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Xing C, Zhao L, Zou W, Peng X, Xing XL, Li J. NOS2 as a prognostic biomarker for early-onset colorectal cancer based on public data and clinical validation analysis. Sci Rep 2025; 15:4300. [PMID: 39905237 PMCID: PMC11794712 DOI: 10.1038/s41598-025-88966-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 02/03/2025] [Indexed: 02/06/2025] Open
Abstract
Early-onset colorectal cancer (EOCRC) was characterized by strong aggressiveness and high malignancy. The aim of this study was to screen suitable biomarkers for patients with EOCRC. EOCRC from The Cancer Genome Atlas Program (TCGA) database and Gene Expression Mapping (GEO) database were used to screen biomarkers for prognosis and treatment guidance. Clinical samples were used to verify the expression situation of these candidate biomarkers. The results showed the immune-related gene nitric oxide synthase 2 (NOS2) was independently associated with the poor prognosis of EOCRC patients in both TGCA and GEO database. The Immune Dysfunction and Exclusion (TIDE) analysis showed that multiple immunotherapy signatures, such as TIDE, Exclusion, and CAF, were difference among EOCRC patients with different risk scores, and significantly correlated with the expression of NOS2. Sensitivity analysis of chemotherapy drugs showed that NOS2 was significantly correlated with several chemotherapy drugs, such as MG.132_1862, BMS.754807_2171, and GEN.317_1926. Clinical validation analysis showed that the expression of NOS2 and its related genes CXCL1 and CXCL2 were significantly decreased in EOCRC patients. The results suggested that NOS2 can be used as a potential biomarker for EOCRC, which can be used for prognosis and guidance of immunotherapy and chemotherapy.
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Affiliation(s)
- Chaoqun Xing
- The First Affiliated Hospital of Hunan Medical University, Hunan University of Medicine, Huaihua, 418000, Hunan, P. R. China
- Hunan University of Medicine, Huaihua, 418000, Hunan, P. R. China
| | - Lipeng Zhao
- The Second People's Hospital of Huaihua, Huaihua, 418000, Hunan, P. R. China
| | - Weiwei Zou
- The Second People's Hospital of Huaihua, Huaihua, 418000, Hunan, P. R. China
| | - Xie Peng
- The Second People's Hospital of Huaihua, Huaihua, 418000, Hunan, P. R. China
| | - Xiao-Liang Xing
- The First Affiliated Hospital of Hunan Medical University, Hunan University of Medicine, Huaihua, 418000, Hunan, P. R. China.
- Hunan University of Medicine, Huaihua, 418000, Hunan, P. R. China.
| | - Jie Li
- Hunan University of Medicine, Huaihua, 418000, Hunan, P. R. China.
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Sabatelle RC, Colson YL, Sachdeva U, Grinstaff MW. Drug Delivery Opportunities in Esophageal Cancer: Current Treatments and Future Prospects. Mol Pharm 2024; 21:3103-3120. [PMID: 38888089 PMCID: PMC11331583 DOI: 10.1021/acs.molpharmaceut.4c00246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2024]
Abstract
With one of the highest mortality rates of all malignancies, the 5-year survival rate for esophageal cancer is under 20%. Depending on the stage and extent of the disease, the current standard of care treatment paradigm includes chemotherapy or chemoradiotherapy followed by surgical esophagogastrectomy, with consideration for adjuvant immunotherapy for residual disease. This regimen has high morbidity, due to anatomic changes inherent in surgery, the acuity of surgical complications, and off-target effects of systemic chemotherapy and immunotherapy. We begin with a review of current treatments, then discuss new and emerging targets for therapies and advanced drug delivery systems. Recent and ongoing preclinical and early clinical studies are evaluating traditional tumor targets (e.g., human epidermal growth factor receptor 2), as well as promising new targets such as Yes-associated protein 1 or mammalian target of rapamycin to develop new treatments for this disease. Due the function and location of the esophagus, opportunities also exist to pair these treatments with a drug delivery strategy to increase tumor targeting, bioavailability, and intratumor concentrations, with the two most common delivery platforms being stents and nanoparticles. Finally, early results with antibody drug conjugates and chimeric antigenic receptor T cells show promise as upcoming therapies. This review discusses these innovations in therapeutics and drug delivery in the context of their successes and failures, with the goal of identifying those solutions that demonstrate the most promise to shift the paradigm in treating this deadly disease.
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Affiliation(s)
- Robert C. Sabatelle
- Departments of Biomedical Engineering and Chemistry, Boston University, Boston, MA, 02215, USA
| | - Yolonda L. Colson
- Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Uma Sachdeva
- Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Mark W. Grinstaff
- Departments of Biomedical Engineering and Chemistry, Boston University, Boston, MA, 02215, USA
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3
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Chen T. Unveiling the significance of inducible nitric oxide synthase: Its impact on cancer progression and clinical implications. Cancer Lett 2024; 592:216931. [PMID: 38701892 DOI: 10.1016/j.canlet.2024.216931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/14/2024] [Accepted: 04/29/2024] [Indexed: 05/05/2024]
Abstract
The intricate role of inducible nitric oxide synthase (iNOS) in cancer pathophysiology has garnered significant attention, highlighting the complex interplay between tumorigenesis, immune response, and cellular metabolism. As an enzyme responsible for producing nitric oxide (NO) in response to inflammatory stimuli. iNOS is implicated in various aspects of cancer development, including DNA damage, angiogenesis, and evasion of apoptosis. This review synthesizes the current findings from both preclinical and clinical studies on iNOS across different cancer types, reflecting the variability depending on cellular context and tumor microenvironment. We explore the molecular mechanisms by which iNOS modulates cancer cell growth, survival, and metastasis, emphasizing its impact on immune surveillance and response to treatment. Additionally, the potential of targeting iNOS as a therapeutic strategy in cancer treatment is examined. By integrating insights from recent advances, this review aims to elucidate the significant role of iNOS in cancer and pave the way for novel diagnostic and therapeutic approaches.
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Affiliation(s)
- Tong Chen
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, 43210, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA.
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Shang Z, Ma Z, Wu E, Chen X, Tuo B, Li T, Liu X. Effect of metabolic reprogramming on the immune microenvironment in gastric cancer. Biomed Pharmacother 2024; 170:116030. [PMID: 38128177 DOI: 10.1016/j.biopha.2023.116030] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/03/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
Gastric cancer (GC) is a malignant tumor of the gastrointestinal tract with a high mortality rate worldwide, a low early detection rate and a poor prognosis. The rise of metabolomics has facilitated the early detection and treatment of GC. Metabolism in the GC tumor microenvironment (TME) mainly includes glucose metabolism, lipid metabolism and amino acid metabolism, which provide energy and nutrients for GC cell proliferation and migration. Abnormal tumor metabolism can influence tumor progression by regulating the functions of immune cells and immune molecules in the TME, thereby contributing to tumor immune escape. Thus, in this review, we summarize the impact of metabolism on the TME during GC progression. We also propose novel strategies to modulate antitumor immune responses by targeting metabolism.
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Affiliation(s)
- Zhengye Shang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Zhiyuan Ma
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Enqin Wu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Xingzhao Chen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Taolang Li
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Dalian Road 149, Zunyi 563000, China.
| | - Xuemei Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China.
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5
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Mannan A, Dhiamn S, Garg N, Singh TG. Pharmacological modulation of Sonic Hedgehog signaling pathways in Angiogenesis: A mechanistic perspective. Dev Biol 2023; 504:58-74. [PMID: 37739118 DOI: 10.1016/j.ydbio.2023.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 09/13/2023] [Accepted: 09/18/2023] [Indexed: 09/24/2023]
Abstract
The Sonic hedgehog (SHh) signaling pathway is an imperative operating network that helps in regulates the critical events during the development processes like multicellular embryo growth and patterning. Disruptions in SHh pathway regulation can have severe consequences, including congenital disabilities, stem cell renewal, tissue regeneration, and cancer/tumor growth. Activation of the SHh signal occurs when SHh binds to the receptor complex of Patch (Ptc)-mediated Smoothened (Smo) (Ptc-smo), initiating downstream signaling. This review explores how pharmacological modulation of the SHh pathway affects angiogenesis through canonical and non-canonical pathways. The canonical pathway for angiogenesis involves the activation of angiogenic cytokines such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), placental growth factor (PGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), stromal cell-derived factor 1α, transforming growth factor-β1 (TGF-β1), and angiopoietins (Ang-1 and Ang-2), which facilitate the process of angiogenesis. The Non-canonical pathway includes indirect activation of certain pathways like iNOS/Netrin-1/PKC, RhoA/Rock, ERK/MAPK, PI3K/Akt, Wnt/β-catenin, Notch signaling pathway, and so on. This review will provide a better grasp of the mechanistic approach of SHh in mediating angiogenesis, which can aid in the suppression of certain cancer and tumor growths.
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Affiliation(s)
- Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Sonia Dhiamn
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Nikhil Garg
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
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Panneerselvan P, Vasanthakumar K, Muthuswamy K, Krishnan V, Subramaniam S. Insights on the functional dualism of nitric oxide in the hallmarks of cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:189001. [PMID: 37858621 DOI: 10.1016/j.bbcan.2023.189001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 10/09/2023] [Accepted: 10/09/2023] [Indexed: 10/21/2023]
Abstract
Nitric oxide (NO), a gaseous radical, governs a variety of physiological and pathological processes, including cancer, pro-inflammatory signalling, and vasodilation. The family of nitric oxide synthases (NOS), which comprises the constitutive forms, nNOS and eNOS, and the inducible form, iNOS, produces NO enzymatically. Additionally, NO can be generated non-enzymatically from the nitrate-nitrite-NO pathway. The anti- and pro-oxidant properties of NO and its functional dualism in cancer is due to its highly reactive nature. Numerous malignancies have NOS expression, which interferes with the tumour microenvironment to modulate the tumour's growth in both favourable and unfavourable ways. NO regulates a number of mechanisms in the tumour microenvironment, including metabolism, cell cycle, DNA repair, angiogenesis, and apoptosis/necrosis, depending on its concentration and spatiotemporal profile. This review focuses on the bi-modal impact of nitric oxide on the alteration of a few cancer hallmarks.
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Affiliation(s)
- Prabha Panneerselvan
- Molecular Physiology Laboratory, Department of Biochemistry, Bharathiar University, Coimbatore, Tamil Nadu 641046, India
| | - Keerthana Vasanthakumar
- Molecular Physiology Laboratory, Department of Biochemistry, Bharathiar University, Coimbatore, Tamil Nadu 641046, India
| | - Karthi Muthuswamy
- Molecular Physiology Laboratory, Department of Biochemistry, Bharathiar University, Coimbatore, Tamil Nadu 641046, India
| | - Vasanth Krishnan
- Molecular Biology Laboratory, Department of Botany, Bharathiar University, Coimbatore, Tamil Nadu 641046, India
| | - Selvakumar Subramaniam
- Molecular Physiology Laboratory, Department of Biochemistry, Bharathiar University, Coimbatore, Tamil Nadu 641046, India.
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Mesmar J, Abdallah R, Hamade K, Baydoun S, Al-Thani N, Shaito A, Maresca M, Badran A, Baydoun E. Ethanolic extract of Origanum syriacum L. leaves exhibits potent anti-breast cancer potential and robust antioxidant properties. Front Pharmacol 2022; 13:994025. [PMID: 36299882 PMCID: PMC9589507 DOI: 10.3389/fphar.2022.994025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/12/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Breast cancer (BC) is the second most common cancer overall. In women, BC is the most prevalent cancer and the leading cause of cancer-related mortality. Triple-negative BC (TNBC) is the most aggressive BC, being resistant to hormonal and targeted therapies. Hypothesis/Purpose: The medicinal plant Origanum syriacum L. is a shrubby plant rich in bioactive compounds and widely used in traditional medicine to treat various diseases. However, its therapeutic potential against BC remains poorly investigated. In the present study, we screened the phytochemical content of an ethanolic extract of O. syriacum (OSEE) and investigated its anticancer effects and possible underlying mechanisms of action against the aggressive and highly metastatic human TNBC cell line MDA-MB-231. Methods: MTT, trans-well migration, and scratch assays were used to assess cell viability, invasion, or migration, respectively. Antioxidant potential was evaluated in vitro using the DPPH radical-scavenging assay and levels of reactive oxygen species (ROS) were assessed in cells in culture using DHE staining. Aggregation assays were used to determine cell-cell adhesion. Flow cytometry was used to analyze cell cycle progression. Protein levels of markers of apoptosis (BCL-2, pro-Caspase3, p53), proliferation (p21, Ki67), cell migration, invasion, or adhesion (FAK, E-cadherin), angiogenesis (iNOS), and cell signaling (STAT3, p38) were determined by immunoblotting. A chorioallantoic Membrane (CAM) assay evaluated in ovo angiogenesis. Results: We demonstrated that OSEE had potent radical scavenging activity in vitro and induced the generation of ROS in MDA-MB-231 cells, especially at higher OSEE concentrations. Non-cytotoxic concentrations of OSEE attenuated cell proliferation and induced G0/G1 cell cycle arrest, which was associated with phosphorylation of p38 MAPK, an increase in the levels of tumor suppressor protein p21, and a decrease of proliferation marker protein Ki67. Additionally, only higher concentrations of OSEE were able to attenuate inhibition of proliferation induced by the ROS scavenger N-acetyl cysteine (NAC), indicating that the anti-proliferative effects of OSEE could be ROS-dependent. OSEE stimulated apoptosis and its effector Caspase-3 in MDA-MB-231 cells, in correlation with activation of the STAT3/p53 pathway. Furthermore, the extract reduced the migration and invasive properties of MDA-MB-231 cells through the deactivation of focal adhesion kinase (FAK). OSEE also reduced the production of inducible nitric oxide synthase (iNOS) and inhibited in ovo angiogenesis. Conclusion: Our findings reveal that OSEE is a rich source of phytochemicals and has robust anti-breast cancer properties that significantly attenuate the malignant phenotype of MD-MB-231 cells, suggesting that O. syriacum may not only act as a rich source of potential TNBC therapeutics but may also provide new avenues for the design of novel TNBC drugs.
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Affiliation(s)
- Joelle Mesmar
- Department of Biology, American University of Beirut, Beirut, Lebanon
| | - Rola Abdallah
- Department of Biology, American University of Beirut, Beirut, Lebanon
| | - Kamar Hamade
- UMRT INRE 1158 BioEcoAgro, Laboratorie BIOPI, University of Picardie Jules Verne, Amiens, France
| | - Serine Baydoun
- Breast Imaging Section, Imaging Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Najlaa Al-Thani
- Research and Development Department, Barzan Holdings, Doha, Qatar
| | - Abdullah Shaito
- Biomedical Research Center, College of Medicine, and Department of Biomedical Sciences at College of Health Sciences, Qatar University, Doha, Qatar
- *Correspondence: Abdullah Shaito, ; Marc Maresca, ; Elias Baydoun,
| | - Marc Maresca
- Aix-Marseille University, CNRS, Centrale Marseille, iSm2, Marseille, France
- *Correspondence: Abdullah Shaito, ; Marc Maresca, ; Elias Baydoun,
| | - Adnan Badran
- Department of Nutrition, University of Petra, Amman, Jordan
| | - Elias Baydoun
- Department of Biology, American University of Beirut, Beirut, Lebanon
- *Correspondence: Abdullah Shaito, ; Marc Maresca, ; Elias Baydoun,
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A Network Pharmacology Approach for Uncovering the Antitumor Effects and Potential Mechanisms of the Sijunzi Decoction for the Treatment of Gastric Cancer. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:9364313. [PMID: 35463069 PMCID: PMC9019414 DOI: 10.1155/2022/9364313] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/11/2022] [Accepted: 03/15/2022] [Indexed: 12/15/2022]
Abstract
Background Sijunzi decoction (SJZD), a classic Chinese formula, has been clinically used for the treatment of gastrointestinal disorders. However, few studies have uncovered its antitumor effects and its potential mechanisms against gastric cancer (GC). Therefore, this work aimed to identify the active compounds and putative targets of the SJZD and to further explore the potential mechanisms involved in the treatment of GC. Materials and Methods The active compounds and potential targets of the SJZD and related genes for GC treatment were collected from a public database. Traditional Chinese medicine (TCM)-compound-target-disease networks, Venn diagrams, protein–protein interactions (PPIs), gene ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to obtain the bioactive compounds, key targets, and potential pathways. Next, the human gastric adenocarcinoma cell line NUGC-4 was inoculated subcutaneously into the right flank of NCG mice to build a tumor-bearing mouse model to further verify the findings. Results There were 117 compounds in the SJZD in total. The SJZD and GC had 161 and 3288 potential targets, respectively, among which 123 targets overlapped. The network analysis showed that quercetin, kaempferol formononetin, ginsenoside, atractylenolide III, etc., were bioactive molecules. The tumor necrosis factor (TNF), interleukin-6 (IL-6), cellular tumor antigen p53 (TP53), transcription factor AP-1 (JUN), and vascular endothelial growth factor A (VEGFA) were potential targets. A KEGG pathway enrichment analysis revealed 110 pathways involved in the pathways for cancer, including the PI3K-AKT signaling pathway. Validation experiments showed that the SJZD inhibited tumor growth and induced apoptosis in tumor cells. In addition, the SJZD downregulated expressions of VEGFA, iNOS, COX-2, and Bax/Bcl2 and inhibited the expressions of p-PI3K and p-AKT. Conclusion The SJZD treats GC by inhibiting blood vessel hyperplasia and inducing cell apoptosis by regulating the PI3K/AKT pathway.
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The role of extracellular matrix in tumour angiogenesis: the throne has NOx servants. Biochem Soc Trans 2021; 48:2539-2555. [PMID: 33150941 PMCID: PMC7752075 DOI: 10.1042/bst20200208] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/28/2020] [Accepted: 10/05/2020] [Indexed: 02/07/2023]
Abstract
The extracellular matrix (ECM) dynamics in tumour tissue are deregulated compared to the ECM in healthy tissue along with disorganized architecture and irregular behaviour of the residing cells. Nitric oxide (NO) as a pleiotropic molecule exerts different effects on the components of the ECM driving or inhibiting augmented angiogenesis and tumour progression and tumour cell proliferation and metastasis. These effects rely on the concentration of NO within the tumour tissue, the nature of the surrounding microenvironment and the sensitivity of resident cells to NO. In this review article, we summarize the recent findings on the correlation between the levels of NO and the ECM components towards the modulation of tumour angiogenesis in different types of cancers. These are discussed principally in the context of how NO modulates the expression of ECM proteins resulting in either the promotion or inhibition of tumour growth via tumour angiogenesis. Furthermore, the regulatory effects of individual ECM components on the expression of the NO synthase enzymes and NO production were reviewed. These findings support the current efforts for developing effective therapeutics for cancers.
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Wu T, Yao Y, Sun R, Wang H, Zhang J, Yin X, Zhou Q, Huangfu C. Arterial instillation of rapamycin in treatment of rabbit hepatic xenograft tumors and its effects on VEGF, iNOS, HIF-1α, Bcl-2, Bax expression and microvessel density. Sci Prog 2021; 104:368504211026417. [PMID: 34392719 PMCID: PMC10364938 DOI: 10.1177/00368504211026417] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma is one of the leading causes of malignant tumor related death word wide with poor prognosis. Chemotherapy and TACE are main treatment methods for advanced stage cases. Rapamycin, a macrolide compound that initially used to coat coronary stents, can inhibit the growth of a variety of cancer cells especially hepatocellular carcinoma. Twenty-four healthy adult New Zealand white rabbits underwent CT-guided puncture to prepare a model of VX2 liver xenograft tumor. The rabbits were randomly divided into four groups with six in each group and received the following treatments: APR-TACE1: arterial perfusion of high-dose rapamycin combined with TACE; APR-TACE2: arterial perfusion of low-dose rapamycin combined with TACE; TACE: TACE alone; and IVR-TACE: intravenous injection of rapamycin combined with TACE. Two weeks after TACE treatment, the rabbits received CT scan and DSA angiography examination, and then killed by air embolism. The non-necrotic region and surrounding tissues were obtained from the peripheral tumor for iNOS, HIF-1α, VEGF, Bcl-2, and Bax protein expression analysis. Protein expression of iNOS, HIF-1α, VEGF, and Bcl-2 in APR-TACE1 were significantly lower than those in groups APR-TACE2, TACE, and IVR-TACE (p < 0.05). iNOS, HIF-1α, and VEGF in APR-TACE2 were lower than those in TACE (p < 0.05). iNOS and VEGF in APR-TACE2 were significantly lower than those in IVR-TACE (p < 0.05). iNOS in IVR-TACE was significantly lower than that in TACE (p < 0.05). The expression levels of Bcl-2 and Bax were statistically significant between APR-TACE2 and TACE (p < 0.05). The MVD of the tumor tissue in APR-TACE1 was lower than that of groups APR-TACE2, TACE, IVR-TACE with statistical difference (p < 0.05). However, MVD of APR-TACE2 was lower than that of groups TACE, IVR-TACE with significant statistical difference (p < 0.05). Arterial instillation of rapamycin+TACE in treatment of rabbit hepatic xenograft tumors can reduce tumor neovascularization and inhibit iNOS, HIF-1α, VEGF, Bcl-2, and Bax protein expression.
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Affiliation(s)
- Tao Wu
- Department of Radiology Intervention, The First affiliated Hospital of Henan University of Traditional Chinese Medicine (TMC), Zhengzhou, Henan, P.R. China
- Department of Radiology Intervention, The First Affiliated Hospital of Henan University, Kaifeng, Henan, P.R. China
| | - Yihui Yao
- Department of Radiology Intervention, The First Affiliated Hospital of Henan University, Kaifeng, Henan, P.R. China
| | - Ruimin Sun
- Department of Radiology Intervention, The First affiliated Hospital of Henan University of Traditional Chinese Medicine (TMC), Zhengzhou, Henan, P.R. China
| | - Huili Wang
- Department of Radiology Intervention, The First affiliated Hospital of Henan University of Traditional Chinese Medicine (TMC), Zhengzhou, Henan, P.R. China
| | - Junna Zhang
- Department of Pathology, The First Affiliated Hospital of Henan University, Kaifeng, Henan, P.R. China
| | - Xiaoxiang Yin
- Department of Radiology Intervention, The First Affiliated Hospital of Henan University, Kaifeng, Henan, P.R. China
| | - Qing Zhou
- Department of Radiology Intervention, The First Affiliated Hospital of Henan University, Kaifeng, Henan, P.R. China
| | - Chaoshen Huangfu
- College of Basic Medicine, Henan University, Kaifeng, Henan, P.R. China
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Association between Inflammation and Function of Cell Adhesion Molecules Influence on Gastrointestinal Cancer Development. Cells 2021; 10:cells10010067. [PMID: 33406733 PMCID: PMC7824562 DOI: 10.3390/cells10010067] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/09/2020] [Accepted: 12/29/2020] [Indexed: 12/16/2022] Open
Abstract
Gastrointestinal cancer is highly associated with inflammatory processes inducing the release of cytokines from cancer or immune cells, including interferons, interleukins, chemokines, colony-stimulating factors, and growth factors, which promote or suppress tumor progression. Inflammatory cytokines within the tumor microenvironment promote immune cell infiltration. Infiltrating immune, and tumor-surrounding stromal cells support tumor growth, angiogenesis, metastasis, and immunosuppression through communication with inflammatory cytokines and cell adhesion molecules. Notably, infiltrating immune and tumor cells present immunosuppressive molecules, such as programmed death-ligand 1 (PD-L1) and CD80/CD86. Suppression of cytotoxic T cells promotes tumor avoidance of immune surveillance and greater malignancy. Moreover, glycosylation and sialylation of proteins hyperexpressed on the cancer cell surface have been shown to enhance immune escape and metastasis. Cytokine treatments and immune checkpoint inhibitors are widely used in clinical practice. However, the tumor microenvironment is a rapidly changing milieu involving several factors. In this review, we have provided a summary of the interactions of inflammation and cell adhesion molecules between cancer and other cell types, to improve understanding of the tumor microenvironment.
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12
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Lu M, Wu S, Cheng G, Xu C, Chen Z. Integrative Bioinformatics Analysis of iNOS/NOS2 in gastric and colorectal cancer. Pteridines 2020. [DOI: 10.1515/pteridines-2020-0011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Abstract
Objective The aim of the present work was to investigate the expression of nitric oxide synthase 2 (iNOS/ NOS2) in colorectal and gastric cancers and evaluate its association with patient’s prognosis by integrated bioinformatics analysis.
Methods The data for present study was obtained from the TCGA, GTEx, and STRING database. iNOS/NOS2 mRNA expression in normal tissue and colorectal, and gastric cancer tissuea were investigated through the GTEx and TCGA database. iNOS/NOS2 gene mutations and frequency were analyzed in the TCGA database using the cBioPortal online data analysis tool. The protein-protein interaction (PPI) network of iNOS/NOS2 was constructed by STRING database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of iNOS/NOS2 and relevant proteins involved in the PPI network were enriched and demonstrated by the bubble plot. Comparison of the overall survival(OS) and disease free survival(DFS) between samples expressing high and low levels of iNOS/NOS2 was analysis based on the TCGA databases through the GEPIA online data analysis tool.
Results For colon adenocarcinoma (COAD) and rectal adenocarcinoma(READ) iNOS/NOS2 mRNA expression levels in tumor tissue were significant higher than those of corresponding normal colorectal tissue (p<0.05). iNOS/NOS2 mutations were identified in both colorectal cancer and gastric cancer. Missense substitutions and synonymous substitution were the top two mutation types for colorectal and gastric cancer. The top positive and negative co-expressed genes correlated with iNOS/ NOS2 were TRIM40 (rpearson=0.56, p<0.05) and GDPD5 (rpearson=-0.41, p<0.05) in colorectal cancer respectively andCASP5 (rpearson=0.63,p<0.05) and PIAS3 (rpearson=-0.43,p<0.05) in gastric cancer. Twenty one proteins were included in the PPI network with 51 nodes and 345 edges which indicated the PPI enrichment wassignificant (p=1.0e-16). The KEGG of the included genes were mainly enriched in metabolic pathway and Jak-STAT signaling pathway. There was a significant difference indisease free survival (DFS) between samples expressing high and low iNOS/NOS2 (HR=0.37, p=0.044) in rectal cancer. The difference was not statistical between iNOS/NOS2 high and low expressing groups for overall survival(OS) or DFS in the colon cancer or gastric cancer(p>0.05).
Conclusions iNOS/NOS2 mRNA isup-regulated in tumor tissue compared to corresponding normal tissue in colorectal and gastric cancer which implement it in the development of colorectal and gastric cancers.
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Affiliation(s)
- Mingbei Lu
- Department of Thyroid and Breast Surgery , Lishui People’s Hospital , Lishui 323000, Zhejiang Province , China
| | - Suping Wu
- Department of ICU , Lishui People’s Hospital , Lishui 323000, Zhejiang Province , China
| | - Guoxiong Cheng
- Department of Gastrointestinal Surgery , Lishui People’s Hospital , Lishui 323000, Zhejiang Province , China
| | - Chaobo Xu
- Department of Gastrointestinal Surgery , Lishui People’s Hospital , Lishui 323000, Zhejiang Province , China
| | - Zhengwei Chen
- Department of Gastrointestinal Surgery , Lishui People’s Hospital , Lishui 323000, Zhejiang Province , China
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13
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Imatinib exhibit synergistic pleiotropy in the prevention of colorectal cancer by suppressing proinflammatory, cell survival and angiogenic signaling. Cell Signal 2020; 76:109803. [PMID: 33022360 DOI: 10.1016/j.cellsig.2020.109803] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/26/2020] [Accepted: 09/30/2020] [Indexed: 12/24/2022]
Abstract
Recent global incidences and mortality rates have placed colorectal cancer (CRC) at third and second positions, respectively, among both sexes of all ages. Resistance during chemotherapy is a big problem in the treatment and disease-free survival of CRC patients. Discovery of new anticancer drug(s) is a time taking process and therefore, invites studies for repurposing the known therapeutics. The present study was conceived to analyze the anticancer role of Imatinib in experimental CRC at early stages. Different experimental procedures e.g. tumor incidences or histoarchitectural changes, gene and protein expression analysis, estimations of intracellular calcium, ROS, mitochondrial membrane potential, apoptotic index and molecular docking was performed to support the hypothesis. It was observed that Imatinib could function as an immunomodulator by breaking the feed-back loop between the proinflammatory cytokines (IL-1β and TNF-α) and transcription factors (NF-κB, Jak3/Stat3) knowingly involved in increased cell proliferation during tumorigenesis via activating different intracellular signaling. Also, Imatinib could independently deregulate the other cell survival and proliferation signaling e.g. PI3-K/Akt/mTOR, Wnt/β-catenin and MAPK. Proinflammatory cytokines orchestrated intracellular signaling also involve angiogenic factors to be upregulated during CRC which were also seemed to be independently suppressed by Imatinib. Restoration of physiological apoptosis by increasing the release of intracellular calcium to generate ROS thereby reducing the mitochondrial membrane potential for the release of cytochrome c and activation of caspase-3 was also reported with Imatinib administration. Thus, it may be suggested that Imatinib show synergistic pleiotropy in suppressing the interlinked tumorigenic signaling pathways independently.
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14
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Zhang L, Wang H, Feng M, Zhang X. Bioinformatics analysis of the expression of inducible nitric oxide synthases (iNOS/NOS2) in human glioma and its correlation with patients’ prognoses. Pteridines 2020. [DOI: 10.1515/pteridines-2020-0019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Abstract
Objective To evaluate the expression of inducible nitric oxide synthases (iNOS/NOS2) in human glioma and its correlation with patients’ prognoses.
Methods IiNOS/NOS2 expression in tumor and corresponding normal tissues of glioma patients was analyzed using the TCGA database and the online analysis tool GEPIA. The mutation statuses of iNOS/NOS2 genes were also explored in the TCGA database using cBioPortal. Co-expressed genes relevant to iNOS/NOS2 were screened by LinkedOmics. Gene ontology (GO) and KEGG pathway enrichment for iNOS/NOS2 and co-expressed genes was performed using LinkedOmics. Overall survival (OS) and disease-free survival (DFS) outcomes between iNOS/NOS2 mRNA high and low expression groups were compared using a log-rank test. Twenty-two glioma patients who underwent operation were included in the present work. A real-time PCR assay was used to detect iNOS/NOS2 mRNA expression in tumor tissue and normal brain tissue.
Results There was no statistical difference in iNOS/NOS2 mRNA expression levelss between tumor and normal tissues of glioma. A real-time PCR assay indicated that iNOS/NOS2 mRNA expression in tumor tissue and normal brain tissues were not statistical difference (p>0.05). A mutation rate of 0.8% for the iNOS/NOS2 gene was found using 1044 glioma patients from two datasets. The mutation types include deep deletion (0.4%), truncating (0.2%) and missense (0.2%). The top positive and negative co-expressed gene with iNOS/NOS2 were COL25A1 (rpearson=0.4734, p<0.05) and ALCAM (rpearson=0.4734, p<0.05), respectively. For KEGG pathway analysis, iNOS/NOS2 was mainly enriched in calcium signaling pathway, Wnt signaling pathway, GnRH signaling pathway, HIF-1 signaling pathway and pathways in cancer. The overall survival (HR=2.0, p<0.05) and disease-free survival (HR=1.6, p<0.05) values were significantly different between iNOS/NOS2 high and low expression groups.
Conclusion OS and DFS were significantly decreased in high iNOS/NOS2 mRNA expression groups. iNOS/NOS2 can be used as a poor prognostic biomarker for glioma.
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Affiliation(s)
- Liping Zhang
- Department of Neuroelectrophysiology , Tianjin Huanhu Hospital , Tianjin 300350 PR China
| | - Huanyu Wang
- Department of Neurosurgery , Tianjin Huanhu Hospital , Tianjin 300350 PR China
| | - Mei Feng
- Department of Neuroelectrophysiology , Tianjin Huanhu Hospital , Tianjin 300350 PR China
| | - Xueqing Zhang
- Department of Neuroelectrophysiology , Tianjin Huanhu Hospital , Tianjin 300350 PR China
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15
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Leach DG, Newton JM, Florez MA, Lopez-Silva TL, Jones AA, Young S, Sikora AG, Hartgerink JD. Drug-Mimicking Nanofibrous Peptide Hydrogel for Inhibition of Inducible Nitric Oxide Synthase. ACS Biomater Sci Eng 2019; 5:6755-6765. [PMID: 33304997 DOI: 10.1021/acsbiomaterials.9b01447] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In this work, we develop a drug-mimicking nanofibrous peptide hydrogel that shows long-term bioactivity comparable to a small-molecule inhibitor of inducible nitric oxide synthase (iNOS). The iNOS inhibitor, N 6-(1-iminoethyl)-l-lysine (l-NIL), is a positively charged amino acid whose structure could be readily integrated into the framework of a positively charged multidomain peptide (MDP) through the modification of lysine side chains. This new l-NIL-MDP maintains the self-assembling properties of the base peptide, forming β-sheet nanofibers, which entangle into a thixotropic hydrogel. The l-NIL-MDP hydrogel supports cell growth in vitro and allows syringe-directed delivery that persists in a targeted location in vivo for several weeks. Multiple characterization assays demonstrate the bioactivity of the l-NIL-MDP hydrogel to be comparable to the l-NIL small molecule. This includes iNOS inhibition of macrophages in vitro, reduced nitrotyrosine immunostaining in murine subcutaneous histology, and reduced serum levels of vascular endothelial growth factor in vivo. This study expands the toolbox of available peptide hydrogel scaffold designs that can modify biological activity without the need for any additional small-molecule drugs, proteins, or cells.
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Affiliation(s)
- David G Leach
- Department of Chemistry and Department of Bioengineering, Rice University, Houston, Texas 77005, United States
| | - Jared M Newton
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas 77030, United States.,Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Marcus A Florez
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas 77030, United States.,Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Tania L Lopez-Silva
- Department of Chemistry and Department of Bioengineering, Rice University, Houston, Texas 77005, United States
| | - Adrianna A Jones
- Department of Chemistry and Department of Bioengineering, Rice University, Houston, Texas 77005, United States
| | - Simon Young
- Department of Oral & Maxillofacial Surgery, University of Texas Health Science Center, Houston, Texas 77054, United States
| | - Andrew G Sikora
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas 77030, United States
| | - Jeffrey D Hartgerink
- Department of Chemistry and Department of Bioengineering, Rice University, Houston, Texas 77005, United States
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16
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Imatinib modulates pro-inflammatory microenvironment with angiostatic effects in experimental lung carcinogenesis. Inflammopharmacology 2019; 28:231-252. [PMID: 31676982 DOI: 10.1007/s10787-019-00656-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 10/10/2019] [Indexed: 10/25/2022]
Abstract
Lung cancer has second highest rate of incidence and mortality around the world. Smoking cigarettes is the main stream cause of lung carcinogenesis along with other factors such as spontaneous mutations, inactivation of tumor suppressor genes. The present study was aimed to identify the mechanistic role of Imatinib in the chemoprevention of experimental lung carcinogenesis in rat model. Gross morphological observations for tumor formation, histological examinations, RT-PCR, Western blotting, fluorescence spectroscopy and molecular docking studies were performed to elucidate the chemopreventive effects of Imatinib and support our hypothesis by various experiments. It is evident that immuno-compromised microenvironment inside solid tumors is responsible for tumor progression and drug resistance. Therefore, it is inevitable to modulate the pro-inflammatory signaling inside solid tumors to restrict neoangiogenesis. In the present study, we observed that Imatinib could downregulate the inflammatory signaling and also attributed angiostatic effects. Moreover, Imatinib also altered the biophysical properties of BAL cells such as plasma membrane potential, fluidity and microviscosity to restrict their infiltration and thereby accumulation to mount immuno-compromised environment inside the solid tumors during angiogenesis. Our molecular docking studies suggest that immunomodulatory and angiostatic properties of Imatinib could be either independent of each other or just a case of synergistic pleiotropy. Imatinib was observed to activate the intrinsic or mitochondrial pathway of apoptosis to achieve desired effects in cancer cell killings. Interestingly, binding of Imatinib inside the catalytic domain of PARP-1 also suggests that it has caspase-independent properties in promoting cancer cell deaths.
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17
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Tiwari SK, Shaik AS, Shaik AP, Alyousef AA, Bardia A, Habeeb MA, Khan AA. Gene expression patterns of COX-1, COX-2 and iNOS in H. Pylori infected histopathological conditions. Microb Pathog 2019; 135:103634. [PMID: 31325568 DOI: 10.1016/j.micpath.2019.103634] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 07/17/2019] [Accepted: 07/17/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Research indicates that Helicobacter pylori can inflict severe histological damage through the modulation of host-related genes. The current study investigated the effect of H. pylori genotypes in the outcome of disease, and the expression of anti-apoptotic related genes, COX-1, COX-2, and iNOS genes in benign, pre-malignant, and malignant lesions of gastric carcinogenesis. MATERIALS AND METHODS Tissue samples from H. pylori positive patients were graded based on the genotype of the infected H. pylori strain. Expression of COX-1, COX-2 and iNOS was assessed using a combination of real-time PCR and immunohistochemistry. RESULTS Gene expression studies confirmed that COX-2 and iNOS expression was highly and selectively induced in epithelium with premalignant changes such as atrophic conditions, metaplasia and dysplasia, suggesting an important role of these genes in the sequence to gastric carcinoma of the intestinal type. Furthermore, the expression of COX-2 and iNOS was also dependent on the genotype of H. pylori and subjects with genotype-1 exhibited significantly higher expressions of COX-2 and iNOS compared to other genotypes. Comparison of the expression levels among infected and uninfected individuals demonstrated significant difference in the expression pattern of COX-2 gene whereas iNOS expression was found only in subjects infected H. pylori (p < 0.001). Immunohistochemical staining showed 1.5619 folds higher propensity of COX-2 and 3.2941 folds higher intensity of iNOS expression in subjects infected with H. pylori genotype 1. CONCLUSION The up-regulation of COX-2 and iNOS was associated with the genotype of the H. pylori strain and the presence of certain genotype may greatly affect early events during carcinogenesis.
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Affiliation(s)
- Santosh K Tiwari
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, Telangana, India
| | - Asma Sultana Shaik
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Abjal Pasha Shaik
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Abdullah A Alyousef
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Avinash Bardia
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, Telangana, India
| | - Md Aejaz Habeeb
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, Telangana, India
| | - Aleem A Khan
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, Telangana, India.
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18
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Ruan D, Zhu T, Huang J, Le H, Hu Y, Zheng Z, Tang C, Chen Y, Ran J, Chen X, Yin Z, Qian S, Pioletti D, Heng BC, Chen W, Shen W, Ouyang HW. Knitted Silk-Collagen Scaffold Incorporated with Ligament Stem/Progenitor Cells Sheet for Anterior Cruciate Ligament Reconstruction and Osteoarthritis Prevention. ACS Biomater Sci Eng 2019; 5:5412-5421. [PMID: 33464061 DOI: 10.1021/acsbiomaterials.9b01041] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Current surgical management of anterior cruciate ligament (ACL) rupture still remains an intractable challenge in ACL regeneration due to the weak self-healing capability of ACL. Inadequate cell numbers and vascularization within the articular cavity contribute mainly to the poor prognosis. This time, we fabricated a new tissue engineering scaffold by adding ligament stem/progenitor cell (LSPC) sheets to our previous knitted silk-collagen sponge scaffold, which overcame these limitations by providing sufficient numbers of seed cells and a natural extracellular matrix to facilitate regeneration. LSPCs display excellent proliferation and multilineage differentiation capacity. Upon ectopic implantation, the knitted silk-collagen sponge scaffold incorporated with an LSPC sheet exhibited less immune cells but more fibroblast-like cells, deposited ECM and neovascularization, and better tissue ingrowth. In a rabbit model, we excised the ACL and performed a reconstructive surgery with our scaffold. Increased expression of ligament-specific genes and better collagen fibril formation could be observed after orthotopic transplantation. After 6 months, the LSPC sheet group showed better results on ligament regeneration and ligament-bone healing. Furthermore, no obvious cartilage and meniscus degeneration were observed at 6 months postoperation. In conclusion, these results indicated that the new tissue engineering scaffold can promote ACL regeneration and slow down the progression of osteoarthritis, thus suggesting its high clinical potential as an ideal graft in ACL reconstruction.
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Affiliation(s)
- Dengfeng Ruan
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, China.,Department of Orthopedics, Research Institute of Zhejiang University, Zhejiang, 310027, China
| | - Ting Zhu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, China.,Department of Orthopedics, Research Institute of Zhejiang University, Zhejiang, 310027, China.,Department of Cardiothoracic Surgery, Shaoxing People's Hospital, Shaoxin Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, People's Republic of China
| | - Jiayun Huang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, China.,Department of Orthopedics, Research Institute of Zhejiang University, Zhejiang, 310027, China.,Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Zhejiang, 310009, China
| | - Huihui Le
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, China.,Department of Orthopedics, Research Institute of Zhejiang University, Zhejiang, 310027, China
| | - Yejun Hu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, China.,Department of Orthopedics, Research Institute of Zhejiang University, Zhejiang, 310027, China.,Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Zhejiang, 310009, China
| | - Zefeng Zheng
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, China.,Department of Orthopedics, Research Institute of Zhejiang University, Zhejiang, 310027, China.,Department of Orthopedic Surgery, Children's Hospital, Zhejiang University School of Medicine, Zhejiang, 310052, China
| | - Chenqi Tang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, China.,Department of Orthopedics, Research Institute of Zhejiang University, Zhejiang, 310027, China.,Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Zhejiang, 310009, China
| | - Yangwu Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, China.,Department of Orthopedics, Research Institute of Zhejiang University, Zhejiang, 310027, China.,Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Zhejiang, 310009, China
| | - Jisheng Ran
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, China.,Department of Orthopedics, Research Institute of Zhejiang University, Zhejiang, 310027, China
| | - Xiao Chen
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Zhejiang, 310009, China.,China Orthopaedic Regenerative Medicine (CORMed), Hangzhou, China
| | - Zi Yin
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Zhejiang, 310009, China
| | - Shengjun Qian
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, China.,Department of Orthopedics, Research Institute of Zhejiang University, Zhejiang, 310027, China
| | | | | | - Weishan Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, China.,Department of Orthopedics, Research Institute of Zhejiang University, Zhejiang, 310027, China
| | - Weiliang Shen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, 310009, China.,Department of Orthopedics, Research Institute of Zhejiang University, Zhejiang, 310027, China.,Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Zhejiang, 310009, China.,Laboratory of Biomechanical Orthopedics, EPFL, Lausanne, Switzerland.,China Orthopaedic Regenerative Medicine (CORMed), Hangzhou, China
| | - Hong-Wei Ouyang
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Zhejiang, 310009, China.,China Orthopaedic Regenerative Medicine (CORMed), Hangzhou, China
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19
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Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, Carlesi R, Das M, Shah MA, Karaseva NA, Kowalyszyn RD, Hernandez CA, Csoszi T, De Vita F, Pfeiffer P, Sugimoto N, Kocsis J, Csilla A, Bodoky G, Garnica Jaliffe G, Protsenko S, Madi A, Wojcik E, Brenner B, Folprecht G, Sarosiek T, Peltola KJ, Bono P, Ayala H, Aprile G, Gerardo CG, Huitzil Melendez FD, Falcone A, Di Costanzo F, Tehfe M, Mineur L, García Alfonso P, Obermannova R, Senellart H, Petty R, Samuel L, Acs PI, Hussein MA, Nechaeva MN, Erdkamp F, Won E, Bendell JC, Gallego Plazas J, Lorenzen S, Melichar B, Escudero MA, Pezet D, Phelip JM, Kaen DL, Reeves JAJ, Longo Muñoz F, Madhusudan S, Barone C, Fein LE, Gomez Villanueva A, Hebbar M, Prausova J, Visa Turmo L, Vidal Barrull J, Yilmaz MKN, Beny A, Van Laarhoven H, DiCarlo BA, Esaki T, Fujitani K, Geboes K, Geva R, Kadowaki S, Leong S, Machida N, Raj MS, Ramirez Godinez FJ, Ruzsa A, Ford H, Lawler WE, Maisey NR, Petera J, Shacham-Shmueli E, Sinapi I, et alFuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, Carlesi R, Das M, Shah MA, Karaseva NA, Kowalyszyn RD, Hernandez CA, Csoszi T, De Vita F, Pfeiffer P, Sugimoto N, Kocsis J, Csilla A, Bodoky G, Garnica Jaliffe G, Protsenko S, Madi A, Wojcik E, Brenner B, Folprecht G, Sarosiek T, Peltola KJ, Bono P, Ayala H, Aprile G, Gerardo CG, Huitzil Melendez FD, Falcone A, Di Costanzo F, Tehfe M, Mineur L, García Alfonso P, Obermannova R, Senellart H, Petty R, Samuel L, Acs PI, Hussein MA, Nechaeva MN, Erdkamp F, Won E, Bendell JC, Gallego Plazas J, Lorenzen S, Melichar B, Escudero MA, Pezet D, Phelip JM, Kaen DL, Reeves JAJ, Longo Muñoz F, Madhusudan S, Barone C, Fein LE, Gomez Villanueva A, Hebbar M, Prausova J, Visa Turmo L, Vidal Barrull J, Yilmaz MKN, Beny A, Van Laarhoven H, DiCarlo BA, Esaki T, Fujitani K, Geboes K, Geva R, Kadowaki S, Leong S, Machida N, Raj MS, Ramirez Godinez FJ, Ruzsa A, Ford H, Lawler WE, Maisey NR, Petera J, Shacham-Shmueli E, Sinapi I, Yamaguchi K, Hara H, Beck JT, Błasińska-Morawiec M, Villalobos Valencia R, Alcindor T, Bajaj M, Berry S, Gomez CM, Dammrich D, Patel R, Taieb J, Ten Tije A, Burkes RL, Cabanillas F, Firdaus I, Chua CC, Hironaka S, Hofheinz RD, Lim HJ, Nordsmark M, Piko B, Verma U, Wadsley J, Yukisawa S, Gutiérrez Delgado F, Denlinger CS, Kallio R, Pikiel J, Wojcik-Tomaszewska J, Brezden-Masley C, Jang RWJ, Pribylova J, Sakai D, Bartoli MA, Cats A, Grootscholten M, Dichmann RA, Hool H, Shaib W, Tsuji A, Van den Eynde M, Velez-Cortez H, Asmis TR. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20:420-435. [PMID: 30718072 DOI: 10.1016/s1470-2045(18)30791-5] [Show More Authors] [Citation(s) in RCA: 221] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 10/03/2018] [Accepted: 10/16/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. METHODS For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1-5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. FINDINGS Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607-0·935, p=0·0106; median progression-free survival 5·7 months [5·5-6·5] vs 5·4 months [4·5-5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768-1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801-1·156, p=0·6757; median overall survival 11·2 months [9·9-11·9] in the ramucirumab group vs 10·7 months [9·5-11·9] in the placebo group). The most common grade 3-4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). INTERPRETATION Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population. FUNDING Eli Lilly and Company.
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Affiliation(s)
- Charles S Fuchs
- Yale Cancer Center, Smilow Cancer Hospital, New Haven, CT, USA.
| | - Kohei Shitara
- National Cancer Center Hospital East, Kashiwa, Japan
| | | | | | - Salah-Eddin Al-Batran
- Institute of Clinical Cancer Research at Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt, Germany
| | - Eric Van Cutsem
- University Hospitals Gasthuisberg, Leuven and KULeuven, Belgium
| | - David H Ilson
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria Alsina
- Vall d'Hebron University Hospital and Institute of Oncology, Barcelona, Spain
| | - Ian Chau
- Royal Marsden Hospital, Sutton, Surrey, United Kingdom
| | - Jill Lacy
- Yale Cancer Center, Smilow Cancer Hospital, New Haven, CT, USA
| | - Michel Ducreux
- Gustave Roussy Cancer Centre, Grand Paris, Villejuif, France; Université Paris-Saclay, France
| | | | | | | | | | | | | | - Zev A Wainberg
- David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | | | - David Ferry
- Eli Lilly and Company, New York City, NY, USA
| | - Ji Lin
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | - Mayukh Das
- Eli Lilly and Company, Indianapolis, IN, USA
| | - Manish A Shah
- Weill Cornell Medical College, NY, USA; New York Presbyterian Hospital, New York, NY, USA
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Dahdaleh FS, Turaga KK. Evolving Treatment Strategies and Outcomes in Advanced Gastric Cancer with Peritoneal Metastasis. Surg Oncol Clin N Am 2018; 27:519-537. [PMID: 29935687 DOI: 10.1016/j.soc.2018.02.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Gastric cancer (GC) has a predilection to metastasize to the peritoneum, denoting a poor prognosis. Treatment strategies available for advanced GC have significantly evolved over time and can be categorized into systemic, regional, and surgical. Although systemic therapies have been the mainstay for the treatment of advanced GC, their ability in achieving long-term survival in patients with peritoneal involvement is modest at best. This article describes advances in combined modality treatment of peritoneal metastases, specifically with an emphasis on peritoneal-directed therapies.
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Affiliation(s)
- Fadi S Dahdaleh
- Complex General Surgical Oncology, Section of General Surgery/Surgical Oncology, The University of Chicago Medicine, 5841 South Maryland Avenue, Room S214, MC 5094, Chicago, IL 60637, USA
| | - Kiran K Turaga
- The University of Chicago Medicine, Section of General Surgery/Surgical Oncology, 5841 South Maryland Avenue, Room G207, MC 5094, Chicago, IL 60637, USA.
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Maniyar R, Chakraborty S, Suriano R. Ethanol Enhances Estrogen Mediated Angiogenesis in Breast Cancer. J Cancer 2018; 9:3874-3885. [PMID: 30410590 PMCID: PMC6218769 DOI: 10.7150/jca.25581] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 08/20/2018] [Indexed: 01/15/2023] Open
Abstract
Angiogenesis, a highly regulated process, is exploited by tumors like breast cancer to ensure a constant supply of oxygen and nutrients and is key for tumor survival and progression. Estrogen and alcohol independently have been observed to contribute to angiogenesis in breast cancer but their combinatorial effects have never been evaluated. The exact mechanism by which estrogen and alcohol contribute to breast cancer angiogenesis remains to be elucidated. In this study, we defined the in vitro effects of the combination of estrogen and alcohol in breast cancer angiogenesis using the tubulogenesis and scratch wound assays. Conditioned media, generated by culturing the murine mammary cancer cell line, TG1-1, in estrogen and ethanol, enhanced tubule formation and migration as well as modulated the MAP Kinase pathway in the murine endothelial cell line, SVEC4-10. Additionally, estrogen and ethanol in combination enhanced the expression of the pro-angiogenic factors VEGF, MMP-9, and eNOS, and modulated Akt activation. These observations suggest that TG1-1 cells secrete pro-angiogenic molecules in response to the combination of estrogen and ethanol that modulate the morphological and migratory properties of endothelial cells. The data presented in this study, is the first in attempting to link the cooperative activity between estrogen and ethanol in breast cancer progression, underscoring correlations first made by epidemiological observations linking the two.
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Affiliation(s)
- Rachana Maniyar
- Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, United States of America
| | - Sanjukta Chakraborty
- Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, United States of America
| | - Robert Suriano
- Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, United States of America
- Division of Natural Sciences, College of Mount Saint Vincent, Bronx. New York, United States of America
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Li X, Guo X, Cheng Y, Zhao X, Fang Z, Luo Y, Xia S, Feng Y, Chen J, Yuan WE. pH-Responsive Cross-Linked Low Molecular Weight Polyethylenimine as an Efficient Gene Vector for Delivery of Plasmid DNA Encoding Anti-VEGF-shRNA for Tumor Treatment. Front Oncol 2018; 8:354. [PMID: 30319959 PMCID: PMC6167493 DOI: 10.3389/fonc.2018.00354] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 08/10/2018] [Indexed: 01/23/2023] Open
Abstract
RNA interference (RNAi) is a biological process through which gene expression can be inhibited by RNA molecules with high selectivity and specificity, providing a promising tool for tumor treatment. Two types of molecules are often applied to inactivate target gene expression: synthetic double stranded small interfering RNA (siRNA) and plasmid DNA encoding short hairpin RNA (shRNA). Vectors with high transfection efficiency and low toxicity are essential for the delivery of siRNA and shRNA. In this study, TDAPEI, the synthetic derivative of low-molecular-weight polyethylenimine (PEI), was cross-linked with imine bonds by the conjugation of branched PEI (1.8 kDa) and 2,5-thiophenedicarboxaldehyde (TDA). This biodegradable cationic polymer was utilized as the vector for the delivery of plasmid DNA expressing anti-VEGF-shRNA. Compared to PEI (25 kDa), TDAPEI had a better performance since experimental results suggest its higher transfection efficiency as well as lower toxicity both in cell and animal studies. TDAPEI did not stimulate innate immune response, which is a significant factor that should be considered in vector design for gene delivery. All the results suggested that TDAPEI delivering anti-VEGF-shRNA may provide a promising method for tumor treatment.
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Affiliation(s)
- Xiaoming Li
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoshuang Guo
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Yuan Cheng
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaotian Zhao
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Zhiwei Fang
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Yanli Luo
- Department of Pathology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Shujun Xia
- Department of Ultrasound, Rui Jin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yun Feng
- Department of Respiration, Institute of Respiratory Diseases, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jianjun Chen
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Wei-En Yuan
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
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Curea FG, Hebbar M, Ilie SM, Bacinschi XE, Trifanescu OG, Botnariuc I, Anghel RM. Current Targeted Therapies in HER2-Positive Gastric Adenocarcinoma. Cancer Biother Radiopharm 2018; 32:351-363. [PMID: 29265917 DOI: 10.1089/cbr.2017.2249] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is one of the most common types of cancer in the world, usually diagnosed at an advanced stage. Despite the advances in specific anticancer agents' development, the survival rates remain modest, even in early stages. In 15%-20% of cases, the human epidermal growth factor receptor 2 (HER2) overexpression was identified. We conducted a general review to summarize the progress that has been made in the targeted treatment of HER2-positive esogastric junction or gastric adenocarcinoma. According to our findings, trastuzumab is the only validated anti-HER2 agent in locally advanced or metastatic disease and its adjuvant effectiveness is assessed in a RTOG phase III study. In a previously treated advanced disease, the maytansine derivate TDM 1 failed to be approved as a second-line regimen, and the tyrosine kinase inhibitor, lapatinib, shows modest results. The antiangiogenics have not been analyzed in specific populations and targeting the mesenchymal-epithelial transition factor (MET) receptor, overexpressed in up to 46% of the advanced disease, seems encouraging. Regarding the checkpoint inhibitors, based on KEYNOTE 059 multilevel ongoing trial, stratified according to the HER2 and programmed death-ligand (PD-L) 1 status, pembrolizumab was approved for third-line treatment of gastric or gastroesophageal junction adenocarcinoma.
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Affiliation(s)
- Fabiana G Curea
- 1 Department of Oncology-Radiotherapy, Institute of Oncology "Prof. Dr. Alexandru Trestioreanu," Bucharest, Romania
| | - Mohamed Hebbar
- 2 Department of Medical Oncology, University Hospital , Lille, France
| | - Silvia M Ilie
- 1 Department of Oncology-Radiotherapy, Institute of Oncology "Prof. Dr. Alexandru Trestioreanu," Bucharest, Romania .,3 University of Medicine and Pharmacy "Carol Davila," Bucharest, Romania
| | - Xenia E Bacinschi
- 1 Department of Oncology-Radiotherapy, Institute of Oncology "Prof. Dr. Alexandru Trestioreanu," Bucharest, Romania .,3 University of Medicine and Pharmacy "Carol Davila," Bucharest, Romania
| | - Oana G Trifanescu
- 1 Department of Oncology-Radiotherapy, Institute of Oncology "Prof. Dr. Alexandru Trestioreanu," Bucharest, Romania .,3 University of Medicine and Pharmacy "Carol Davila," Bucharest, Romania
| | - Inga Botnariuc
- 1 Department of Oncology-Radiotherapy, Institute of Oncology "Prof. Dr. Alexandru Trestioreanu," Bucharest, Romania
| | - Rodica M Anghel
- 1 Department of Oncology-Radiotherapy, Institute of Oncology "Prof. Dr. Alexandru Trestioreanu," Bucharest, Romania .,3 University of Medicine and Pharmacy "Carol Davila," Bucharest, Romania
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Zhu Y, Jiang H, Chen Z, Lu B, Li J, Peng Y, Shen X. The genetic association between iNOS and eNOS polymorphisms and gastric cancer risk: a meta-analysis. Onco Targets Ther 2018; 11:2497-2507. [PMID: 29765229 PMCID: PMC5939909 DOI: 10.2147/ott.s161925] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Objective There are a number of susceptible factors for an increased risk of gastric cancer. Nitric oxide (NO) is considered to be associated with the development of a range of cancers. In particular, inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) are known to play a central role in the production of NO. Published studies relating to the association between eNOS rs1799983, rs2070744, and iNOS rs2297518 polymorphisms and the risk of gastric cancer risk are conflicting and inconclusive and require further analysis. Materials and methods This study involved a meta-analysis of case–control studies relating to eNOS rs1799983, rs2070744, and iNOS rs2297518 polymorphisms published prior to January 2018. Literature searches were carried out in PubMed, Embase, Web of Science, the Cochrane Library databases, and the Chinese National Knowledge Infrastructure. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of association based on genotype data. Results A total of 1,356 cases and 1,791 controls were included from nine case–control studies involving eNOS rs1799983 (G894T), rs2070744 (T-786C), and iNOS rs2297518 (C150T) polymorphisms. Data analysis indicated that iNOS rs2297518 was a risk factor for Helicobacter pylorus-positive gastric cancer when compared with H. pylorus-negative gastric cancer (p=0.003, OR [95% CI] =2.19 [1.31–3.66]). In addition, the allelic, dominant, and recessive models of eNOS rs2070744 were significantly associated with a risk of gastric cancer (allelic model: p<0.00001, OR [95% CI] =0.23 [0.16–0.34]; dominant model: p<0.00001, OR [95% CI] =0.25 [0.15–0.42]; recessive model: p<0.00001, OR [95% CI] =0.16 [0.08–0.30]). No association was identified between eNOS rs1799983 and the risk of gastric cancer (p>0.05). Conclusion iNOS rs2297518 and eNOS rs2070744 polymorphisms may represent susceptible factors for gastric cancer.
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Affiliation(s)
- Yi Zhu
- Department of Gastroenterological Surgery, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
| | - Honggang Jiang
- Department of Gastroenterological Surgery, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
| | - Zhiheng Chen
- Department of Gastroenterological Surgery, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
| | - Bohao Lu
- Department of Gastroenterological Surgery, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
| | - Jin Li
- Department of Gastroenterological Surgery, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
| | - Yuping Peng
- Department of Gastroenterological Surgery, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
| | - Xuning Shen
- Department of Gastroenterological Surgery, The First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
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Lupu M, Caruntu A, Caruntu C, Papagheorghe LML, Ilie MA, Voiculescu V, Boda D, Constantin C, Tanase C, Sifaki M, Drakoulis N, Mamoulakis C, Tzanakakis G, Neagu M, Spandidos DA, Izotov BN, Tsatsakis AM. Neuroendocrine factors: The missing link in non‑melanoma skin cancer (Review). Oncol Rep 2017; 38:1327-1340. [PMID: 28713981 PMCID: PMC5549028 DOI: 10.3892/or.2017.5817] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 06/29/2017] [Indexed: 02/06/2023] Open
Abstract
Non‑melanoma skin cancer (NMSC) is the most common form of cancer worldwide, comprising 95% of all cutaneous malignancies and approximately 40% of all cancers. In spite of intensive efforts aimed towards awareness campaigns and sun‑protective measures, epidemiological data indicate an increase in the incidence of NMSC. This category of skin cancers has many common environmental triggers. Arising primarily on sun‑exposed skin, it has been shown that ultraviolet radiation is, in the majority of cases, the main trigger involved in the pathogenesis of NMSC. Aside from the well‑known etiopathogenic factors, studies have indicated that several neuroactive factors are involved in the carcinogenesis of two of the most common types of NMSC, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with the exception of penile SCC, for which a paucity of specific data on their pathogenic role exists. The complex interaction between the peripheral nervous system and target cells in the skin appears to be mediated by locally released neuroendocrine factors, such as catecholamines, substance P, calcitonin gene‑related peptide and somatostatin, as well as neurohormones, such as proopiomelanocortin and its derived peptides, α‑melanocyte‑stimulating hormone and adrenocorticotropin. All these factors have been, at least at some point, a subject of debate regarding their precise role in the pathogenesis of NMSC. There is also a significant body of evidence indicating that psychological stress is a crucial impact factor influencing the course of skin cancers, including SCC and BCC. Numerous studies have suggested that neuroendocrine factor dysregulation, as observed in stress reactions, may be involved in tumorigenesis, accelerating the development and progression, and suppressing the regression of NMSC. Further studies are required in order to elucidate the exact mechanisms through which neuroactive molecules promote or inhibit cutaneous carcinogenesis, as this could lead to the development of more sophisticated and tailored treatment protocols, as well as open new perspectives in skin cancer research.
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Affiliation(s)
- Mihai Lupu
- Department of Dermatology, MEDAS Medical Center, 030442 Bucharest, Romania
| | - Ana Caruntu
- Department of Oral and Maxillofacial Surgery, ‘Carol Davila’ Central Military Emergency Hospital, 010825 Bucharest, Romania
- ‘Titu Maiorescu’ University, Faculty of Medicine, 031593 Bucharest, Romania
| | - Constantin Caruntu
- Department of Physiology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Dermatology, ‘Prof. N. Paulescu’ National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
| | | | - Mihaela Adriana Ilie
- Dermatology Research Laboratory, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Vlad Voiculescu
- Department of Dermatology and Allergology, Elias Emergency University Hospital, 011461 Bucharest, Romania
| | - Daniel Boda
- Dermatology Research Laboratory, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Carolina Constantin
- ‘Victor Babes’ National Institute of Pathology, 050096 Bucharest, Romania
- Colentina University Hospital, 020125 Bucharest, Romania
| | - Cristiana Tanase
- ‘Titu Maiorescu’ University, Faculty of Medicine, 031593 Bucharest, Romania
- ‘Victor Babes’ National Institute of Pathology, 050096 Bucharest, Romania
| | - Maria Sifaki
- Laboratory of Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Nikolaos Drakoulis
- Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15771 Athens, Greece
| | - Charalampos Mamoulakis
- Department of Urology, University General Hospital of Heraklion, University of Crete Medical School, 71003 Heraklion, Greece
| | - George Tzanakakis
- Laboratory of Anatomy-Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Monica Neagu
- ‘Victor Babes’ National Institute of Pathology, 050096 Bucharest, Romania
- Colentina University Hospital, 020125 Bucharest, Romania
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Boris N. Izotov
- Department of Analytical Toxicology, Pharmaceutical Chemistry and Pharmacognosy, Sechenov University, 119991 Moscow, Russia
| | - Aristides M. Tsatsakis
- Laboratory of Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
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Buijs N, Oosterink JE, Jessup M, Schierbeek H, Stolz DB, Houdijk AP, Geller DA, van Leeuwen PA. A new key player in VEGF-dependent angiogenesis in human hepatocellular carcinoma: dimethylarginine dimethylaminohydrolase 1. Angiogenesis 2017; 20:557-565. [PMID: 28741166 PMCID: PMC5660142 DOI: 10.1007/s10456-017-9567-4] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 07/14/2017] [Indexed: 01/15/2023]
Abstract
BACKGROUND Anti-angiogenic therapies, targeting VEGF, are a promising treatment for hepatocellular carcinoma (HCC). To enhance this potential therapy, identification of novel targets in this pathway is of major interest. Nitric oxide (NO) plays a crucial role in VEGF-dependent angiogenesis. NO production depends on arginine as substrate and asymmetric dimethylarginine (ADMA) as inhibitor. Dimethylarginine dimethylaminohydrolase 1 (DDAH-1) catabolizes ADMA and therefore regulates NO and VEGF expression. This study unravels additional mechanisms to improve VEGF targeting therapies. METHODS The expression of DDAH-1 was examined in HCC specimen and non-tumorous background liver of 20 patients undergoing liver resection. Subsequently, arginine/ADMA balance, NO production, and VEGF expression were analyzed. The influence of hypoxia on DDAH-1 and angiogenesis promoting factors was evaluated in HepG2 cells and primary human hepatocytes. RESULTS DDAH-1 expression was significantly induced in primary HCC tumors compared to non-tumorous background liver. This was associated with an increased arginine/ADMA ratio, higher NO formation, and higher VEGF expression in human HCC compared to non-tumorous liver. Hypoxia induced DDAH-1, iNOS, and VEGF expression in a time-dependent manner in HepG2 cells. CONCLUSIONS Our results indicate that DDAH-1 expression is increased in human HCC, which is associated with an increase in the arginine/ADMA ratio and enhanced NO formation. Hypoxia may be an initiating factor for the increase in DDAH-1 expression. DDAH-1 expression is associated with promotion of angiogenesis stimulating factor VEGF. Together, our findings for the first time identified DDAH-1 as a key player in the regulation of angiogenesis in human HCC, and by understanding this mechanism, future therapeutic strategies targeting VEGF can be improved.
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Affiliation(s)
- Nikki Buijs
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. .,Department of Surgery, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands. .,Department of Surgery, Medical Center Alkmaar, Trial Center Holland Health, Alkmaar, The Netherlands.
| | - J Efraim Oosterink
- Department of Pediatrics, Academic Medical Center, Emma Children's Hospital, Amsterdam, The Netherlands
| | - Morgan Jessup
- Department of Cell Biology and Physiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Henk Schierbeek
- Department of Pediatrics, Academic Medical Center, Emma Children's Hospital, Amsterdam, The Netherlands
| | - Donna B Stolz
- Department of Cell Biology and Physiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Alexander P Houdijk
- Department of Surgery, Medical Center Alkmaar, Trial Center Holland Health, Alkmaar, The Netherlands
| | - David A Geller
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Paul A van Leeuwen
- Department of Surgery, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands
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de Oliveira GA, Cheng RYS, Ridnour LA, Basudhar D, Somasundaram V, McVicar DW, Monteiro HP, Wink DA. Inducible Nitric Oxide Synthase in the Carcinogenesis of Gastrointestinal Cancers. Antioxid Redox Signal 2017; 26:1059-1077. [PMID: 27494631 PMCID: PMC5488308 DOI: 10.1089/ars.2016.6850] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
SIGNIFICANCE Gastrointestinal (GI) cancer taken together constitutes one of the most common cancers worldwide with a broad range of etiological mechanisms. In this review, we have examined the impact of nitric oxide (NO) on the etiology of colon, colorectal, gastric, esophageal, and liver cancers. Recent Advances: Despite differences in etiology, initiation, and progression, chronic inflammation has been shown to be a common element within these cancers showing interactions of numerous pathways. NO generated at the inflammatory site contributes to the initiation and progression of disease. The amount of NO generated, time, and site vary and are an important determinant of the biological effects initiated. Among the nitric oxide synthase enzymes, the inducible isoform has the most diverse range, participating in numerous carcinogenic processes. There is emerging evidence showing that inducible nitric oxide synthase (NOS2) plays a central role in the process of tumor initiation and/or development. CRITICAL ISSUES Redox inflammation through NOS2 and cyclooxygenase-2 participates in driving the mechanisms of initiation and progression in GI cancers. FUTURE DIRECTIONS Understanding the underlying mechanism involved in NOS2 activation can provide new insights into important prevention and treatment strategies. Antioxid. Redox Signal. 26, 1059-1077.
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Affiliation(s)
- Graciele Almeida de Oliveira
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
| | - Robert Y S Cheng
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
| | - Lisa A Ridnour
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
| | - Debashree Basudhar
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
| | - Veena Somasundaram
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
| | - Daniel W McVicar
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
| | - Hugo Pequeno Monteiro
- 2 Laboratório de Sinalização Celular, Universidade Federal de São Paulo , São Paulo, Brazil
| | - David A Wink
- 1 Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, Maryland
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Neumann L, Mueller M, Moos V, Heller F, Meyer TF, Loddenkemper C, Bojarski C, Fehlings M, Doerner T, Allers K, Aebischer T, Ignatius R, Schneider T. Mucosal Inducible NO Synthase-Producing IgA+ Plasma Cells in Helicobacter pylori-Infected Patients. THE JOURNAL OF IMMUNOLOGY 2016; 197:1801-8. [PMID: 27456483 DOI: 10.4049/jimmunol.1501330] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 06/20/2016] [Indexed: 12/20/2022]
Abstract
The mucosal immune system is relevant for homeostasis, immunity, and also pathological conditions in the gastrointestinal tract. Inducible NO synthase (iNOS)-dependent production of NO is one of the factors linked to both antimicrobial immunity and pathological conditions. Upregulation of iNOS has been observed in human Helicobacter pylori infection, but the cellular sources of iNOS are ill defined. Key differences in regulation of iNOS expression impair the translation from mouse models to human medicine. To characterize mucosal iNOS-producing leukocytes, biopsy specimens from H. pylori-infected patients, controls, and participants of a vaccination trial were analyzed by immunohistochemistry, along with flow cytometric analyses of lymphocytes for iNOS expression and activity. We newly identified mucosal IgA-producing plasma cells (PCs) as one major iNOS(+) cell population in H. pylori-infected patients and confirmed intracellular NO production. Because we did not detect iNOS(+) PCs in three distinct infectious diseases, this is not a general feature of mucosal PCs under conditions of infection. Furthermore, numbers of mucosal iNOS(+) PCs were elevated in individuals who had cleared experimental H. pylori infection compared with those who had not. Thus, IgA(+) PCs expressing iNOS are described for the first time, to our knowledge, in humans. iNOS(+) PCs are induced in the course of human H. pylori infection, and their abundance seems to correlate with the clinical course of the infection.
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Affiliation(s)
- Laura Neumann
- Medical Clinic I, Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine Berlin, 12203 Berlin, Germany;
| | - Mattea Mueller
- Medical Clinic I, Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine Berlin, 12203 Berlin, Germany
| | - Verena Moos
- Medical Clinic I, Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine Berlin, 12203 Berlin, Germany
| | - Frank Heller
- Practice for Gastroenterology, 12163 Berlin, Germany
| | - Thomas F Meyer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany
| | | | - Christian Bojarski
- Medical Clinic I, Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine Berlin, 12203 Berlin, Germany
| | - Michael Fehlings
- Department of Molecular Biology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany
| | - Thomas Doerner
- Department of Medicine, Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, 10117 Berlin, Germany
| | - Kristina Allers
- Medical Clinic I, Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine Berlin, 12203 Berlin, Germany
| | | | - Ralf Ignatius
- Institute for Microbiology and Hygiene, Charité-University Medicine Berlin, 12203 Berlin, Germany
| | - Thomas Schneider
- Medical Clinic I, Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine Berlin, 12203 Berlin, Germany
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Jureidini R, da Cunha JEM, Takeda F, Namur GN, Ribeiro TC, Patzina R, Figueira ERR, Ribeiro U, Bacchella T, Cecconello I. Evaluation of microvessel density and p53 expression in pancreatic adenocarcinoma. Clinics (Sao Paulo) 2016; 71:315-9. [PMID: 27438564 PMCID: PMC4930662 DOI: 10.6061/clinics/2016(06)05] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 03/21/2016] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVE To evaluate the prognostic significance of microvessel density and p53 expression in pancreatic cancer. METHODS Between 2008 and 2012, 49 patients with pancreatic adenocarcinoma underwent resection with curative intention. The resected specimens were immunohistochemically stained with anti-p53 and anti-CD34 antibodies. Microvessel density was assessed by counting vessels within ten areas of each tumoral section a highpower microscope. RESULTS The microvessel density ranged from 21.2 to 54.2 vessels/mm2. Positive nuclear staining for p53 was found in 20 patients (40.6%). The overall median survival rate after resection was 24.1 months and there were no differences in survival rates related to microvessel density or p53 positivity. Microvessel density was associated with tumor diameter greater than 3.0 cm and with R0 resection failure. CONCLUSIONS Microvessel density was associated with R1 resection and with larger tumors. p53 expression was not correlated with intratumoral microvessel density in pancreatic adenocarcinoma.
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Affiliation(s)
- Ricardo Jureidini
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia
- E-mail:
| | | | - Flavio Takeda
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia
| | | | - Thiago Costa Ribeiro
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia
| | | | - Estela RR Figueira
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia
| | - Ulysses Ribeiro
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia
| | - Telesforo Bacchella
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia
| | - Ivan Cecconello
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia
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Assawasuparerk K, Rawangchue T, Phonarknguen R. Scabraside D Derived from Sea Cucumber Induces Apoptosis and Inhibits Metastasis via iNOS and STAT-3 Expression in Human Cholangiocarcinoma Xenografts. Asian Pac J Cancer Prev 2016; 17:2151-7. [PMID: 27221911 DOI: 10.7314/apjcp.2016.17.4.2151] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Scabraside D, a sulfated triterpene glycoside, was extracted from the sea cucumber Holothuria scabra. It shows anti-proliferation in many of cancer cell lines, but the function and mechanisms of action of scabraside D in human cholangiocarcinoma (HuCCA) have not previously determined. In this study, we investigated the activity of scabraside D on HuCCA cell apoptosis, lymphangiogenesis and metastasis in a nude mouse model. Scabraside D induced signs of apoptosis, such as cell shrinkage, nuclear condensation, nuclear fragmentation and DNA fragmentation on TUNEL assays, while effectively decreasing expression of BCl-2 but increasing caspase-3 gene level expression. Immunohistochemistry revealed that scabraside D significantly reduced lymphatic vessel density (LVD). Moreover, scabraside D treatment significantly decreased VEGF-C, MMP-9 and uPA gene expression, which play important roles in the lymphangiogenesis and invasion of cancer cells in metastasis processes. Quantitative real-time PCR showed that scabraside D significantly decreased iNOS and STAT-3 gene expression. This study demonstrated that scabraside D plays a role in activation of HuCCA tumor apoptosis and inhibition of lymphangiogenesis, invasion and metastasis through decreasing BCl-2, MMP-9, uPA and VEGF-C and increasing caspase-3 expression by suppression of iNOS and STAT-3 expression. Therefore, scabraside D could be a promising candidate for cholangiocarcinoma treatment.
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MEHIBEL MANAL, SINGH SIMENDRA, COWEN RACHELL, WILLIAMS KAYEJ, STRATFORD IANJ. Radiation enhances the therapeutic effect of Banoxantrone in hypoxic tumour cells with elevated levels of nitric oxide synthase. Oncol Rep 2016; 35:1925-32. [PMID: 26782976 PMCID: PMC4774668 DOI: 10.3892/or.2016.4555] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 10/16/2015] [Indexed: 11/06/2022] Open
Abstract
Banoxantrone (AQ4N) is a prototype hypoxia selective cytotoxin that is activated by haem containing reductases such as inducible nitric oxide synthase (iNOS). In the present study, we evaluate whether elevated levels of iNOS in human tumour cells will improve their sensitivity to AQ4N. Further, we examine the potential of radiation to increase cellular toxicity of AQ4N under normoxic (aerobic) and hypoxic conditions. We employed an expression vector containing the cDNA for human iNOS to transfect human fibrosarcoma HT1080 tumour cells. Alternatively, parental cells were exposed to a cytokine cocktail to induce iNOS gene expression and enzymatic activity. The cells were then treated with AQ4N alone and in combination with radiation in the presence or absence of the iNOS inhibitor N-methyl-L‑arginine. In parental cells, AQ4N showed little difference in toxicity under hypoxic verses normoxic conditions. Notably, cells with upregulated iNOS activity showed a significant increase in sensitivity to AQ4N, but only under conditions of reduced oxygenation. When these cells were exposed to the combination of AQ4N and radiation, there was much greater cell killing than that observed with either modality alone. In the clinical development of hypoxia selective cytotoxins it is likely they will be used in combination with radiotherapy. In the present study, we demonstrated that AQ4N can selectively kill hypoxic cells via an iNOS-dependent mechanism. This hypoxia-selective effect can be augmented by combining AQ4N with radiation without increasing cytotoxicity to well‑oxygenated tissues. Collectively, these results suggest that targeting hypoxic tumours with high levels of iNOS with a combination of AQ4N and radiotherapy could be a useful clinical therapeutic strategy.
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Affiliation(s)
- MANAL MEHIBEL
- Experimental Oncology Group, Manchester Pharmacy School, University of Manchester, Manchester, UK
| | - SIMENDRA SINGH
- Experimental Oncology Group, Manchester Pharmacy School, University of Manchester, Manchester, UK
- School of Engineering and Technology, Sharda University, Greater Noida, India
| | - RACHEL L. COWEN
- Experimental Oncology Group, Manchester Pharmacy School, University of Manchester, Manchester, UK
| | - KAYE J. WILLIAMS
- Hypoxia and Therapeutics group, Manchester Pharmacy School, University of Manchester, Manchester, UK
| | - IAN J. STRATFORD
- Experimental Oncology Group, Manchester Pharmacy School, University of Manchester, Manchester, UK
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Fontana E, Smyth EC. Novel targets in the treatment of advanced gastric cancer: a perspective review. Ther Adv Med Oncol 2016; 8:113-25. [PMID: 26929787 PMCID: PMC4753351 DOI: 10.1177/1758834015616935] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer is responsible for a high burden of disease globally. Although more extensive use of chemotherapy together with the recent introduction of the two targeted agents trastuzumab and ramucirumab have contributed to marginal outcome prolongation, overall survival for patients with advanced stage disease remains poor. Over the last decade, a number of novel agents have been examined in clinical trials with largely disappointing results. Potential explanations for this are the absence of molecularly selected trial populations or weak predictive biomarkers within the context of a highly heterogeneous disease. In the recently published gastric cancer The Cancer Genome Atlas (TCGA) project a new classification of four different tumour subtypes according to different molecular characteristics has been proposed. With some overlap, several relatively distinct and potentially targetable pathways have been identified for each subtype. In this perspective review we match recent trial results with the subtypes described in the gastric cancer TCGA aiming to highlight data regarding novel agents under evaluation and to discuss whether this publication might provide a framework for future drug development.
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Digklia A, Wagner AD. Advanced gastric cancer: Current treatment landscape and future perspectives. World J Gastroenterol 2016; 22:2403-14. [PMID: 26937129 PMCID: PMC4768187 DOI: 10.3748/wjg.v22.i8.2403] [Citation(s) in RCA: 399] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 09/10/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer currently ranks fourth in cancer-related mortality worldwide. In the western world, it is most often diagnosed at an advanced stage, after becoming metastatic at distant sites. Patients with advanced disease (locally advanced or metastatic) have a somber prognosis, with a median overall survival of 10-12 mo, and palliative chemotherapy is the mainstay of treatment. In recent years, novel approaches using inhibition of human epidermal growth factor receptor 2 (HER2) have demonstrated significant improvements in progression-free and overall survival, compared with chemotherapy alone, in first-line treatment of patients with overexpression of HER2. In addition, both second-line chemotherapy and treatment with the vascular endothelial growth factor receptor-inhibitor ramucirumab demonstrated significant benefits in terms of overall survival, compared with best supportive care, in randomized studies. Moreover, ramucirumab in combination with chemotherapy demonstrated further significant benefits in terms of progression-free and overall survival, compared with chemotherapy alone, in second-line treatment for patients with metastatic gastric cancer. A recently published molecular classification of gastric cancer is expected to improve patient stratification and selection for clinical trials and provide a roadmap for future drug development. Nevertheless, despite these developments the prognosis of patients with advanced gastric cancer remains poor. In this review we discuss current standards of care and outline major topics of drug development in gastric cancer.
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Saeidi H, Nasiri MRG, Shahidsales S, Kermani AT, Hematti S, Roodbari SS, Shahri MHM, Chagharvand S. Evaluation of estrogen receptor expression and its relationship with clinicopathologic findings in gastric cancer. Adv Biomed Res 2015; 4:177. [PMID: 26605216 PMCID: PMC4617152 DOI: 10.4103/2277-9175.164013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 12/06/2014] [Indexed: 01/22/2023] Open
Abstract
Background: The presence of estrogen receptor alpha has been reported in the cell and tissue levels in gastric cancer; however, its impact on patients’ survival remains unclear. The aim of this study was to investigate the expression of estrogen receptor in gastric carcinoma as well as its relationship with the clinicopathologic findings of the patients. Materials and Methods: The study was performed on 100 endoscopic biopsies of gastric adenocarcinoma for estrogen receptor expression using an immunohistochemical method, and their relationship with the clinicopathologic findings of the patients, such as age, gender, tumor site, size, grade, depth of tumor invasion (T), and lymphatic status (N), were analyzed using independent sample t-test and Pearson Chi-square test. A P < 0.05 was considered significant in all analyses. Results: Using an immunohistochemical method on endoscopic biopsies of 74 males and 26 females with the mean age of 63 years, estrogen receptor was found to be positive in 41% of patients. No significant difference was found between estrogen receptor expression and other clinicopathologic findings (P = 0.75). There was a significant difference between estrogen receptor (+) and estrogen receptor (−) groups in nodal involvement (P = 0.001). The estrogen receptor (+) patients had more number of lymph nodes involved. Conclusion: This study showed that lymph node involvement has a significant relationship with estrogen receptor expression. However, no significant relationship was found between estrogen receptor expression and other clinicopathologic findings such as age, gender, tumor site in stomach, tumor size, tumor grade, and T-stage.
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Affiliation(s)
- Hamid Saeidi
- Cancer Research Center, Guilan University of Medical Science (GUMS), Guilan, Iran
| | | | - Soodabeh Shahidsales
- Cancer Research Center, Faculty of Medicine, Isfahan University of Medical Sciences (IUMS), Isfahan, Iran
| | - Ali Taghizadeh Kermani
- Cancer Research Center, Faculty of Medicine, Isfahan University of Medical Sciences (IUMS), Isfahan, Iran
| | - Simin Hematti
- Department of Radiotherapy and Oncology, School of Medicine, Isfahan University of Medical Sciences (IUMS), Isfahan, Iran
| | | | | | - Sepideh Chagharvand
- Cancer Research Center, Guilan University of Medical Science (GUMS), Guilan, Iran
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Kim G, Kim TH, Kang MJ, Choi JA, Pack DY, Lee IR, Kim MG, Han SS, Kim BY, Oh SM, Lee KB, Kim DJ, Park JH. Inhibitory effect of withaferin A on Helicobacter pylori‑induced IL‑8 production and NF‑κB activation in gastric epithelial cells. Mol Med Rep 2015; 13:967-72. [PMID: 26647855 DOI: 10.3892/mmr.2015.4602] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 11/06/2015] [Indexed: 11/06/2022] Open
Abstract
Withaferin A (WA), a withanolide purified from Withania somnifera, has been known to exert anti-inflammatory effects. The present study sought to determine the effects of WA on Helicobacter (H.) pylori-mediated inflammation in the AGS gastric epithelial cell line. Cellular production of interleukin (IL)-8 and vascular endothelial growth factor (VEGF) was measured by ELISA. Western blot analysis was performed to determine the activation of nuclear factor (NF)-κB and mitogen-activated protein kinases (MAPKs) as well as hypoxia-inducible factor 1α stabilization. Bacterial growth was also examined by measuring the optical density. Pre-treatment or co-treatment with WA efficiently reduced IL-8 production by AGS cells in response to H. pylori infection. H. pylori-induced activation of NF-κB, but not MAPKs, was also inhibited by pre-treatment of WA in the cells. However, WA did not affect VEGF production and HIF-1α stabilization induced by H. pylori in AGS cells. In addition, WA did not influence the growth of H. pylori, suggesting that the anti-inflammatory effect of WA was not due to any bactericidal effect. These findings indicate that WA is a potential preventive or therapeutic agent for H. pylori-mediated gastric inflammation.
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Affiliation(s)
- Green Kim
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon 302‑718, Republic of Korea
| | - Tae-Hyoun Kim
- Laboratory Animal Medicine, College of Veterinary Medicine, Seoul University, Seoul 151‑742, Republic of Korea
| | - Min-Jung Kang
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon 302‑718, Republic of Korea
| | - Jin-A Choi
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon 302‑718, Republic of Korea
| | - Da-Young Pack
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon 302‑718, Republic of Korea
| | - Ik-Rae Lee
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon 302‑718, Republic of Korea
| | - Min-Gyu Kim
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon 302‑718, Republic of Korea
| | - Sang-Seop Han
- Graduate School of Pre‑Clinical Laboratory Science, Konyang University, Daejeon 302‑718, Republic of Korea
| | - Bo-Yeon Kim
- World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Cheongwon‑Gun, Choongbuk 363‑883, Republic of Korea
| | - Sang-Muk Oh
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon 302‑718, Republic of Korea
| | - Kyung-Bok Lee
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon 302‑718, Republic of Korea
| | - Dong-Jae Kim
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon 302‑718, Republic of Korea
| | - Jong-Hwan Park
- World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Cheongwon‑Gun, Choongbuk 363‑883, Republic of Korea
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Fan X, Wang Y, Wang K, Liu S, Liu Y, Ma J, Li S, Jiang T. Anatomical specificity of vascular endothelial growth factor expression in glioblastomas: a voxel-based mapping analysis. Neuroradiology 2015; 58:69-75. [PMID: 26453565 DOI: 10.1007/s00234-015-1602-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 09/28/2015] [Indexed: 10/22/2022]
Abstract
INTRODUCTION The expression of vascular endothelial growth factor (VEGF) is a common genetic alteration in malignant gliomas and contributes to the angiogenesis of tumors. This study aimed to investigate the anatomical specificity of VEGF expression levels in glioblastomas using voxel-based neuroimaging analysis. METHODS Clinical information, MR scans, and immunohistochemistry stains of 209 patients with glioblastomas were reviewed. All tumor lesions were segmented manually and subsequently registered to standard brain space. Voxel-based regression analysis was performed to correlate the brain regions of tumor involvement with the level of VEGF expression. Brain regions identified as significantly associated with high or low VEGF expression were preserved following permutation correction. RESULTS High VEGF expression was detected in 123 (58.9 %) of the 209 patients. Voxel-based statistical analysis demonstrated that high VEGF expression was more likely in tumors located in the left frontal lobe and the right caudate and low VEGF expression was more likely in tumors that occurred in the posterior region of the right lateral ventricle. CONCLUSION Voxel-based neuroimaging analysis revealed the anatomic specificity of VEGF expression in glioblastoma, which may further our understanding of genetic heterogeneity during tumor origination. This finding provides primary theoretical support for potential future application of customized antiangiogenic therapy.
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Affiliation(s)
- Xing Fan
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing, 100050, People's Republic of China
| | - Yinyan Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing, 100050, People's Republic of China.,Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People's Republic of China
| | - Kai Wang
- Department of Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Shuai Liu
- Departments of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Yong Liu
- Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Jun Ma
- Department of Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Shaowu Li
- Department of Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China.
| | - Tao Jiang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantan Xili, Dongcheng District, Beijing, 100050, People's Republic of China. .,Department of Clinical Oncology, Beijing Academy of Critical Illness in Brain, Beijing, People's Republic of China.
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Thompson PA, Khatami M, Baglole CJ, Sun J, Harris S, Moon EY, Al-Mulla F, Al-Temaimi R, Brown D, Colacci A, Mondello C, Raju J, Ryan E, Woodrick J, Scovassi I, Singh N, Vaccari M, Roy R, Forte S, Memeo L, Salem HK, Amedei A, Hamid RA, Lowe L, Guarnieri T, Bisson WH. Environmental immune disruptors, inflammation and cancer risk. Carcinogenesis 2015; 36 Suppl 1:S232-S253. [PMID: 26106141 PMCID: PMC4492068 DOI: 10.1093/carcin/bgv038] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 01/09/2015] [Accepted: 01/14/2015] [Indexed: 12/16/2022] Open
Abstract
An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E2, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented.
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Affiliation(s)
- Patricia A. Thompson
- *To whom correspondence should be addressed. Tel: +1 631 444 6818; Fax: +1 631 444 3424;
| | - Mahin Khatami
- Inflammation and Cancer Research, National Cancer Institute (NCI) (Retired), NIH, Bethesda, MD 20817, USA
| | - Carolyn J. Baglole
- Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada
| | - Jun Sun
- Department of Biochemistry, Rush University, Chicago, IL 60612, USA
| | - Shelley Harris
- Prevention and Cancer Control, Cancer Care Ontario, 620 University Avenue, Toronto, Ontario M5G 2L3, Canada
| | - Eun-Yi Moon
- Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Republic of South Korea
| | - Fahd Al-Mulla
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | | | - Dustin Brown
- Department of Environmental and Radiological Health Sciences, Colorado State University, Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Annamaria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy
| | - Chiara Mondello
- The Institute of Molecular Genetics, National Research Council, 27100 Pavia, Italy
| | - Jayadev Raju
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
| | - Elizabeth Ryan
- Department of Environmental and Radiological Health Sciences, Colorado State University, Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Jordan Woodrick
- Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA
| | - Ivana Scovassi
- The Institute of Molecular Genetics, National Research Council, 27100 Pavia, Italy
| | - Neetu Singh
- Advanced Molecular Science Research Centre, King George’s Medical University, Lucknow, Uttar Pradesh 226003, India
| | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy
| | - Rabindra Roy
- Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA
| | - Stefano Forte
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy
| | - Lorenzo Memeo
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy
| | - Hosni K. Salem
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, 50134 Florence, Italy
| | - Roslida A. Hamid
- Faculty of Medicine and Health Sciences, Universiti Putra, Malaysia, Serdang, Selangor 43400, Malaysia
| | - Leroy Lowe
- Getting to Know Cancer, Room 229A, 36 Arthur St, Truro, Nova Scotia B2N 1X5, Canada
| | - Tiziana Guarnieri
- Department of Biology, Geology and Environmental Sciences, Alma Mater Studiorum Università di Bologna, Via Francesco Selmi, 3, 40126 Bologna, Italy
- Center for Applied Biomedical Research, S. Orsola-Malpighi University Hospital, Via Massarenti, 9, 40126 Bologna, Italy,
- National Institute of Biostructures and Biosystems, Viale Medaglie d’ Oro, 305, 00136 Roma, Italy and
| | - William H. Bisson
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97331, USA
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Shen L, Li J, Xu J, Pan H, Dai G, Qin S, Wang L, Wang J, Yang Z, Shu Y, Xu R, Chen L, Liu Y, Yu S, Bu L, Piao Y. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer 2015; 18:168-76. [PMID: 24557418 PMCID: PMC4544634 DOI: 10.1007/s10120-014-0351-5] [Citation(s) in RCA: 195] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Accepted: 02/01/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND In the AVAGAST study, fluoropyrimidine and cisplatin plus bevacizumab did not significantly improve overall survival (OS) versus fluoropyrimidine and cisplatin plus placebo in patients with advanced gastric cancer. Geographic differences in efficacy were observed in AVAGAST, but the study only included 12 Chinese patients. AVATAR, a study similar in design to AVAGAST, was a randomized, double-blind, phase III study conducted in Chinese patients with advanced gastric cancer. METHODS Patients more than 18 years of age with gastric adenocarcinoma were randomized 1:1 to capecitabine-cisplatin plus either bevacizumab or placebo. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS) and safety. RESULTS In total, 202 patients were included (placebo n = 102; bevacizumab n = 100). Baseline characteristics were well balanced. The primary analysis result did not show a difference in OS for the bevacizumab arm compared to the placebo arm [hazard ratio, 1.11 (95% CI, 0.79-1.56); P = 0.5567]. Median PFS was also similar in both arms. Bevacizumab plus capecitabine-cisplatin was well tolerated. Grade 3-5 adverse events (AEs) occurred in 60% of bevacizumab-treated and 68% of placebo-treated patients, respectively. Grade 3-5 AEs of special interest with bevacizumab occurred in 8% of bevacizumab-treated patients and 15% of placebo-treated patients, mainly grade 3-5 hemorrhage (bevacizumab 4%, placebo 12%). CONCLUSIONS Addition of bevacizumab to capecitabine-cisplatin in Chinese patients with advanced gastric cancer did not improve outcomes in AVATAR. There was no difference in OS between the two arms and PFS was similar in both arms. Safety findings were as previously experienced with bevacizumab, including AVAGAST; no new safety signals were reported.
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Affiliation(s)
- Lin Shen
- Peking University Cancer Hospital and Institute, No 52 Fucheng Road, Haidian District, Beijing, China
| | - Jin Li
- Fudan University Cancer Hospital, Shanghai, China
| | | | | | | | | | - Liwei Wang
- Shanghai First People’s Hospital, Shanghai, China
| | | | - Zhenzhou Yang
- Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | | | - Ruihua Xu
- Zhongshan University Cancer Hospital, Guangzhou, China
| | - Lei Chen
- Shantou Medical University Cancer Hospital, Shantou, China
| | - Yunpeng Liu
- 1st Affiliated Hospital of China Medical University, Shenyang, China
| | - Shiying Yu
- Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Lilian Bu
- Roche Product Development in Asia Pacific, Shanghai, China
| | - Yongzhe Piao
- Roche Product Development in Asia Pacific, Shanghai, China
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Kang MJ, Song EJ, Kim BY, Kim DJ, Park JH. Helicobacter pylori induces vascular endothelial growth factor production in gastric epithelial cells through hypoxia-inducible factor-1α-dependent pathway. Helicobacter 2014; 19:476-83. [PMID: 25231285 DOI: 10.1111/hel.12169] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Although Helicobacter pylori have been known to induce vascular endothelial growth factor (VEGF) production in gastric epithelial cells, the precise mechanism for cellular signaling is incompletely understood. In this study, we investigated the role of bacterial virulence factor and host cellular signaling in VEGF production of H. pylori-infected gastric epithelial cells. MATERIALS AND METHODS We evaluated production of VEGF, activation of nuclear factor nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPKs) and hypoxia-inducible factor-1α (HIF-1α) stabilization in gastric epithelial cells infected with H. pylori WT or isogenic mutants deficient in type IV secretion system (T4SS). RESULTS H. pylori induced VEGF production in gastric epithelial cells via both T4SS-dependent and T4SS-independent pathways, although T4SS-independent pathway seems to be the dominant signaling. The inhibitor assay implicated that activation of NF-κB and MAPKs is dispensable for H. pylori-induced VEGF production in gastric epithelial cells. H. pylori led to HIF-1α stabilization in gastric epithelial cells independently of T4SS, NF-κB, and MAPKs, which was essential for VEGF production in these cells. N-acetyl-cysteine (NAC), a reactive oxygen species (ROS) inhibitor, treatment impaired H. pylori-induced HIF-1α stabilization and VEGF production in gastric epithelial cells. CONCLUSION We defined the important role of ROS-HIF-1α axis in VEGF production of H. pylori-infected gastric epithelial cells, and bacterial T4SS has a minor role in H. pylori-induced VEGF production of gastric epithelial cells.
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Affiliation(s)
- Min-Jung Kang
- Department of Biochemistry, College of Medicine, Konyang University, Daejeon, Korea; World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang-Eup, Cheongwon-Gun, Choongbuk, Korea
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Connection between expression of inducible nitric oxide synthase (iNOS) in skull base chordoma and lower urinary tract symptoms. Int Urol Nephrol 2014; 46:2109-16. [PMID: 25113512 DOI: 10.1007/s11255-014-0806-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Accepted: 07/26/2014] [Indexed: 10/24/2022]
Abstract
OBJECTIVE To provide first insights into the potential role of iNOS expressed by skull base chordoma, which causes brainstem compression in and around Barrington's nucleus, and its effect on the micturition center. METHODS Urodynamic testing of 22 symptomatic patients was performed. All women and men with skull base chordoma treated in two hospitals in Germany between 1986 and 2007 were studied. Lower urinary tract symptoms (LUTS) were documented in patients with acute brainstem compression due to local chordoma growth positive for iNOS expression. Brain magnetic resonance (MRI) images of the lesions of the symptomatic patients were performed. RESULTS Of 74 treated patients, 22 (7 women, 15 men) with a median age of 37 years were evaluated with voiding diaries and computer urodynamic investigation. Urodynamic testing of 22 symptomatic patients with positive iNOS expression of skull base chordoma revealed detrusor overactivity in 55 %, low-compliance bladder in 14 %, detrusor sphincter dyssynergia in 45 % and uninhibited sphincter relaxation in 27 %. There was a significant correlation between strong iNOS expression (score 3-6) in skull base chordoma and severe urinary symptoms (p = 0.003, Spearman ρ = 0.526). CONCLUSIONS The expression of iNOS in skull base chordoma compressing the dorsolateral pons, in and around Barrington's nucleus, may influence the pontine micturition center (PMC) and be responsible for lower urinary tract symptoms. Nitric oxide may possibly act as a neurotransmitter. We assume that the high infiltration of chordoma with monocyte/macrophages enhances the release of nitric oxide, as monocyte/macrophages are the main source of iNOS.
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Prognostic significance of immunohistochemical expression of VEGFR2 and iNOS in spinal chordoma. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2014; 23:2416-22. [DOI: 10.1007/s00586-014-3417-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Revised: 06/10/2014] [Accepted: 06/10/2014] [Indexed: 11/26/2022]
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Barzi A, Thara E. Angiogenesis in esophageal and gastric cancer: a paradigm shift in treatment. Expert Opin Biol Ther 2014; 14:1319-32. [DOI: 10.1517/14712598.2014.921677] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383:31-39. [PMID: 24094768 DOI: 10.1016/s0140-6736(13)61719-5] [Citation(s) in RCA: 1561] [Impact Index Per Article: 141.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. METHODS We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24-87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384. FINDINGS 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3-9·9) in patients in the ramucirumab group and 3·8 months (1·7-7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603-0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605-0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. INTERPRETATION Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer. FUNDING ImClone Systems.
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Affiliation(s)
- Charles S Fuchs
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
| | - Jiri Tomasek
- Department of Complex Oncology Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Cho Jae Yong
- Department of Medical Oncology, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Filip Dumitru
- Oncology Department, Emergency County Hospital "Dr Constantin Opris", Baia Mare, Romania
| | | | - Chanchal Goswami
- Department of Medical Oncology, B P Poddar Hospital and Medical Research, Kolkata, West Bengal
| | - Howard Safran
- Department of Medicine, The Brown University Oncology Group, Brown University, Providence, RI, USA
| | - Lucas Vieira Dos Santos
- Medical Oncology Department, Gastrointestinal Oncology Division, Hospital de Câncer de Barretos and Hemomed Instituto de Oncologia e Hematologia, São Paulo, Brazil
| | - Giuseppe Aprile
- Department of Oncology, University and General Hospital, Udine, Italy
| | - David R Ferry
- Department of Medical Oncology, New Cross Hospital, West Midlands, UK
| | - Bohuslav Melichar
- Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, CzechRepublic
| | - Mustapha Tehfe
- Department of Medical Oncology, Hôpital Notre Dame de CHUM, Montreal, Quebec
| | - Eldar Topuzov
- State Budgetary Educational Institution of Higher Professional Education (SBEIHPE), "Northwest State Medical University na II Mechnikov", Ministry of Healthcare of the Russian Federation, Russia
| | - John Raymond Zalcberg
- Division of Cancer Medicine, Peter McCallum Cancer Centre, East Melbourne, VIC, Australia; Departments of Medicine and Oncology, Faculty of Medicine, University of Melbourne, Australia
| | - Ian Chau
- Department of Medicine, Royal Marsden Hospital, London and Surrey, England
| | - William Campbell
- Department of Oncology, Hospital Herrera Llerandi-Clinicas Médicas, Guatemala
| | | | | | | | - Yanzhi Hsu
- ImClone Systems LLC, Bridgewater, NJ, USA
| | | | - Ling Gao
- ImClone Systems LLC, Bridgewater, NJ, USA
| | | | - Josep Tabernero
- Medical Oncology Department Vall d'Hebron University Hospital, UniversitatAutònoma de Barcelona, Barcelona, Spain
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Smyth EC, Tarazona N, Chau I. Ramucirumab: targeting angiogenesis in the treatment of gastric cancer. Immunotherapy 2014; 6:1177-86. [PMID: 25496333 DOI: 10.2217/imt.14.85] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Gastroesophageal cancer is responsible for over 1 million deaths annually worldwide; for patients with advanced disease treatment options are limited. Angiogenesis is an attractive therapeutic target that has been successfully exploited in other cancers. Ramucirumab, a fully humanized monoclonal antibody targeting VEGFR-2 has demonstrated efficacy as a single agent and in combination with paclitaxel in two large randomized trials (REGARD and RAINBOW) for the treatment of advanced previously treated gastroesophageal cancer. In combination with paclitaxel chemotherapy ramucirumab treated patients demonstrated increased rates of neutropenia, and ramucirumab is also associated with hypertension consistent with other antiangiogenic agents. Ramucirumab has been US FDA approved for patients with advanced gastroesophageal cancer who have progressed during or after treatment with fluoropyrimidine- or platinum-containing chemotherapy.
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Affiliation(s)
- Elizabeth C Smyth
- Department of Gastrointestinal Oncology, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK
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Qiu MZ, Xu RH. The progress of targeted therapy in advanced gastric cancer. Biomark Res 2013; 1:32. [PMID: 24330856 PMCID: PMC3878836 DOI: 10.1186/2050-7771-1-32] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 12/02/2013] [Indexed: 12/13/2022] Open
Abstract
Although palliative chemotherapy has been shown to prolong survival and improve quality of life, the survival of advanced gastric cancer (AGC) patients remains poor. With the advent of targeted therapy, many molecular targeted agents have been evaluated in clinical studies. Trastuzumab, an anti-HER2 monoclonal antibody, has shown activity against HER2-positive AGC and becomes the first targeted agent approved in AGC. Drugs that target epidermal growth factor receptor, including monoclonal antibody and tyrosine kinase inhibitor, do not bring survival benefit to patients with AGC. Additionally, vascular endothelial growth factor inhibitors are also under investigation. Ramucirumab has shown promising result. Other targeted agents are in preclinical or early clinical development, such as mammalian target of rapamycinm inhibitors and c-MET inhibitors.
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Affiliation(s)
- Miao-zhen Qiu
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou 510060, China
| | - Rui-hua Xu
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou 510060, China
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Vaish V, Piplani H, Rana C, Sanyal SN. Angiostatic properties of sulindac and celecoxib in the experimentally induced inflammatory colorectal cancer. Cell Biochem Biophys 2013; 66:205-27. [PMID: 23149858 DOI: 10.1007/s12013-012-9469-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Initiation of various cancers has been observed to be regulated via a prolonged inflammatory state in the tissues. However, molecular role of such a localized inflammation is not clear in the advanced stages of colorectal cancer. In this study, we have elaborated the role of various pro- and anti-inflammatory cytokines, transcription, and angiogenic factors in the progression of the 1,2-dimethylhydrazine dihydrochloride (DMH)-induced late phage colorectal cancer and also observed the chemopreventive role of the two non-steroidal anti-inflammatory drugs (NSAIDs), viz., Sulindac and Celecoxib. Carcinogenic changes were observed with morphological and histopathological studies, whereas mRNA and protein regulations of various biomolecules were identified via RT- or qRT-PCR, western blot and immunofluorescence analysis, respectively. Activity of inducible nitric oxide (NO) and cyclooxygenase-2 enzymes were analyzed using standard NO assay and prostaglandin E2 immunoassay, whereas activities of matrix metalloproteinases (MMP-2 and-9) were identified by gelatin zymography. Flowcytometry was performed for the relative quantification of the apoptotic events. Molecular docking studies of Sulindac and Celecoxib were also performed with different target proteins to observe their putative mechanisms of action. As a result, we found that DMH-treated animals were having over-expression of various pro-inflammatory cytokines (IL-1β, IL-2, and IFNγ), aberrant nuclear localization of activated cell survival transcription factors (NF-κB and Stat3) along with the increased incidence of activated angiogenic factors (MMP-2 and MMP-9) suggesting a marked role of inflammation in the tumor progression. However, NSAIDs co-administration has significantly reduced the angiogenic potential of the growing neoplasm.
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Affiliation(s)
- Vivek Vaish
- Department of Biophysics, Panjab University, Chandigarh, 160 014, India
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Expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in skull base chordoma: a series of 145 tumors. Neurosurg Rev 2013; 37:79-88. [DOI: 10.1007/s10143-013-0495-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2012] [Revised: 01/17/2013] [Accepted: 01/21/2013] [Indexed: 12/12/2022]
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Vascular endothelial growth factor and survivin immunostaining in gastric adenocarcinoma. POLISH JOURNAL OF SURGERY 2013; 84:341-7. [PMID: 22935455 DOI: 10.2478/v10035-012-0057-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
UNLABELLED Two molecules - vascular endothelial growth factor involved in new vessels formation and survivin - antiapoptotic protein, reported to be associated with worse prognosis in various malignancies have been chosen for the study. Both are potential target for novel therapies. THE AIM OF THE STUDY Was to determine the immunostaining of VEGF and survivin in gastric carcinoma and to analyse their relationship to the selected clinicopathological features and survival. MATERIAL AND METHODS Formalin-fixed, paraffin-embedded sections from 41 gastric adenocarcinomas were used for immunohistochemical reaction with monoclonal antibodies against vascular endothelial growth factor and survivin. The results were compared with selected clinicopathological features and survival. RESULTS Positive immunohistochemical reaction for vascular endothelial growth factor and survivin was revealed in 24 (58,53%) and 30 (73,17%), gastric carcinomas respectively. Vascular endothelial growth factor-negative gastric carcinomas were significantly more common in cases without metastases to regional lymph nodes and distant organs and in less advanced cases. Similar, distant metastases were also statistically less common in survivin-negative carcinomas. The differences in immunohistochemical reactions for survivin between less and more advanced cases almost reach statistical significance. The only factors significantly influenced 1, 2 and 3-year survival were vascular endothelial growth factor and survivin status. Statistically significant higher percentage of survival was noted in patients with vascular endothelial growth factor- and survivin-negative tumors. CONCLUSIONS It seems that vascular endothelial growth factor and survivin play role in local invasion and spread of gastric adenocarcinoma and negatively influences survival. However, further studies are required to assess their true usefulness in the clinical practice.
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Liu YF, Guo S, Zhao R, Chen YG, Wang XQ, Xu KS. Correlation of vascular endothelial growth factor expression with tumor recurrence and poor prognosis in patients with pN0 gastric cancer. World J Surg 2012; 36:109-17. [PMID: 21773953 DOI: 10.1007/s00268-011-1192-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 play important roles in tumor angiogenesis, development, and progression. This study investigates the expression of VEGF combined with MMP-9, their correlation with clinical characteristics, and their effect on the prognosis for patients with pN0 gastric cancer after curative surgery. METHODS A total of 55 patients were enrolled in the study. They were analyzed by immunohistochemistry, and their correlation with clinical characteristics was then investigated. Their relations and the survival time of patients were retrospectively analyzed. RESULTS VEGF and MMP-9 were positively expressed in 24 (43.6%) and 16 (29.1%) patients, respectively, and had a positive correlation (r = 0.324, p = 0.016) in the Spearman rank correlation analysis. Univariate analysis showed that VEGF, MMP-9 expression, vascular invasion, T stage, and tumor size were associated with tumor recurrence as well as the disease-specific (DSS) and overall (OS) survival rates. Patients with positive VEGF expression showed significantly higher recurrence and poorer DSS and OS rates compared with those with negative VEGF expression. Multivariate analysis showed that VEGF expression, vascular invasion, T stage (serosal invasion), and tumor size were significant independent prognostic factors for tumor recurrence, DSS, and OS in patients with pN0 gastric cancer with the exception that T stage was not for DSS. CONCLUSIONS VEGF expression, vascular invasion, T stage (serosal invasion), and tumor size can be used as valuable prognosticators in predicting tumor recurrence and prognosis for patients with pN0 gastric cancer after curative surgery. VEGF may have a synergistic effect with MMP-9 during tumor angiogenesis, development, and progression.
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Affiliation(s)
- Yan-Feng Liu
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, 107#, Wenhua Xi Road, Jinan 250012, China
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Liu L, Wu N, Li J. Novel targeted agents for gastric cancer. J Hematol Oncol 2012; 5:31. [PMID: 22709792 PMCID: PMC3411478 DOI: 10.1186/1756-8722-5-31] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2012] [Accepted: 06/18/2012] [Indexed: 12/16/2022] Open
Abstract
Contemporary advancements have had little impact on the treatment of gastric cancer (GC), the world’s second highest cause of cancer death. Agents targeting human epidermal growth factor receptor mediated pathways have been a common topic of contemporary cancer research, including monoclonal antibodies (mAbs) and receptor tyrosine kinase inhibitors (TKIs). Trastuzumab is the first target agent evidencing improvements in overall survival in HER2-positive (human epidermal growth factor receptor 2) gastric cancer patients. Agents targeting vascular epithelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and other biological pathways are also undergoing clinical trials, with some marginally positive results. Effective targeted therapy requires patient selection based on predictive molecular biomarkers. Most phase III clinical trials are carried out without patient selection; therefore, it is hard to achieve personalized treatment and to monitor patient outcome individually. The trend for future clinical trials requires patient selection methods based on current understanding of GC biology with the application of biomarkers.
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Affiliation(s)
- Lian Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
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