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Mahaki H, Nobari S, Tanzadehpanah H, Babaeizad A, Kazemzadeh G, Mehrabzadeh M, Valipour A, Yazdinezhad N, Manoochehri H, Yang P, Sheykhhasan M. Targeting VEGF signaling for tumor microenvironment remodeling and metastasis inhibition: Therapeutic strategies and insights. Biomed Pharmacother 2025; 186:118023. [PMID: 40164047 DOI: 10.1016/j.biopha.2025.118023] [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: 01/22/2025] [Revised: 03/18/2025] [Accepted: 03/27/2025] [Indexed: 04/02/2025] Open
Abstract
The tumor microenvironment (TME) plays a pivotal role in cancer progression and metastasis, with vascular endothelial growth factor (VEGF) signaling serving as a key regulator of tumor angiogenesis and immune evasion. VEGF induces abnormal blood vessel formation, promoting tumor growth, immune suppression, and metastasis through epithelialmesenchymal transition (EMT). As a result, VEGF signaling has become a critical therapeutic target in cancer treatment. This review examines the molecular mechanisms driving VEGF-mediated tumor growth and angiogenesis, with a focus on the interaction between tumor and endothelial cells and the dual role of VEGF in fostering vascularization and immune suppression. Current anti-VEGF therapies, including monoclonal antibodies (e.g., bevacizumab) and tyrosine kinase inhibitors (TKIs), have demonstrated efficacy and have received FDA approval for various cancers; however, therapeutic resistance remains a significant challenge. Strategies to overcome resistance, such as novel VEGF inhibitors, vascular normalization approaches, and combination therapies with immune checkpoint inhibitors, have been explored. Additionally, future directions emphasize the need for personalized approaches to improve treatment efficacy and reduce metastasis. A comprehensive understanding of VEGF signaling in the TME may pave the way for more effective cancer therapies.
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Affiliation(s)
- Hanie Mahaki
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sima Nobari
- Deputy of Health, Iran University of Medical Science, Tehran, Iran
| | - Hamid Tanzadehpanah
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Babaeizad
- Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Gholamhosein Kazemzadeh
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Mehrabzadeh
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arezoo Valipour
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nader Yazdinezhad
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Manoochehri
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Piao Yang
- Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, OH 43210, USA
| | - Mohsen Sheykhhasan
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
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2
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Selvaraj A, McManus G, Healy CM, Moran GP. Fusobacterium nucleatum induces invasive growth and angiogenic responses in malignant oral keratinocytes that are cell line- and bacterial strain-specific. Front Cell Infect Microbiol 2024; 14:1417946. [PMID: 39286811 PMCID: PMC11402903 DOI: 10.3389/fcimb.2024.1417946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 08/13/2024] [Indexed: 09/19/2024] Open
Abstract
Fusobacterium nucleatum is an anaerobic commensal of the oral cavity recently reported to be associated with cancers of the gastrointestinal tract and oral squamous cell carcinoma (OSCC). In this study, we investigate the impact on oral keratinocytes of infection with a genetically diverse set of strains of F. nucleatum subsp. polymorphum recovered from patients with oral dysplasia (n=6). We employed H357 oral keratinocytes derived from a stage 1 OSCC and H376 cells derived from a stage 3 OSCC. Adhesion phenotypes were strain specific, with 3/6 clinical isolates examined exhibiting higher adherence to the stage 3 H376 cell line. Conversely, intracellular invasion was greatest in the H357 cells and was associated with specific transcriptional responses including autophagy and keratinization. Infection of both H357 and H376 cell lines induced transcriptional and cytokine responses linked to cancer cell migration and angiogenesis. F. nucleatum infection induced greater levels of MMP9 secretion in the H376 cell line which was associated with enhanced motility and invasion phenotypes. Additionally, the degree of F. nucleatum induced invasive growth by H376 cells varied between different clinical isolates of F. nucleatum subsp. polymorphum. Blockage of CCL5 signalling using the inhibitor metCCL5 resulted in reduced keratinocyte invasion. F. nucleatum infection also induced expression of the pro-angiogenic chemokine MCP-1 and the angiogenic growth factor VEGF-A resulting in increased capillary-like tube formation in HUVEC cells, most significantly in H376 cells. Treatment of HUVEC cells with resveratrol, a VEGF-A signalling inhibitor, significantly attenuated F. nucleatum induced tube formation. Our data indicate that the outcomes of F. nucleatum-oral cell interactions can vary greatly depending on the bacterial genotype and the malignant phenotype of the host cell.
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Affiliation(s)
- Ajith Selvaraj
- Division of Oral Biosciences, Dublin Dental University Hospital and School of Dental Science, Trinity College Dublin, Dublin, Ireland
| | - Gavin McManus
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Claire M Healy
- Division of Oral and Maxillofacial Surgery, Oral Medicine and Oral Pathology, Dublin Dental University Hospital and School of Dental Science, Trinity College Dublin, Dublin, Ireland
| | - Gary P Moran
- Division of Oral Biosciences, Dublin Dental University Hospital and School of Dental Science, Trinity College Dublin, Dublin, Ireland
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3
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Cong L, Wang J, Li X, Tian Y, Xu S, Liang C, Xu W, Wang W, Xu S. Microfluidic Droplet-SERS Platform for Single-Cell Cytokine Analysis via a Cell Surface Bioconjugation Strategy. Anal Chem 2022; 94:10375-10383. [PMID: 35815899 DOI: 10.1021/acs.analchem.2c01249] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A microfluidic-based surface-enhanced Raman scattering (SERS) platform for analyzing cytokines secreted by single cells is reported based on the elaborate bioconjugation of the immuno-sandwich complex on the probed cell surface. This platform integrates the dual functions of microfluidic droplet separation of single cells and SERS measurement. Two immune nanoprobes (capture probe and SERS probe) are introduced into a microfluidic droplet along with a single cell. They were anchored to the cell membrane protein surface by capturing secreted cytokines to form an immune sandwich structure, realizing the enrichment effect of cytokines above the cell membrane surface and the amplification effect of SERS detection probes. This single-cell analytical platform was applied to track specific cell-secreted vascular endothelial growth factor (VEGF) of different cell lines (MCF-7, SGC, and T24), and highly sensitive detection of VEGF was achieved. Chemometric methods (principal component analysis and t-distributed stochastic neighbor embedding) were adopted for the SERS data analysis, and the support vector machine (SVM) discriminant model was established to test the data. These chemometric methods successfully identify significant differences in the secreting ability of cytokines among three kinds of cancer cell lines, revealing cell heterogeneity. In addition, the behavior of single cells secreting VEGF was monitored time-dependently and was shown to increase with time. This work demonstrates the importance of tracking specific cells secreting cytokines based on the cell surface bioconjugation strategy. Our developed platform provides guidelines for using the single-cell exocytosis factors as biomarkers to assess the early diagnosis of cancer and provide physiological cues for learning single-cell secretions.
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Affiliation(s)
- Lili Cong
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Jiaqi Wang
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Xinli Li
- HOOKE Instruments Ltd., Changchun 130033, P. R. China
| | - Yu Tian
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Shizhi Xu
- Institute of Frontier Medical Science, Jilin University, Changchun 130021, P. R. China
| | - Chongyang Liang
- Institute of Frontier Medical Science, Jilin University, Changchun 130021, P. R. China
| | - Weiqing Xu
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China.,Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Weigang Wang
- No. 2 Department of Urology, The First Hospital of Jilin University, Changchun 130021, P. R. China
| | - Shuping Xu
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China.,Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130012, P. R. China.,Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun 130012, P. R. China
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4
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Cong L, Tian Y, Huo Z, Xu W, Hou C, Shi W, Wang W, Liang C, Xu S. Single-Cell VEGF Analysis by Fluorescence Imaging-Microfluidic Droplet Platform: An Immunosandwich Strategy on the Cell Surface. Anal Chem 2022; 94:6591-6598. [PMID: 35446550 DOI: 10.1021/acs.analchem.2c00695] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Despite recent advances in single-cell analysis techniques, the ability of single-cell analysis platforms to track specific cells that secreted cytokines remains limited. Here, we report a microfluidic droplet-based fluorescence imaging platform that can analyze single cell-secreted vascular endothelial growth factor (VEGF), an important regulator of physiological and pathological angiogenesis, to explore cellular physiological clues at the single-cell level. Two kinds of silica nanoparticle (NP)-based immunoprobes were developed, and they were bioconjugated to the membrane proteins of the probed cell surface via the bridging of secreted VEGF. Thus, an immunosandwich assay was built above the probed cell via fluorescence imaging analysis of each cell in isolated droplets. This analytical platform was used to compare the single-cell VEGF secretion ability of three cell lines (MCF-7, HeLa, and H8), which experimentally demonstrates the cellular heterogeneity of cells in secreting cytokines. The uniqueness of this method is that the single-cell assay is carried out above the cell of interest, and no additional carriers (beads or reporter cells) for capturing analytes are needed, which dramatically improves the availability of microdroplets. This single-cell analytical platform can be applied for determining other secreted cytokines at the single-cell level by changing other immune pairs, which will be an available tool for exploring single-cell metabonomics.
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Affiliation(s)
- Lili Cong
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Yu Tian
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China.,State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Zepeng Huo
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Weiqing Xu
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China.,Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Chunxi Hou
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Wei Shi
- Key Lab for Molecular Enzymology & Engineering of Ministry of Education, Jilin University, Changchun 130012, P. R. China
| | - Weigang Wang
- No. 2 Department of Urology, The First Hospital of Jilin University, Changchun 130021, P. R. China
| | - Chongyang Liang
- Institute of Frontier Medical Science, Jilin University, Changchun 130021, P. R. China
| | - Shuping Xu
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China.,Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130012, P. R. China.,Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun 130012, P. R. China
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Zhao L, Guo Y, Guo Y, Ji X, Fan D, Chen C, Yuan W, Sun Z, Ji Z. Effect and mechanism of circRNAs in tumor angiogenesis and clinical application. Int J Cancer 2021; 150:1223-1232. [PMID: 34724210 DOI: 10.1002/ijc.33863] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 09/27/2021] [Accepted: 09/30/2021] [Indexed: 12/12/2022]
Abstract
Tumor blood vessels provide oxygen and necessary nutrients for the tumor, which provides the basis for tumor metastasis. Therefore, tumor angiogenesis plays a very important role in tumor growth and metastasis. In contrast to linear RNAs, circRNAs represent a type of closed-loop RNA with diverse biological functions. At the same time, circRNAs have strong stability, timeliness, tissue specificity and disease specificity. With the rapid development of next-generation sequencing and bioinformatics, there have been an increasing number of studies on circRNAs. At present, a large number of studies have reported that circRNAs regulate tumor growth, invasion, metastasis, tumor metabolism, tumor immunity and other biological functions. Increasing evidence has shown that circRNAs also play an important role in tumor angiogenesis. In this review, we briefly introduced tumor angiogenesis and circRNAs and outlined the main ways that circRNAs affect tumor angiogenesis from multiple aspects. Finally, we further explored the potential clinical application value of circRNAs in the context of tumor angiogenesis.
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Affiliation(s)
- Luyang Zhao
- BGI College, Zhengzhou University, Zhengzhou, Henan, China.,Henan Institute of Medical and Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, China.,School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Yuying Guo
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yaxin Guo
- Henan Institute of Medical and Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, China.,Department of Basic Medical, Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Xiang Ji
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Dandan Fan
- Henan Institute of Medical and Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, China
| | - Chen Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Weitang Yuan
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhenqiang Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Zhenyu Ji
- Henan Institute of Medical and Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, China.,Department of Basic Medical, Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan, China
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6
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Chen L, Lin G, Chen K, Liang R, Wan F, Zhang C, Tian G, Zhu X. VEGF promotes migration and invasion by regulating EMT and MMPs in nasopharyngeal carcinoma. J Cancer 2020; 11:7291-7301. [PMID: 33193893 PMCID: PMC7646165 DOI: 10.7150/jca.46429] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 10/04/2020] [Indexed: 12/12/2022] Open
Abstract
Background: Vascular endothelial growth factor (VEGF) is an important pro-angiogenic factor. Accumulating data have indicated that VEGF is involved in tumour metastasis. However, the mechanism through which VEGF regulates nasopharyngeal carcinoma (NPC) metastasis is largely unknown. This study aimed to examine the biological function of VEGF in NPC metastasis and its underlying mechanism. Methods: We used western blotting and qPCR to examine the difference in VEGF expression between NPC cells and the immortalized nasopharyngeal epithelial cell line NP69. Wound healing assays, transwell assays and animal experiments were used to further verify the role of VEGF in the invasion and migration of NPC cells. The protein levels of the epithelial-mesenchymal transition (EMT) and matrix metalloproteinase (MMP) family were analysed by immunofluorescence (IF) and western blotting. Enzyme-linked immunosorbent assay (ELISA) and transwell assays were used to determine whether VEGF enhanced the invasion and migration of NPC cells in an autocrine manner. Western blotting was used to examine how autocrine VEGF-VEGFR2 signalling regulated EMT and MMPs. Results: We observed higher levels of VEGF in NPC cells than that in NP69 cells and identified an association between high VEGF levels and tumour invasion and migration. Mechanistically, the VEGF-mediated increase in EMT markers, MMP2 and MMP9 promoted NPC cell invasion and migration. Additionally, NPC cells secreted VEGF to promote cell invasion, migration and angiogenesis. Autocrine VEGF-VEGFR2 signalling increased ERK1/2 phosphorylation, promoted EMT process and MMPs at the indicated times. Conclusion: This study revealed that VEGF plays a role in controlling NPC cell metastasis by regulating EMT markers and MMPs in an autocrine manner.
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Affiliation(s)
- Li Chen
- Department of Oncology, Affiliated Wuming Hospital of Guangxi Medical University, Nanning, Guangxi, 530010, People's Republic of China.,Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People's Republic of China
| | - Guoxiang Lin
- Department of Oncology, Affiliated Wuming Hospital of Guangxi Medical University, Nanning, Guangxi, 530010, People's Republic of China
| | - Kaihua Chen
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People's Republic of China
| | - Renba Liang
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People's Republic of China
| | - Fangzhu Wan
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People's Republic of China
| | - Chuxiao Zhang
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People's Republic of China
| | - Ge Tian
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People's Republic of China
| | - Xiaodong Zhu
- Department of Oncology, Affiliated Wuming Hospital of Guangxi Medical University, Nanning, Guangxi, 530010, People's Republic of China.,Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People's Republic of China.,Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
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7
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Liu J, Luthuli S, Yang Y, Cheng Y, Zhang Y, Wu M, Choi J, Tong H. Therapeutic and nutraceutical potentials of a brown seaweed Sargassum fusiforme. Food Sci Nutr 2020; 8:5195-5205. [PMID: 33133523 PMCID: PMC7590327 DOI: 10.1002/fsn3.1835] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/24/2020] [Accepted: 07/25/2020] [Indexed: 12/11/2022] Open
Abstract
Sargassum fusiforme, also known as Yangqicai () in Chinese and Hijiki in Japanese, is a brown seaweed that grows abundantly along the rocky coastlines of Asian countries such as Japan, Korea, and China. The first use of S. fusiforme as a traditional Chinese medicinal plant was recorded in the Shennong Bencao Jing, dated 200 AD. It was referred to as Haizao (seaweed), renowned for treating Yinglu (tumor-like induration), dysuria, and edema. Currently, it is commonly used in traditional cuisine as it is rich in dietary fiber and minerals such as calcium, iron, and magnesium. Owing to its health benefits, S. fusiforme remains popular in China, Korea, and Japan, as well as in the UK and in North America. Currently, there is a lack of research on S. fusiforme; thus, we review the therapeutic effects of S. fusiforme, such as anticancer, antiangiogenic, and antiviral effects, in vitro and in vivo as reported during the past two decades. This review may promote further research on the therapeutic uses of S. fusiforme. Furthermore, we discuss the processes and considerations involved in using drugs produced from marine sources.
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Affiliation(s)
- Jian Liu
- College of Life and Environmental ScienceWenzhou UniversityWenzhouChina
- Department of Biotechnology and BioengineeringChonnam National UniversityGwangjuKorea
| | - Sibusiso Luthuli
- College of Life and Environmental ScienceWenzhou UniversityWenzhouChina
| | - Yue Yang
- College of Life and Environmental ScienceWenzhou UniversityWenzhouChina
| | - Yang Cheng
- College of Life and Environmental ScienceWenzhou UniversityWenzhouChina
| | - Ya Zhang
- College of Life and Environmental ScienceWenzhou UniversityWenzhouChina
| | - Mingjiang Wu
- College of Life and Environmental ScienceWenzhou UniversityWenzhouChina
| | - Jong‐il Choi
- Department of Biotechnology and BioengineeringChonnam National UniversityGwangjuKorea
| | - Haibin Tong
- College of Life and Environmental ScienceWenzhou UniversityWenzhouChina
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Kim M, Ma DJ, Calligaris D, Zhang S, Feathers RW, Vaubel RA, Meaux I, Mladek AC, Parrish KE, Jin F, Barriere C, Debussche L, Watters J, Tian S, Decker PA, Eckel-Passow JE, Kitange GJ, Johnson AJ, Parney IF, Anastasiadis PZ, Agar NYR, Elmquist WF, Sarkaria JN. Efficacy of the MDM2 Inhibitor SAR405838 in Glioblastoma Is Limited by Poor Distribution Across the Blood-Brain Barrier. Mol Cancer Ther 2018; 17:1893-1901. [PMID: 29970480 DOI: 10.1158/1535-7163.mct-17-0600] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 10/24/2017] [Accepted: 06/25/2018] [Indexed: 01/12/2023]
Abstract
Controversy exists surrounding whether heterogeneous disruption of the blood-brain barrier (BBB), as seen in glioblastoma (GBM), leads to adequate drug delivery sufficient for efficacy in GBM. This question is especially important when using potent, targeted agents that have a poor penetration across an intact BBB. Efficacy of the murine double minute-2 (MDM2) inhibitor SAR405838 was tested in patient-derived xenograft (PDX) models of GBM. In vitro efficacy of SAR405838 was evaluated in PDX models with varying MDM2 expression and those with high (GBM108) and low (GBM102) expression were evaluated for flank and orthotopic efficacy. BBB permeability, evaluated using TexasRed-3 kDa dextran, was significantly increased in GBM108 through VEGFA overexpression. Drug delivery, MRI, and orthotopic survival were compared between BBB-intact (GBM108-vector) and BBB-disrupted (GBM108-VEGFA) models. MDM2-amplified PDX lines with high MDM2 expression were sensitive to SAR405838 in comparison with MDM2 control lines in both in vitro and heterotopic models. In contrast with profound efficacy observed in flank xenografts, SAR405838 was ineffective in orthotopic tumors. Although both GBM108-vector and GBM108-VEGFA readily imaged on MRI following gadolinium contrast administration, GBM108-VEGFA tumors had a significantly enhanced drug and gadolinium accumulation, as determined by MALDI-MSI. Enhanced drug delivery in GBM108-VEGFA translated into a marked improvement in orthotopic efficacy. This study clearly shows that limited drug distribution across a partially intact BBB may limit the efficacy of targeted agents in GBM. Brain penetration of targeted agents is a critical consideration in any precision medicine strategy for GBM. Mol Cancer Ther; 17(9); 1893-901. ©2018 AACR.
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Affiliation(s)
- Minjee Kim
- University of Minnesota, Minneapolis, Minnesota
| | | | - David Calligaris
- Brigham and Women's Hospital, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts
| | | | | | | | | | | | | | - Fang Jin
- Mayo Clinic, Rochester, Minnesota
| | | | | | | | | | | | | | | | | | | | | | - Nathalie Y R Agar
- Brigham and Women's Hospital, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts.,Dana Farber Cancer Institute, Boston, Massachusetts
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Campani V, Giarra S, De Rosa G. Lipid-based core-shell nanoparticles: Evolution and potentialities in drug delivery. OPENNANO 2018. [DOI: 10.1016/j.onano.2017.12.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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10
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Ding X, Su Y, Wang C, Zhang F, Chen K, Wang Y, Li M, Wang W. Synergistic Suppression of Tumor Angiogenesis by the Co-delivering of Vascular Endothelial Growth Factor Targeted siRNA and Candesartan Mediated by Functionalized Carbon Nanovectors. ACS APPLIED MATERIALS & INTERFACES 2017; 9:23353-23369. [PMID: 28617574 DOI: 10.1021/acsami.7b04971] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Single-walled carbon nanotubes (SWNTs) with unique physicochemical properties have exhibited promising biomedical applications as drug and gene carriers. In this study, polyethylenimine (PEI)-modified SWNT conjugates linked with candesartan (CD) were developed to deliver vascular endothelial growth factor (VEGF)-targeted siRNA (siVEGF) for the synergistic and targeted treatment of tumor angiogenesis. The characterization results revealed that SWNT-PEI-CD conjugates were successfully synthesized and exhibited desirable dispersibility and superior stability. Confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) results showed that SWNT-PEI-CD/siVEGF complexes could achieve high cellular uptake and specific intracellular distribution of siRNA in AT1R overexpressed PANC-1 cells. Strong down-regulation of VEGF was also verified by qualitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot in complex-treated PANC-1 cells. The in vitro angiogenesis assay showed that SWNT-PEI-CD/siVEGF complexes highly inhibited tube formation of human umbilical vein endothelial cells. Furthermore, in vivo observation in PANC-1 xenografted nude mice demonstrated that SWNT-PEI-CD/siVEGF complexes exhibited significant distribution at tumor sites and caused obvious inhibition of tumor growth and tumor-associated angiogenesis repression induced by the drug combination of CD and siVEGF. Finally, a WST-1 assay indicated that SWNT-PEI-CD possessed low cytotoxicity, and a hemolysis test showed good biocompatibility of SWNT-PEI-CD. Hematological and histological analyses confirmed that SWNT-PEI-CD/siVEGF complexes did not cause any obvious toxic effects to blood and major organs. These findings suggested that the SWNT-PEI-CD/siVEGF co-delivery system with tumor-targeting specificity, improved endosomal escaping properties, and collaboration of angiogenesis inhibition could be a prospective method for efficient tumor antiangiogenic therapy.
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Affiliation(s)
- Xuefang Ding
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China
- School of Pharmaceutical Science, Nanjing Tech University , 30 South Puzhu Road, Nanjing 211816, China
| | - Yujie Su
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China
| | - Cheng Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China
| | - Fangrong Zhang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China
| | - Kerong Chen
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China
| | - Yu Wang
- Department of Pharmacology, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University , 140 Hanzhong Road, Nanjing 210029, China
| | - Min Li
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China
| | - Wei Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China
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Shen X, Li T, Chen Z, Geng Y, Xie X, Li S, Yang H, Wu C, Liu Y. Luminescent/magnetic PLGA-based hybrid nanocomposites: a smart nanocarrier system for targeted codelivery and dual-modality imaging in cancer theranostics. Int J Nanomedicine 2017; 12:4299-4322. [PMID: 28652734 PMCID: PMC5473604 DOI: 10.2147/ijn.s136766] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Cancer diagnosis and treatment represent an urgent medical need given the rising cancer incidence over the past few decades. Cancer theranostics, namely, the combination of diagnostics and therapeutics within a single agent, are being developed using various anticancer drug-, siRNA-, or inorganic materials-loaded nanocarriers. Herein, we demonstrate a strategy of encapsulating quantum dots, superparamagnetic Fe3O4 nanocrystals, and doxorubicin (DOX) into biodegradable poly(d,l-lactic-co-glycolic acid) (PLGA) polymeric nanocomposites using the double emulsion solvent evaporation method, followed by coupling to the amine group of polyethyleneimine premodified with polyethylene glycol-folic acid (PEI-PEG-FA [PPF]) segments and adsorption of vascular endothelial growth factor (VEGF)-targeted small hairpin RNA (shRNA). VEGF is important for tumor growth, progression, and metastasis. These drug-loaded luminescent/magnetic PLGA-based hybrid nanocomposites (LDM-PLGA/PPF/VEGF shRNA) were fabricated for tumor-specific targeting, drug/gene delivery, and cancer imaging. The data showed that LDM-PLGA/PPF/VEGF shRNA nanocomposites can codeliver DOX and VEGF shRNA into tumor cells and effectively suppress VEGF expression, exhibiting remarkable synergistic antitumor effects both in vitro and in vivo. The cell viability waŝ14% when treated with LDM-PLGA/PPF/VEGF shRNA nanocomposites ([DOX] =25 μg/mL), and in vivo tumor growth data showed that the tumor volume decreased by 81% compared with the saline group at 21 days postinjection. Magnetic resonance and fluorescence imaging data revealed that the luminescent/magnetic hybrid nanocomposites may also be used as an efficient nanoprobe for enhanced T2-weighted magnetic resonance and fluorescence imaging in vitro and in vivo. The present work validates the great potential of the developed multifunctional LDM-PLGA/PPF/VEGF shRNA nanocomposites as effective theranostic agents through the codelivery of drugs/genes and dual-modality imaging in cancer treatment.
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Affiliation(s)
- Xue Shen
- Department of Biophysics, School of Life Science and Technology
| | - Tingting Li
- Department of Biophysics, School of Life Science and Technology
| | - Zhongyuan Chen
- Department of Biophysics, School of Life Science and Technology
| | - Yue Geng
- Department of Biophysics, School of Life Science and Technology
| | - Xiaoxue Xie
- Department of Biophysics, School of Life Science and Technology
| | - Shun Li
- Department of Biophysics, School of Life Science and Technology.,Center for Information in Biology, University of Electronic Science and Technology of China, Chengdu, Sichuan, People's Republic of China
| | - Hong Yang
- Department of Biophysics, School of Life Science and Technology.,Center for Information in Biology, University of Electronic Science and Technology of China, Chengdu, Sichuan, People's Republic of China
| | - Chunhui Wu
- Department of Biophysics, School of Life Science and Technology.,Center for Information in Biology, University of Electronic Science and Technology of China, Chengdu, Sichuan, People's Republic of China
| | - Yiyao Liu
- Department of Biophysics, School of Life Science and Technology.,Center for Information in Biology, University of Electronic Science and Technology of China, Chengdu, Sichuan, People's Republic of China
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12
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Zhang Y, Liu J, Lin J, Zhou L, Song Y, Wei B, Luo X, Chen Z, Chen Y, Xiong J, Xu X, Ding L, Ye Q. The transcription factor GATA1 and the histone methyltransferase SET7 interact to promote VEGF-mediated angiogenesis and tumor growth and predict clinical outcome of breast cancer. Oncotarget 2016; 7:9859-75. [PMID: 26848522 PMCID: PMC4891089 DOI: 10.18632/oncotarget.7126] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 01/18/2016] [Indexed: 01/26/2023] Open
Abstract
Angiogenesis is essential for tumor growth. Vascular endothelial growth factor (VEGF) is the most important regulator of tumor angiogenesis. However, how transcription factors interact with histone-modifying enzymes to regulate VEGF transcription and tumor angiogenesis remains unclear. Here, we show that transcription factor GATA1 associates with the histone methyltransferase SET7 to promote VEGF transcription and breast tumor angiogenesis. Using chromatin immunoprecipitation assay, we found that GATA1 was required for recruitment of SET7, RNA polymerase II and transcription factor II B to VEGF core promoter. GATA1 enhanced breast cancer cell (MCF7, ZR75-1 and MDA-MB-231)-secreted VEGF via SET7, which promoted vascular endothelial cell (HUVEC) proliferation, migration and tube formation. SET7 was required for GATA1-induced breast tumor angiogenesis and growth in nude mice. Immunohistochemical staining showed that expression of GATA1 and SET7 was upregulated and positively correlated with VEGF expression and microvessel number in 80 breast cancer patients. GATA1 and SET7 are independent poor prognostic factors in breast cancer. Our data provide novel insights into VEGF transcriptional regulation and suggest GATA1/SET7 as cancer therapeutic targets.
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Affiliation(s)
- Yanan Zhang
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.,Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Liaoning, People's Republic of China
| | - Jie Liu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China
| | - Jing Lin
- First Affiliated Hospital, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Lei Zhou
- Beijing Shijitan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Yuhua Song
- The Affiliated Hospital of Qing Dao University, Qingdao, People's Republic of China
| | - Bo Wei
- Department of General Surgery, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Xiaoli Luo
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China
| | - Zhida Chen
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.,Department of General Surgery, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Yingjie Chen
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.,The Affiliated Hospital of Qing Dao University, Qingdao, People's Republic of China
| | - Jiaxiu Xiong
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.,Department of General Surgery, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Xiaojie Xu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China
| | - Lihua Ding
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China
| | - Qinong Ye
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, People's Republic of China.,Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Liaoning, People's Republic of China
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13
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Comparison of (18)F-fluorodeoxyglucose PET/CT findings with vascular endothelial growth factors and receptors in colorectal cancer. Tumour Biol 2015; 37:3871-7. [PMID: 26476536 DOI: 10.1007/s13277-015-4218-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 10/12/2015] [Indexed: 02/06/2023] Open
Abstract
The purpose of this study was to evaluate the association of (18)F-fluorodeoxyglucose (FDG)-PET/CT findings with the vascular endothelial growth factor (VEGF) family and its receptor (VEGFR) levels in metastatic and nonmetastatic colorectal cancer (CRC). Fluorine-18 FDG-PET/CT scans were performed for initial staging and restaging of patients with CRC. FDG-PET/CT findings of tumor (such as the presence of a primary tumor, the lymphatic or distance metastases, and the maximum standardized uptake value (SUVmax) of the primary tumor), serum VEGF A-C-D-E levels, and serum VEGF receptor 1-2-3 levels were analyzed. A total of 63 patients were included into the study (35 males, mean age 61.3 ± 11.9 years). Patients were divided into two groups, based on positive and negative PET/CT findings. Patients were also categorized according to the presence of metastasis. All evaluated parameters were significantly higher in the PET/CT-positive group than the PET/CT-negative group (p < 0.001). All those parameters were also positively correlated with each other. The highest correlation for SUVmax of primary tumor was found with VEGFR-3 (p < 0.001, r = 0.665). Patients with metastases had high levels of VEGF-D, VEGF-A, VEGF-C, VEGF-E, and VEGFR-3 than those without metastases. These parameters had better specificity and sensitivity values than the SUVmax of the primary tumor for detection of metastases. However, VEGF-D was the best indicator of metastasis in all of those parameters (VEGF-D vs SUVmax; sensitivity 100 vs 100 %; specificity 76 vs 76 %; AUC 0.903 vs 0.835; p < 0.001, respectively). Vascular endothelial growth factor family and its receptors were significantly higher in metastatic CRC patients. VEGF-D was the best indicator of metastasis than all VEGF family, VEGFR-3, and primary tumor SUVmax. VEGF family (A-C-D-E) and VEGFR-3 may help to determine the prognosis and management of CRC.
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14
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Chen Q, Chen P, Pang X, Hu Y, Zhang Y. Adrenomedullin Up-regulates the Expression of Vascular Endothelial Growth Factor in Epithelial Ovarian Carcinoma Cells via JNK/AP-1 Pathway. Int J Gynecol Cancer 2015; 25:953-60. [PMID: 26098087 PMCID: PMC4485736 DOI: 10.1097/igc.0000000000000465] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Revised: 03/18/2015] [Accepted: 03/19/2015] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE Adrenomedullin (AM), a potent vasodilator peptide, presents in various kinds of tumors and promotes angiogenesis. We have previously reported that AM is expressed in epithelial ovarian carcinoma tissue. Here, we investigated the hypothesis that AM might regulate production of vascular endothelial growth factor (VEGF) in epithelial ovarian carcinoma and further promote angiogenic processes. METHODS The messenger RNA expression of VEGF in human epithelial ovarian carcinoma cells (HO-8910) was examined by real-time polymerase chain reaction. Transcriptional control was analyzed by transient transfection assay of VEGF promoter-luciferase hybrid genes and chromatin immunoprecipitation assay. Activation of c-Jun N-terminal kinase (JNK) was detected by Western blotting. The formation of capillarylike structures by EA.hy926 cells cocultured with HO-8910 cells on Matrigel was also studied. RESULTS We found that in HO-8910 cells, AM (10⁻¹⁰ to 10⁻⁷ mol/L) enhanced VEGF messenger RNA expression in a time- and concentration-dependent manner, as well as promoter activity. Furthermore, JNK was activated by AM stimulation. The AM-induced increase in VEGF expression was significantly attenuated by SP600125, a specific JNK inhibitor. Chromatin immunoprecipitation assay and promoter activity analysis showed that VEGF expression induced by AM required the activator protein 1 motif on the VEGF promoter. In an in vitro angiogenesis system for endothelial cells (EA.hy926) cocultured with HO-8910 cells, we observed that the addition of AM stimulated endothelial cell tube formation, which could be abolished by VEGF neutralizing antibody. CONCLUSIONS Our findings suggest that the JNK/Activator protein 1 pathway is involved in AM-induced VEGF expression in HO-8910 cells.
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MESH Headings
- Adrenomedullin/pharmacology
- Antihypertensive Agents/pharmacology
- Blotting, Western
- Carcinoma, Ovarian Epithelial
- Chromatin Immunoprecipitation
- Female
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- JNK Mitogen-Activated Protein Kinases/genetics
- JNK Mitogen-Activated Protein Kinases/metabolism
- Neoplasms, Glandular and Epithelial/drug therapy
- Neoplasms, Glandular and Epithelial/metabolism
- Neoplasms, Glandular and Epithelial/pathology
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/metabolism
- Ovarian Neoplasms/drug therapy
- Ovarian Neoplasms/metabolism
- Ovarian Neoplasms/pathology
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Regulatory Elements, Transcriptional/drug effects
- Regulatory Elements, Transcriptional/genetics
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
- Transcription Factor AP-1/genetics
- Transcription Factor AP-1/metabolism
- Transcriptional Activation
- Tumor Cells, Cultured
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
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Affiliation(s)
- Qingqing Chen
- *Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; and †Department of Gynecology and Obstetrics, Jin hua Municipal Central Hosptial, Jin hua, Zhejiang, China
| | - Pan Chen
- *Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; and †Department of Gynecology and Obstetrics, Jin hua Municipal Central Hosptial, Jin hua, Zhejiang, China
| | - Xiaoyan Pang
- *Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; and †Department of Gynecology and Obstetrics, Jin hua Municipal Central Hosptial, Jin hua, Zhejiang, China
| | - Yanling Hu
- *Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; and †Department of Gynecology and Obstetrics, Jin hua Municipal Central Hosptial, Jin hua, Zhejiang, China
| | - Yi Zhang
- *Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; and †Department of Gynecology and Obstetrics, Jin hua Municipal Central Hosptial, Jin hua, Zhejiang, China
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15
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Chandrasekharan P, Yang CT, Nasrallah FA, Tay HC, Chuang KH, Robins EG. Pharmacokinetics of Gd(DO3A-Lys) and MR imaging studies in an orthotopic U87MG glioma tumor model. CONTRAST MEDIA & MOLECULAR IMAGING 2015; 10:237-44. [DOI: 10.1002/cmmi.1634] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 08/22/2014] [Accepted: 11/19/2014] [Indexed: 01/10/2023]
Affiliation(s)
- Prashant Chandrasekharan
- Laboratory of Molecular Imaging; Singapore Bioimaging Consortium; Agency for Science, Technology and Research (A*STAR); 11 Biopolis Way, #02-02 Helios Singapore 138667
| | - Chang-Tong Yang
- Laboratory of Molecular Imaging; Singapore Bioimaging Consortium; Agency for Science, Technology and Research (A*STAR); 11 Biopolis Way, #02-02 Helios Singapore 138667
- The Lee Kong Chian School of Medicine; Nanyang Technological University; 50 Nanyang Drive Singapore 637553
| | - Fatima Ali Nasrallah
- Laboratory of Molecular Imaging; Singapore Bioimaging Consortium; Agency for Science, Technology and Research (A*STAR); 11 Biopolis Way, #02-02 Helios Singapore 138667
| | - Hui Chien Tay
- Laboratory of Molecular Imaging; Singapore Bioimaging Consortium; Agency for Science, Technology and Research (A*STAR); 11 Biopolis Way, #02-02 Helios Singapore 138667
| | - Kai-Hsiang Chuang
- Laboratory of Molecular Imaging; Singapore Bioimaging Consortium; Agency for Science, Technology and Research (A*STAR); 11 Biopolis Way, #02-02 Helios Singapore 138667
- Clinical Imaging Research Centre, Yong Loo Lin School of Medicine; National University of Singapore; 14 Medical Drive #B1-01 Singapore 117599
| | - Edward G. Robins
- Laboratory of Molecular Imaging; Singapore Bioimaging Consortium; Agency for Science, Technology and Research (A*STAR); 11 Biopolis Way, #02-02 Helios Singapore 138667
- Clinical Imaging Research Centre, Yong Loo Lin School of Medicine; National University of Singapore; 14 Medical Drive #B1-01 Singapore 117599
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16
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Feng Q, Yu MZ, Wang JC, Hou WJ, Gao LY, Ma XF, Pei XW, Niu YJ, Liu XY, Qiu C, Pang WH, Du LL, Zhang Q. Synergistic inhibition of breast cancer by co-delivery of VEGF siRNA and paclitaxel via vapreotide-modified core-shell nanoparticles. Biomaterials 2014; 35:5028-38. [PMID: 24680191 DOI: 10.1016/j.biomaterials.2014.03.012] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 03/07/2014] [Indexed: 01/05/2023]
Abstract
A somatostatin analog, vapreotide (VAP), can be used as a ligand for targeting drug delivery based on its high affinity to somatostatin receptors (SSTRs), which is overexpressed in many tumor cells. RNA interference plays an important role on downregulation of vascular endothelial growth factor (VEGF), which is important for tumor growth, progression and metastasis. To improve tumor therapy efficacy, the vapreotide-modified core-shell type nanoparticles co-encapsulating VEGF targeted siRNA (siVEGF) and paclitaxel (PTX), termed as VAP-PLPC/siRNA NPs, were developed in this study. When targeted via somatostatin receptors to tumor cells, the VAP-PLPC/siRNA NPs could simultaneously delivery siVEGF and PTX into cells and achieve a synergistic inhibition of tumor growth. Interestingly, in vitro cell uptake and gene silencing experiments demonstrated that the targeted VAP-PLPC/siRNA NPs exhibited significant higher intracellular siRNA accumulation and VEGF downregulation in human breast cancer MCF-7 cells, compared to those of the non-targeted PEG-PLPC/siRNA NPs. More importantly, in vivo results further demonstrated that the targeted VAP-PLPC/siRNA NPs had significant stronger drug distribution in tumor tissues and tumor growth inhibition efficacy via receptor-mediated targeting delivery, accompany with an obvious inhibition of neovascularization induced by siVEGF silencing. These results suggested that the co-delivery of siRNA and paclitaxel via vapreotide-modified core-shell nanoparticles would be a promising approach for tumor targeted therapy.
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Affiliation(s)
- Qiang Feng
- State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking University, Beijing 100191, PR China
| | - Min-Zhi Yu
- State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking University, Beijing 100191, PR China
| | - Jian-Cheng Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking University, Beijing 100191, PR China.
| | - Wen-Jie Hou
- State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking University, Beijing 100191, PR China
| | - Ling-Yan Gao
- State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking University, Beijing 100191, PR China
| | - Xiao-Fei Ma
- State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking University, Beijing 100191, PR China
| | - Xi-Wei Pei
- State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking University, Beijing 100191, PR China
| | - Yu-Jie Niu
- State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking University, Beijing 100191, PR China
| | - Xiao-Yan Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking University, Beijing 100191, PR China
| | - Chong Qiu
- State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking University, Beijing 100191, PR China
| | - Wen-Hao Pang
- State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking University, Beijing 100191, PR China
| | - Li-Li Du
- State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking University, Beijing 100191, PR China
| | - Qiang Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking University, Beijing 100191, PR China
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17
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Steinberg JD, Raju A, Chandrasekharan P, Yang CT, Khoo K, Abastado JP, Robins EG, Townsend DW. Negative contrast Cerenkov luminescence imaging of blood vessels in a tumor mouse model using [68Ga]gallium chloride. EJNMMI Res 2014; 4:15. [PMID: 24606872 PMCID: PMC3974015 DOI: 10.1186/2191-219x-4-15] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 02/21/2014] [Indexed: 01/14/2023] Open
Abstract
Background Cerenkov luminescence imaging (CLI) is an emerging imaging technique where visible light emitted from injected beta-emitting radionuclides is detected with an optical imaging device. CLI research has mostly been focused on positive contrast imaging for ascertaining the distribution of the radiotracer in a way similar to other nuclear medicine techniques. Rather than using the conventional technique of measuring radiotracer distribution, we present a new approach of negative contrast imaging, where blood vessel attenuation of Cerenkov light emitted by [68Ga]GaCl3 is used to image vasculature. Methods BALB/c nude mice were injected subcutaneously in the right flank with HT-1080 fibrosarcoma cells 14 to 21 days prior to imaging. On the imaging day, [68Ga]GaCl3 was injected and the mice were imaged from 45 to 90 min after injection using an IVIS Spectrum in vivo imaging system. The mice were imaged one at a time, and manual focus was used to bring the skin into focus. The smallest view with pixel size around 83 μm was used to achieve a sufficiently high image resolution for blood vessel imaging. Results The blood vessels in the tumor were clearly visible, attenuating 7% to 18% of the light. Non-tumor side blood vessels had significantly reduced attenuation of 2% to 4%. The difference between the attenuation of light of tumor vessels (10% ± 4%) and the non-tumor vessels (3% ± 1%) was significant. Moreover, a necrotic core confirmed by histology was clearly visible in one of the tumors with a 21% reduction in radiance. Conclusions The negative contrast CLI technique is capable of imaging vasculature using [68Ga]GaCl3. Since blood vessels smaller than 50 μm in diameter could be imaged, CLI is able to image structures that conventional nuclear medicine techniques cannot. Thus, the negative contrast imaging technique shows the feasibility of using CLI to perform angiography on superficial blood vessels, demonstrating an advantage over conventional nuclear medicine techniques.
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Affiliation(s)
- Jeffrey D Steinberg
- Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore, Singapore.
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18
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Marotta V, Franzese MD, Del Prete M, Chiofalo MG, Ramundo V, Esposito R, Marciello F, Pezzullo L, Carratù A, Vitale M, Colao A, Faggiano A. Targeted therapy with kinase inhibitors in aggressive endocrine tumors. Expert Opin Pharmacother 2013; 14:1187-203. [PMID: 23675883 DOI: 10.1517/14656566.2013.796931] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
INTRODUCTION Kinase inhibitors (KIs) are a class of anticancer drugs that inhibit activity of the enzymes protein kinases, which regulate crucial cellular processes and have a demonstrated role in human oncogenesis. Treatment of advanced forms of endocrine cancer which are not responsive to cytotoxic chemotherapies is challenging and use of KIs is gaining a growing role in this field. AREAS COVERED The authors summarize the main genetic alterations known to be linked to endocrine tumors, indicating the rationale for utilizing KIs. Furthermore, they present an updated analysis of clinical trials available on PubMed Central, which were pertinent to the activities of KIs in aggressive endocrine cancer. The authors also discuss the adverse effects of KIs and summarize likely involved underlying mechanisms. EXPERT OPINION KIs are effective in obtaining a radiological disease control and an improvement of progression-free survival in several forms of endocrine cancer but will never deliver a knockout blow of the disease, due to mechanisms of adaptation to circumvent the specific molecular blockade. The new frontier of KIs treatment is to identify agents that could synergize activity of KIs. The true goal will be to perform an overall genotyping of each tumor, thus predicting the impact of combined targeted therapies in the context of a particular constellation of mutant genes.
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Affiliation(s)
- Vincenzo Marotta
- Federico II University, Department of Clinical Medicine and Surgery, Italy.
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19
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Yoshino T, Yamazaki K, Yamaguchi K, Doi T, Boku N, Machida N, Onozawa Y, Asayama M, Fujino T, Ohtsu A. A phase I study of intravenous aflibercept with FOLFIRI in Japanese patients with previously treated metastatic colorectal cancer. Invest New Drugs 2013; 31:910-7. [PMID: 23179335 PMCID: PMC3717157 DOI: 10.1007/s10637-012-9895-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Accepted: 10/29/2012] [Indexed: 12/27/2022]
Abstract
Aflibercept, a recombinant fusion protein, is a potent inhibitor of vascular endothelial growth factor (VEGF)-A, VEGF-B, and the placental growth factor (PlGF). The present study was an open-label, sequential-cohort, dose-escalation trial of intravenous aflibercept administered every 2 weeks in combination with 5-fluorouracil, levofolinate, and irinotecan (FOLFIRI) in patients with previously treated metastatic colorectal cancer (mCRC). We aimed to assess the safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary efficacy of the combination therapy to determine the recommended phase II dose (RPTD) for Japanese patients. Two doses of aflibercept (2.0 and 4.0 mg/kg) were set, and DLTs were evaluated in the first 2 cycles. The subjects comprised 16 patients (n = 3 and 13 for 2.0 and 4.0 mg/kg aflibercept, respectively) who received a total of 149 cycles of aflibercept with FOLFIRI. No DLTs were observed at both doses. The frequent adverse events encountered were leukopenia, neutropenia, anemia, diarrhea, fatigue, decreased appetite, stomatitis, dysphonia, nausea, and epistaxis. The most common grade 3/4 adverse events were neutropenia for both doses and hypertension for the 4.0 mg/kg dose. Free aflibercept exposure increased with the dose, whereas exposure to VEGF-bound aflibercept remained similar at both doses. The response rate and progression-free survival at 4.0 mg/kg was 8.3 % and 7.59 months, respectively. In conclusion, the combination of aflibercept and FOLFIRI was well tolerated at both doses. The RPTD of aflibercept in combination with FOLFIRI for Japanese patients with mCRC was determined to be 4.0 mg/kg every 2 weeks. ClinicalTrials.gov identifier: NCT00921661.
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Affiliation(s)
- Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwashi, Chiba 277-8577, Japan.
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20
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Gupta P, Adkins C, Lockman P, Srivastava SK. Metastasis of Breast Tumor Cells to Brain Is Suppressed by Phenethyl Isothiocyanate in a Novel In Vivo Metastasis Model. PLoS One 2013; 8:e67278. [PMID: 23826254 PMCID: PMC3695065 DOI: 10.1371/journal.pone.0067278] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 05/16/2013] [Indexed: 01/28/2023] Open
Abstract
Breast tumor metastasis is a leading cause of cancer-related deaths worldwide. Breast tumor cells frequently metastasize to brain and initiate severe therapeutic complications. The chances of brain metastasis are further elevated in patients with HER2 overexpression. In the current study, we evaluated the anti-metastatic effects of phenethyl isothiocyanate (PEITC) in a novel murine model of breast tumor metastasis. The MDA-MB-231-BR (BR-brain seeking) breast tumor cells stably transfected with luciferase were injected into the left ventricle of mouse heart and the migration of cells to brain was monitored using a non-invasive IVIS bio-luminescent imaging system. In order to study the efficacy of PEITC in preventing the number of tumor cells migrating to brain, mice were given 10 µmol PEITC by oral gavage for ten days prior to intra-cardiac injection of tumor cells labeled with quantum dots. To evaluate the tumor growth suppressive effects, 10 µmol PEITC was given to mice every day starting 14(th) day after intra-cardiac cell injection. Based on the presence of quantum dots in the brain section of control and treated mice, our results reveal that PEITC significantly prevented the metastasis of breast cancer cells to brain. Our results demonstrate that the growth of metastatic brain tumors in PEITC treated mice was about 50% less than that of control. According to Kaplan Meir's curve, median survival of tumor bearing mice treated with PEITC was prolonged by 20.5%. Furthermore as compared to controls, we observed reduced HER2, EGFR and VEGF expression in the brain sections of PEITC treated mice. To the best of our knowledge, our study for the first time demonstrates the anti-metastatic effects of PEITC in vivo in a novel breast tumor metastasis model and provides the rationale for further clinical investigation.
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Affiliation(s)
- Parul Gupta
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
- Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
| | - Chris Adkins
- Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
| | - Paul Lockman
- Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
| | - Sanjay K. Srivastava
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
- Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
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21
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Pang L, Zhang Y, Yu Y, Zhang S. Resistin promotes the expression of vascular endothelial growth factor in ovary carcinoma cells. Int J Mol Sci 2013; 14:9751-66. [PMID: 23652833 PMCID: PMC3676810 DOI: 10.3390/ijms14059751] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Revised: 04/18/2013] [Accepted: 04/24/2013] [Indexed: 12/16/2022] Open
Abstract
Resistin is a novel hormone that is secreted by human adipocytes and mononuclear cells and is associated with obesity, insulin resistance and inflammation. Recently, resistin has been postulated to play a role in angiogenesis. Here, we investigated the hypothesis that resistin regulates ovary carcinoma production of vascular endothelial growth factor (VEGF) and the angiogenic processes. We found that in human ovarian epithelial carcinoma cells (HO-8910), resistin (10–150 ng/mL) enhanced both VEGF protein and mRNA expression in a time- and concentration-dependent manner, as well as promoter activity. Furthermore, resistin enhanced DNA-binding activity of Sp1 with VEGF promoter in a PI3K/Akt-dependent manner. PI3K/Akt activated by resistin led to increasing interaction with Sp1, triggering a progressive phosphorylation of Sp1 on Thr453 and Thr739, resulting in the upregulation of VEGF expression. In an in vitro angiogenesis system for endothelial cells (EA.hy926) co-cultured with HO-8910 cells, we observed that the addition of resistin stimulated endothelial cell tube formation, which could be abolished by VEGF neutralizing antibody. Our findings suggest that the PI3K/Akt-Sp1 pathway is involved in resistin-induced VEGF expression in HO-8910 cells and indicates that antiangiogenesis therapy may be beneficial treatment against ovarian epithelial carcinoma, especially in obese patients.
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Affiliation(s)
- Li Pang
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang 110004, Liaoning, China; E-Mails: (L.P.); (Y.Y.)
| | - Yi Zhang
- Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning, China; E-Mail:
| | - Yu Yu
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang 110004, Liaoning, China; E-Mails: (L.P.); (Y.Y.)
| | - Shulan Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang 110004, Liaoning, China; E-Mails: (L.P.); (Y.Y.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel./Fax: +86-24-966-151-41211
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22
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Nosaka C, Adachi H, Sawa R, Nakae K, Atsumi S, Kinoshita N, Kubota Y, Igarashi M, Sei Y, Yamaguchi K, Shibuya M, Nishimura Y, Akamatsu Y. Vegfrecine, an inhibitor of VEGF receptor tyrosine kinases isolated from the culture broth of Streptomyces sp. JOURNAL OF NATURAL PRODUCTS 2013; 76:715-719. [PMID: 23414235 DOI: 10.1021/np300535c] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
A new inhibitor of VEGF receptor tyrosine kinases, vegfrecine (1), was isolated from the culture broth of Streptomyces sp. MK931-CF8. The molecular structure of 1 was determined by NMR and MS analysis combined with synthesis. Compound 1 showed potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR) tyrosine kinases in in vitro enzyme assays, but platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR) responded only weakly. Compound 1 is a promising new selective VEGFR inhibitor for investigating new treatments of cancer and inflammatory diseases.
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Affiliation(s)
- Chisato Nosaka
- Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
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23
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Terrasi M, Bazan V, Caruso S, Insalaco L, Amodeo V, Fanale D, Corsini LR, Contaldo C, Mercanti A, Fiorio E, Lo Re G, Cicero G, Surmacz E, Russo A. Effects of PPARγ agonists on the expression of leptin and vascular endothelial growth factor in breast cancer cells. J Cell Physiol 2013; 228:1368-74. [DOI: 10.1002/jcp.24295] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Accepted: 11/27/2012] [Indexed: 11/11/2022]
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24
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Liu P, Wu D, Zhou W, Li Y, Lian C, Yang Y, Feng Z. Association of VEGF gene polymorphisms with advanced retinopathy of prematurity: a meta-analysis. Mol Biol Rep 2012; 39:10731-7. [PMID: 23065202 DOI: 10.1007/s11033-012-1964-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Accepted: 10/01/2012] [Indexed: 10/27/2022]
Abstract
Published data on the association of vascular endothelial growth factor (VEGF) gene polymorphisms with retinopathy of prematurity (ROP) are inconclusive. The aim of the study was to assess the association by using meta-analysis. Data were collected from the following electronic databases: PubMed, Elsevier Science Direct, Excerpta Medica Database, Cochrane Library and China National Knowledge Infrastructure, with the last report up to 30 April, 2012. The odds ratio (OR) and its 95 % confidence interval (95 %CI) were used to assess the strength of the association. Meta-analysis was performed in a fixed/random effect model by using the software Review Manager 4.2. A total of 7 studies based on the search criteria were involved in this meta-analysis. Meta-analysis was performed for four VEGF gene polymorphisms (-634G/C, -460T/C, -2578C/A and 936C/T). Significant association was found for -460T/C polymorphism (C vs T: OR = 0.74, 95 %CI = 0.57-0.95, P = 0.02; TC+CC vs TT: OR = 0.75, 95 %CI = 0.47-1.21, P = 0.24; CC vs TT+TC: OR = 0.45, 95 %CI = 0.26-0.76, P = 0.003; CC vs TT: OR = 0.45, 95 %CI = 0.24-0.84, P = 0.01; TC vs TT: OR = 0.96, 95 %CI = 0.59-1.57, P = 0.87) in the VEGF gene, but not for other polymorphisms (-634G/C, -2578C/A and 936C/T). This meta-analysis demonstrates that advanced ROP is associated with VEGF gene -460T/C polymorphism, but not -634G/C, -2578C/A and 936C/T.
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Affiliation(s)
- Peihui Liu
- Department of Pediatrics, Affiliated Shenzhen Maternity & Child Healthcare Hospital of Southern Medical University, Shenzhen, 518028, China
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25
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Shamloo BK, Chhabra P, Freedman AN, Potosky A, Malin J, Weiss Smith S. Novel adverse events of bevacizumab in the US FDA adverse event reporting system database: a disproportionality analysis. Drug Saf 2012; 35:507-18. [PMID: 22612854 DOI: 10.2165/11597600-000000000-00000] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Bevacizumab is the first in its class, vascular endothelial growth factor (VEGF) inhibitor that was initially approved by the US FDA in 2004 for the treatment of metastatic colon cancer and other solid tumors. Preapproval clinical trials, particularly for oncology drugs, are limited in their ability to detect certain adverse effects and, therefore, the FDA and pharmaceutical sponsors collect and monitor reports of adverse events (AEs) following approval. OBJECTIVE The purpose of this study was to screen the FDA's Adverse Event Reporting System (AERS) database for novel AEs that may be attributed to bevacizumab. METHODS The FDA AERS database was used to identify all AE reports for bevacizumab from February 2004 to September 2009. Disproportionality analysis was conducted for bevacizumab against all other drugs in the background by setting statistical significance at proportional reporting ratio (PRR) ≥2, observed case count ≥3 and chi-square ≥4. Subsequent clinical evaluation was performed to determine the clinical relevance of the findings and to group related events. RESULTS A total of 523 Preferred Terms (PTs) were disproportionally reported; following clinical review 63 (12%) were found to be both unlabelled and of clinical importance. These PTs were grouped into 15 clinical disorder groups. Among the clinical disorders, electrolyte abnormalities had the greatest number of reports (n = 426) followed by cardiovascular events (n = 421), gastrointestinal events (n = 345), nervous system disorders (n = 106) and pneumonitis (n = 96). On sensitivity analysis, a number of clinically important unlabelled disorders, such as necrotizing fasciitis, vessel wall disorders, arrhythmia and conduction disorder and autoimmune thrombocytopenia still met the statistical significance criteria. CONCLUSIONS During the study period, out of 12 010 AE reports mentioning bevacizumab, it was listed as the suspect drug in 94.2% of the reports. Our disproportionality analysis identified many events that are already recognized as AEs of bevacizumab, but it also identified a number of clinically important unlabelled terms, which if confirmed in future studies would have potential implications for use of bevacizumab in clinical practice.
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Affiliation(s)
- Behrooz K Shamloo
- University of Nevada School of Medicine-Nevada Cancer Institute, Las Vegas, NV, USA
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26
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Ellabban AA, Tsujikawa A, Ogino K, Ooto S, Yamashiro K, Oishi A, Yoshimura N. Choroidal thickness after intravitreal ranibizumab injections for choroidal neovascularization. Clin Ophthalmol 2012; 6:837-44. [PMID: 22701085 PMCID: PMC3373228 DOI: 10.2147/opth.s30907] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
PURPOSE To study changes in choroidal thickness with ranibizumab treatment for choroidal neovascularization (CNV). DESIGN Prospective case series. METHODS This prospective study consisted of 60 CNV-affected eyes of 60 patients treated with intravitreal injections of ranibizumab using an on-demand protocol after an initial loading phase. The eyes studied included 20 with age-related macular degeneration (AMD), 20 with polypoidal choroidal vasculopathy (PCV), and 20 with myopic CNV. In the eyes with AMD and PCV, choroidal thickness at the fovea was measured with optical coherence tomography using enhanced depth imaging. In eyes with myopic CNV, the choroidal thickness was measured using standard optical coherence tomography without the enhanced depth imaging technique. RESULTS With ranibizumab treatment, central retinal thickness decreased significantly (P < 0.001) and visual acuity improved significantly (P < 0.001). However, central choroidal thickness (167.2 ± 108.3 μm) showed no significant change at 1 month after the loading phase (165.2 ± 107.8 μm, P = 0.120) or at final examination (164.8 ± 107.7 μm, P = 0.115). At baseline, central retinal thickness in eyes with AMD was significantly greater that those with PCV (P = 0.005) or high myopia (P = 0.029). However, central choroidal thickness in eyes with myopic CNV was significantly thinner than in eyes with AMD (P < 0.001) or PCV (P < 0.001). In each type of disease, there was no significant change in central choroidal thickness with ranibizumab treatment. CONCLUSION The effect of ranibizumab on the choroidal thickness is minimal, if any.
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Affiliation(s)
- Abdallah A Ellabban
- Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Akitaka Tsujikawa
- Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Ken Ogino
- Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Sotaro Ooto
- Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kenji Yamashiro
- Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Akio Oishi
- Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Nagahisa Yoshimura
- Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
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27
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Liu Z, Yuan Q, Zhang X, Xiong C, Xue P, Ruan J. RY10-4, a novel anti-tumor compound, exhibited its anti-angiogenesis activity by down-regulation of the HIF-1α and inhibition phosphorylation of AKT and mTOR. Cancer Chemother Pharmacol 2012; 69:1633-40. [DOI: 10.1007/s00280-012-1873-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2012] [Accepted: 04/22/2012] [Indexed: 12/17/2022]
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Yang L, You S, Kumar V, Zhang C, Cao Y. In vitro the behaviors of metastasis with suppression of VEGF in human bone metastatic LNCaP-derivative C4-2B prostate cancer cell line. J Exp Clin Cancer Res 2012; 31:40. [PMID: 22549243 PMCID: PMC3511813 DOI: 10.1186/1756-9966-31-40] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2012] [Accepted: 04/12/2012] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. VEGF is believed to implicate poor prognosis in various cancers. The overexpression of VEGF may be an early step in the process of metastasis. METHODS ELISA was used to investigate the levels of VEGF, bFGF and IL8 in human bone metastatic LNCaP-derivative C4-2B prostate cancer cell line and its parental cell line, LNCaP and to determine the effect of bevacizumab on reducing the level of VEGF. Cell proliferation assay, invasion assay and in vitro angiogenesis assay were performed under the condition with bevacizumab or control IgG. RESULTS Human bone metastatic LNCaP-derivative C4-2B prostate cancer cell line expressed a higher level of VEGF than its parental primary prostate cancer cell line LNCaP. The effect of bevacizumab is dose-dependent and time-dependent: 100 μg/mL of bevacizumab and 3-day treatment was more effective than low-dose and lesser-day treatment for decreasing the level of VEGF. Bevacizumab is able to suppress cell proliferation, angiogenesis and invasion in human bone metastatic C4-2B prostatic cancer cell line. CONCLUSIONS The overexpression of VEGF can be inhibited by bevacizumab in human bone metastatic cancer cell line. The behaviors of metastasis involving proliferation, angiogenesis and invasion are suppressed by anti-VEGF therapy.
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Affiliation(s)
- Lei Yang
- Department of Orthopedics, the Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, China
| | - Shuo You
- Department of Endocrinology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Vikas Kumar
- School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Chaoyue Zhang
- Department of Orthopedics, the Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, China
| | - Ya Cao
- Cancer Research Institute of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China
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Avni R, Cohen B, Neeman M. Hypoxic stress and cancer: imaging the axis of evil in tumor metastasis. NMR IN BIOMEDICINE 2011; 24:569-81. [PMID: 21793071 PMCID: PMC3558740 DOI: 10.1002/nbm.1632] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2010] [Revised: 09/16/2010] [Accepted: 09/24/2010] [Indexed: 05/04/2023]
Abstract
Tumors emerge as a result of the sequential acquisition of genetic, epigenetic and somatic alterations promoting cell proliferation and survival. The maintenance and expansion of tumor cells rely on their ability to adapt to changes in their microenvironment, together with the acquisition of the ability to remodel their surroundings. Tumor cells interact with two types of interconnected microenvironments: the metabolic cell autonomous microenvironment and the nonautonomous cellular-molecular microenvironment comprising interactions between tumor cells and the surrounding stroma. Hypoxia is a central player in cancer progression, affecting not only tumor cell autonomous functions, such as cell division and invasion, resistance to therapy and genetic instability, but also nonautonomous processes, such as angiogenesis, lymphangiogenesis and inflammation, all contributing to metastasis. Closely related microenvironmental stressors affecting cancer progression include, in addition to hypoxia, elevated interstitial pressure and oxidative stress. Noninvasive imaging offers multiple means to monitor the tumor microenvironment and its consequences, and can thus assist in the understanding of the biological basis of hypoxia and microenvironmental stress in cancer progression, and in the development of strategies to monitor therapies targeted at stress-induced tumor progression.
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Affiliation(s)
- Reut Avni
- Department of Biological Regulation, Weizmann Institute, Rehovot, Israel
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30
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Li Q, Wang D, Li J, Chen P. Clinicopathological and prognostic significance of HER-2/neu and VEGF expression in colon carcinomas. BMC Cancer 2011; 11:277. [PMID: 21708009 PMCID: PMC3144457 DOI: 10.1186/1471-2407-11-277] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2010] [Accepted: 06/27/2011] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND HER-2/neu and VEGF expression is correlated with disease behaviors in various cancers. However, evidence for their expression in colon cancer is rather contradictory both for the protein expression status and prognostic value. HER-2/neu is found to participate in VEGF regulation, and has known correlation with VEGF expression in some tumors. In this study, we investigated HER-2/neu and VEGF expression in Chinese colon patients and explored whether there was any correlation between their expression patterns. METHODS HER-2/neu and VEGF were investigated immunohistochemically using tumor samples obtained from 317 colon cancer patients with all tumor stages. Correlation of the degree of staining with clinicopathological parameters and survival was investigated. RESULTS Positive expression rates of HER-2/neu and VEGF in colon cancer were 15.5% and 55.5% respectively. HER-2/neu expression was significantly correlated with tumor size and distant metastases (P < 0.05), but was not an independent prognostic marker of survival (P > 0.05). Expression of VEGF was significantly correlated with tumor size, tumor stage, lymph node metastases, and distant metastases (P < 0.05). The 5-year survival rate in patients with negative and positive VEGF expression was 70.2% and 61.9% respectively; the difference was not statistically significant (P = 0.146). No correlation between HER-2/neu and VEGF expression was detected (P = 0.151). CONCLUSIONS HER-2/neu and VEGF are not important prognostic markers of colon cancer. The present results do not support any association between HER2/neu and VEGF expression in this setting.
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Affiliation(s)
- Qingguo Li
- Department of General Surgery, First Clinic Medical School of Yangzhou University, Yangzhou, China
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Chang CC, Hsieh YY, Lin WH, Lin CS. Leiomyoma and Vascular Endothelial Growth Factor Gene Polymorphisms: A Systematic Review. Taiwan J Obstet Gynecol 2010; 49:247-53. [DOI: 10.1016/s1028-4559(10)60056-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2010] [Indexed: 01/19/2023] Open
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Yang H, Jager MJ, Grossniklaus HE. Bevacizumab suppression of establishment of micrometastases in experimental ocular melanoma. Invest Ophthalmol Vis Sci 2010; 51:2835-42. [PMID: 20089875 PMCID: PMC2874122 DOI: 10.1167/iovs.09-4755] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2009] [Revised: 12/16/2009] [Accepted: 01/10/2010] [Indexed: 02/06/2023] Open
Abstract
PURPOSE This study was undertaken to determine whether anti-vascular endothelial growth factor (VEGF) therapy inhibits growth of primary uveal melanoma and spread of its hepatic micrometastases. METHODS The human uveal melanoma cell lines Mel290 and Mel 270, HUVECs, mouse B16LS9 melanoma cells, and mouse vascular endothelial cells were separately cultured or co-cultured and incubated with bevacizumab or IgG1. The level of VEGF protein in the culture medium was measured by ELISA. In vitro angiogenesis and invasion assays were performed under bevacizumab or IgG1 treatment. Mel290 or B16LS9 cells were inoculated into NU/NU or C57Bl/6 mouse eyes which were enucleated after 7 days. The sizes of the intraocular tumors were determined. Time and dosage experiments were performed by using 50 or 250 microg bevacizumab starting at day 1 or 4 after inoculation. Hepatic micrometastases were enumerated. Proliferation, apoptosis, and angiogenesis markers were detected in the ocular tumor by immunofluorescence staining. RESULTS Bevacizumab significantly reduced the level of VEGF in the culture media from human uveal melanoma cells, mouse melanoma cells, and co-cultured cells. It also inhibited cell tube formation and decreased in vitro invasion of tumor cells. In the mouse model, bevacizumab suppressed primary ocular melanoma growth and the formation of hepatic micrometastases in a dose-dependent manner. Furthermore, immunohistochemical staining showed decreased Ki67 and unchanged caspase 3 expression after treatment with bevacizumab. CONCLUSIONS Treatment with bevacizumab suppressed in vitro growth and in vivo hepatic micrometastasis of ocular melanoma cells. Bevacizumab is a potential therapeutic agent for the treatment of uveal melanoma micrometastases.
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MESH Headings
- Angiogenesis Inhibitors/therapeutic use
- Animals
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Humanized
- Apoptosis
- Bevacizumab
- Caspase 3/metabolism
- Cell Proliferation
- Coculture Techniques
- Dose-Response Relationship, Drug
- Enzyme-Linked Immunosorbent Assay
- Female
- Humans
- Ki-67 Antigen/metabolism
- Liver Neoplasms/blood supply
- Liver Neoplasms/drug therapy
- Liver Neoplasms/secondary
- Melanoma, Experimental/blood supply
- Melanoma, Experimental/drug therapy
- Melanoma, Experimental/secondary
- Mice
- Mice, Inbred C57BL
- Mice, Nude
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/metabolism
- Tumor Cells, Cultured
- Uveal Neoplasms/blood supply
- Uveal Neoplasms/drug therapy
- Uveal Neoplasms/pathology
- Vascular Endothelial Growth Factor A/antagonists & inhibitors
- Vascular Endothelial Growth Factor A/metabolism
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Affiliation(s)
- Hua Yang
- From the Departments of Ophthalmology and
| | - Martine J. Jager
- the Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
| | - Hans E. Grossniklaus
- From the Departments of Ophthalmology and
- Pathology, Emory University School of Medicine, Atlanta, Georgia; and
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VanCleave TT, Moore JH, Benford ML, Brock GN, Kalbfleisch T, Baumgartner RN, Lillard JW, Kittles RA, Kidd LCR. Interaction among variant vascular endothelial growth factor (VEGF) and its receptor in relation to prostate cancer risk. Prostate 2010; 70:341-52. [PMID: 19908237 PMCID: PMC4433472 DOI: 10.1002/pros.21067] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Prostate cancer (PCa) incidence and mortality are disproportionately high among African-American (AA) men. Its detection and perhaps its disparities could be improved through the identification of genetic susceptibility biomarkers within essential biological pathways. Interactions among highly variant genes, central to angiogenesis, may modulate susceptibility for prostate cancer, as previous demonstrated. This study evaluates the interplay among three highly variant genes (i.e., IL-10, TGFbetaR-1, VEGF), their receptors and their influence on PCa within a case-control study consisting of an under-served population. METHODS This study evaluated single gene and joint modifying effects on PCa risk in a case-control study comprised of 859 AA men (193 cases and 666 controls) using TaqMan qPCR. Interaction among polymorphic IL-10, TGFbetaR-1 and VEGF was analyzed using conventional logistic regression analysis (LR) models, multi-dimensionality reduction (MDR) and interaction entropy graphs. Symbolic modeling allowed validation of gene-gene interaction findings identified by MDR. RESULTS No significant single gene effects were demonstrated in relation to PCa risk. However, carriers of the VEGF 2482T allele had a threefold increase in the risk of developing aggressive PCa. The presence of VEGF 2482T combined with VEGFR IVS6 + 54 loci were highly significant for the risk of PCa based on MDR and symbolic modeling analyses. These findings were substantiated by 1,000-fold cross validation permutation testing (P = 0.04), respectively. CONCLUSION These findings suggest the inheritance of VEGF and VEGFR IVS6 + 54 sequence variants may jointly modify PCa susceptibility through their influence on angiogenesis. Larger sub-population studies are needed to validate these findings and evaluate whether the VEGF-VEGR axis may serve as predictors of disease prognosis and ultimately clinical response to available treatment strategies.
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Affiliation(s)
- Tiva T. VanCleave
- Department of Pharmacology & Toxicology, University of Louisville (UofL), Louisville, Kentucky
- Cancer Prevention & Control Program, James Graham Brown Cancer Center, University of Louisville (UofL), Louisville, Kentucky
| | - Jason H. Moore
- Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Marnita L. Benford
- Department of Pharmacology & Toxicology, University of Louisville (UofL), Louisville, Kentucky
- Cancer Prevention & Control Program, James Graham Brown Cancer Center, University of Louisville (UofL), Louisville, Kentucky
| | - Guy N. Brock
- Department of Bioinformatics & Biostatistics, School of Public Health and Information Science (SPHIS), University of Louisville (UofL), Louisville, Kentucky
| | - Ted Kalbfleisch
- Department of Biochemistry and Molecular Biology, University of Louisville (UofL), Louisville, Kentucky
| | - Richard N. Baumgartner
- Department of Epidemiology, SPHIS, University of Louisville (UofL), Louisville, Kentucky
| | - James W. Lillard
- Department of Pharmacology & Toxicology, University of Louisville (UofL), Louisville, Kentucky
- Department of Microbiology and Immunology, University of Louisville (UofL), Louisville, Kentucky
| | - Rick A. Kittles
- Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, Illinois
| | - La Creis R. Kidd
- Department of Pharmacology & Toxicology, University of Louisville (UofL), Louisville, Kentucky
- Cancer Prevention & Control Program, James Graham Brown Cancer Center, University of Louisville (UofL), Louisville, Kentucky
- Department of Epidemiology, SPHIS, University of Louisville (UofL), Louisville, Kentucky
- Correspondence to: La Creis R. Kidd, PhD, MPH, 580 South Preston Street, 304A Delia Baxter II Research Building, Louisville, KY 40202.
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Chen J, Li Q, Wang C, Wu J, Zhao G. Prognostic significance of c-erbB-2 and vascular endothelial growth factor in colorectal liver metastases. Ann Surg Oncol 2010; 17:1555-63. [PMID: 20069460 DOI: 10.1245/s10434-009-0897-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2009] [Indexed: 12/22/2022]
Abstract
BACKGROUND The prognostic value of c-erbB-2 and vascular endothelial growth factor (VEGF) expression in colorectal liver metastases (CLM) is unclear. The purpose of this study was to clarify the relationship of c-erbB-2 and VEGF with the clinicopathological parameters and the survival results in CLM. METHODS For 44 patients who had undergone liver resection for CLM at Fudan University Cancer Hospital from 2000 to 2007, the expression of c-erbB-2 and VEGF in CLM and the corresponding primary cancer specimens were evaluated immunohistochemically. The correlations among c-erbB-2 and VEGF, clinicopathologic factors, and survival were then statistically analyzed. RESULTS Positive expression rates of c-erbB-2 and VEGF in CLM lesions were 38.64% and 52.72%, respectively. The expression of c-erbB-2 and VEGF in CLM were similar to that of corresponding primary tumor. c-erbB-2 expression correlated with number of metastatic lesions and the distribution of liver metastases. The expression of VEGF correlated with the size of liver metastatic lesion and distribution of liver metastases. A statistically significant association between the expression of c-erbB-2 and VEGF in both CLM and primary tumor was noted. Univariate analysis showed that VEGF was a prognostic factor. However, on multivariate analysis, expression of VEGF was not an independent prognostic marker. Patients with both negative expression of c-erbB-2 and VEGF expression had a better outcome than others. CONCLUSIONS VEGF might be a statistically significant prognostic factor. The combined analysis of c-erbB-2 and VEGF is of added prognostic value. An association exists between c-erbB-2 and VEGF. However, further studies are required to confirm this issue.
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Affiliation(s)
- Jinggui Chen
- Department of Abdominal Surgery, Cancer Hospital, Fudan University, Shanghai, People's Republic of China
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35
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Blanche EA, Maskell L, Colucci MA, Whatmore JL, Moody CJ. Synthesis of potential prodrug systems for reductive activation. Prodrugs for anti-angiogenic isoflavones and VEGF receptor tyrosine kinase inhibitory oxindoles. Tetrahedron 2009. [DOI: 10.1016/j.tet.2009.04.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Mongerard-Coulanges M, Migianu-Griffoni E, Lecouvey M, Jolles B. Impact of alendronate and VEGF-antisense combined treatment on highly VEGF-expressing A431 cells. Biochem Pharmacol 2009; 77:1580-5. [PMID: 19426694 DOI: 10.1016/j.bcp.2009.02.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2009] [Revised: 02/18/2009] [Accepted: 02/19/2009] [Indexed: 01/01/2023]
Abstract
Bisphosphonates, and more specially nitrogen-containing bisphosphonates, which are in current use for the treatment of bone diseases, demonstrate proapoptotic, antiproliferative, antiangiogenic and anti-invasive properties on tumor cells. The amino-bisphosphonate alendronate is considered as a potential anticancer drug. In the case of A431 cells, which express high levels of VEGF, it had a two-step effect. At 24h, the antitumor properties of alendronate were counterbalanced by a survival process, which consisted of an enhancement of VEGF expression (mRNA and protein secretion) and TGF alpha secretion. It was only at 48 h that alendronate displayed the expected antiproliferative and antiangiogenic properties. The first step, in which the PI3K pathway was engaged, could be prevented by the use of a VEGF-antisense oligonucleotide. The combination of such an antisense with small concentrations of alendronate (approximately 2 microM), which is of the order of clinically used concentrations, was shown to have an antiangiogenic effect as soon as 12h.
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Raig ET, Jones NB, Varker KA, Benniger K, Go MR, Biber JL, Lesinski GB, Carson WE. VEGF secretion is inhibited by interferon-alpha in several melanoma cell lines. J Interferon Cytokine Res 2009; 28:553-61. [PMID: 18771339 DOI: 10.1089/jir.2008.0118] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Interferon-alpha (IFN-alpha) is employed in the treatment of malignant melanoma; however, it mediates regression of disease in only 10-15% of patients. Currently, its mechanism of action is uncharacterized. Low-dose IFN-alpha exerts anti-angiogenic effects when used in the treatment of life-threatening hemangiomas of infancy, suggesting anti-angiogenesis as a mechanism of action. IFN-alpha may exert its anti-tumor effect in the setting of advanced malignancy by inhibiting the secretion of vascular endothelial growth factor (VEGF), a pro-angiogenic substance. We hypothesized that IFN-alpha would decrease the release of VEGF by melanoma tumors. We studied the effect of IFN-alpha on VEGF production in nine human melanoma cell lines. We also examined VEGF levels in 49 patients with advanced malignancies who received low-dose IFN-alpha and interleukin-12 (IL-12) on an NCI-sponsored phase I trial. Human melanoma cell lines produced varying amounts of VEGF in vitro (60-1500 pg/mL at 48 h). Certain melanoma cell lines such as 18105 MEL secreted low levels of VEGF (152 pg/mL) after 48 h of culture, whereas other lines secreted very high levels (FO-1 3,802 pg/mL). Treatment of melanoma cells with IFN-alpha (2000 U/mL) decreased VEGF secretion by 40-60% in VEGF-high cell lines; however, this effect was not demonstrated in VEGF-low cell lines. In cancer patients, pretreatment VEGF plasma levels varied from 471 to 4200 pg/mL. A decrease in VEGF plasma levels after treatment directly correlated with the number of treatment cycles administered (Pearson correlation, p = 0.04). In summary, IFN-alpha inhibits VEGF secretion by melanoma cell lines in vitro and may have similar actions in malignancies that respond to IFN-alpha treatment.
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Affiliation(s)
- Ene T Raig
- Integrated Biomedical Sciences Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA
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Backer MV, Hamby CV, Backer JM. Inhibition of vascular endothelial growth factor receptor signaling in angiogenic tumor vasculature. ADVANCES IN GENETICS 2009; 67:1-27. [PMID: 19914448 DOI: 10.1016/s0065-2660(09)67001-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Neovascularization takes place in a large number of pathologies, including cancer. Significant effort has been invested in the development of agents that can inhibit this process, and an increasing number of such agents, known as antiangiogenic drugs, are entering clinical trials or being approved for clinical use. The key players involved in the development and maintenance of tumor neovasculature are vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), and therefore VEGF/VEGFR signaling pathways have been a focus of anticancer therapies for several decades. This review focuses on two main approaches designed to selectively target VEGFRs, inhibiting VEGFR with small molecule inhibitors of receptor tyrosine kinase activity and inhibiting the binding of VEGF to VEGFRs with specific antibodies or soluble decoy VEGF receptors. The major problem with these strategies is that they appeared to be effective only in relatively small and unpredictable subsets of patients. An alternative approach would be to subvert VEGFR for intracellular delivery of cytotoxic molecules. We describe here one such molecule, SLT-VEGF, a fusion protein containing VEGF121 and the highly cytotoxic catalytic subunit of Shiga-like toxin.
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Affiliation(s)
| | - Carl V Hamby
- Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 10595, USA
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Nagy JA, Dvorak AM, Dvorak HF. VEGF-A and the induction of pathological angiogenesis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2008; 2:251-75. [PMID: 18039100 DOI: 10.1146/annurev.pathol.2.010506.134925] [Citation(s) in RCA: 292] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Tumors, wounds, and chronic inflammatory disorders generate a new vascular supply by a process known as pathological angiogenesis. Whereas formation of the normal blood vasculature requires the interaction of many different agonists and inhibitors, including vascular endothelial growth factor-A (VEGF-A) and other members of the vascular permeability factor/VEGF family, pathological angiogenesis is a cruder, simpler process that can be replicated by a single VEGF-A isoform, VEGF-A(164/5). VEGF-A(164/5) induces the formation of several distinctly different types of new blood vessels that differ from normal blood vessels with respect to organization, structure, and function. Elucidating the properties of these new vessels has led to a better understanding of angiogenesis and will hopefully lead to new approaches to antiangiogenic therapy.
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Affiliation(s)
- Janice A Nagy
- Department of Pathology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
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Banerjee S, Mehta S, Haque I, Sengupta K, Dhar K, Kambhampati S, Van Veldhuizen PJ, Banerjee SK. VEGF-A165 induces human aortic smooth muscle cell migration by activating neuropilin-1-VEGFR1-PI3K axis. Biochemistry 2008; 47:3345-51. [PMID: 18284215 DOI: 10.1021/bi8000352] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Vascular smooth muscle cells (SMCs), one of the major cell types of the vascular wall, play a critical role in the process of angiogenesis under both physiological and pathophysiological conditions, including the cancer microenvironment. Previous studies have shown that VEGF-A 165 augments vascular SMC migration via VEGFR2 (KDR/Flk1) pathways. In this study, we found that VEGF-A 165 (recombinant protein or breast tumor cell-secreted) is also capable of inducing migration of VEGFR2-negative human aortic smooth muscle cells (hAOSMCs), and this induction is mediated through a molecular cross-talk of neuropilin-1 (NRP-1), VEGFR1 (Flt-1), and phosphoinositide 3-kinase (PI3K)/Akt signaling kinase. We found that VEGF-A 165 induces hAOSMC migration parallel with the induction of NRP-1 and VEGFR1 expressions and their associations along with the activation of PI3K/Akt. Neutralization of VEGF action by its antibody or inhibition of VEGF-induced PI3K/Akt kinase activation by wortmannin, a PI3K/Akt specific inhibitor, results in inhibition of VEGF-induced hAOSMC migration. Moreover, RNAi-mediated elimination of the NRP-1 expression or blocking of the activity of VEGFR1 by its antibody in hAOSMCs impairs the VEGF-A 165-induced migration of these cells as well as activation of PI3K/Akt kinase. Collectively, these results establish, for the first time, a mechanistic link among VEGF-A 165, NRP-1, VEGFR1, and PI3K/Akt in the regulation of migration of human vascular smooth muscle cells that eventually could be involved in the angiogenic switch.
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Affiliation(s)
- Snigdha Banerjee
- Stem Cell Research Laboratory, Cancer Research Unit, VA Medical Center, Kansas City, Missouri 64128, USA.
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41
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Wu TTL, Wang JS, Jiann BP, Yu CC, Tsai JY, Lin JT, Huang JK. Expression of vascular endothelial growth factor in Taiwanese benign and malignant prostate tissues. J Chin Med Assoc 2007; 70:380-4. [PMID: 17908652 DOI: 10.1016/s1726-4901(08)70024-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND The expression of vascular endothelium growth factor (VEGF) has been correlated to the grading and stage of prostate cancers. However, data regarding Taiwanese prostate cancer patients are lacking. The aim of the present study was to examine VEGF expression in our radical prostatectomy specimens. METHODS Fifty-one radical prostatectomy specimens with prostate cancer (15 stage pT2N0, 25 pT3N0, 11 pT2-4 N1) were stained using goat anti-human VEGF polyclonal antibody (AB-293NA; R&D Systems Inc., Minneapolis, MN, USA). The VEGF expression in malignant and nonmalignant prostate tissues was compared. The correlations of VEGF immunoreactivity with Gleason scores and pathologic stages were examined. MannWhitney U test was used for comparison of preoperative prostate-specific antigen levels between patients with and without VEGF expression. RESULTS Positive VEGF staining was observed in 80.4% of malignant epithelia, 39.2% of peritumoral stroma, 68.6% of benign hyperplastic glands, and 25.5% of adjacent stroma. There was no difference in VEGF expression between malignant and nonmalignant areas. Advanced disease had significantly higher frequency of stroma but not epithelium VEGF staining as compared to organ-confined disease (p = 0.002 and p = 0.412, respectively). The Gleason 7 and higher tumors had significantly higher frequency of VEGF staining in stroma but not glandular epithelium (p = 0.041 and p = 0.353, respectively). Tumors with positive epithelium VEGF staining had significantly higher PSA levels (21.3 18.1 vs. 10.8 6.8 ng/mL; p = 0.013). CONCLUSION There was no difference in VEGF immunoreactivity between malignant and benign prostatic epithelium in Taiwanese. High Gleason grade tumors and advanced disease had significantly higher frequency of VEGF expression in stroma but not glandular epithelium. Tumors with positive epithelium VEGF staining had significantly higher PSA levels.
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Affiliation(s)
- Tony Tong-Lin Wu
- Division of Urology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC.
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42
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Maskell L, Blanche EA, Colucci MA, Whatmore JL, Moody CJ. Synthesis and evaluation of prodrugs for anti-angiogenic pyrrolylmethylidenyl oxindoles. Bioorg Med Chem Lett 2007; 17:1575-8. [PMID: 17254788 DOI: 10.1016/j.bmcl.2006.12.108] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2006] [Revised: 12/21/2006] [Accepted: 12/26/2006] [Indexed: 11/24/2022]
Abstract
Potential prodrugs of inhibitors of VEGF-induced angiogenesis have been investigated. The prodrug systems studied were the 4-nitrobenzyl, 2-nitrophenylacetyl and 3-methyl-3-(3,6-dimethylbenzo-1,4-quinon-2-yl)butanoyl groups, readily attached to acidic OH or NH groups in drug molecules, and released upon bioreductive activation. The anti-angiogenic compounds studied were the pyrrolylmethylidenyl oxindole SU5416 (semaxanib) and its novel 6-hydroxy derivative. The potentially pro-anti-angiogenic compounds were assayed for their ability to block VEGF-induced angiogenesis in HUVECS in comparison to the free agents.
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Affiliation(s)
- Lesley Maskell
- Peninsula Medical School, St. Luke's Campus, Exeter EX1 2LU, UK
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Lizée G, Radvanyi LG, Overwijk WW, Hwu P. Improving antitumor immune responses by circumventing immunoregulatory cells and mechanisms. Clin Cancer Res 2006; 12:4794-803. [PMID: 16914564 DOI: 10.1158/1078-0432.ccr-06-0944] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Although numerous immunotherapeutic strategies have been studied in patients with cancer, consistent induction of clinical responses remains a formidable challenge. Cancer vaccines are often successful at generating elevated numbers of tumor-specific T lymphocytes in peripheral blood, however, despite this, tumors usually continue to grow unabated. Recent evidence suggests that endogenous regulatory cells, known to play a major role in the induction of immune tolerance to self and prevention of autoimmunity, as well as suppressive myeloid cells invoked in the tumor-bearing state, may be largely responsible for preventing effective antitumor immune responses. This review will focus on the major regulatory cell subtypes, including CD4(+)CD25(+) T-regulatory cells, type 1 regulatory T cells, natural killer T cells, and immature myeloid cells. Studies in humans and in animal models have shown a role for all of these cells in tumor progression, although the mechanisms by which they act to suppress immunity remain largely undefined. Elucidation of the dominant molecular mechanisms mediating immune suppression in vivo will allow more precise targeting of the relevant regulatory cell populations, as well as the development of novel strategies and clinical reagents that will directly block molecules that induce the suppression of antitumor immunity.
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Affiliation(s)
- Gregory Lizée
- Department of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
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44
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Hongo T, Kajikawa M, Ishida S, Ozawa S, Ohno Y, Sawada JI, Ishikawa Y, Honda H. Gene expression property of high-density three-dimensional tissue of HepG2 cells formed in radial-flow bioreactor. J Biosci Bioeng 2006; 101:243-50. [PMID: 16716926 DOI: 10.1263/jbb.101.243] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2005] [Accepted: 12/20/2005] [Indexed: 11/17/2022]
Abstract
In our previous study, we examined three-dimensional culture using 5-ml radial-flow bioreactor (RFB) and showed that genes encoding cell cycle related proteins were suppressed in a stable phase. In this study, we analyzed the gene expression profiles of RFB-cultivated HepG2 cells and found that vascular endothelial growth factor (VEGF) production was strongly induced in the stable phase compared with the growth phase or static two-dimensional culture. When human umbilical vein endothelial cells (HUVECs) were grown under the conditioned medium of the stable phase, it was found that the formation of new blood vessels was induced in the angiogenesis model. DNA microarray analysis showed that the expression levels of both genes related to cell cycle arrest and which are known as tumor markers have increased in the stable phase. This result suggests that HepG2 cells in the stable phase maintain an active tumor phenotype. In addition, the expression of genes induced in the hypoxic condition was also induced in the stable phase. When the culture was carried out under a higher dissolved oxygen (DO) concentration, VEGF production did not decrease significantly and the new blood-vessel-forming ability of the conditioned medium was not suppressed. This suggests that the induction of VEGF production in a stable phase is not affected by DO during the tested level. These results suggest that the RFB cell culture system may be used to assess tumor progression mechanism under three-dimensional condition in vitro.
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Affiliation(s)
- Tomokatsu Hongo
- ABLE Corporation, 4-15 Higashigoken-cho, Shinjyuku-ku, Tokyo 162-0813, Japan
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Roodink I, van der Laak J, Kusters B, Wesseling P, Verrijp K, de Waal R, Leenders W. Development of the tumor vascular bed in response to hypoxia-induced VEGF-A differs from that in tumors with constitutive VEGF-A expression. Int J Cancer 2006; 119:2054-62. [PMID: 16804907 DOI: 10.1002/ijc.22072] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Tumors arise initially as avascular masses in which central hypoxia induces expression of vascular endothelial growth factor-A (VEGF-A) and subsequently tumor vascularization. However, VEGF-A can also be constitutively expressed as a result of genetic events. VEGF-A is alternatively spliced to yield at least 6 different isoforms. Of these, VEGF-A(121) is freely diffusible whereas basically charged domains in the larger isoforms confer affinity for cell surface or extracellular matrix components. We previously reported that in a mouse brain metastasis model of human melanoma, VEGF-A(121) induced a qualitatively different tumor vascular phenotype than VEGF-A(165) and VEGF-A(189): in contrast to the latter ones, and VEGF-A(121) did not induce a neovascular bed but rather led to leakage and dilatation of preexistent brain vessels. Here, we correlate vascular phenotypes with spatial VEGF-A expression profiles in clinical brain tumors (low grade gliomas; n = 6, melanoma metastases; n = 4, adenocarcinoma metastases; n = 4, glioblastoma multiforme; n = 3, sarcoma metastasis; n = 1, renal cell carcinoma metastasis; n = 1). We show that tumors that constitutively express VEGF-A present with different vascular beds than tumors in which VEGF-A is expressed as a response to central hypoxia. This phenotypic difference is consistent with a model where in tumors with constitutive VEGF-A expression, all isoforms exert their effects on vasculature, resulting in a classical angiogenic phenotype. In tumors where only central parts express hypoxia-induced VEGF-A, the larger angiogenic isoforms are retained by extracellular matrix, leaving only freely diffusible VEGF-A(121) to exert its dilatation effects on distant vessels.
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Affiliation(s)
- Ilse Roodink
- Department of Pathology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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Neurath KM, Keough MP, Mikkelsen T, Claffey KP. AMP-dependent protein kinase alpha 2 isoform promotes hypoxia-induced VEGF expression in human glioblastoma. Glia 2006; 53:733-43. [PMID: 16518831 DOI: 10.1002/glia.20326] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Tumor cells respond to hypoxic stress by upregulating a variety of genes involved in glucose uptake, glycolysis, and angiogenesis, all essential to maintaining nutrient availability and intracellular ATP levels. Adenosine monophosphate-dependent kinase (AMPK) is a key sensor for cellular homeostasis and is highly sensitive to changes in AMP:ATP ratios. The two catalytic AMPK alpha isoforms (AMPKalpha1, AMPKalpha2) were investigated with respect to their expression, cellular distribution, and contribution to VEGF expression under hypoxic stress in human U373 glioblastoma cells. Quantitative real-time PCR analysis showed AMPKalpha1 mRNA to be constitutively expressed in normoxia and hypoxia, whereas AMPKalpha2 mRNA levels were low in normoxia and significantly induced in hypoxia. Fluorescent immunohistochemistry showed that AMPKalpha2 protein redistributed to the nucleus under hypoxia, whereas AMPKalpha1 remained distributed throughout the cell. The AMPK chemical inhibitor, 5-iodotubericidin, effectively repressed the hypoxic induction of VEGF mRNA levels and hypoxia inducible factor-1 dependent transcription. AMPKalpha2 repression with RNA interference reduced hypoxia-induced VEGF mRNA and HIF-1 transcription, whereas AMPKalpha1 repression did not. Human glioblastoma cell lines U118 and U138 also showed hypoxia-induction of AMPKalpha2 as well as VEGF. Immunohistochemistry analysis of human astrocytoma/glioma samples revealed AMPKalpha2 present in high grade gliomas within hypoxic pseudopalisading microenvironments. These data suggest that prolonged hypoxia promotes the expression and functional activation of AMPKalpha2 and VEGF production in glioma cell lines and glioblastoma multiform tumors, thus contributing to tumor survival and angiogenesis in high grade human gliomas.
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Affiliation(s)
- Kathryn M Neurath
- Department of Cell Biology, Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030-3501, USA
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Canoz O, Gunes T, Deniz K, Akgun H, Balkanli S. Perinatal expression of HSP70 and VEGF in neonatal rat lung vessels exposed to nicotine during gestation. APMIS 2006; 114:10-4. [PMID: 16499655 DOI: 10.1111/j.1600-0463.2006.apm_176.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
We assessed the influence of maternal nicotine exposure during gestation on perinatal expression of HSP70 and VEGF in rat lung parenchyma and lung vessels. Adult white Sprague-Dawley virgin rats were mated with adult male rats over 2 days, with two females for every male. After confirming pregnancy, 30 gravid rats (dams) were then randomly assigned to two equal groups (one experimental and one control; n=15 in each). Experimental dams were treated with subcutaneus (s.c.) (-)-nicotine tartrate, 3 mg/kg body weight/day, during pregnancy from gestational days 9 through 21. After sacrifice, lungs were removed en bloc and formalin-fixed, and paraffinembedded tissue sections were evaluated by immunohistochemistry using a three-step streptavidin-biotin-peroxidase method with monoclonal antibodies directed against HSP70 or VEGF. HSP70 and VEGF expression was increased in the vascular smooth muscle cells of the experimental group (t1) compared to the control group (t(2))t(1)=7.593, t(2)=4.666, p<0.05). The number of bronchioles that stained positively with HSP70 was higher in the nicotineexposed group than in the control group (t(1)=9.274, t(2)=6.956, p<0.05). In conclusion, gestational nicotine exposure increased the expression of VEGF and HSP70 in rat lung parenchyma, especially in the airway epithelium and vascular smooth muscle cells. In vascular smooth muscle cells, these molecules may contribute to nicotine-related hypoxic pulmonary hypertension.
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Affiliation(s)
- Ozlem Canoz
- Erciyes University Medical Faculty, Kayseri, Turkey.
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Pratap J, Javed A, Languino LR, van Wijnen AJ, Stein JL, Stein GS, Lian JB. The Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion. Mol Cell Biol 2005; 25:8581-91. [PMID: 16166639 PMCID: PMC1265732 DOI: 10.1128/mcb.25.19.8581-8591.2005] [Citation(s) in RCA: 246] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
The Runx2 (Cbfa1/AML3) transcription factor and matrix metalloproteinase 9 (MMP9) are key regulators of growth plate maturation and bone formation. The genes for both proteins are characteristic markers of breast and prostate cancer cells that metastasize to bone. Here we experimentally addressed the compelling question of whether Runx2 and MMP are functionally linked. By cDNA expression array analysis, we identified MMP9 as a novel downstream target of Runx2. Like that of MMP13, MMP9 expression is nearly depleted in Runx2 mutant mice. Chromatin immunoprecipitation and electrophoretic mobility shift assays revealed the recruitment of Runx2 to the MMP9 promoter. We show by mutational analysis that the Runx2 site mediates transactivation of the MMP9 promoter in osteoblasts (MC3T3-E1) and nonosseous (HeLa) cells. The overexpression of Runx2 by adenovirus delivery in nonmetastatic (MCF-7) and metastatic breast (MDA-MB-231) and prostate (PC3) cancer cell lines significantly increases the endogenous levels of MMP9. The knockdown of Runx2 by RNA interference decreases MMP9 expression, as well as that of other Runx2 target genes, including the genes for MMP13 and vascular endothelial growth factor. Importantly, we have demonstrated using a cell invasion assay that Runx2-regulated MMP9 levels are functionally related to the invasion properties of cancer cells. These results are consistent with Runx2 control of multiple genes that contribute to the metastatic properties of cancer cells and their activity in the bone microenvironment.
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MESH Headings
- 3T3 Cells
- Adenoviridae/genetics
- Animals
- Blotting, Western
- Bone Neoplasms/metabolism
- Bone Neoplasms/pathology
- Bone Neoplasms/secondary
- Cell Line, Tumor
- Cell Nucleus/metabolism
- Chromatin Immunoprecipitation
- Core Binding Factor Alpha 1 Subunit/physiology
- DNA, Complementary/metabolism
- Gene Expression Regulation, Enzymologic
- HeLa Cells
- Humans
- Matrix Metalloproteinase 9/biosynthesis
- Matrix Metalloproteinase 9/genetics
- Mice
- Mice, Mutant Strains
- Models, Biological
- Models, Genetic
- Neoplasm Invasiveness
- Neoplasm Metastasis
- Osteoblasts/metabolism
- Promoter Regions, Genetic
- RNA/chemistry
- RNA Interference
- RNA, Messenger/metabolism
- RNA, Small Interfering/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
- Transcriptional Activation
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Affiliation(s)
- Jitesh Pratap
- Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
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Pearce HL, Alice Miller M. The evolution of cancer research and drug discovery at Lilly Research Laboratories. ACTA ACUST UNITED AC 2005; 45:229-55. [PMID: 16143373 DOI: 10.1016/j.advenzreg.2005.02.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
This review highlights the discovery and development of chemotherapy at Eli Lilly & Company over the past 30 years from the Vinca alkaloids-vincristine, vinblastine, and vindesine-to targeted therapy. During the late 1970s, Lilly began an exploration of new synthetic compounds based on solid tumor screening models. Several novel antimetabolites with the potential to treat solid tumors were identified. Two such agents, gemcitabine and pemetrexed, underwent clinical development and are now among Lilly's portfolio of approved anticancer drugs. Gemcitabine, a pyrimidine nucleoside that has a profound effect on DNA synthesis, has been approved for the treatment of pancreatic, non-small cell lung, bladder, and most recently, breast, and ovarian cancer. Pemetrexed, a novel antifolate with potent cytotoxic effects, is distinguished from other antifolates by virtue of its ability to inhibit multiple folate-dependent enzymes. Pemetrexed, given in combination with cisplatin, has been recently approved for the treatment of malignant pleural mesothelioma and as second-line treatment for non-small cell lung cancer. Spurred by advances in the understanding of cancer as a disease process, Lilly's anticancer drug program began to transition to a more "targeted" approach during the 1990s. These efforts have recently culminated in the identification and development of enzastaurin, a PKCbeta inhibitor with potent anti-angiogenic properties. Enzastaurin has shown promising single-agent activity in patients with relapsed diffuse large B-cell lymphoma and recurrent glioblastoma multiforme, and is an excellent candidate for combination with cytotoxic agents.
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Affiliation(s)
- Homer L Pearce
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
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Lacković V, Kostić V, Sternić N, Kanjuh V, Vuković I. [Angiogenesis in the central nervous system: a role of vascular endothelial growth factor]. VOJNOSANIT PREGL 2005; 62:59-67. [PMID: 15715351 DOI: 10.2298/vsp0501059l] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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