Department of Clinical and Experimental Medicine, Neonatology and Neonatal Intensive Care UnitUniversity of PisaPisaItaly
| | - Alessandro Pini
- Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
| | - Maurizio Cammalleri
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
| | - Paola Bagnoli
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
| | - Massimo Dal Monte
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
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30
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Shim J, Goldsmith KC. A New Player in Neuroblastoma: YAP and Its Role in the Neuroblastoma Microenvironment. Cancers (Basel) 2021; 13:cancers13184650. [PMID: 34572875 PMCID: PMC8472533 DOI: 10.3390/cancers13184650] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/11/2021] [Accepted: 09/13/2021] [Indexed: 12/13/2022] Open
Abstract
Neuroblastoma is the most common extra-cranial pediatric solid tumor that accounts for more than 15% of childhood cancer-related deaths. High risk neuroblastomas that recur during or after intense multimodal therapy have a <5% chance at a second sustained remission or cure. The solid tumor microenvironment (TME) has been increasingly recognized to play a critical role in cancer progression and resistance to therapy, including in neuroblastoma. The Yes-Associated Protein (YAP) in the Hippo pathway can regulate cancer proliferation, tumor initiation, and therapy response in many cancer types and as such, its role in the TME has gained interest. In this review, we focus on YAP and its role in neuroblastoma and further describe its demonstrated and potential effects on the neuroblastoma TME. We also discuss the therapeutic strategies for inhibiting YAP in neuroblastoma.
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Affiliation(s)
- Jenny Shim
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA;
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA
| | - Kelly C. Goldsmith
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA;
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA 30322, USA
- Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
- Correspondence: ; Tel.: +1-404-727-2655
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31
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Otero-Albiol D, Carnero A. Cellular senescence or stemness: hypoxia flips the coin. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:243. [PMID: 34325734 PMCID: PMC8323321 DOI: 10.1186/s13046-021-02035-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/05/2021] [Indexed: 01/10/2023]
Abstract
Cellular senescence is a complex physiological state whose main feature is proliferative arrest. Cellular senescence can be considered the reverse of cell immortalization and continuous tumor growth. However, cellular senescence has many physiological functions beyond being a putative tumor suppressive trait. It remains unknown whether low levels of oxygen or hypoxia, which is a feature of every tissue in the organism, modulate cellular senescence, altering its capacity to suppress the limitation of proliferation. It has been observed that the lifespan of mammalian primary cells is increased under low oxygen conditions. Additionally, hypoxia promotes self-renewal and pluripotency maintenance in adult and embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and cancer stem cells (CSCs). In this study, we discuss the role of hypoxia facilitating senescence bypass during malignant transformation and acquisition of stemness properties, which all contribute to tumor development and cancer disease aggressiveness.
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Affiliation(s)
- Daniel Otero-Albiol
- Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Avda. Manuel Siurot s/n, 41013, Seville, Spain.,CIBER de CANCER, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Avda. Manuel Siurot s/n, 41013, Seville, Spain. .,CIBER de CANCER, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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32
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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33
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Tan C, Wu J, Wen Z. Doxorubicin-Loaded MnO 2@Zeolitic Imidazolate Framework-8 Nanoparticles as a Chemophotothermal System for Lung Cancer Therapy. ACS OMEGA 2021; 6:12977-12983. [PMID: 34056448 PMCID: PMC8158835 DOI: 10.1021/acsomega.0c05922] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 04/27/2021] [Indexed: 05/05/2023]
Abstract
Doxorubicin-loaded MnO2@zeolitic imidazolate framework-8 (DOX/MnO2@ZIF-8) nanoparticles, a smart multifunctional therapeutic platform, were prepared for the treatment of lung cancer. The morphology, structure, and redox and photothermal properties of MnO2@ZIF-8 were characterized by the corresponding methods. The anticancer drug DOX released from the DOX/MnO2@ZIF-8 nanoparticles was measured. The cell viability of Lewis lung cancer (LLC) cells treated with MnO2@ZIF-8 or DOX/MnO2@ZIF-8 nanoparticles was determined using the cell counting kit-8 (CCK-8) method. The cellular uptake of DOX/MnO2@ZIF-8 nanoparticles into LLC cells was observed using a confocal laser scanning microscope. TUNEL staining was performed to evaluate the in vivo therapeutic efficacy of DOX/MnO2@ZIF-8 nanoparticles. The results showed that the as-prepared MnO2@ZIF-8 nanoparticles had an average particle size of 155.59 ± 13.61 nm and the DOX loading efficiency was 12 wt %. MnO2@ZIF-8 could react with H2O2 to generate O2 and showed a great photothermal conversion effect both in vitro and in vivo. Up to 82% of total DOX could be released from DOX/MnO2@ZIF-8 nanoparticles at pH = 5.0. The CCK-8 assay showed that MnO2@ZIF-8 had low cytotoxicity to LLC cells, while DOX/MnO2@ZIF-8 can significantly reduce the cell viability. DOX/MnO2@ZIF-8 can be accumulated in LLC cells over time. Compared with PBS and DOX/MnO2@ZIF-8 groups, the mice in the DOX/MnO2@ZIF-8 + NIR group had the most apoptotic cells and significantly reduced tumor volume. In conclusion, these findings suggest that the as-prepared MnO2@ZIF-8 nanoparticles with synergetic therapeutic effects by photothermal therapy and improved tumor microenvironment and as a pH-responsive nanocarrier for delivering the nonspecific anticancer drug DOX might be applied in the treatment of lung cancer.
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Asif M, Usman M, Ayub S, Farhat S, Huma Z, Ahmed J, Kamal MA, Hussein D, Javed A, Khan I. Role of ATP-Binding Cassette Transporter Proteins in CNS Tumors: Resistance- Based Perspectives and Clinical Updates. Curr Pharm Des 2021; 26:4747-4763. [PMID: 32091329 DOI: 10.2174/1381612826666200224112141] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 01/22/2020] [Indexed: 12/24/2022]
Abstract
Despite gigantic advances in medical research and development, chemotherapeutic resistance remains a major challenge in complete remission of CNS tumors. The failure of complete eradication of CNS tumors has been correlated with the existence of several factors including overexpression of transporter proteins. To date, 49 ABC-transporter proteins (ABC-TPs) have been reported in humans, and the evidence of their strong association with chemotherapeutics' influx, dissemination, and efflux in CNS tumors, is growing. Research studies on CNS tumors are implicating ABC-TPs as diagnostic, prognostic and therapeutic biomarkers that may be utilised in preclinical and clinical studies. With the current advancements in cell biology, molecular analysis of genomic and transcriptomic interplay, and protein homology-based drug-transporters interaction, our research approaches are streamlining the roles of ABC-TPs in cancer and multidrug resistance. Potential inhibitors of ABC-TP for better clinical outcomes in CNS tumors have emerged. Elacridar has shown to enhance the chemo-sensitivity of Dasatanib and Imatinib in various glioma models. Tariquidar has improved the effectiveness of Temozolomide's in CNS tumors. Although these inhibitors have been effective in preclinical settings, their clinical outcomes have not been as significant in clinical trials. Thus, to have a better understanding of the molecular evaluations of ABC-TPs, as well as drug-interactions, further research is being pursued in research labs. Our lab aims to better comprehend the biological mechanisms involved in drug resistance and to explore novel strategies to increase the clinical effectiveness of anticancer chemotherapeutics, which will ultimately improve clinical outcomes.
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Affiliation(s)
- M Asif
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
| | - M Usman
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
| | - Shahid Ayub
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan,Department of Neurosurgery, Hayatabad Medical Complex, KPK Medical Teaching Institute, Peshawar, Pakistan
| | - Sahar Farhat
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
| | - Zilli Huma
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
| | - Jawad Ahmed
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
| | - Mohammad A Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia,4Enzymoics; Novel Global Community Educational Foundation, 7 Peterlee Place, Hebersham, NSW 2770, Australia
| | - Deema Hussein
- Neurooncology Translational Group, Medical Technology, College of Applied Medical Sciences, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Aneela Javed
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology,
Islamabad 44000, Pakistan,Department of Infectious diseases, Brigham and Women Hospital, Harvard Medical School, Cambridge, Boston, MA 02139, USA
| | - Ishaq Khan
- Cancer Cell Culture & Precision Oncomedicine Lab, Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan
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Lee JY, Ryu D, Lim SW, Ryu KJ, Choi ME, Yoon SE, Kim K, Park C, Kim SJ. Exosomal miR-1305 in the oncogenic activity of hypoxic multiple myeloma cells: a biomarker for predicting prognosis. J Cancer 2021; 12:2825-2834. [PMID: 33854583 PMCID: PMC8040895 DOI: 10.7150/jca.55553] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Background: Exosomes have emerged as important mediators of tumor progression, and a prognostic role for serum exosomal miRNAs has been suggested in multiple myeloma (MM). Given the association of hypoxia with tumor aggressiveness, including cancer stem cell-like phenotypes, we explored exosomal miRNAs from MM cells under hypoxic conditions and analyzed their diverse roles both in promoting oncogenic activity and in predicting prognosis. Methods: The human MM cell line, RPMI 8226, was cultured under hypoxic conditions and their exosome production and exosomal miRNA profiles were compared with those of normoxic parental cells. The survival outcome of myeloma patients was compared using serum levels of exosomal miRNAs, and the effects of exosomal miRNAs on the target genes of MM cells and adjacent immune cells were analyzed. Results: Increased expression of stem cell markers and exosome production were observed in hypoxic MM cells. Exosome miRNA analysis identified a higher expression of miR-1305 in exosomes isolated from hypoxic MM cells than in those of normoxic parental cells. The overall survival of patients with high exosomal miR-1305 was poorer than it was in patients with low exosomal miR-1305. In hypoxic MM cells, an increase of exosomal miR-1305 led to a decrease of cellular miR-1305 and increased expression of the miR-1305 target genes, MDM2, IGF1 and FGF2 resulted in the promotion of oncogenic activity of MM. Exosomal miR-1305 was also transferred from MM cells to macrophages, and miR-1305-transferred macrophages showed tumor-promoting, M2-macrophage phenotypes. Conclusions: Exosome-mediated secretion of miR-1305 in MM cells promoted oncogenic activity of hypoxic MM cells and high serum levels of exosomal miR-1305.
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Affiliation(s)
- Ji Young Lee
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea
| | - Daeun Ryu
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Won Lim
- Division of Hematology-Oncology, Department of Medicine, H plus Yangji hospital, Seoul, Korea
| | - Kyung Ju Ryu
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea
| | - Myung Eun Choi
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea
| | - Sang Eun Yoon
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kihyun Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Chaehwa Park
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea
| | - Seok Jin Kim
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.,Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Berger K, Rhost S, Rafnsdóttir S, Hughes É, Magnusson Y, Ekholm M, Stål O, Rydén L, Landberg G. Tumor co-expression of progranulin and sortilin as a prognostic biomarker in breast cancer. BMC Cancer 2021; 21:185. [PMID: 33618683 PMCID: PMC7898426 DOI: 10.1186/s12885-021-07854-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 01/28/2021] [Indexed: 12/09/2022] Open
Abstract
Background The growth factor progranulin has been implicated in numerous biological processes such as wound healing, inflammation and progressive tumorigenesis. Both progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and have been associated with various clinical properties including tamoxifen resistance. Recent data further suggest that progranulin, via its receptor sortilin, drives breast cancer stem cell propagation in vitro and increases metastasis formation in an in vivo breast cancer xenograft model. In this retrospective biomarker analysis, we aimed to determine whether tumor co-expression of progranulin and sortilin has prognostic and treatment predictive values for breast cancer patients. Methods We explored how co-expression of progranulin and sortilin was associated with established clinical markers by analyzing a tissue microarray including 560 randomized premenopausal breast cancer patients receiving either 2 years of tamoxifen treatment or no adjuvant treatment, with a median follow-up time of 28 years. Breast cancer-specific survival was analyzed using Kaplan-Meier and Cox Proportional Hazards regression models to assess the prognostic and predictive value of progranulin and sortilin in relation to known clinical markers. Results Co-expression of progranulin and sortilin was observed in 20% of the breast cancer samples. In untreated patients, prognostic considerations could be detailed separately from treatment prediction and the high progranulin and sortilin expressing subgroup was significantly associated with breast cancer-specific death in multivariable analyses (HR=2.188, CI: 1.317–3.637, p=0.003) along with tumor size, high tumor grade and lymph node positivity. When comparing the untreated patients with tamoxifen treated patients in the ERα positive subgroup, co-expression of progranulin and sortilin was not linked to tamoxifen resistance. Conclusion Data suggest that co-expression of progranulin and its receptor sortilin is a novel prognostic biomarker combination identifying a highly malignant subgroup of breast cancer. Importantly, this subpopulation could potentially be targeted with anti-sortilin based therapies. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-07854-0.
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Affiliation(s)
- Karoline Berger
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Box 425, Medicinaregatan 1G, SE-13 90, Gothenburg, Sweden
| | - Sara Rhost
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Box 425, Medicinaregatan 1G, SE-13 90, Gothenburg, Sweden
| | - Svanheiður Rafnsdóttir
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Box 425, Medicinaregatan 1G, SE-13 90, Gothenburg, Sweden.,Present address: Department of Surgery, National University Hospital of Iceland, 13-A Hringbraut, Reykjavik, Iceland
| | - Éamon Hughes
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Box 425, Medicinaregatan 1G, SE-13 90, Gothenburg, Sweden
| | - Ylva Magnusson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Box 425, Medicinaregatan 1G, SE-13 90, Gothenburg, Sweden
| | - Maria Ekholm
- Department of Oncology, Region Jönköping County, Jönköping, Sweden.,Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.,Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden
| | - Olle Stål
- Department of Oncology, Region Jönköping County, Jönköping, Sweden.,Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Lisa Rydén
- Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden
| | - Göran Landberg
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Box 425, Medicinaregatan 1G, SE-13 90, Gothenburg, Sweden.
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Metabolic Regulation of Epigenetic Modifications and Cell Differentiation in Cancer. Cancers (Basel) 2020; 12:cancers12123788. [PMID: 33339101 PMCID: PMC7765496 DOI: 10.3390/cancers12123788] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/07/2020] [Accepted: 12/11/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Cancer cells change their metabolism to support a chaotic and uncontrolled growth. In addition to meeting the metabolic needs of the cell, these changes in metabolism also affect the patterns of gene activation, changing the identity of cancer cells. As a consequence, cancer cells become more aggressive and more resistant to treatments. In this article, we present a review of the literature on the interactions between metabolism and cell identity, and we explore the mechanisms by which metabolic changes affect gene regulation. This is important because recent therapies under active investigation target both metabolism and gene regulation. The interactions of these new therapies with existing chemotherapies are not known and need to be investigated. Abstract Metabolic reprogramming is a hallmark of cancer, with consistent rewiring of glucose, glutamine, and mitochondrial metabolism. While these metabolic alterations are adequate to meet the metabolic needs of cell growth and proliferation, the changes in critical metabolites have also consequences for the regulation of the cell differentiation state. Cancer evolution is characterized by progression towards a poorly differentiated, stem-like phenotype, and epigenetic modulation of the chromatin structure is an important prerequisite for the maintenance of an undifferentiated state by repression of lineage-specific genes. Epigenetic modifiers depend on intermediates of cellular metabolism both as substrates and as co-factors. Therefore, the metabolic reprogramming that occurs in cancer likely plays an important role in the process of the de-differentiation characteristic of the neoplastic process. Here, we review the epigenetic consequences of metabolic reprogramming in cancer, with particular focus on the role of mitochondrial intermediates and hypoxia in the regulation of cellular de-differentiation. We also discuss therapeutic implications.
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Chen J, Li Y, Cui H. Preoperative low hematocrit is an adverse prognostic biomarker in ovarian cancer. Arch Gynecol Obstet 2020; 303:767-775. [PMID: 33011886 DOI: 10.1007/s00404-020-05822-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 09/25/2020] [Indexed: 11/29/2022]
Abstract
OBJECTIVE The study aimed to investigate the prognostic value of preoperative hematocrit (HCT) on the survival of epithelial ovarian cancer (EOC) patients. METHODS Patients who underwent primary debulking surgery (PDS) in our institution, from January 2010 to December 2015, were enrolled. The preoperative HCT, hemoglobin (Hb), tumor stage, ascites volume, age, albumin, BMI, ASA score, diabetes and other factors were collected and analyzed to find the risk factors for poor prognosis of EOC patients using Cox regression. Survival analysis was conducted with Kaplan-Meier method and log-rank test. RESULTS 192 patients met the inclusion criteria. HCT < 35% (P = 0.031, HR: 1.715, 95% CI 1.050-2.802) was an independent risk factor for poor overall survival in patients. The mean survival time was 83.7 months in patients with preoperative HCT ≥ 35% and 61.7 months in patients with HCT < 35% (P = 0.002). Patients with low HCT (< 35%) had a poor prognosis compared with patients with normal HCT, specifically in the patients of stage III/IV, age ≥ 65 years, BMI ≥ 25.0 kg/m2, ascites volume ≤ 500 mL, ASA score < 3, albumin ≥ 35 g/L and nondiabetic. Low HCT was more likely to occur in patients with advanced stage (III/IV), anemia (Hb < 110 g/mL), low albumin (< 35 g/L), high ASA score (≥ 3) and platelet > 400 × 109/L. CONCLUSIONS Preoperative low HCT was a valuable predictor for EOC patients' poor prognosis, specifically in obese, nondiabetic, elder, advanced stage but having relatively good performance status patients.
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Affiliation(s)
- Junchen Chen
- Center of Gynecologic Oncology, Peking University People's Hospital, Beijing, China.,Department of Obstetrics and Gynecology, Peking University People's Hospital, No. 11, Xi-Zhi-Men South Street, Xi Cheng District, Beijing, 100044, China
| | - Yi Li
- Center of Gynecologic Oncology, Peking University People's Hospital, Beijing, China. .,Department of Obstetrics and Gynecology, Peking University People's Hospital, No. 11, Xi-Zhi-Men South Street, Xi Cheng District, Beijing, 100044, China.
| | - Heng Cui
- Center of Gynecologic Oncology, Peking University People's Hospital, Beijing, China. .,Department of Obstetrics and Gynecology, Peking University People's Hospital, No. 11, Xi-Zhi-Men South Street, Xi Cheng District, Beijing, 100044, China.
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Renfrow JJ, Soike MH, West JL, Ramkissoon SH, Metheny-Barlow L, Mott RT, Kittel CA, D'Agostino RB, Tatter SB, Laxton AW, Frenkel MB, Hawkins GA, Herpai D, Sanders S, Sarkaria JN, Lesser GJ, Debinski W, Strowd RE. Attenuating hypoxia driven malignant behavior in glioblastoma with a novel hypoxia-inducible factor 2 alpha inhibitor. Sci Rep 2020; 10:15195. [PMID: 32938997 PMCID: PMC7495485 DOI: 10.1038/s41598-020-72290-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 08/27/2020] [Indexed: 12/31/2022] Open
Abstract
Hypoxia inducible factor (HIFs) signaling contributes to malignant cell behavior in glioblastoma (GBM). We investigated a novel HIF2α inhibitor, PT2385, both in vitro, with low-passage patient-derived cell lines, and in vivo, using orthotopic models of glioblastoma. We focused on analysis of HIF2α expression in situ, cell survival/proliferation, and survival in brain tumor-bearing mice treated with PT2385 alone and in combination with standard of care chemoradiotherapy. HIF2α expression increased with glioma grade, with over half of GBM specimens HIF2α positive. Staining clustered in perivascular and perinecrotic tumor regions. Cellular phenotype including proliferation, viability, migration/invasion, and also gene expression were not altered after PT2385 treatment. In the animal model, PT2385 single-agent treatment did improve median overall survival compared to placebo (p = 0.04, n = 21) without a bioluminescence correlate (t = 0.67, p = 0.52). No difference in animal survival was seen in combination treatment with radiation (RT)/temozolomide (TMZ)/PT2385 (p = 0.44, n = 10) or mean tumor bioluminescence (t 1.13, p = 0.32). We conclude that HIF2α is a reasonable novel therapeutic target as expressed in the majority of glioblastomas in our cohort. PT2385 as a single-agent was efficacious in vivo, however, an increase in animal survival was not seen with PT2385 in combination with RT/TMZ. Further study for targeting HIF2α as a therapeutic approach in GBM is warranted.
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Affiliation(s)
- Jaclyn J Renfrow
- Department of Neurological Surgery, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.
- Brain Tumor Center of Excellence, Wake Forest Comprehensive Cancer Center, Winston-Salem, NC, USA.
- One Medical Center Drive, Department of Neurosurgery, Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157, USA.
| | - Michael H Soike
- Department of Radiation Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - James L West
- Department of Neurological Surgery, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Shakti H Ramkissoon
- Department of Pathology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
- Foundation Medicine, Inc., Morrisville, NC, USA
| | - Linda Metheny-Barlow
- Department of Radiation Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
- Brain Tumor Center of Excellence, Wake Forest Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Ryan T Mott
- Department of Pathology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
- Brain Tumor Center of Excellence, Wake Forest Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Carol A Kittel
- Department of Biostatistical Sciences, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Ralph B D'Agostino
- Brain Tumor Center of Excellence, Wake Forest Comprehensive Cancer Center, Winston-Salem, NC, USA
- Department of Biostatistical Sciences, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Stephen B Tatter
- Department of Neurological Surgery, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
- Brain Tumor Center of Excellence, Wake Forest Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Adrian W Laxton
- Department of Neurological Surgery, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
- Brain Tumor Center of Excellence, Wake Forest Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Mark B Frenkel
- Department of Neurological Surgery, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Gregory A Hawkins
- Department of Biochemistry, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Denise Herpai
- Brain Tumor Center of Excellence, Wake Forest Comprehensive Cancer Center, Winston-Salem, NC, USA
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Stephanie Sanders
- Brain Tumor Center of Excellence, Wake Forest Comprehensive Cancer Center, Winston-Salem, NC, USA
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Jann N Sarkaria
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
| | - Glenn J Lesser
- Brain Tumor Center of Excellence, Wake Forest Comprehensive Cancer Center, Winston-Salem, NC, USA
- Department of Internal Medicine - Section on Hematology and Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Waldemar Debinski
- Brain Tumor Center of Excellence, Wake Forest Comprehensive Cancer Center, Winston-Salem, NC, USA
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Roy E Strowd
- Brain Tumor Center of Excellence, Wake Forest Comprehensive Cancer Center, Winston-Salem, NC, USA
- Department of Internal Medicine - Section on Hematology and Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
- Department of Neurology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
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Hypoxic colorectal cancer cells promote metastasis of normoxic cancer cells depending on IL-8/p65 signaling pathway. Cell Death Dis 2020; 11:610. [PMID: 32737283 PMCID: PMC7395770 DOI: 10.1038/s41419-020-02797-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/14/2020] [Accepted: 07/14/2020] [Indexed: 12/17/2022]
Abstract
Tumor heterogeneity is an important feature of malignant tumors, and cell subpopulations may positively interact to facilitate tumor progression. Studies have shown that hypoxic cancer cells possess enhanced metastatic capacity. However, it is still unclear whether hypoxic cancer cells may promote the metastasis of normoxic cells, which have greater access to the blood circulation. When cocultured with hypoxic CRC cells or treated with hypoxic CRC cell-derived CM, normoxic CRC cells possessed increased metastatic capacity. Furthermore, hypoxic CRC cell-derived CM was enriched in interleukin 8. Hypoxic CRC cell-derived CM and recombinant human IL-8 both enhanced the metastatic capacity of normoxic cells by increasing the phosphorylation of p65 and then by inducing epithelial-mesenchymal transition. Knockdown of IL-8 in hypoxic CRC cells or the use of an anti-IL-8 antibody attenuated the CM- or rhIL-8-induced prometastatic capacity of normoxic CRC cells. Inhibition or knockdown of p65 abrogated IL-8-induced prometastatic effects. Most importantly, hypoxia-treated xenograft tumors enhanced the metastasis of normoxic CRC cells. Hypoxic CRC cell-derived IL-8 promotes the metastatic capacity of normoxic cells, and novel therapies targeting the positive interactions between hypoxic and normoxic cells should be developed.
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41
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Chen W, Goldys EM, Deng W. Light-induced liposomes for cancer therapeutics. Prog Lipid Res 2020; 79:101052. [DOI: 10.1016/j.plipres.2020.101052] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 07/05/2020] [Accepted: 07/08/2020] [Indexed: 12/13/2022]
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Hammarlund EU, Amend SR, Pienta KJ. The issues with tissues: the wide range of cell fate separation enables the evolution of multicellularity and cancer. Med Oncol 2020; 37:62. [PMID: 32535731 PMCID: PMC7293661 DOI: 10.1007/s12032-020-01387-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 06/03/2020] [Indexed: 12/24/2022]
Abstract
Our understanding of the rises of animal and cancer multicellularity face the same conceptual hurdles: what makes the clade originate and what makes it diversify. Between the events of origination and diversification lies complex tissue organization that gave rise to novel functionality for organisms and, unfortunately, for malignant transformation in cells. Tissue specialization with distinctly separated cell fates allowed novel functionality at organism level, such as for vertebrate animals, but also involved trade-offs at the cellular level that are potentially disruptive. These trade-offs are under-appreciated and here we discuss how the wide separation of cell phenotypes may contribute to cancer evolution by (a) how factors can reverse differentiated cells into a window of phenotypic plasticity, (b) the reversal to phenotypic plasticity coupled with asexual reproduction occurs in a way that the host cannot adapt, and (c) the power of the transformation factor correlates to the power needed to reverse tissue specialization. The role of reversed cell fate separation for cancer evolution is strengthened by how some tissues and organisms maintain high cell proliferation and plasticity without developing tumours at a corresponding rate. This demonstrates a potential proliferation paradox that requires further explanation. These insights from the cancer field, which observes tissue evolution in real time and closer than any other field, allow inferences to be made on evolutionary events in animal history. If a sweet spot of phenotypic and reproductive versatility is key to transformation, factors stimulating cell fate separation may have promoted also animal diversification on Earth.
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Affiliation(s)
- Emma U Hammarlund
- Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
- Nordic Center for Earth Evolution, University of Southern Denmark, Odense, DK, Denmark.
| | - Sarah R Amend
- The Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA
| | - Kenneth J Pienta
- The Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA
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Cui P, Zhang P, Zhang Y, Sun L, Cui G, Guo X, Wang H, Zhang X, Shi Y, Yu Z. HIF-1α/Actl6a/H3K9ac axis is critical for pluripotency and lineage differentiation of human induced pluripotent stem cells. FASEB J 2020; 34:5740-5753. [PMID: 32112486 DOI: 10.1096/fj.201902829rr] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 02/02/2020] [Accepted: 02/18/2020] [Indexed: 12/13/2022]
Abstract
Pluripotent stem cells (PSCs) are important models for analyzing cellular metabolism and individual development. As a hypoxia-inducible factor subunit, HIF-1α plays an important role in maintaining the pluripotency of PSCs under hypoxic conditions. However, the mechanisms underlying the self-renewal and pluripotency maintenance of human induced pluripotent stem cells (hiPSCs) via regulating HIF-1α largely remain elusive. In this study, we found that disrupting the expression of HIF-1α reduced self-renewal and pluripotency of hiPSCs. Additionally, HIF-1α-knockdown led to lower mitochondrial membrane potential (ΔΨm ) and higher reactive oxygen species production in hiPSCs. However, HIF-1α-overexpression increased ATP content in hiPSCs, while the role of HIF-1α-knockdown was opposite. The embryoid body (EB) and teratoma formation assays showed that HIF-1α-knockdown promoted endoderm differentiation and development in vitro and in vivo. In terms of the underlying molecular mechanisms, HIF-1α-knockdown inhibited the expression of Actl6a and histone H3K9ac acetylation (H3K9ac). Actl6a knockdown reduced the expression of H3K9ac and the pluripotency of hiPSCs, and also affected endoderm differentiation. These data suggest that hindering HIF-1α expression causes the changes in mitochondrial properties and metabolic disorders in hiPSCs. Furthermore, HIF-1α affects hiPSC pluripotency, and germ layer differentiation via Actl6a and histone acetylation.
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Affiliation(s)
- Peng Cui
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Ping Zhang
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Yanmin Zhang
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Lihua Sun
- Department of Hematology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Guanghui Cui
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Xin Guo
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - He Wang
- Department of Medical Laboratory, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Xiaowei Zhang
- School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yu Shi
- Department of Research and Teaching, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Zhendong Yu
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China
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Onderdonk BE, Gutiontov SI, Chmura SJ. The Evolution (and Future) of Stereotactic Body Radiotherapy in the Treatment of Oligometastatic Disease. Hematol Oncol Clin North Am 2020; 34:307-320. [DOI: 10.1016/j.hoc.2019.09.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Kubota S, Tanaka M, Endo H, Ito Y, Onuma K, Ueda Y, Kamiura S, Yoshino K, Kimura T, Kondo J, Inoue M. Dedifferentiation of neuroendocrine carcinoma of the uterine cervix in hypoxia. Biochem Biophys Res Commun 2020; 524:398-404. [PMID: 32007268 DOI: 10.1016/j.bbrc.2020.01.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Accepted: 01/03/2020] [Indexed: 11/28/2022]
Abstract
Neuroendocrine carcinoma of small cell type (SCNEC) is a rare pathological subtype in cervical cancer, which has a worse prognosis than other histological cell types. Due to its low incidence and the lack of experimental platforms, the molecular characteristics of SCNEC in the cervix remain largely unknown. Using the cancer tissue-originated spheroid (CTOS) method-an ex vivo 3D culture system that preserves the differentiation status of the original tumors-we established a panel of CTOS lines of SCNEC. We demonstrated that xenograft tumors and CTOSs, respectively, exhibited substantial intra-tumor and intra-CTOS variation in the expression levels of chromogranin A (CHGA), a neuroendocrine tumor marker. Since hypoxia affects differentiation in various tumors and in stem cells, we also investigated how hypoxia affected neuroendocrine differentiation of SCNEC of the uterine cervix. In the CTOS line cerv21, hypoxia suppressed expression of the neuroendocrine markers CHGA and synaptophysin (SYP). Flow cytometry analysis using CD99 (a membrane protein marker of SCNEC) revealed decreased CD99 expression in a subset of cells under hypoxic conditions. These expression changes were attenuated by HIF-1α knockdown, and by a Notch inhibitor, suggesting that these molecules played a role in the regulation of neuroendocrine differentiation. The examined SCNEC markers were suppressed under hypoxia in multiple CTOS lines. Overall, our present results indicated that neuroendocrine differentiation in SCNEC of the uterus is a variable phenotype, and that hypoxia may be one of the factors regulating the differentiation status.
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Affiliation(s)
- Satoshi Kubota
- Department of Biochemistry, Osaka International Cancer Institute, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Mie Tanaka
- Department of Biochemistry, Osaka International Cancer Institute, Osaka, Japan; Department of Clinical Bio-resource Research and Development, Graduate School of Medicine Kyoto University, Kyoto, Japan; Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hiroko Endo
- Department of Biochemistry, Osaka International Cancer Institute, Osaka, Japan
| | - Yu Ito
- Department of Biochemistry, Osaka International Cancer Institute, Osaka, Japan; Department of Clinical Bio-resource Research and Development, Graduate School of Medicine Kyoto University, Kyoto, Japan; Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kunishige Onuma
- Department of Clinical Bio-resource Research and Development, Graduate School of Medicine Kyoto University, Kyoto, Japan
| | - Yutaka Ueda
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Shoji Kamiura
- Department of Gynecology, Osaka International Cancer Institute, Osaka, Japan
| | - Kiyoshi Yoshino
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tadashi Kimura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Jumpei Kondo
- Department of Biochemistry, Osaka International Cancer Institute, Osaka, Japan; Department of Clinical Bio-resource Research and Development, Graduate School of Medicine Kyoto University, Kyoto, Japan
| | - Masahiro Inoue
- Department of Biochemistry, Osaka International Cancer Institute, Osaka, Japan; Department of Clinical Bio-resource Research and Development, Graduate School of Medicine Kyoto University, Kyoto, Japan.
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Li Z, Shan X, Chen Z, Gao N, Zeng W, Zeng X, Mei L. Applications of Surface Modification Technologies in Nanomedicine for Deep Tumor Penetration. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 8:2002589. [PMID: 33437580 PMCID: PMC7788636 DOI: 10.1002/advs.202002589] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 10/03/2020] [Indexed: 05/04/2023]
Abstract
The impermeable barrier of solid tumors due to the complexity of their components limits the treatment effect of nanomedicine and hinders its clinical translation. Several methods are available to increase the penetrability of nanomedicine, yet they are too complex to be effective, operational, or practical. Surface modification employs the characteristics of direct contact between multiphase surfaces to achieve the most direct and efficient penetration of solid tumors. Furthermore, their simple operation makes their use feasible. In this review, the latest surface modification strategies for the penetration of nanomedicine into solid tumors are summarized and classified into "bulldozer strategies" and "mouse strategies." Additionally, the evaluation methods, existing problems, and the development prospects of these technologies are discussed.
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Affiliation(s)
- Zimu Li
- Institute of PharmaceuticsSchool of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107China
| | - Xiaoting Shan
- Institute of PharmaceuticsSchool of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107China
| | - Zhidong Chen
- Institute of PharmaceuticsSchool of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107China
| | - Nansha Gao
- Institute of PharmaceuticsSchool of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107China
| | - Wenfeng Zeng
- Institute of PharmaceuticsSchool of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107China
| | - Xiaowei Zeng
- Institute of PharmaceuticsSchool of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107China
| | - Lin Mei
- Institute of PharmaceuticsSchool of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107China
- Tianjin Key Laboratory of Biomedical MaterialsKey Laboratory of Biomaterials and Nanotechnology for Cancer ImmunotherapyInstitute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192China
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Amino Acid-Mediated Metabolism: A New Power to Influence Properties of Stem Cells. Stem Cells Int 2019; 2019:6919463. [PMID: 31885621 PMCID: PMC6915148 DOI: 10.1155/2019/6919463] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 11/05/2019] [Accepted: 11/15/2019] [Indexed: 01/10/2023] Open
Abstract
The self-renewal and differentiation potentials of stem cells are dependent on amino acid (AA) metabolism. We review the literature on the metabolic preference of both cancer and noncancer stem cells. The balance in AA metabolism is responsible for maintaining the functionality of noncancer stem cells, and altering the levels of AAs can influence the malignant biological behavior of cancer stem cells. AAs are considered nutrients participating in metabolism and playing a critical role in maintaining the activity of normal stem cells and the effect of therapy of cancer stem cells. Targeting AA metabolism helps inhibit the stemness of cancer stem cells and remodels the function of normal stem cells. This review summarizes the metabolic characteristics and regulation pathways of AA in different stem cells, not only from the nutritional perspective but also from the genomic perspective that have been reported in the recent five years. In addition, we briefly survey new therapeutic modalities that may help eradicate cancer stem cells by exploiting nutrient deprivation. Understanding AA uptake characteristics helps researchers define the preference for AA in different stem cells and enables clinicians make timely interventions to specifically target the cell behavior.
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Hypoxia in the Initiation and Progression of Neuroblastoma Tumours. Int J Mol Sci 2019; 21:ijms21010039. [PMID: 31861671 PMCID: PMC6982287 DOI: 10.3390/ijms21010039] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 12/16/2019] [Accepted: 12/17/2019] [Indexed: 12/16/2022] Open
Abstract
Neuroblastoma is the most frequent extracranial solid tumour in children, causing 10% of all paediatric oncology deaths. It arises in the embryonic neural crest due to an uncontrolled behaviour of sympathetic nervous system progenitors, giving rise to heterogeneous tumours. Low local or systemic tissue oxygen concentration has emerged as a cellular stimulus with important consequences for tumour initiation, evolution and progression. In neuroblastoma, several evidences point towards a role of hypoxia in tumour initiation during development, tumour cell differentiation, survival and metastatic spreading. However, the heterogeneous nature of the disease, its developmental origin and the lack of suitable experimental models have complicated a clear understanding of the effect of hypoxia in neuroblastoma tumour progression and the molecular mechanisms implicated. In this review, we have compiled available evidences to try to shed light onto this important field. In particular, we explore the effect of hypoxia in neuroblastoma cell transformation and differentiation. We also discuss the experimental models available and the emerging alternatives to study this problem, and we present hypoxia-related therapeutic avenues being explored in the field.
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Kobliakov VA. The Mechanisms of Regulation of Aerobic Glycolysis (Warburg Effect) by Oncoproteins in Carcinogenesis. BIOCHEMISTRY (MOSCOW) 2019; 84:1117-1128. [DOI: 10.1134/s0006297919100018] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Aller MA, Arias N, Blanco-Rivero J, Arias J. Metabolism in Acute-On-Chronic Liver Failure: The Solution More than the Problem. Arch Med Res 2019; 50:271-284. [PMID: 31593852 DOI: 10.1016/j.arcmed.2019.09.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 09/09/2019] [Indexed: 12/13/2022]
Abstract
Chronic inflammatory liver disease with an acute deterioration of liver function is named acute-on-chronic inflammation and could be regulated by the metabolic impairments related to the liver dysfunction. In this way, the experimental cholestasis model is excellent for studying metabolism in both types of inflammatory responses. Along the evolution of this model, the rats develop biliary fibrosis and an acute-on-chronic decompensation. The acute decompensation of the liver disease is associated with encephalopathy, ascites, acute renal failure, an acute phase response and a splanchnic increase of pro- and anti-inflammatory cytokines. This multiorgan inflammatory dysfunction is mainly associated with a splanchnic and systemic metabolic switch with dedifferentiation of the epithelial, endothelial and mesothelial splanchnic barriers. Furthermore, a splanchnic infiltration by mast cells occurs, which suggests that these cells could carry out a compensatory metabolic role, especially through the modulation of hepatic and extrahepatic mitochondrial-peroxisome crosstalk. For this reason, we propose the hypothesis that mastocytosis in the acute-on-chronic hepatic insufficiency could represent the development of a survival metabolic mechanisms that mitigates the noxious effect of the hepatic functional deficit. A better understanding the pathophysiological response of the mast cells in liver insufficiency and portal hypertension would help to find new pathways for decreasing the high morbidity and mortality rate of these patients.
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Affiliation(s)
- Maria-Angeles Aller
- Department of Surgery, School of Medicine, Complutense University of Madrid, Madrid, Spain.
| | - Natalia Arias
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; INEUROPA (Instituto de Neurociencias del Principado de Asturias), Oviedo, Spain
| | - Javier Blanco-Rivero
- Department of Physiology, School of Medicine, Autonoma University of Madrid, Madrid, Spain, Instituto de Investigación Biomédica La Paz (IdIPAZ), Madrid, España; Centro de Investigación Biomédica en Red (Ciber) de Enfermedades Cardiovasculares, Madrid, España
| | - Jaime Arias
- Department of Surgery, School of Medicine, Complutense University of Madrid, Madrid, Spain
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