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Oliver S, Williams M, Jolly MK, Gonzalez D, Powathil G. Exploring the role of EMT in ovarian cancer progression using a multiscale mathematical model. NPJ Syst Biol Appl 2025; 11:36. [PMID: 40246908 PMCID: PMC12006308 DOI: 10.1038/s41540-025-00508-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 03/19/2025] [Indexed: 04/19/2025] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) plays a key role in the progression of cancer tumours, significantly reducing the success of treatment. EMT occurs when a cell undergoes phenotypical changes, resulting in enhanced drug resistance, higher cell plasticity, and increased metastatic abilities. Here, we employ a 3D agent-based multiscale modelling framework using PhysiCell to explore the role of EMT over time in two cell lines, OVCAR-3 and SKOV-3. This approach allows us to investigate the spatiotemporal progression of ovarian cancer and the impacts of the conditions in the microenvironment. OVCAR-3 and SKOV-3 cell lines possess highly contrasting tumour layouts, allowing a wide range of different tumour dynamics and morphologies to be tested and studied. Along with performing sensitivity analysis on the model, simulation results capture the biological observations and trends seen in tumour growth and development, thus helping to obtain further insights into OVCAR-3 and SKOV-3 cell line dynamics.
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Affiliation(s)
- Samuel Oliver
- Department of Mathematics, Swansea University, Swansea, UK.
| | - Michael Williams
- Department of Biomedical Sciences, Swansea University, Swansea, UK
| | - Mohit Kumar Jolly
- Department of Bioengineering, Indian Institute of Science, Bangalore, India
| | | | - Gibin Powathil
- Department of Mathematics, Swansea University, Swansea, UK.
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2
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Ding S, Ding W, Zhang Y, Chen Y, Tang H, Jiang X, Chen J. Serum HIF-1α, IGF-1 and IGFBP-3 correlate to recurrence and overall survival in early-stage hepatocellular carcinoma patients. Biomark Med 2024; 18:1027-1036. [PMID: 39552593 PMCID: PMC11633424 DOI: 10.1080/17520363.2024.2421149] [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: 06/19/2024] [Accepted: 10/22/2024] [Indexed: 11/19/2024] Open
Abstract
Aim: Recurrence of hepatocellular carcinoma (HCC) after ultrasound-guided microwave ablation (UGMWA) was a critical issue. Therefore, it is significant to identify the role of hypoxia-inducible factor 1 α (HIF-1α), insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) in recurrence.Materials & methods: HCC patients receiving UGMWA were divided into recurrence and no-recurrence groups. The preoperative and postoperative risk factors were compared between these two groups.Results: Preoperative and postoperative serum levels of HIF-1α, IGF-1 and IGFBP-3 were closely associated with the recurrence of HCC. Serum HIF-1α level was increased, while serum levels of IGF-1 and IGFBP-3 were decreased in HCC patients with recurrence.Conclusion: HIF-1α, IGF-1 and IGFBP-3 were associated with and predicted the recurrence of HCC after UGMWA, respectively or in combination.
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Affiliation(s)
- Shujun Ding
- Department of Ultrasonography, Wuxi People's Hospital Affiliated to Nanjing Medical University, Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Wei Ding
- Department of Interventional Radiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Ye Zhang
- Department of General Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Yunbao Chen
- Department of Ultrasonography, Wuxi People's Hospital Affiliated to Nanjing Medical University, Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Hongtao Tang
- Department of Ultrasonography, Wuxi People's Hospital Affiliated to Nanjing Medical University, Qingyang Road, Wuxi, 214023, Jiangsu, China
| | - Xiao Jiang
- Department of Ultrasonography, Shanghai Yangpu District Shidong Hospital, No. 999 Shiguang Road, Shanghai, 200438, China
| | - Jun Chen
- Department of Ultrasonography, Wuxi People's Hospital Affiliated to Nanjing Medical University, Qingyang Road, Wuxi, 214023, Jiangsu, China
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3
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Agrawal S, Singh GK, Tiwari S. Focused starvation of tumor cells using glucose oxidase: A comprehensive review. Int J Biol Macromol 2024; 281:136444. [PMID: 39389487 DOI: 10.1016/j.ijbiomac.2024.136444] [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: 06/12/2024] [Accepted: 10/07/2024] [Indexed: 10/12/2024]
Abstract
Starvation therapy targets the high metabolic demand of tumor cells. It primarily leans over the consumption of intracellular glucose and simultaneous blockade of alternative metabolic pathways. The strategy involves the use of glucose oxidase (GOx) for catalyzing the conversion of glucose into gluconic acid and hydrogen peroxide. Under these conditions, metabolic re-programming of tumor cells enables the utilization of substrates such as amino acids, fatty acids and lipids. This can be overcome by co-administration of chemo-, photo- and immuno-therapeutics together with glucose oxidase. Targeted delivery of glucose oxidase at tumor site can be enabled with the use of nanoformulations. In this review, we highlight that the outcomes of starvation therapy can be improved using rationally developed nano-formulations. It is possible to load synergistically acting bioactives in these formulations and deliver in site-specific manner and hence achieve the elimination of tumors cells with greater efficacy.
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Affiliation(s)
- Shivanshu Agrawal
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) - Raebareli, Lucknow 226002, India
| | - Gireesh K Singh
- Department of Pharmacy, School of Health Science, Central University of South Bihar, Gaya 824236, India
| | - Sanjay Tiwari
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) - Raebareli, Lucknow 226002, India.
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4
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Dai D, Li C, Xia H, Qi C, Lyu M, Yao Z, Zhang F, Zhu Y, Qi M, Cao X. SVIL promotes ovarian cancer progression and epithelial-mesenchymal transition under hypoxic conditions through the TGF-β/Smad pathway. Gynecol Oncol 2024; 190:167-178. [PMID: 39197416 DOI: 10.1016/j.ygyno.2024.07.688] [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: 03/06/2024] [Revised: 07/18/2024] [Accepted: 07/31/2024] [Indexed: 09/01/2024]
Abstract
OBJECTIVE Ovarian cancer is the malignant tumor with the highest mortality rate in gynecology. We aimed to identify novel genes that promote ovarian cancer progression and epithelial-mesenchymal transition under hypoxic conditions. METHODS We screened SVIL as a hypoxia-associated target in ovarian cancer and explored the related molecular mechanisms. We assessed the effects of SVIL on ovarian cancer progression and metastasis in clinical samples and cellular hypoxia models. Further, we investigated the relevant pathways of SVIL and confirmed the effects of SVIL on ovarian cancer progression by using nude mouse in situ tumor models. RESULTS We found that SVIL was significantly highly expressed in the hypoxic environment of ovarian cancer, and SVIL expression correlated with patient prognosis.CCK8, Wound-healing assay, Transwell assay, Western Blot, and apoptosis assays revealed that knockdown of SVIL inhibited the activation of the TGFβ1/smad2/3 pathway, which attenuated the progression and epithelial-mesenchymal transition(EMT) of ovarian cancer and alleviated cisplatin resistance by increasing cisplatin-induced apoptosis. Furthermore, in a nude mouse ovarian cancer in situ model, we found that the knockdown of SVIL significantly inhibited tumor growth and metastasis. CONCLUSION SVIL highly expressed in the hypoxic microenvironment can increase ovarian cancer progression and cisplatin resistance by activating TGFβ1/smad2/3 pathway. Our study demonstrated that SVIL may be a novel target for the treatment of ovarian cancer.
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Affiliation(s)
- Dongfang Dai
- Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing 210009, China.
| | - Congzhu Li
- Department of Gynecologic Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515041, China.
| | - Hongping Xia
- Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University & School of Chemistry and Chemical Engineering, Nanjing 210009, China; The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China.
| | - Chenxue Qi
- Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing 210009, China; Department of Gynecologic Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515041, China; Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University & School of Chemistry and Chemical Engineering, Nanjing 210009, China; The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China
| | - Mengmeng Lyu
- Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Zhipeng Yao
- The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China
| | - Fan Zhang
- Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University & School of Chemistry and Chemical Engineering, Nanjing 210009, China; The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China
| | - Yan Zhu
- Department of Gynecologic Oncology, Cancer Hospital of Shantou University Medical College, Shantou 515041, China
| | - Min Qi
- The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China
| | - Xiaoxiang Cao
- The Translational Research Institute for Neurological Disorders, Department of Neurosurgery, the First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu 241000, China
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5
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Luo X, Zou W, Wei Z, Yu S, Zhao Y, Wu Y, Wang A, Lu Y. Inducing vascular normalization: A promising strategy for immunotherapy. Int Immunopharmacol 2022; 112:109167. [PMID: 36037653 DOI: 10.1016/j.intimp.2022.109167] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/12/2022] [Accepted: 08/12/2022] [Indexed: 11/30/2022]
Abstract
In solid tumors, the vasculature is highly abnormal in structure and function, resulting in the formation of an immunosuppressive tumor microenvironment by limiting immune cells infiltration into tumors. Vascular normalization is receiving much attention as an alternative strategy to anti-angiogenic therapy, and its potential therapeutic targets include signaling pathways, angiogenesis-related genes, and metabolic pathways. Endothelial cells play an important role in the formation of blood vessel structure and function, and their metabolic processes drive blood vessel sprouting in parallel with the control of genetic signals in cancer. The feedback loop between vascular normalization and immunotherapy has been discussed extensively in many reviews. In this review, we summarize the impact of aberrant tumor vascular structure and function on drug delivery, metastasis, and anti-tumor immune responses. In addition, we present evidences for the mutual regulation of immune vasculature. Based on the importance of endothelial metabolism in controlling angiogenesis, we elucidate the crosstalk between endothelial cells and immune cells from the perspective of metabolic pathways and propose that targeting abnormal endothelial metabolism to achieve vascular normalization can be an alternative strategy for cancer treatment, which provides a new theoretical basis for future research on the combination of vascular normalization and immunotherapy.
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Affiliation(s)
- Xin Luo
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Wei Zou
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zhonghong Wei
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Suyun Yu
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yang Zhao
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yuanyuan Wu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Aiyun Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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6
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Hu H, Ma T, Liu N, Hong H, Yu L, Lyu D, Meng X, Wang B, Jiang X. Immunotherapy checkpoints in ovarian cancer vasculogenic mimicry: Tumor immune microenvironments, and drugs. Int Immunopharmacol 2022; 111:109116. [PMID: 35969899 DOI: 10.1016/j.intimp.2022.109116] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 02/09/2023]
Abstract
Vasculogenic mimicry (VM), a vessel-like structure independent of endothelial cells, commonly exists in solid tumors which requires blood vessels to grow. As a special source of blood supply for tumor progression to a more aggressive state, VM has been observed in a variety of human malignant tumors and is tightly associated with tumor proliferation, invasion, metastasis, and poor patient prognosis. So far, various factors, including immune cells and cytokines, were reported to regulate ovarian cancer progression by influencing VM formation. Herein, we review the mechanisms that regulate VM formation in ovarian cancer and the effect of cells, cytokines, and signaling molecules in the tumor microenvironment on VM formation, Furthermore, we summarize the current clinical application of drugs targeting VM formation.
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Affiliation(s)
- Haitao Hu
- Cancer Hospital of China Medical University, No. 44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, PR China.
| | - Ting Ma
- Department of Biochemistry and Molecular Biology, College of Life Science, China Medical University, Shenyang 110122, Liaoning Province, PR China.
| | - Nanqi Liu
- Department of Biochemistry and Molecular Biology, College of Life Science, China Medical University, Shenyang 110122, Liaoning Province, PR China.
| | - Hong Hong
- Department of Geriatrics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, PR China.
| | - Lujiao Yu
- Department of Geriatrics, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, PR China.
| | - Dantong Lyu
- Department of Biochemistry and Molecular Biology, College of Life Science, China Medical University, Shenyang 110122, Liaoning Province, PR China.
| | - Xin Meng
- Department of Biochemistry and Molecular Biology, College of Life Science, China Medical University, Shenyang 110122, Liaoning Province, PR China.
| | - Biao Wang
- Department of Biochemistry and Molecular Biology, College of Life Science, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, Liaoning Province, PR China.
| | - Xuefeng Jiang
- Department of Immunology, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, PR China.
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7
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Liu Y, Xu X, Zhang Y, Mo Y, Sun X, Shu L, Ke Y. Paradoxical role of β8 integrin on angiogenesis and vasculogenic mimicry in glioblastoma. Cell Death Dis 2022; 13:536. [PMID: 35676251 PMCID: PMC9177864 DOI: 10.1038/s41419-022-04959-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 05/14/2022] [Accepted: 05/17/2022] [Indexed: 01/21/2023]
Abstract
Glioblastoma multiforme (GBM) is the most aggressive and highly vascularized brain tumor with poor prognosis. Endothelial cell-dependent angiogenesis and tumor cell-dependent Vasculogenic mimicry (VM) synergistically contribute to glioma vascularization and progression. However, the mechanism underlying GBM vascularization remains unclear. In this study, GBM stem cells (GSCs) were divided into high and low β8 integrin (ITGB8) subpopulations. Co-culture assays followed by Cell Counting Kit-8 (CCK-8), migration, Matrigel tube formation, and sprouting assays were conducted to assess the proliferative, migratory and angiogenic capacity of GBM cells and human brain microvascular endothelial cells (hBMECs). An intracranial glioma model was constructed to assess the effect of ITGB8 on tumor vascularization in vivo. Our results indicated that ITGB8 expression was elevated in GSCs and positively associated with stem cell markers in glioma tissues, and could be induced by hypoxia and p38 activation. ITGB8 in GSCs inhibited the angiogenesis of hBMECs in vitro, while it promoted the ability of network formation and expression of VM-related proteins. The orthotopic GBM model showed that ITGB8 contributed to decreased angiogenesis, meanwhile enhanced invasiveness and VM formation. Mechanistic studies indicated that ITGB8-TGFβ1 axis modulates VM and epithelial-mesenchymal transition (EMT) process via Smad2/3-RhoA signaling. Together, our findings demonstrated a differential role for ITGB8 in the regulation of angiogenesis and VM formation in GBM, and suggest that pharmacological inhibition of ITGB8 may represent a promising therapeutic strategy for treatment of GBM.
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Affiliation(s)
- Yang Liu
- grid.284723.80000 0000 8877 7471Department of Neuro-oncological Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 P. R. China ,grid.284723.80000 0000 8877 7471The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 P. R. China
| | - Xiangdong Xu
- grid.284723.80000 0000 8877 7471Department of Neuro-oncological Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 P. R. China ,grid.284723.80000 0000 8877 7471The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 P. R. China
| | - Yuxuan Zhang
- grid.284723.80000 0000 8877 7471Department of Neuro-oncological Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 P. R. China ,grid.284723.80000 0000 8877 7471The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 P. R. China
| | - Yunzhao Mo
- grid.284723.80000 0000 8877 7471Department of Neuro-oncological Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 P. R. China ,grid.284723.80000 0000 8877 7471The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 P. R. China
| | - Xinlin Sun
- grid.284723.80000 0000 8877 7471Department of Neuro-oncological Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 P. R. China ,grid.284723.80000 0000 8877 7471The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 P. R. China
| | - Lingling Shu
- grid.488530.20000 0004 1803 6191State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060 P. R. China ,grid.488530.20000 0004 1803 6191Department of Hematological Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060 P. R. China ,grid.194645.b0000000121742757State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, P. R. China
| | - Yiquan Ke
- grid.284723.80000 0000 8877 7471Department of Neuro-oncological Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 P. R. China ,grid.284723.80000 0000 8877 7471The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 P. R. China
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8
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HIF-1α inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer. Cancer Lett 2022; 531:39-56. [DOI: 10.1016/j.canlet.2022.01.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/17/2021] [Accepted: 01/21/2022] [Indexed: 12/30/2022]
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9
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Winter SJ, Miller HA, Steinbach-Rankins JM. Multicellular Ovarian Cancer Model for Evaluation of Nanovector Delivery in Ascites and Metastatic Environments. Pharmaceutics 2021; 13:1891. [PMID: 34834307 PMCID: PMC8625169 DOI: 10.3390/pharmaceutics13111891] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 12/14/2022] Open
Abstract
A novel multicellular model composed of epithelial ovarian cancer and fibroblast cells was developed as an in vitro platform to evaluate nanovector delivery and ultimately aid the development of targeted therapies. We hypothesized that the inclusion of peptide-based scaffold (PuraMatrix) in the spheroid matrix, to represent in vivo tumor microenvironment alterations along with metastatic site conditions, would enhance spheroid cell growth and migration and alter nanovector transport. The model was evaluated by comparing the growth and migration of ovarian cancer cells exposed to stromal cell activation and tissue hypoxia. Fibroblast activation was achieved via the TGF-β1 mediated pathway and tissue hypoxia via 3D spheroids incubated in hypoxia. Surface-modified nanovector transport was assessed via fluorescence and confocal microscopy. Consistent with previous in vivo observations in ascites and at distal metastases, spheroids exposed to activated stromal microenvironment were denser, more contractile and with more migratory cells than nonactivated counterparts. The hypoxic conditions resulted in negative radial spheroid growth over 5 d compared to a radial increase in normoxia. Nanovector penetration attenuated in PuraMatrix regardless of surface modification due to a denser environment. This platform may serve to evaluate nanovector transport based on ovarian ascites and metastatic environments, and longer term, it provide a means to evaluate nanotherapeutic efficacy.
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Affiliation(s)
- Stephen J. Winter
- School of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA;
| | - Hunter A. Miller
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
| | - Jill M. Steinbach-Rankins
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
- Department of Bioengineering, University of Louisville Speed School of Engineering, Louisville, KY 40202, USA
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Center for Predictive Medicine, University of Louisville, Louisville, KY 40202, USA
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10
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Malkov MI, Lee CT, Taylor CT. Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines. Cells 2021; 10:cells10092340. [PMID: 34571989 PMCID: PMC8466990 DOI: 10.3390/cells10092340] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/27/2021] [Accepted: 09/02/2021] [Indexed: 12/28/2022] Open
Abstract
Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), on the regulation of HIF-dependent signaling at sites of inflammation. We report extensive evidence for these cytokines directly impacting upon HIF signaling through the regulation of HIF at transcriptional and post-translational levels. We conclude that multi-level crosstalk between inflammatory and hypoxic signaling pathways plays an important role in shaping the nature and degree of inflammation occurring at hypoxic sites.
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Affiliation(s)
- Mykyta I. Malkov
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; (M.I.M.); (C.T.L.)
- School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
| | - Chee Teik Lee
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; (M.I.M.); (C.T.L.)
- School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
| | - Cormac T. Taylor
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; (M.I.M.); (C.T.L.)
- School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
- Correspondence:
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11
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Liang Z, Liu H, Zhang Y, Xiong L, Zeng Z, He X, Wang F, Wu X, Lan P. Cyr61 from adipose-derived stem cells promotes colorectal cancer metastasis and vasculogenic mimicry formation via integrin α V β 5. Mol Oncol 2021; 15:3447-3467. [PMID: 33999512 PMCID: PMC8637569 DOI: 10.1002/1878-0261.12998] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/14/2021] [Accepted: 05/14/2021] [Indexed: 01/11/2023] Open
Abstract
Adipose‐derived stem cells (ADSCs) play a vital role in colorectal cancer (CRC) progression, but the mechanism remains largely unknown. Herein, we found that ADSCs isolated from CRC patients produced more cysteine‐rich 61 (Cyr61) than those from healthy donors, and the elevated serum Cyr61 levels were associated with advanced TNM stages. Moreover, serum Cyr61 displayed a better diagnostic value for CRC compared to carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19‐9). Mechanistically, integrin αVβ5 was identified as the functional receptor by which Cyr61 promotes CRC cell metastasis in vitro and in vivo by activating the αVβ5/FAK/NF‐κB signaling pathway. In addition, Cyr61 promotes vasculogenic mimicry (VM) formation, thereby promoting tumor growth and metastasis through a αVβ5/FAK/HIF‐1α/STAT3/MMP2 signaling cascade. Histologically, xenografts and clinical samples of CRC both exhibited VM, which was correlated with HIF‐1α and MMP2 activation. Notably, we demonstrated the synergistic effect of combined anti‐VM therapy (integrin αVβ5 inhibitor) and anti‐VEGF therapy (bevacizumab) in patient‐derived xenograft models. Further investigation showed that CRC cell‐derived exosomal STAT3 promoted Cyr61 transcription in ADSCs. These findings indicate that Cyr61 derived from ADSCs plays a critical role in promoting CRC progression via integrin αVβ5 and provides a novel antitumor strategy by targeting Cyr61/αVβ5.
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Affiliation(s)
- Zhenxing Liang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China
| | - Huashan Liu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China
| | - Yunfeng Zhang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li Xiong
- Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ziwei Zeng
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaowen He
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Fengwei Wang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xianrui Wu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China
| | - Ping Lan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China
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12
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Nisar MA, Zheng Q, Saleem MZ, Ahmmed B, Ramzan MN, Ud Din SR, Tahir N, Liu S, Yan Q. IL-1β Promotes Vasculogenic Mimicry of Breast Cancer Cells Through p38/MAPK and PI3K/Akt Signaling Pathways. Front Oncol 2021; 11:618839. [PMID: 34055597 PMCID: PMC8160375 DOI: 10.3389/fonc.2021.618839] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 02/22/2021] [Indexed: 12/12/2022] Open
Abstract
Vasculogenic mimicry (VM), a micro vessel-like structure formed by the cancer cells, plays a pivotal role in cancer malignancy and progression. Interleukin-1 beta (IL-1β) is an active pro-inflammatory cytokine and elevated in many tumor types, including breast cancer. However, the effect of IL-1β on the VM of breast cancer has not been clearly elucidated. In this study, breast cancer cells (MCF-7 and MDA-MB-231) were used to study the effect of IL-1β on the changes that can promote VM. The evidence for VM stimulated by IL-1β was acquired by analyzing the expression of VM-associated biomarkers (VE-cadherin, VEGFR-1, MMP-9, MMP-2, c-Fos, and c-Jun) via western blot, immunofluorescent staining, and Immunohistochemistry (IHC). Additionally, morphological evidence was collected via Matrigel-based cord formation assay under normoxic/hypoxic conditions and microvessel examination through Hematoxylin and Eosin staining (H&E). Furthermore, the STRING and Gene Ontology database was also used to analyze the VM-associated interacting molecules stimulated by IL-β. The results showed that the expression of VM biomarkers was increased in both MCF-7 and MDA-MB-231 cells after IL-1β treatment. The increase in VM response was observed in IL-1β treated cells under both normoxia and hypoxia. IL-1β also increased the activation of transcription factor AP-1 complex (c-Fos/c-Jun). The bioinformatics data indicated that p38/MAPK and PI3K/Akt signaling pathways were involved in the IL-1β stimulation. It was further confirmed by the downregulated expression of VM biomarkers and reduced formation of the intersections upon the addition of the signaling pathway inhibitors. The study suggests that IL-1β stimulates the VM and its associated events in breast cancer cells via p38/MAPK and PI3K/Akt signaling pathways. Aiming the VM-associated molecular targets promoted by IL-1β may offer a novel anti-angiogenic therapeutic strategy to control the aggressiveness of breast cancer cells.
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Affiliation(s)
- Muhammad Azhar Nisar
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Qin Zheng
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Muhammad Zubair Saleem
- Department of Pathology and Pathophysiology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Bulbul Ahmmed
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Muhammad Noman Ramzan
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Syed Riaz Ud Din
- Department of Microbiology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Naeem Tahir
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Shuai Liu
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Qiu Yan
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, China
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13
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Wei X, Chen Y, Jiang X, Peng M, Liu Y, Mo Y, Ren D, Hua Y, Yu B, Zhou Y, Liao Q, Wang H, Xiang B, Zhou M, Li X, Li G, Li Y, Xiong W, Zeng Z. Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments. Mol Cancer 2021; 20:7. [PMID: 33397409 PMCID: PMC7784348 DOI: 10.1186/s12943-020-01288-1] [Citation(s) in RCA: 258] [Impact Index Per Article: 64.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 11/24/2020] [Indexed: 02/08/2023] Open
Abstract
Background Vasculogenic mimicry (VM) is a recently discovered angiogenetic process found in many malignant tumors, and is different from the traditional angiogenetic process involving vascular endothelium. It involves the formation of microvascular channels composed of tumor cells; therefore, VM is considered a new model for the formation of new blood vessels in aggressive tumors, and can provide blood supply for tumor growth. Many studies have pointed out that in recent years, some clinical treatments against angiogenesis have not been satisfactory possibly due to the activation of VM. Although the mechanisms underlying VM have not been fully elucidated, increasing research on the soil “microenvironment” for tumor growth suggests that the initial hypoxic environment in solid tumors is inseparable from VM. Main body In this review, we describe that the stemness and differentiation potential of cancer stem cells are enhanced under hypoxic microenvironments, through hypoxia-induced epithelial-endothelial transition (EET) and extracellular matrix (ECM) remodeling to form the specific mechanism of vasculogenic mimicry; we also summarized some of the current drugs targeting VM through these processes, suggesting a new reference for the clinical treatment of tumor angiogenesis. Conclusion Overall, the use of VM inhibitors in combination with conventional anti-angiogenesis treatments is a promising strategy for improving the effectiveness of targeted angiogenesis treatments; further, considering the importance of hypoxia in tumor invasion and metastasis, drugs targeting the hypoxia signaling pathway seem to achieve good results.
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Affiliation(s)
- Xiaoxu Wei
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yunhua Chen
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xianjie Jiang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Miao Peng
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Yiduo Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Yongzhen Mo
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Daixi Ren
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Yuze Hua
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Boyao Yu
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Yujuan Zhou
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Qianjin Liao
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Hui Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Bo Xiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ming Zhou
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaoling Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yong Li
- Department of Medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China. .,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China. .,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
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14
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Du Q, Han J, Gao S, Zhang S, Pan Y. Hypoxia-induced circular RNA hsa_circ_0008450 accelerates hepatocellular cancer progression via the miR-431/AKAP1 axis. Oncol Lett 2020; 20:388. [PMID: 33193848 PMCID: PMC7656113 DOI: 10.3892/ol.2020.12251] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 08/04/2020] [Indexed: 12/18/2022] Open
Abstract
Hypoxia facilitates the progression of numerous cancers. Circular RNAs (circRNA) have been revealed to be involved in the process of tumors mediated by hypoxia. However, the role and molecular mechanism of circular RNA hsa_circ_0008450 (circ_0008450) in hepatocellular cancer (HCC) under hypoxic conditions has been rarely reported. Expression levels of circ_0008450, microRNA(miR)-431 and A-kinase anchor protein 1 (AKAP1) were examined using reverse transcription-quantitative PCR. Cell viability, apoptosis and glycolysis were assessed via Cell Counting Kit-8, flow cytometry and glycolysis assays, respectively. The association between circ_0008450 or AKAP1 and miR-431 was verified via dual-luciferase reporter assays. Protein levels of AKAP1 were detected by western blotting. Effect of hsa_circ_0008450 on tumor growth in vivo was confirmed by xenograft assays. Circ_0008450 was upregulated in HCC tissues and hypoxia-disposed HCC cells. Depletion of circ_0008450 suppressed tumor growth in vivo and reversed the repression of apoptosis and the acceleration of viability and glycolysis of HCC cells induced by hypoxia treatment in vitro. Notably, circ_0008450 regulated AKAP1 expression by sponging miR-431. Furthermore, miR-431 inhibition reversed the circ_0008450 silencing-mediated effects on viability, apoptosis and glycolysis in hypoxia-treated HCC cells. Additionally, AKAP1 enhancement abolished the effects of miR-431 upregulation on the viability, apoptosis and glycolysis in hypoxia-treated HCC cells. In conclusion, circ_0008450 repression mitigated the progression of HCC under hypoxia by downregulating AKAP1 via miR-431, providing a potential target for HCC treatment.
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Affiliation(s)
- Qiajun Du
- Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Jie Han
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730030, P.R. China
| | - Shan Gao
- Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Shangdi Zhang
- Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Yunyan Pan
- Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
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15
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Kim H, Kim MK, Jang H, Kim B, Kim DR, Lee CH. Sensor-Instrumented Scaffold Integrated with Microporous Spongelike Ultrabuoy for Long-Term 3D Mapping of Cellular Behaviors and Functions. ACS NANO 2019; 13:7898-7904. [PMID: 31244034 DOI: 10.1021/acsnano.9b02291] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Real-time monitoring of cellular behaviors and functions with sensor-instrumented scaffolds can provide a profound impact on fundamental studies of the underlying biophysics and disease modeling. Although quantitative measurement of predictive data for in vivo tests and physiologically relevant information in these contexts is important, the long-term reliable monitoring of cellular functions in three-dimensional (3D) environments is limited by the required set under wet cell culture conditions that are unfavorable to electronic instrument settings. Here, we introduce an ultrabuoyant 3D instrumented scaffold that can remain afloat on the surface of culture medium and thereby provides favorable environments for the entire electronic components in the air while the cells reside and grow underneath. This setting enables high-fidelity recording of electrical cell-substrate impedance and electrophysiological signals for a long period of time (weeks). Comprehensive in vitro studies reveal the utility of this platform as an effective tool for drug screening and tissue development.
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Affiliation(s)
- Hyungjun Kim
- Weldon School of Biomedical Engineering , Purdue University , 206 South Martin Jischke Drive , West Lafayette , Indiana 47907 , United States
| | - Min Ku Kim
- Weldon School of Biomedical Engineering , Purdue University , 206 South Martin Jischke Drive , West Lafayette , Indiana 47907 , United States
| | - Hanmin Jang
- School of Mechanical Engineering , Hanyang University , 222 Wangsimni-ro , Seongdong-gu, Seoul 04763 , Republic of Korea
| | - Bongjoong Kim
- School of Mechanical Engineering , Purdue University , 610 Purdue Mall , West Lafayette , Indiana 47907 , United States
| | - Dong Rip Kim
- School of Mechanical Engineering , Hanyang University , 222 Wangsimni-ro , Seongdong-gu, Seoul 04763 , Republic of Korea
| | - Chi Hwan Lee
- Weldon School of Biomedical Engineering , Purdue University , 206 South Martin Jischke Drive , West Lafayette , Indiana 47907 , United States
- School of Mechanical Engineering , Purdue University , 610 Purdue Mall , West Lafayette , Indiana 47907 , United States
- Department of Speech, Language, and Hearing Sciences , Purdue University , West Lafayette , Indiana 47907 , United States
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16
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Salinas-Vera YM, Gallardo-Rincón D, García-Vázquez R, Hernández-de la Cruz ON, Marchat LA, González-Barrios JA, Ruíz-García E, Vázquez-Calzada C, Contreras-Sanzón E, Resendiz-Hernández M, Astudillo-de la Vega H, Cruz-Colin JL, Campos-Parra AD, López-Camarillo C. HypoxamiRs Profiling Identify miR-765 as a Regulator of the Early Stages of Vasculogenic Mimicry in SKOV3 Ovarian Cancer Cells. Front Oncol 2019; 9:381. [PMID: 31157166 PMCID: PMC6528691 DOI: 10.3389/fonc.2019.00381] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 04/23/2019] [Indexed: 12/12/2022] Open
Abstract
Vasculogenic mimicry (VM) is a novel cancer hallmark in which malignant cells develop matrix-associated 3D tubular networks with a lumen under hypoxia to supply nutrients needed for tumor growth. Recent studies showed that microRNAs (miRNAs) may have a role in VM regulation. In this study, we examined the relevance of hypoxia-regulated miRNAs (hypoxamiRs) in the early stages of VM formation. Data showed that after 48 h hypoxia and 12 h incubation on matrigel SKOV3 ovarian cancer cells undergo the formation of matrix-associated intercellular connections referred hereafter as 3D channels-like structures, which arose previous to the apparition of canonical tubular structures representative of VM. Comprehensive profiling of 754 mature miRNAs at the onset of hypoxia-induced 3D channels-like structures showed that 11 hypoxamiRs were modulated (FC>1.5; p < 0.05) in SKOV3 cells (9 downregulated and 2 upregulated). Bioinformatic analysis of the set of regulated miRNAs showed that they might impact cellular pathways related with tumorigenesis. Moreover, overall survival analysis in a cohort of ovarian cancer patients (n = 485) indicated that low miR-765, miR-193b, miR-148a and high miR-138 levels were associated with worst patients outcome. In particular, miR-765 was severely downregulated after hypoxia (FC < 32.02; p < 0.05), and predicted to target a number of protein-encoding genes involved in angiogenesis and VM. Functional assays showed that ectopic restoration of miR-765 in SKOV3 cells resulted in a significant inhibition of hypoxia-induced 3D channels-like formation that was associated with a reduced number of branch points and patterned tubular-like structures. Mechanistic studies confirmed that miR-765 decreased the levels of VEGFA, AKT1 and SRC-α transducers and exerted a negative regulation of VEGFA by specific binding to its 3'UTR. Finally, overall survival analysis of a cohort of ovarian cancer patients (n = 1435) indicates that high levels of VEGFA, AKT1 and SRC-α and low miR-765 expression were associated with worst patients outcome. In conclusion, here we reported a novel hypoxamiRs signature which constitutes a molecular guide for further clinical and functional studies on the early stages of VM. Our data also suggested that miR-765 coordinates the formation of 3D channels-like structures through modulation of VEGFA/AKT1/SRC-α axis in SKOV3 ovarian cancer cells.
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Affiliation(s)
- Yarely M. Salinas-Vera
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de Mexico, Mexico City, Mexico
| | - Dolores Gallardo-Rincón
- Laboratorio de Medicina Translacional y Departamento de Tumores Gastro-Intestinales, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Raúl García-Vázquez
- Programa en Biomedicina Molecular y Red de Biotecnología, Instituto Politécnico Nacional, Mexico City, Mexico
| | | | - Laurence A. Marchat
- Programa en Biomedicina Molecular y Red de Biotecnología, Instituto Politécnico Nacional, Mexico City, Mexico
| | | | - Erika Ruíz-García
- Laboratorio de Medicina Translacional y Departamento de Tumores Gastro-Intestinales, Instituto Nacional de Cancerología, Mexico City, Mexico
| | | | | | | | - Horacio Astudillo-de la Vega
- Laboratorio de Investigación Translacional en Cáncer y Terapia Celular, Hospital de Oncología, Centro Médico Nacional Siglo XXI, Mexico City, Mexico
| | - José L. Cruz-Colin
- Subdirección de Investigación Básica, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Alma D. Campos-Parra
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de Mexico, Mexico City, Mexico
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17
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Zheng D, Wu W, Dong N, Jiang X, Xu J, Zhan X, Zhang Z, Hu Z. Mxd1 mediates hypoxia-induced cisplatin resistance in osteosarcoma cells by repression of the PTEN tumor suppressor gene. Mol Carcinog 2017; 56:2234-2244. [PMID: 28543796 DOI: 10.1002/mc.22676] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 05/12/2017] [Accepted: 05/19/2017] [Indexed: 12/18/2022]
Abstract
Hypoxia-induced chemoresistance remains a major obstacle to treating osteosarcoma effectively. Mxd1, a member of the Myc/Max/Mxd family, was shown to be involved in the development of drug resistance under hypoxia. However, the effect of Mxd1 on hypoxia-induced cisplatin (CDDP) resistance and its mechanism in osteosarcoma have not been fully elucidated. In this study, we demonstrated that HIF-1α-induced Mxd1 contributed to CDDP resistance in hypoxic U-2OS and MG-63 cells. The knockdown of Mxd1 expression elevated PTEN expression at both protein and RNA levels in these hypoxic cells. Using Luciferase reporter and ChIP assays, we confirmed that Mxd1 directly bound to the E-box sites within the PTEN promoter region. We further demonstrated that PTEN knockdown decreased CDDP sensitivity in Mxd1 siRNA-transfected U-2OS and MG-63 cells under hypoxia. Our results also showed that Mxd1 deficiency in hypoxic U-2OS and MG-63 cells lead to inactivation of PI3K/AKT signaling, which is the downstream of PTEN. Furthermore, blockade of PI3K/AKT signal re-sensitized hypoxic U-2OS and MG-63 cells to CDDP. Taken together, these findings suggest that HIF-1α-induced Mxd1 up-regulation suppresses the expression of PTEN under hypoxia, which leads to the activation of PI3K/AKT antiapoptotic and survival pathway. As a result CDDP resistance in osteosarcoma cells is induced.
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Affiliation(s)
- Datong Zheng
- Clinical Molecular Diagnostic Laboratory, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
- The Second Clinical School, Nanjing Medical University, Nanjing, Jiangsu, P. R. China
- Children's Health Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
| | - Weiling Wu
- The Second Clinical School, Nanjing Medical University, Nanjing, Jiangsu, P. R. China
- Children's Health Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
| | - Na Dong
- The Second Clinical School, Nanjing Medical University, Nanjing, Jiangsu, P. R. China
- Children's Health Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
| | - Xiuqin Jiang
- Clinical Molecular Diagnostic Laboratory, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
| | - Jinjin Xu
- Clinical Molecular Diagnostic Laboratory, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
| | - Xi Zhan
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland
| | - Zhengdong Zhang
- School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P. R. China
| | - Zhenzhen Hu
- Clinical Molecular Diagnostic Laboratory, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China
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18
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Wang Y, Liu P, Wang X, Mao H. Role of X‑linked inhibitor of apoptosis‑associated factor‑1 in vasculogenic mimicry in ovarian cancer. Mol Med Rep 2017; 16:325-330. [PMID: 28534973 DOI: 10.3892/mmr.2017.6597] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 02/09/2017] [Indexed: 11/06/2022] Open
Abstract
X-linked inhibitor of apoptosis‑associated factor 1 (XAF1) was identified as a novel X-linked inhibitor of apoptosis (XIAP) binding partner that may reverse the anti‑apoptotic effect of XIAP. Previous studies have revealed that XAF1 serves an important role in cancer angiogenesis. Vasculogenic mimicry (VM) describes the formation of fluid‑conducting channels by highly invasive and genetically dysregulated tumor cells. VM is critical for tumor blood supply and is associated with aggressive actions and metastasis. The aim of present study was to investigate the potential association between XAF1 expression with VM of ovarian cancer, and evaluate the role of XAF1 in tumor cell migration and invasion of SKOV3 cells. VM structure and XAF1 expression were detected in 94 tissue samples of advanced epithelial ovarian cancer (EOC). Invasion and migration of the SKOV3 human ovarian carcinoma cell line were identified by Transwell assay. It was revealed that the presence of VM was associated with high grade advanced ovarian cancer. Reduced XAF1 expression was significantly associated with presence of VM. Overexpression of XAF1 significantly reduced invasion and migration of SKOV3 cells, and inhibited vascular endothelial growth factor protein expression. Furthermore, vasculature was suppressed by overexpression of XAF1 in vivo in xenograft models. In conclusion, XAF1 expression was associated with VM in ovarian cancer, suggesting a potential role of XAF1 in the formation of VM in EOC. These findings may facilitate the development of novel therapeutic agents for the treatment of ovarian cancer.
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Affiliation(s)
- Yunxia Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Peishu Liu
- Department of Obstetrics and Gynaecology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xietong Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Hongluan Mao
- Department of Obstetrics and Gynaecology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
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19
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Wang M, Zhao X, Zhu D, Liu T, Liang X, Liu F, Zhang Y, Dong X, Sun B. HIF-1α promoted vasculogenic mimicry formation in hepatocellular carcinoma through LOXL2 up-regulation in hypoxic tumor microenvironment. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:60. [PMID: 28449718 PMCID: PMC5408450 DOI: 10.1186/s13046-017-0533-1] [Citation(s) in RCA: 156] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 04/21/2017] [Indexed: 02/07/2023]
Abstract
Background The incidence and mortality rates of hepatocellular carcinoma (HCC) have steadily increased in recent years. A hypoxic microenvironment is one of the most important characteristics of solid tumors which has been shown to promote tumor metastasis, epithelial-mesenchymal transition and angiogenesis. Epithelial-mesenchymal transition and vasculogenic mimicry have been regarded as crucial contributing factors to cancer progression. HIF-1α functions as a master transcriptional regulator in the adaptive response to hypoxia. Lysyl oxidases like 2 (LOXL2) is a member of the lysyl oxidase family, which main function is to catalyze the covalent cross-linkages of collagen and elastin in the extracellular matrix. Recent work has demonstrated that HIF-1α promotes the expression of LOXL2, which is believed to amplify tumor aggressiveness. LOXL2 has shown to promote metastasis and is correlated with poor prognosis in hepatocellular carcinoma. The purpose of our study is to explore the role of HIF-1α in progression and metastasis of hepatocellular carcinoma by promoting the expression of LOXL2 as well as the potential regulatory mechanism. Methods HIF-1α, LOXL2 expression and CD31/periodic acid-Schiff double staining in HCC patient samples were examined by immunohistochemical staining. shRNA plasmids against HIF-1α was used to determine whether LOXL2 been increased by HIF-1α. We monitored a series of rescue assays to demonstrate our hypothesis that LOXL2 is required and sufficient for HIF-1α induced EMT and VM formation, which mediates cellular transformation and takes effect in cellular invasion. Then we performed GeneChip® Human Transcriptome Array (HTA) 2.0 in HepG2 cells, HepG2 cells overexpressed LOXL2 and HepG2 cells treated with CoCl2. Results In clinical HCC tissues, it confirmed a positive relationship between HIF-1α and LOXL2 protein. Importantly, HIF-1α and LOXL2 high expression and the presence of vasculogenic mimicry were correlated to poor prognosis. HIF-1α was found to induce EMT, HCC cell migration, invasion and VM formation by regulating LOXL2. The results of microarray assays were analyzed. Conclusion HIF-1α plays an important role in the development of HCC by promoting HCC metastasis, EMT and VM through up-regulating LOXL2. This study highlights the potential therapeutic value of targeting LOXL2 for suppression of HCC metastasis and progression. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0533-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Meili Wang
- Department of Pathology, Tianjin Medical University, Tianjin, 300070, China
| | - Xiulan Zhao
- Department of Pathology, Tianjin Medical University, Tianjin, 300070, China. .,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China.
| | - Dongwang Zhu
- Department of Surgery, Stomatological Hospital of Tianjin Medical University, Tianjin, 300070, China
| | - Tieju Liu
- Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China
| | - Xiaohui Liang
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China
| | - Fang Liu
- Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China
| | - Yanhui Zhang
- Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, 300060, China
| | - Xueyi Dong
- Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China
| | - Baocun Sun
- Department of Pathology, Tianjin Medical University, Tianjin, 300070, China. .,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, 300052, China.
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20
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[STAT3 activation by hypoxia in in vitro models of cervix cancer and endothelial cells]. BIOMEDICA 2017; 37:119-130. [PMID: 28527256 DOI: 10.7705/biomedica.v37i2.3225] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 06/20/2016] [Indexed: 12/30/2022]
Abstract
INTRODUCTION The biological behavior of cancer cells is influenced by the tumor microenvironment in which they develop. In this context, stressor stimuli such as hypoxia are considered critical for tumor development and therapeutic management. Cellular response to various stimuli is evidenced in the activation of intracellular signaling pathways such as JAK/STAT, which is one of the most important for its effects in differentiation and cell proliferation. OBJECTIVE To evaluate the condition of the JAK/STAT pathway through the expression/activation of the STAT3 protein in cervix cancer cells (HeLa) and endothelial cells (EA.hy926) subjected to hypoxia. MATERIAL AND METHODS Cell lines were subjected to physical (1% O2) or chemical (deferoxamine, DFO, 100 μM) hypoxia for 2, 6 and 24 hours. Changes in the expression and activation of STAT3, and its subcellular localization by indirect immunofluorescence, were determined by western blot. RESULTS Hypoxia was evidenced by the activation and translocation to the nucleus of HIF-1. Neither physical nor chemical hypoxia altered STAT3 expression, but it did affect its activation, as seen in its phosphorylation and translocation to the nucleus in the two models under study. CONCLUSIONS The present study highlights the importance of hypoxia as a stimulus that modifies the activation of the STAT3 protein in HeLa and EA.hy926 cells, which makes it an important factor in the design of therapeutic strategies against cancer.
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21
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The hypoxia-related signaling pathways of vasculogenic mimicry in tumor treatment. Biomed Pharmacother 2016; 80:127-135. [DOI: 10.1016/j.biopha.2016.03.010] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2015] [Revised: 03/13/2016] [Accepted: 03/13/2016] [Indexed: 12/20/2022] Open
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22
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Li NA, Wang H, Zhang J, Zhao E. Knockdown of hypoxia inducible factor-2α inhibits cell invasion via the downregulation of MMP-2 expression in breast cancer cells. Oncol Lett 2016; 11:3743-3748. [PMID: 27313686 DOI: 10.3892/ol.2016.4471] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2015] [Accepted: 03/15/2016] [Indexed: 12/22/2022] Open
Abstract
Hypoxia inducible factors (HIFs) are important regulatory molecules of the intracellular oxygen-signaling pathway. The role of HIF-1α has been confirmed in breast carcinoma; however, little is understood concerning the function of HIF-2α. The present study treated human breast adenocarcinoma MCF-7 cells with the HIF activator cobalt chloride, and transfected HIF-2α small interfering RNAs (siRNAs) into MCF-7 cells to suppress HIF-2α expression. The siRNAs significantly reduced the levels of HIF-2α and matrix metalloproteinase (MMP)-2 in the treated MCF-7 cells. An invasion assay demonstrated that the siRNAs targeting HIF-2α inhibited the invasion potency of the cells. The present study concludes that loss of HIF-2α may be associated with a decreased risk for the progression of human breast cancer, due to the downregulation of the expression of MMP-2.
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Affiliation(s)
- N A Li
- Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Hongxing Wang
- Department of Clinical Immunology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Jie Zhang
- Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Erchen Zhao
- Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
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Hypoxia induced epithelial-mesenchymal transition and vasculogenic mimicry formation by promoting Bcl-2/Twist1 cooperation. Exp Mol Pathol 2015; 99:383-91. [PMID: 26318343 DOI: 10.1016/j.yexmp.2015.08.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 08/20/2015] [Indexed: 10/23/2022]
Abstract
Hypoxia plays a pivotal role in tumor progression. The functions of hypoxia and subsequent Bcl-2/Twist1 activation in epithelial-mesenchymal transition (EMT) and vasculogenic mimicry (VM) formation are currently unclear. This study aimed to investigate the role of Bcl-2/Twist1 cooperation in hypoxia-induced EMT and VM formation. In in vitro experiments, we found that hypoxia resulted in co-overexpression of Bcl-2 and Twist1, facilitated Twist1 nuclear translocation and promoted EMT and VM formation. Co-overexpression of Bcl-2 and Twist1 under normoxia could also induce EMT and promote VM formation. Furthermore, blocking Bcl-2 or Twist1 attenuated the effects of hypoxia on EMT progress and VM formation in hepatocellular carcinoma cells. In in vivo experiments, the mechanism by which hypoxia promoted Bcl-2 and Twist1 co-overexpression and induced EMT process and VM formation was demonstrated using murine xenograft models. These results above suggest that hypoxia could activate the cooperation of Bcl-2 and Twist1, Bcl-2 plays an important role in assisting Twist1 nuclear translocation which could change the expression of a wide range of genes and lead to the induction of EMT and VM formation.
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LIU KUN, SUN BAOCUN, ZHAO XIULAN, WANG XUDONG, LI YANLEI, QIU ZHIQIANG, LIU TIEJU, GU QIANG, DONG XUEYI, ZHANG YANHUI, WANG YONG, ZHAO NAN. Hypoxia promotes vasculogenic mimicry formation by the Twist1-Bmi1 connection in hepatocellular carcinoma. Int J Mol Med 2015. [DOI: 10.3892/ijmm.2015.2293] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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25
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Yu XL, Xia JY, Ye HQ, Li X, Zhang YJ, Mao XG. Retinoic acid aliphatic amide inhibits the AMPK-HIF-1α pathway in human ovarian cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:6416-6424. [PMID: 26261517 PMCID: PMC4525851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 03/21/2015] [Accepted: 05/22/2015] [Indexed: 06/04/2023]
Abstract
Ovarian carcinoma the commonly observed gynecological cancers has a high mortality rate. In the present study effect of retinoic acid aliphatic amide (RACA) in ovarian cancer cells was investigated using proliferation, migration and invasion assays. Western blot was used to examine the Bcl-2, cleaved caspase 3, p-ERK, MMP-2, p-FAK, P-P38, p-AMPKα and HIF-1α protein expression. CoCl2 was used to induce HIF-1α expression in SKOV3ip. 1 and HEY-A8 cells. The results revealed that RACA treatment prompted cell proliferation, invasion and migration but inhibited apoptosis of SKOV3ip. 1 and HEY-A8 cells. RACA treatment also induced upregulation of Bcl-2 and MMP-2, activation of p-P38, p-ERK and p-FAK, inhibition of cleaved caspase 3. RACA treatment also caused upregulatation of HIF-1α in ovarian cells with the activation of p-AMPKα. Upregulation of HIF-1α expression in CoCl2-treated cancer cells resulted in decrease in SDHB. Thus RACA plays a key role in cell proliferation, invasion, migration and apoptosis of human ovarian carcinoma through AMPK-HIF-1α pathway.
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Affiliation(s)
- Xiao-Lan Yu
- Department of Obstetrics and Gynecology, The Affiliated TCM Hospital of Sichuan Medical UniversitySichuan, 646000, China
| | - Ji-Yi Xia
- Researh Center for Drug and Functional Food of Sichuan Medical UniversitySichuan, 646000, China
| | - Hai-Qiong Ye
- Department of Obstetrics and Gynecology, Affiliated Hospital of Sichuan Medical UniversitySichuan, 646000, China
| | - Xia Li
- Department of Obstetrics and Gynecology, The Hosipital of Traditional Chinese Medicine of LeshanSichuan, 614000, China
| | - Yu-Jiao Zhang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Sichuan Medical UniversitySichuan, 646000, China
| | - Xi-Guang Mao
- Department of Obstetrics and Gynecology, Affiliated Hospital of Sichuan Medical UniversitySichuan, 646000, China
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Ataie-Kachoie P, Pourgholami MH, Bahrami-B F, Badar S, Morris DL. Minocycline attenuates hypoxia-inducible factor-1α expression correlated with modulation of p53 and AKT/mTOR/p70S6K/4E-BP1 pathway in ovarian cancer: in vitro and in vivo studies. Am J Cancer Res 2015; 5:575-588. [PMID: 25973298 PMCID: PMC4396050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 01/05/2015] [Indexed: 06/04/2023] Open
Abstract
Hypoxia-inducible factor (HIF)-1α is the key cellular survival protein under hypoxia, and is associated with tumor progression and angiogenesis. We have recently shown the inhibitory effects of minocycline on ovarian tumor growth correlated with attenuation of vascular endothelial growth factor (VEGF) and herein report a companion laboratory study to test if these effects were the result of HIF-1α inhibition. In vitro, human ovarian carcinoma cell lines (A2780, OVCAR-3 and SKOV-3) were utilized to examine the effect of minocycline on HIF-1 and its upstream pathway components to elucidate the underlying mechanism of action of minocycline. Mice harboring OVCAR-3 xenografts were treated with minocycline to assess the in vivo efficacy of minocycline in the context of HIF-1. Minocycline negatively regulated HIF-1α protein levels in a concentration-dependent manner and induced its degradation by a mechanism that is independent of prolyl-hydroxylation. The inhibition of HIF-1α was found to be associated with up-regulation of endogenous p53, a tumor suppressor with confirmed role in HIF-1α degradation. Further studies demonstrated that the effect of minocycline was not restricted to proteasomal degradation and that it also caused down-regulation of HIF-1α translation by suppressing the AKT/mTOR/p70S6K/4E-BP1 signaling pathway. Minocycline treatment of mice bearing established ovarian tumors, led to suppression of HIF-1α accompanied by up-regulation of p53 protein levels and inactivation of AKT/mTOR/p70S6K/4E-BP1 pathway. These data reveal the therapeutic potential of minocycline in ovarian cancer as an agent that targets the pro-oncogenic factor HIF-1α through multiple mechanisms.
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Affiliation(s)
| | | | - Farnaz Bahrami-B
- University of New South Wales Department of Surgery, St George and Sutherland Clinical SchoolSydney, Australia
| | - Samina Badar
- University of New South Wales Department of Surgery, St George and Sutherland Clinical SchoolSydney, Australia
| | - David L Morris
- Department of Surgery, St George HospitalSydney, Australia
- University of New South Wales Department of Surgery, St George and Sutherland Clinical SchoolSydney, Australia
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Wu X, Zhi X, Ji M, Wang Q, Li Y, Xie J, Zhao S. Midkine as a potential diagnostic marker in epithelial ovarian cancer for cisplatin/paclitaxel combination clinical therapy. Am J Cancer Res 2015; 5:629-638. [PMID: 25973302 PMCID: PMC4396029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 01/05/2015] [Indexed: 06/04/2023] Open
Abstract
The paclitaxel/cisplatin combination therapy commonly is used as the first-line treatment for advanced ovarian cancer patients. Midkine (MK), known as a novel tumor biomarker, has been elevated in the serum of patients with epithelial ovarian cancer (EOC). In this study, we aimed to detect the expression of MK in EOC tissues and evaluate clinical value of MK in diagnosis and therapy of EOC. We perform immunohistochemistry analysis to detect MK in EOC sample with postoperative platinum/paclitaxel combination therapy, we found that 71.4% (85 in 119 samples) of these samples were MK positive (> 10% of the cells were stained), and the expression of MK was significantly associated with disease histology (P = 0.038) as well as differentiation grade (P < 0.001). Moreover, MK positive samples show much more sensitive to cisplatin/paclitaxel combination therapy, compared with MK negative samples (P = 0.029). Those results indicated that MK expression might correlate with paclitaxel and/or cisplatin cytotoxicity in clinical therapy of EOC. Then, we evaluated the sensitivity to cisplatin and paclitaxel in 5 ovarian cancer cell lines (ES2, A2870, HO-8910, SKOV3 and SW626), and ES2, the highest MK expression among those cell lines, show the most sensitive to paclitaxel and cisplatin. Further, we confirmed this correlation between MK and paclitaxel and/or cisplatin cytotoxicity with the gain- and lost- of function. Finally, we demonstrated that MK enhanced the cytotoxicity of paclitaxel and/or cisplatin by accumulated cisplatin and paclitaxel through inhibited the expression of multidrug resistance-associated protein 3 (MRP3). In conclusion, MK could be an effective biomarker in diagnosis and therapy of EOC, especially for the drug selection at the time of initial diagnosis.
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Affiliation(s)
- Xiaoqing Wu
- Nanjing First Hospital, Nanjing Medical UniversityNanjing, China
| | - Xiaogai Zhi
- Nanjing First Hospital, Nanjing Medical UniversityNanjing, China
| | | | - Qingling Wang
- Department of Pathology, Xuzhou Medical CollegeXuzhou, China
| | - Yujuan Li
- Nanjing First Hospital, Nanjing Medical UniversityNanjing, China
| | - Jingyan Xie
- Nanjing First Hospital, Nanjing Medical UniversityNanjing, China
| | - Shuli Zhao
- Nanjing First Hospital, Nanjing Medical UniversityNanjing, China
- State Key Laboratory of Reproductive Medicine, Nanjing Medical UniversityNanjing, China
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Tang NN, Zhu H, Zhang HJ, Zhang WF, Jin HL, Wang L, Wang P, He GJ, Hao B, Shi RH. HIF-1α induces VE-cadherin expression and modulates vasculogenic mimicry in esophageal carcinoma cells. World J Gastroenterol 2014; 20:17894-17904. [PMID: 25548487 PMCID: PMC4273139 DOI: 10.3748/wjg.v20.i47.17894] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Revised: 04/03/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether hypoxia inducible factor (HIF)-1α modulates vasculogenic mimicry (VM) by upregulating VE-cadherin expression in esophageal squamous cell carcinoma (ESCC). METHODS Esophageal squamous cancer cell lines Eca109 and TE13 were transfected with plasmids harboring small interfering RNAs targeting HIF-1α or VE-cadherin. The proliferation and invasion of esophageal carcinoma cells were detected by MTT and Transwell migration assays. The formation of tubular networks of cells was analyzed by 3D culture in vitro. BALB/c nude mice were used to observe xenograft tumor formation. The relationship between the expression of HIF-1α and VE-cadherin, ephrinA2 (EphA2) and laminin5γ2 (LN5γ2) was measured by Western blot and real-time polymerase chain reaction. RESULTS Knockdown of HIF-1α inhibited cell proliferation (32.3% ± 6.1% for Eca109 cells and 38.6% ± 6.8% for TE13 cells, P < 0.05). Both Eca109 and TE13 cells formed typical tubular networks. The number of tubular networks markedly decreased when HIF-1α or VE-cadherin was knocked down. Expression of VE-cadherin, EphA2 and LN5γ2 was dramatically inhibited, but the expression of matrix metalloproteinase 2 had no obvious change in HIF-1α-silenced cells. Knockdown of VE-cadherin significantly decreased expression of both EphA2 and LN5γ2 (P < 0.05), while HIF-1α expression was unchanged. The time for xenograft tumor formation was 6 ± 1.2 d for Eca109 cells and Eca109 cells transfected with HIF-1α Neo control short hairpin RNA (shRNA) vector, and 8.4 ± 2.1 d for Eca109 cells transfected with an shRNA against HIF-1α. Knockdown of HIF-1α inhibited vasculogenic mimicry (VM) and tumorigenicity in vivo. CONCLUSION HIF-1α may modulate VM in ESCC by regulating VE-cadherin expression, which affects VM formation through EphA2 and LN5γ2.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Apoptosis
- Cadherins/genetics
- Cadherins/metabolism
- Carcinoma, Squamous Cell/blood supply
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/pathology
- Cell Line, Tumor
- Cell Movement
- Cell Proliferation
- Esophageal Neoplasms/blood supply
- Esophageal Neoplasms/genetics
- Esophageal Neoplasms/metabolism
- Esophageal Neoplasms/pathology
- Esophageal Squamous Cell Carcinoma
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Laminin/genetics
- Laminin/metabolism
- Mice, Inbred BALB C
- Mice, Nude
- Molecular Mimicry
- Neoplasm Invasiveness
- Neovascularization, Pathologic
- RNA Interference
- Receptor, EphA2/genetics
- Receptor, EphA2/metabolism
- Signal Transduction
- Time Factors
- Transfection
- Tumor Burden
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Chen L, Liu T, Zhang S, Zhou J, Wang Y, Di W. Succinate dehydrogenase subunit B inhibits the AMPK-HIF-1α pathway in human ovarian cancer in vitro. J Ovarian Res 2014; 7:115. [PMID: 25491408 PMCID: PMC4279696 DOI: 10.1186/s13048-014-0115-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Accepted: 11/27/2014] [Indexed: 11/10/2022] Open
Abstract
Background Ovarian carcinoma is one of the most common gynecological cancers with high mortality rates. Numerous evidences demonstrate that cancer cells undergo metabolic abnormality during tumorigenesis in tumor microenvironment and further facilitate tumor progression. Succinate dehydrogenase (SDH or Complex II) is one of the important enzymes in the tricarboxylic acid (TCA) cycle. Succinate dehydrogenase subunit B (SDHB) gene, which encodes one of the four subunits of SDH, has been recognized as a tumor suppressor. However the role of SDHB in ovarian cancer is still unclear. Methods Using the SDHB specific siRNA and overexpression plasmid, the expression of SDHB was silenced and conversely induced in ovarian cancer cell lines SKOV3 and A2780, respectively. The possible role of SDHB in ovarian cancer was investigated in vitro, using proliferation, migration and invasion assays. To explore the mechanism, proliferation and migration related proteins such as Bcl-2, cleaved caspase 3, p-ERK, MMP-2, and p-FAK were examined by western blot. P-P38, p-AMPKα, and HIF-1α were also examined by western blot. CoCl2 was used to induce HIF-1α expression in SKOV3 and A2780 cells. Results SDHB silencing promoted cell proliferation, invasion, and migration, but inhibited apoptosis of SKOV3 and A2780 cells. In contrast, overexpression of SDHB inhibited cell proliferation, invasion, migration, and promoted apoptosis in SKOV3 cells. It was observed that up-regulation of Bcl-2 and MMP-2, activation of p-P38, p-ERK, and p-FAK, inhibition of cleaved caspase 3 in SDHB-silenced cells. Meanwhile, decreased Bcl-2 and MMP-2, inhibition of p-P38, p-ERK, and p-FAK, activation of cleaved caspase 3 were shown in SDHB-overexpressed SKOV3 cells. HIF-1α, an essential factor in tumor progression, was up-regulated in SDHB-silenced cells with the activation of p-AMPKα and down-regulated in SDHB-overexpressed cancer cells with the decreased p-AMPKα. And SDHB was proved to be decreased due to upregulation of HIF-1α expression in CoCl2-treated cancer cells. Conclusions Our results firstly revealed that SDHB played a key role in cell proliferation, invasion, migration, and apoptosis of human ovarian carcinoma via AMPK-HIF-1α pathway. SDHB-overexpression might be a new approach to inhibit tumor progression in human ovarian carcinoma. Electronic supplementary material The online version of this article (doi:10.1186/s13048-014-0115-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lilan Chen
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China. .,Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, P. R. China.
| | - Ting Liu
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China. .,Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, P. R. China.
| | - Shu Zhang
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China. .,Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, P. R. China.
| | - Jinhua Zhou
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China. .,Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, P. R. China.
| | - Yunfei Wang
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China. .,Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, P. R. China.
| | - Wen Di
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China. .,Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, P. R. China.
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HUANG MIN, KE YIQUAN, SUN XINLIN, YU LI, YANG ZHILIN, ZHANG YONGHONG, DU MOUXUAN, WANG JIHUI, LIU XIAO, HUANG SHUYUN. Mammalian target of rapamycin signaling is involved in the vasculogenic mimicry of glioma via hypoxia-inducible factor-1α. Oncol Rep 2014; 32:1973-80. [DOI: 10.3892/or.2014.3454] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Accepted: 08/14/2014] [Indexed: 11/06/2022] Open
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Li L, Huang K, You Y, Fu X, Hu L, Song L, Meng Y. Hypoxia-induced miR-210 in epithelial ovarian cancer enhances cancer cell viability via promoting proliferation and inhibiting apoptosis. Int J Oncol 2014; 44:2111-20. [PMID: 24715221 DOI: 10.3892/ijo.2014.2368] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 03/11/2014] [Indexed: 11/06/2022] Open
Abstract
miR-210 is upregulated in a HIF-1α-dependent way in several types of cancers. In addition, upregulated miR-210 promotes cancer proliferation, via its anti-apoptotic effects. It is blind to the regulation of miR-210 under hypoxia conditions for ovarian cancer cells and to the effect of miR-210 on ovarian cancer growth. In the present study, we determined the expression of miR-210 in epithelial ovarian cancer specimens, and in ovarian cancer cell lines under hypoxia conditions, and determined in detail the effect of miR-210 overexpression on tumor cell proliferation, and the possible mechanisms of tumor growth by miR-210 regulation. It was shown that miR-210 expression is upregulated, in response to hypoxia conditions in epithelial ovarian cancer specimens as well as epithelial ovarian cancer cell lines, with an association to HIF-1α overexpression. Furthermore, upregulated miR-210 promoted tumor growth in vitro via targeting PTPN1 and inhibiting apoptosis. Therefore, our findings shed light on the mechanism of ovarian cancer adaptation to hypoxia.
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Affiliation(s)
- Li'an Li
- Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Ke Huang
- Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Yanqin You
- Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Xiaoyu Fu
- Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Lingyun Hu
- Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Lei Song
- Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Yuanguang Meng
- Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing 100853, P.R. China
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Xiao L, Yue X, Ming X, Xu L, Ding M, Xu J, Liu Q. The integrin-linked kinase gene up-regulated by hypoxia plays its pro-survival role in colorectal cancer cells. J Recept Signal Transduct Res 2013; 34:64-72. [PMID: 24299190 DOI: 10.3109/10799893.2013.862271] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
CONTEXT Colorectal cancer (CRC) is a leading cause of cancer death in recent years. It is believed that there are hypoxic regions in both early and advanced stage of tumor and hypoxia is able to reinforce the aggressiveness of tumor cells and accelerate the progression of cancer. OBJECTIVE Until now the mechanisms by which hypoxia promotes the progression of CRC are far from well understood. Integrin-linked kinase (ILK) is a crucial mediator and over-expressed in CRC patients. But whether ILK is involved in the process that hypoxia promotes CRC cells growth and silencing the ILK gene results in CRC cells apoptosis is not clear. MATERIALS AND METHODS Lentivirus transfection, invasion assay, TUNEL assay, Bromodeoxyuridine incorporation and mitochondrial function assay were applied to demonstrate our hypothesis. RESULTS In this study, we found that hypoxia induced the expression of ILK in a time-dependent manner, and after knocking down ILK expression with ILK shRNA, the cells proliferation promoted by hypoxia was inhibited in HT29 cell line. Moreover, blocking the ILK pathway led to caspase-3 and caspase-9 activations, the decrease of mitochondrial membrane potential, and cells apoptosis. And the inhibitory effects of hypoxia on cells apoptosis were mediated by the ILK pathway. In addition, hypoxia promoted HT29 cells metastasis and invasion through the ILK pathway. CONCLUSIONS Therefore, we conclude that the CRC cells survival and invasion enhanced by hypoxia are mediated by ILK, and ILK may be an important potential therapeutic target for CRC.
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Affiliation(s)
- Lei Xiao
- Department of General Surgery, the Fourth Affiliated Hospital of Harbin Medical University , Harbin , China
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Cao Z, Shang B, Zhang G, Miele L, Sarkar FH, Wang Z, Zhou Q. Tumor cell-mediated neovascularization and lymphangiogenesis contrive tumor progression and cancer metastasis. BIOCHIMICA ET BIOPHYSICA ACTA 2013; 1836:273-286. [PMID: 23933263 DOI: 10.1016/j.bbcan.2013.08.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 07/22/2013] [Accepted: 08/01/2013] [Indexed: 12/12/2022]
Abstract
Robust neovascularization and lymphangiogenesis have been found in a variety of aggressive and metastatic tumors. Endothelial sprouting angiogenesis is generally considered to be the major mechanism by which new vasculature forms in tumors. However, increasing evidence shows that tumor vasculature is not solely composed of endothelial cells (ECs). Some tumor cells acquire processes similar to embryonic vasculogenesis and produce new vasculature through vasculogenic mimicry, trans-differentiation of tumor cells into tumor ECs, and tumor cell-EC vascular co-option. In addition, tumor cells secrete various vasculogenic factors that induce sprouting angiogenesis and lymphangiogenesis. Vasculogenic tumor cells actively participate in the formation of vascular cancer stem cell niche and a premetastatic niche. Therefore, tumor cell-mediated neovascularization and lymphangiogenesis are closely associated with tumor progression, cancer metastasis, and poor prognosis. Vasculogenic tumor cells have emerged as key players in tumor neovascularization and lymphangiogenesis and play pivotal roles in tumor progression and cancer metastasis. However, the mechanisms underlying tumor cell-mediated vascularity as they relate to tumor progression and cancer metastasis remain unclear. Increasing data have shown that various intrinsic and extrinsic factors activate oncogenes and vasculogenic genes, enhance vasculogenic signaling pathways, and trigger tumor neovascularization and lymphangiogenesis. Collectively, tumor cells are the instigators of neovascularization. Therefore, targeting vasculogenic tumor cells, genes, and signaling pathways will open new avenues for anti-tumor vasculogenic and metastatic drug discovery. Dual targeting of endothelial sprouting angiogenesis and tumor cell-mediated neovascularization and lymphangiogenesis may overcome current clinical problems with anti-angiogenic therapy, resulting in significantly improved anti-angiogenesis and anti-cancer therapies.
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Affiliation(s)
- Zhifei Cao
- Cyrus Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215006, China
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Zhang Y, Sun B, Zhao X, Liu Z, Wang X, Yao X, Dong X, Chi J. Clinical significances and prognostic value of cancer stem-like cells markers and vasculogenic mimicry in renal cell carcinoma. J Surg Oncol 2013; 108:414-9. [PMID: 23996537 DOI: 10.1002/jso.23402] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Accepted: 07/12/2013] [Indexed: 12/28/2022]
Affiliation(s)
- Yanhui Zhang
- Department of Pathology, Tianjin Cancer Hospital; Tianjin Medical University; Tianjin China
| | - Baocun Sun
- Department of Pathology, Tianjin Cancer Hospital; Tianjin Medical University; Tianjin China
- Department of Pathology; Tianjin Medical University; Tianjin China
- Department of Pathology; Tianjin General Hospital; Tianjin Medical University; Tianjin China
| | - Xiulan Zhao
- Department of Pathology; Tianjin Medical University; Tianjin China
- Department of Pathology; Tianjin General Hospital; Tianjin Medical University; Tianjin China
| | - Zhiyong Liu
- Department of Pathology, Tianjin Cancer Hospital; Tianjin Medical University; Tianjin China
| | - Xudong Wang
- Department of Pathology, Tianjin Cancer Hospital; Tianjin Medical University; Tianjin China
| | - Xin Yao
- Department of Pathology, Tianjin Cancer Hospital; Tianjin Medical University; Tianjin China
| | - Xueyi Dong
- Department of Pathology; Tianjin Medical University; Tianjin China
- Department of Pathology; Tianjin General Hospital; Tianjin Medical University; Tianjin China
| | - Jiadong Chi
- Department of Pathology; Tianjin Medical University; Tianjin China
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Petronzi C, Festa M, Peduto A, Castellano M, Marinello J, Massa A, Capasso A, Capranico G, La Gatta A, De Rosa M, Caraglia M, Filosa R. Cyclohexa-2,5-diene-1,4-dione-based antiproliferative agents: design, synthesis, and cytotoxic evaluation. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2013; 32:24. [PMID: 23631805 PMCID: PMC3666920 DOI: 10.1186/1756-9966-32-24] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Accepted: 04/12/2013] [Indexed: 02/03/2023]
Abstract
BACKGROUND Tumors are diseases characterized by uncontrolled cell growth and, in spite of the progress of medicine over the years, continue to represent a major threat to the health, requiring new therapies. Several synthetic compounds, such as those derived from natural sources, have been identified as anticancer drugs; among these compounds quinone represent the second largest class of anticancer agents in use. Several studies have shown that these act on tumor cells through several mechanisms. An important objective of this work is to develop quinoidscompounds showing antitumor activity, but with fewer side effects. The parachinone cannabinol HU-331, is a small molecule that with its core 4-hydroxy-1,4-benzoquinone, exhibits a potent and selective cytotoxic activity on different tumor cell lines. A series of derivatives 3-hydroxy-1,4-benzochinoni were thus developed through HU-331 chemical modifications. The purpose of the work is to test the ability of the compounds to induce proliferative inhibition and study the mechanisms of cell death. METHODS The antitumor activities were evaluated in vitro by examining their cytotoxic effects against different human cancer cell lines. All cell lines tested were plated in 96-multiwell and treated with HU-100-V at different concentrations and cell viability was evaluated byMTT assay. Subsequently via flow cytometry (FACS) it was possible to assess apoptosis by the system of double labeling with PI and Annexin-V, and the effect of the compounds on ROS formation by measuring the dichlorofluorescein fluorescence. RESULTS The substitution by n-hexyl chain considerably enhanced the bioactivity of the compounds. In details, 2-hexyl-5-hydroxycyclohexa-2,5-diene-1,4-dione (V), 2,5-Dimethoxy-3-hexyl-2,5-cyclohexadiene-1,4-dione (XII) and 2-hydroxy-5-methoxy-3-hexyl-cyclohexa-2,5-diene-1,4-dione (XIII) showed most prominent cytotoxicity against almost human tumour cell lines. Compound V was further subjected to downstream apoptotic analysis, demostrating a time-dependent pro-apoptotic activity on human melanoma M14 cell line mediated by caspases activation and poly-(ADP-ribose)-polymerase (PARP) protein cleavage. CONCLUSIONS These findings indicate that 2-hexyl-5-idrossicicloesa-2,5-diene-1,4-dione can be a promising compound for the design of a new class of antineoplastic derivatives.Carmen Petronzi, Michela Festa, Antonella Peduto and Maria Castellano: equally contributed equally to this work.
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Affiliation(s)
- Carmen Petronzi
- Department of Pharmaceutical and Biomedical Sciences, University of Salerno, via Ponte Don Melillo, Fisciano, SA, 84084, Italy
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Tafani M, Pucci B, Russo A, Schito L, Pellegrini L, Perrone GA, Villanova L, Salvatori L, Ravenna L, Petrangeli E, Russo MA. Modulators of HIF1α and NFkB in Cancer Treatment: Is it a Rational Approach for Controlling Malignant Progression? Front Pharmacol 2013; 4:13. [PMID: 23408731 PMCID: PMC3569619 DOI: 10.3389/fphar.2013.00013] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 01/23/2013] [Indexed: 01/17/2023] Open
Abstract
HIF1α and NFkB are two transcription factors very frequently activated in tumors and involved in tumor growth, progression, and resistance to chemotherapy. In fact, HIF1α and NFkB together regulate transcription of over a thousand genes that, in turn, control vital cellular processes such as adaptation to the hypoxia, metabolic reprograming, inflammatory reparative response, extracellular matrix digestion, migration and invasion, adhesion, etc. Because of this wide involvement they could control in an integrated manner the origin of the malignant phenotype. Interestingly, hypoxia and inflammation have been sequentially bridged in tumors by the discovery that alarmin receptors genes such as RAGE, P2X7, and some TLRs, are activated by HIF1α; and that, in turn, alarmin receptors strongly activate NFkB and proinflammatory gene expression, evidencing all the hallmarks of the malignant phenotype. Recently, a large number of drugs have been identified that inhibit one or both transcription factors with promising results in terms of controlling tumor progression. In addition, many of these molecules are natural compounds or off-label drugs already used to cure other pathologies. Some of them are undergoing clinical trials and soon they will be used alone or in combination with standard anti-tumoral agents to achieve a better treatment of tumors with reduction of metastasis formation and, more importantly, with a net increase in survival. This review highlights the central role of HIF1α activated in hypoxic regions of the tumor, of NFkB activation and proinflammatory gene expression in transformed cells to understand their progression toward malignancy. Different molecules and strategies to inhibit these transcription factors will be reviewed. Finally, the central role of a new class of deacetylases called Sirtuins in regulating HIF1α and NFkB activity will be outlined.
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Affiliation(s)
- Marco Tafani
- Department of Experimental Medicine, Sapienza University of Rome Rome, Italy ; Laboratory of Molecular and Cellular Pathology - Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana Rome, Italy
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Abstract
HT1080 - a human fibrosarcoma-derived cell line – forms aggressive angiogenic tumours in immuno-compromised mice. In spite of its extensive use as a model of tumour angiogenesis, the molecular event(s) initiating the angiogenic program in these cells are not known. Since hypoxia stimulates tumour angiogenesis, we examined the hypoxia-induced events evoked in these cells. In contrast to cells grown under normoxic conditions, hypoxia-primed (1% O2) HT1080 cells formed robust tubules on growth factor-reduced matrigel and formed significantly larger tumours in xenograft models in a chetomin-sensitive manner, indicating the role of HIF-1α-mediated transcription in these processes. Immuno-histochemical analyses of tumours formed by GFP-expressing HT1080 cells clearly showed that the tumour cells themselves expressed various angiogenic markers including Neuropilin-1 (NRP-1) and formed functional vessels containing red blood cells, thereby unambiguously demonstrating the vasculogenic mimicry of HT1080 cells in vivo. Experiments performed with the HT1080 cells stably transfected with plasmid constructs expressing shNRP-1 or full-length NRP-1 clearly established that the HIF1α-mediated up-regulation of NRP-1 played a deterministic role in the process. Hypoxia-exposure resulted in an up-regulation of c-Myc and OCT3/4 and a down-regulation of KLF4 mRNAs, suggesting their involvement in the tumour formation and angiogenesis. However, silencing of NRP-1 alone, though not affecting proliferation in culture, was sufficient to abrogate the tumour formation completely; clearly establishing that the hypoxia-mediated HIF-1α-dependent up-regulation of NRP-1 is a critical molecular event involved in the vasculogenic mimicry and tumor formation by HT1080 cells in vivo.
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Affiliation(s)
- Roli M. Misra
- Stem Cell Lab, National Centre for Cell Science, National Centre for Cell Science Complex, University of Pune Campus, Ganeshkhind, Pune, Maharashtra, India
| | - Manmohan S. Bajaj
- Stem Cell Lab, National Centre for Cell Science, National Centre for Cell Science Complex, University of Pune Campus, Ganeshkhind, Pune, Maharashtra, India
| | - Vaijayanti P. Kale
- Stem Cell Lab, National Centre for Cell Science, National Centre for Cell Science Complex, University of Pune Campus, Ganeshkhind, Pune, Maharashtra, India
- * E-mail:
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Wu S, Yu L, Wang D, Zhou L, Cheng Z, Chai D, Ma L, Tao Y. Aberrant expression of CD133 in non-small cell lung cancer and its relationship to vasculogenic mimicry. BMC Cancer 2012; 12:535. [PMID: 23170850 PMCID: PMC3518202 DOI: 10.1186/1471-2407-12-535] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2012] [Accepted: 11/14/2012] [Indexed: 12/28/2022] Open
Abstract
Background To investigate on expressions and clinical significances of CD133 protein and vasculogenic mimicry (VM) in primary non-small cell lung cancer (NSCLC). Methods The specimens of NSCLC from 305 Chinese patients with follow-up were analyzed for CD133 protein expression and VM by immunohistochemical and histochemical staining. Results In NSCLC, positive rates of 48.9% and 35.7% were obtained for CD133 and VM, respectively. The VM and expression of CD133 were significantly higher in carcinoma than in normal. There were a positive relationship between the VM and expression of CD133 and the tumor grade, lymph node metastasis and clinical stage (all P<0.05). The overall mean survival time of the patients with CD133 and VM positive expression was lower than that of patients with negative expression. Microvessel density (MVD) was positive corresponded with the grade, lymph node metastasis and clinical stage (all P<0.05). The overall mean survival time of the patients with MVD≥22’s group was shorter than that of patients with MVD<22’s group. Pathological-tumor-node-metastasis (pTNM) stage, positive expression of CD133 and VM, postoperative therapy and MVD were independent prognostic factors of NSCLC (P<0.05). Immunohistochemistry revealed an important intratumoral heterogeneity in all four CD133 expression profiles. Conclusions VM, MVD and expression of CD133 are related to differentiation, lymph node metastasis, clinical stage, and prognosis. It is suggested that CD133, VM and MVD should be considered as a potential marker for the prognosis.
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Affiliation(s)
- Shiwu Wu
- Department of Pathology, the First Affiliated Hospital of Bengbu Medical College, Bengbu Medical College, Bengbu 233000, Anhui Province, China
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Liang D, Ma Y, Liu J, Trope CG, Holm R, Nesland JM, Suo Z. The hypoxic microenvironment upgrades stem-like properties of ovarian cancer cells. BMC Cancer 2012; 12:201. [PMID: 22642602 PMCID: PMC3407800 DOI: 10.1186/1471-2407-12-201] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2011] [Accepted: 05/29/2012] [Indexed: 12/26/2022] Open
Abstract
Background To study whether hypoxia influences the stem-like properties of ovarian cancer cells and their biological behavior under hypoxia. Method Ovarian cancer cell lines ES-2 and OVCAR-3 were cultivated in different oxygen tensions for proliferation, cell cycling and invasion analyses. The clonogenic potential of cells was examined by colony formation and sphere formation assays. Stem cell surface markers, SP and CD44bright and CD44dim cells were analyzed by flow cytometry. Protein expression of HIF-1α, HIF-2α, Ot3/4 and Sox2 were investigated by Western blotting. Results Both cell lines cultivated at hypoxic condition grew relatively slowly with extended G0/G1 phase. However, if the cells were pre-treated under 1% O2 for 48 hrs before brought back to normoxia, the cells showed significantly higher proliferation rate with higher infiltration capability, and significant more colonies and spheres, in comparison to the cells always cultivated under normoxia. CD44bright cells expressed significantly higher levels of Oct3/4 and Sox2 than the CD44dim cells and formed significantly more clones and spheres examined in vitro. Hypoxic treatment of the cells resulted in stronger CD44 expression in both cell lines, and stronger CD133 expression in the OVCAR-3 cell line. In parallel with these findings, significantly increased number of side population (SP) cells and up-regulated expression of Oct3/4 and Sox2 in both ES-2 and OVCAR-3 cell lines were observed. Conclusion We conclude that ovarian cancer cells survive hypoxia by upgrading their stem-like properties through up-regulation of stemness-related factors and behave more aggressively when brought back to higher oxygen environment.
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Affiliation(s)
- Dongming Liang
- Departments of Pathology, the Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Montebello, Oslo, Norway
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Gest C, Mirshahi P, Li H, Pritchard LL, Joimel U, Blot E, Chidiac J, Poletto B, Vannier JP, Varin R, Mirshahi M, Cazin L, Pujade-Lauraine E, Soria J, Soria C. Ovarian cancer: Stat3, RhoA and IGF-IR as therapeutic targets. Cancer Lett 2012; 317:207-217. [PMID: 22120672 DOI: 10.1016/j.canlet.2011.11.026] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Revised: 10/28/2011] [Accepted: 11/21/2011] [Indexed: 11/16/2022]
Abstract
Seeking to improve ovarian cancer therapy, we compared biological characteristics of the moderately-aggressive OVCAR-3 cell line with two highly aggressive ovarian cancer cell populations: the SK-OV-3 cell line, and HASCJ primary cells isolated from the ascitic fluid of a patient with FIGO stage IV ovarian cancer. Secretion of angiogenic factors was not discriminative, whereas cell invasion through Matrigel and vasculogenic mimicry were much greater in the more aggressive cells. Among 10 agents tested for their ability to decrease cancer cell aggressivity using these two models, inhibitors of Stat3, IGF-IR and Rho GTPase were found to be the most promising.
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Affiliation(s)
- Caroline Gest
- Laboratoire M.E.R.C.I - EA 3829, Faculté de Médecine et de Pharmacie, Université de Rouen, Rouen, France.
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