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Marek K, Armando F, Nippold VM, Rohn K, Plattet P, Brogden G, Gerold G, Baumgärtner W, Puff C. Persistent Infection of a Canine Histiocytic Sarcoma Cell Line with Attenuated Canine Distemper Virus Expressing Vasostatin or Granulocyte-Macrophage Colony-Stimulating Factor. Int J Mol Sci 2022; 23:ijms23116156. [PMID: 35682834 PMCID: PMC9181094 DOI: 10.3390/ijms23116156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 02/04/2023] Open
Abstract
Canine histiocytic sarcoma (HS) represents a neoplasia with poor prognosis. Due to the high metastatic rate of HS, there is urgency to improve treatment options and to prevent tumor metastases. Canine distemper virus (CDV) is a single-stranded negative-sense RNA (ssRNA (-)) virus with potentially oncolytic properties. Moreover, vasostatin and granulocyte-macrophage colony-stimulating factor (GM-CSF) are attractive molecules in cancer therapy research because of their anti-angiogenetic properties and potential modulation of the tumor microenvironment. In the present study, an in vitro characterization of two genetically engineered viruses based on the CDV strain Onderstepoort (CDV-Ond), CDV-Ondneon-vasostatin and CDV-Ondneon-GM-CSF was performed. Canine histiocytic sarcoma cells (DH82 cells) were persistently infected with CDV-Ond, CDV-Ondneon, CDV-Ondneon-vasostatin and CDV-Ondneon-GM-CSF and characterized on a molecular and protein level regarding their vasostatin and GM-CSF production. Interestingly, DH82 cells persistently infected with CDV-Ondneon-vasostatin showed a significantly increased number of vasostatin mRNA transcripts. Similarly, DH82 cells persistently infected with CDV-Ondneon-GM-CSF displayed an increased number of GM-CSF mRNA transcripts mirrored on the protein level as confirmed by immunofluorescence and Western blot. In summary, modified CDV-Ond strains expressed GM-CSF and vasostatin, rendering them promising candidates for the improvement of oncolytic virotherapies, which should be further detailed in future in vivo studies.
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Affiliation(s)
- Katarzyna Marek
- Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; (K.M.); (F.A.); (V.M.N.); (C.P.)
- Center for Systems Neuroscience, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
| | - Federico Armando
- Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; (K.M.); (F.A.); (V.M.N.); (C.P.)
| | - Vanessa Maria Nippold
- Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; (K.M.); (F.A.); (V.M.N.); (C.P.)
| | - Karl Rohn
- Institute for Biometry, Epidemiology and Information Processing, University of Veterinary Medicine Hannover, 30559 Hannover, Germany;
| | - Philippe Plattet
- Division of Experimental Clinical Research, Vetsuisse University Bern, 3012 Bern, Switzerland;
| | - Graham Brogden
- Department of Biochemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; (G.B.); (G.G.)
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, 30559 Hannover, Germany
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, 30625 Hannover, Germany
| | - Gisa Gerold
- Department of Biochemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; (G.B.); (G.G.)
- Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, 30559 Hannover, Germany
- Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, 901 87 Umeå, Sweden
- Department of Clinical Microbiology, Virology, Umeå University, 901 87 Umeå, Sweden
| | - Wolfgang Baumgärtner
- Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; (K.M.); (F.A.); (V.M.N.); (C.P.)
- Center for Systems Neuroscience, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
- Correspondence:
| | - Christina Puff
- Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; (K.M.); (F.A.); (V.M.N.); (C.P.)
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Bee YS, Tu L, Sheu SJ, Lin HC, Tang JH, Wang JH, Prea SM, Dusting GJ, Wu DC, Zhong J, Bui BV, Tai MH, Liu GS. Gene Delivery of Calreticulin Anti-Angiogenic Domain Attenuates the Development of Choroidal Neovascularization in Rats. Hum Gene Ther 2017; 28:403-414. [DOI: 10.1089/hum.2016.035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Youn-Shen Bee
- Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Yuh-Ing Junior College of Health Care and Management, Kaohsiung, Taiwan
- National Defense Medical Center, Taipei, Taiwan
| | - Leilei Tu
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia
- Department of Ophthalmology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Shwu-Jiuan Sheu
- Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Hsiu-Chen Lin
- Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Jia-Hua Tang
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Jiang-Hui Wang
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, Australia
| | - Selwyn M. Prea
- Department of Optometry and Vision Sciences, University of Melbourne, East Melbourne, Australia
| | - Gregory J. Dusting
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, Australia
| | - Deng-Chyang Wu
- Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jingxiang Zhong
- Department of Ophthalmology, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Bang V. Bui
- Department of Optometry and Vision Sciences, University of Melbourne, East Melbourne, Australia
| | - Ming-Hong Tai
- Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
- Center for Neuroscience, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Guei-Sheung Liu
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, Australia
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Abstract
The outcomes for treatment of pancreatic cancer have not improved dramatically in many decades. However, the recent promising results with combination chemotherapy regimens for metastatic disease increase optimism for future treatments. With greater control of overt or occult metastatic disease, there will likely be an expanding role for local treatment modalities, especially given that nearly a third of pancreatic cancer patients have locally destructive disease without distant metastatic disease at the time of death. Technical advances have allowed for the safe delivery of dose-escalated radiation therapy, which can then be combined with chemotherapy, targeted agents, immunotherapy, and nanoparticulate drug delivery techniques to produce novel and improved synergistic effects. Here we discuss recent advances and future directions for multimodality therapy in pancreatic cancer.
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Garbati MR, Welgan CA, Landefeld SH, Newell LF, Agarwal A, Dunlap JB, Chourasia TK, Lee H, Elferich J, Traer E, Rattray R, Cascio MJ, Press RD, Bagby GC, Tyner JW, Druker BJ, Dao KHT. Mutant calreticulin-expressing cells induce monocyte hyperreactivity through a paracrine mechanism. Am J Hematol 2016; 91:211-9. [PMID: 26573090 DOI: 10.1002/ajh.24245] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 11/12/2015] [Indexed: 01/05/2023]
Abstract
Mutations in the calreticulin gene (CALR) were recently identified in approximately 70-80% of patients with JAK2-V617F-negative essential thrombocytosis and primary myelofibrosis. All frameshift mutations generate a recurring novel C-terminus. Here we provide evidence that mutant calreticulin does not accumulate efficiently in cells and is abnormally enriched in the nucleus and extracellular space compared to wildtype calreticulin. The main determinant of these findings is the loss of the calcium-binding and KDEL domains. Expression of type I mutant CALR in Ba/F3 cells confers minimal IL-3-independent growth. Interestingly, expression of type I and type II mutant CALR in a nonhematopoietic cell line does not directly activate JAK/STAT signaling compared to wildtype CALR and JAK2-V617F expression. These results led us to investigate paracrine mechanisms of JAK/STAT activation. Here we show that conditioned media from cells expressing type I mutant CALR exaggerate cytokine production from normal monocytes with or without treatment with a toll-like receptor agonist. These effects are not dependent on the novel C-terminus. These studies offer novel insights into the mechanism of JAK/STAT activation in patients with JAK2-V617F-negative essential thrombocytosis and primary myelofibrosis.
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Affiliation(s)
- Michael R. Garbati
- Knight Cancer Institute, Hematology and Medical Oncology, Oregon Health and Science University; Portland Oregon
| | - Catherine A. Welgan
- Knight Cancer Institute, Hematology and Medical Oncology, Oregon Health and Science University; Portland Oregon
| | - Sally H. Landefeld
- Knight Cancer Institute, Hematology and Medical Oncology, Oregon Health and Science University; Portland Oregon
| | - Laura F. Newell
- Knight Cancer Institute, Hematology and Medical Oncology, Oregon Health and Science University; Portland Oregon
| | - Anupriya Agarwal
- Knight Cancer Institute, Hematology and Medical Oncology, Oregon Health and Science University; Portland Oregon
| | - Jennifer B. Dunlap
- Knight Cancer Institute, Oregon Health and Science University; Portland Oregon
- Department of Pathology; Oregon Health and Science University; Portland Oregon
| | - Tapan K. Chourasia
- Knight Cancer Institute, Hematology and Medical Oncology, Oregon Health and Science University; Portland Oregon
| | - Hyunjung Lee
- Knight Cancer Institute, Hematology and Medical Oncology, Oregon Health and Science University; Portland Oregon
| | - Johannes Elferich
- Department of Biochemistry and Molecular Biology; Oregon Health and Science University; Portland Oregon
| | - Elie Traer
- Knight Cancer Institute, Hematology and Medical Oncology, Oregon Health and Science University; Portland Oregon
| | - Rogan Rattray
- Knight Cancer Institute, Oregon Health and Science University; Portland Oregon
- Department of Pathology; Oregon Health and Science University; Portland Oregon
| | - Michael J. Cascio
- Department of Pathology; Oregon Health and Science University; Portland Oregon
| | - Richard D. Press
- Knight Cancer Institute, Oregon Health and Science University; Portland Oregon
- Department of Pathology; Oregon Health and Science University; Portland Oregon
| | - Grover C. Bagby
- Knight Cancer Institute, Hematology and Medical Oncology, Oregon Health and Science University; Portland Oregon
| | - Jeffrey W. Tyner
- Knight Cancer Institute, Hematology and Medical Oncology, Oregon Health and Science University; Portland Oregon
- Department of Cell, Development, and Cancer Biology; Oregon Health and Science University, Knight Cancer Institute; Portland Oregon
| | - Brian J. Druker
- Knight Cancer Institute, Hematology and Medical Oncology, Oregon Health and Science University; Portland Oregon
- Department of Cell, Development, and Cancer Biology; Oregon Health and Science University, Knight Cancer Institute; Portland Oregon
- Howard Hughes Medical Institute, Oregon Health and Science University; Portland Oregon
| | - Kim-Hien T. Dao
- Knight Cancer Institute, Hematology and Medical Oncology, Oregon Health and Science University; Portland Oregon
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Liu SX, Xia ZS, Zhong YQ. Gene therapy in pancreatic cancer. World J Gastroenterol 2014; 20:13343-68. [PMID: 25309069 PMCID: PMC4188890 DOI: 10.3748/wjg.v20.i37.13343] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 12/29/2013] [Accepted: 06/12/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is a highly lethal disease and notoriously difficult to treat. Only a small proportion of PC patients are eligible for surgical resection, whilst conventional chemoradiotherapy only has a modest effect with substantial toxicity. Gene therapy has become a new widely investigated therapeutic approach for PC. This article reviews the basic rationale, gene delivery methods, therapeutic targets and developments of laboratory research and clinical trials in gene therapy of PC by searching the literature published in English using the PubMed database and analyzing clinical trials registered on the Gene Therapy Clinical Trials Worldwide website (http://www. wiley.co.uk/genmed/ clinical). Viral vectors are main gene delivery tools in gene therapy of cancer, and especially, oncolytic virus shows brighter prospect due to its tumor-targeting property. Efficient therapeutic targets for gene therapy include tumor suppressor gene p53, mutant oncogene K-ras, anti-angiogenesis gene VEGFR, suicide gene HSK-TK, cytosine deaminase and cytochrome p450, multiple cytokine genes and so on. Combining different targets or combination strategies with traditional chemoradiotherapy may be a more effective approach to improve the efficacy of cancer gene therapy. Cancer gene therapy is not yet applied in clinical practice, but basic and clinical studies have demonstrated its safety and clinical benefits. Gene therapy will be a new and promising field for the treatment of PC.
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Giovinazzo F, Schimmack S, Svejda B, Alaimo D, Pfragner R, Modlin I, Kidd M. Chromogranin A and its fragments as regulators of small intestinal neuroendocrine neoplasm proliferation. PLoS One 2013; 8:e81111. [PMID: 24260544 PMCID: PMC3834250 DOI: 10.1371/journal.pone.0081111] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Accepted: 10/17/2013] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Chromogranin A is a neuroendocrine secretory product and its loss is a feature of malignant NEN de-differentiation. We hypothesized that chromogranin A fragments were differentially expressed during NEN metastasis and played a role in the regulation of NEN proliferation. METHODS Chromogranin A mRNA (PCR) and protein (ELISA/western blot) were studied in 10 normal human mucosa, 5 enterochromaffin cell preparations, 26 small intestinal NEN primaries and 9 liver metastases. Cell viability (WST-1 assay), proliferation (bromodeoxyuridine ELISA) and expression of AKT/AKT-P (CASE ELISA/western blot) in response to chromogranin A silencing, inhibition of prohormone convertase and mTOR inhibition (RAD001/AKT antisense) as well as different chromogranin A fragments were examined in 4 SI-NEN cell lines. RESULTS Chromogranin A mRNA and protein levels were increased (37-340 fold, p<0.0001) in small intestinal NENs compared to normal enterochromaffin cells. Western blot identified chromogranin A-associated processing bands including vasostatin in small intestinal NENs as well as up-regulated expression of prohormone convertase in metastases. Proliferation in small intestinal NEN cell lines was decreased by silencing chromogranin A as well as by inhibition of prohormone convertase (p<0.05). This inhibition also decreased secretion of chromogranin A (p<0.05) and 5-HT (p<0.05) as well as expression of vasostatin. Metastatic small intestinal NEN cell lines were stimulated (50-80%, p<0.05) and AKT phosphorylated (Ser473: p<0.05) by vasostatin I, which was completely reversed by RAD001 (p<0.01) and AKT antisense (p<0.05) while chromostatin inhibited proliferation (~50%, p<0.05). CONCLUSION Chromogranin A was differentially regulated in primary and metastatic small intestinal NENs and cell lines. Chromogranin A fragments regulated metastatic small intestinal NEN proliferation via the AKT pathway indicating that CgA plays a far more complex role in the biology of these tumors than previously considered.
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Affiliation(s)
- Francesco Giovinazzo
- Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Laboratory of Translational Surgery-LURM, University of Verona, Verona, Italy
| | - Simon Schimmack
- Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States of America
- University Hospital of General, Visceral- and Transplantation-Surgery of Heidelberg, Heidelberg, Germany
| | - Bernhard Svejda
- Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Pathophysiology and Immunology, University of Graz, Graz, Austria
| | - Daniele Alaimo
- Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Roswitha Pfragner
- Department of Pathophysiology and Immunology, University of Graz, Graz, Austria
| | - Irvin Modlin
- Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Mark Kidd
- Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States of America
- * E-mail:
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Ramírez G, Valck C, Ferreira VP, López N, Ferreira A. Extracellular Trypanosoma cruzi calreticulin in the host-parasite interplay. Trends Parasitol 2011; 27:115-22. [PMID: 21288773 DOI: 10.1016/j.pt.2010.12.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Revised: 12/18/2010] [Accepted: 12/20/2010] [Indexed: 11/24/2022]
Abstract
Calreticulin (CRT) from vertebrates is a calcium-binding protein present mainly in the endoplasmic reticulum (ER). There, it directs the conformation of proteins and controls calcium levels. This review will focus on several extracellular roles of Trypanosoma cruzi CRT (TcCRT) in relation to its capacity to inhibit the complement system, mediate parasite infectivity, interfere with angiogenesis and, as a possible consequence, with tumor growth. The TcCRT antiangiogenic effect parallels with the capacity of T. cruzi infection to inhibit tumor development in vivo. Thus, the TcCRT, complement, and endothelial cell interactions seem to be an evolutionary adaptation to promote prolonged parasite-host relationships.
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Affiliation(s)
- Galia Ramírez
- Programa Disciplinario de Inmunología, ICBM, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile
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Antiangiogenic and antitumor effects of Trypanosoma cruzi Calreticulin. PLoS Negl Trop Dis 2010; 4:e730. [PMID: 20625551 PMCID: PMC2897838 DOI: 10.1371/journal.pntd.0000730] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2009] [Accepted: 05/11/2010] [Indexed: 01/26/2023] Open
Abstract
Background In Latin America, 18 million people are infected with Trypanosoma cruzi, the agent of Chagas' disease, with the greatest economic burden. Vertebrate calreticulins (CRT) are multifunctional, intra- and extracellular proteins. In the endoplasmic reticulum (ER) they bind calcium and act as chaperones. Since human CRT (HuCRT) is antiangiogenic and suppresses tumor growth, the presence of these functions in the parasite orthologue may have consequences in the host/parasite interaction. Previously, we have cloned and expressed T. cruzi calreticulin (TcCRT) and shown that TcCRT, translocated from the ER to the area of trypomastigote flagellum emergence, promotes infectivity, inactivates the complement system and inhibits angiogenesis in the chorioallantoid chicken egg membrane. Most likely, derived from these properties, TcCRT displays in vivo inhibitory effects against an experimental mammary tumor. Methodology and Principal Findings TcCRT (or its N-terminal vasostatin-like domain, N-TcCRT) a) Abrogates capillary growth in the ex vivo rat aortic ring assay, b) Inhibits capillary morphogenesis in a human umbilical vein endothelial cell (HUVEC) assay, c) Inhibits migration and proliferation of HUVECs and the human endothelial cell line Eahy926. In these assays TcCRT was more effective, in molar terms, than HuCRT: d) In confocal microscopy, live HUVECs and EAhy926 cells, are recognized by FITC-TcCRT, followed by its internalization and accumulation around the host cell nuclei, a phenomenon that is abrogated by Fucoidin, a specific scavenger receptor ligand and, e) Inhibits in vivo the growth of the murine mammary TA3 MTXR tumor cell line. Conclusions/Significance We describe herein antiangiogenic and antitumor properties of a parasite chaperone molecule, specifically TcCRT. Perhaps, by virtue of its capacity to inhibit angiogenesis (and the complement system), TcCRT is anti-inflammatory, thus impairing the antiparasite immune response. The TcCRT antiangiogenic effect could also explain, at least partially, the in vivo antitumor effects reported herein and the reports proposing antitumor properties for T. cruzi infection. In Latin America, 18 million people are infected with Trypanosoma cruzi, a protozoan that causes Chagas' disease. Vertebrate calreticulins (CRTs) are multifunctional, intra- and extracellular calcium binding, chaperone proteins. Since human CRT (HuCRT) inhibits capillary growth (angiogenesis) and suppresses tumor growth, the presence of these functions in T. cruzi CRT (TcCRT) may have interesting consequences in the host/parasite interactions. Previously, we have cloned and expressed TcCRT and shown that, when translocated from the endoplasmic reticulum to the area of trypomastigote flagellum emergence, it promotes infectivity, inactivates the complement system, an innate defense arm and inhibits angiogenesis in the chorioallantoid chicken egg membrane. TcCRT inhibits angiogenesis, since it interferes with endothelial cell multiplication, migration and capillary morphogenesis in vitro, as well as angiogenesis in rat aortic rings. The parasite molecule also displays important antitumor effects. In these activities, TcCRT is more effective than the human counterpart. Perhaps, by virtue of its capacity to inhibit angiogenesis, TcCRT is anti-inflammatory, thus impairing the antiparasite immune response. The TcCRT antiangiogenic effect could also explain, at least partially, the in vivo antitumor effects reported herein and the reports proposing antitumor properties for T. cruzi infection.
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The Chick Embryo Chorioallantoic Membrane as an In Vivo Assay to Study Antiangiogenesis. Pharmaceuticals (Basel) 2010; 3:482-513. [PMID: 27713265 PMCID: PMC4033966 DOI: 10.3390/ph3030482] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2010] [Revised: 01/29/2010] [Accepted: 03/02/2010] [Indexed: 12/15/2022] Open
Abstract
Antiangiogenesis, e.g., inhibition of blood vessel growth, is being investigated as a way to prevent the growth of tumors and other angiogenesis-dependent diseases. Pharmacological inhibition interferes with the angiogenic cascade or the immature neovasculature with synthetic or semi-synthetic substances, endogenous inhibitors or biological antagonists.The chick embryo chorioallantoic membrane (CAM) is an extraembryonic membrane, which serves as a gas exchange surface and its function is supported by a dense capillary network. Because its extensive vascularization and easy accessibility, CAM has been used to study morphofunctional aspects of the angiogenesis process in vivo and to study the efficacy and mechanism of action of pro- and anti-angiogenic molecules. The fields of application of CAM in the study of antiangiogenesis, including our personal experience, are illustrated in this review article.
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Chen CN, Chang CC, Su TE, Hsu WM, Jeng YM, Ho MC, Hsieh FJ, Lee PH, Kuo ML, Lee H, Chang KJ. Identification of calreticulin as a prognosis marker and angiogenic regulator in human gastric cancer. Ann Surg Oncol 2008; 16:524-33. [PMID: 19050968 DOI: 10.1245/s10434-008-0243-1] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2008] [Revised: 10/21/2008] [Accepted: 10/21/2008] [Indexed: 12/23/2022]
Abstract
The purpose of this study was to identify genes of interest for a subsequent functional and clinical cohort study using complementary (c)DNA microarrays. cDNA microarray hybridization was performed to identify differentially expressed genes between tumor and nontumor specimens in 30 gastric cancer patients. Subsequent functional studies of the selected gene were carried out, including cell cycle analysis, cell migration analysis, analyses of vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF), and oligo-microarray studies using two pairs of stable cell lines of the selected gene. Another independent cohort study of 79 gastric cancer patients was conducted to evaluate the clinical significance of the selected gene in human gastric cancer. Calreticulin (CRT) was selected for further investigation. Two pairs of stable cell lines of CRT overexpression and CRT knockdown were constructed to perform functional studies. CRT enhanced gastric cancer cell proliferation and migration. Overexpressed CRT upregulated the expression and secretion of PlGF and VEGF. CRT had a reciprocal effect on connective tissue growth factor (CTGF) expression. Positive immunohistochemical staining of calreticulin was significantly correlated with high microvessel density (MVD) (p = 0.014), positive serosal invasion (p = 0.013), lymph node metastasis (p = 0.002), perineural invasion (p = 0.008), and poor patient survival (p = 0.0014). Multivariate survival analysis showed that CRT, MVD, and serosal invasion were independent prognosticators. We conclude that CRT overexpression enhances angiogenesis, and facilitates proliferation and migration of gastric cancer cells, which is in line with the association of CRT with MVD, tumor invasion, lymph node metastasis, and survival in gastric cancer patients.
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Affiliation(s)
- Chiung-Nien Chen
- Department of Surgery, Angiogenesis Research Center, National Taiwan University Hospital and College of Medicine, Taipei
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Sun Q, Xu Q, Dong X, Cao L, Huang X, Hu Q, Hua ZC. A hybrid protein comprising ATF domain of pro-UK and VAS, an angiogenesis inhibitor, is a potent candidate for targeted cancer therapy. Int J Cancer 2008; 123:942-50. [DOI: 10.1002/ijc.23537] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Liu B, Ye D, Song X, Zhao X, Yi L, Song J, Zhang Z, Zhao Q. A novel therapeutic fusion protein vaccine by two different families of heat shock proteins linked with HPV16 E7 generates potent antitumor immunity and antiangiogenesis. Vaccine 2008; 26:1387-96. [DOI: 10.1016/j.vaccine.2007.12.034] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2007] [Revised: 12/06/2007] [Accepted: 12/13/2007] [Indexed: 12/28/2022]
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Cai KX, Tse LY, Leung C, Tam PK, Xu R, Sham MH. Suppression of Lung Tumor Growth and Metastasis in Mice by Adeno-Associated Virus-Mediated Expression of Vasostatin. Clin Cancer Res 2008; 14:939-49. [DOI: 10.1158/1078-0432.ccr-07-1930] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Persano L, Crescenzi M, Indraccolo S. Anti-angiogenic gene therapy of cancer: current status and future prospects. Mol Aspects Med 2007; 28:87-114. [PMID: 17306361 DOI: 10.1016/j.mam.2006.12.005] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2006] [Accepted: 12/18/2006] [Indexed: 12/14/2022]
Abstract
The discovery of endogenous inhibitors of angiogenesis has made it possible to test the hypothesis that blocking the angiogenic switch may keep tumor growth in check, and has added a new investigational arm to the field of cancer gene therapy. Angiogenesis inhibitors are heterogeneous in origin and potency, and their growing list includes proteolysis products of larger molecules with a different function, such as angiostatin, endostatin and vasostatin, modulators of vascular endothelial growth factor activity, such as sFLT-1, and some cytokines/chemokines with marked anti-endothelial activity, such as IL-12, IFN-alpha, and CXCL10. Pre-clinical studies have clearly indicated that these factors are essentially cytostatic and that they need long-term administration in order to obtain prolonged anti-tumor effects, representing a rational basis for their delivery by a gene therapy approach. The experimental approaches attempted to date, reviewed herein, indicate overall that anti-angiogenic gene therapy has efficacy mainly as an early intervention strategy and that a better understanding of the biological mechanisms underlying resistance to angiogenesis inhibition, as well as appropriate combined treatments, are required to generate a conceptual advancement which could drive the field towards successful management of established tumors.
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Affiliation(s)
- Luca Persano
- Department of Oncology and Surgical Sciences, Oncology Section, University of Padova, Via Gattamelata, 64, 35128 Padova, Italy
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Ma L, Luo L, Qiao H, Dong X, Pan S, Jiang H, Krissansen GW, Sun X. Complete eradication of hepatocellular carcinomas by combined vasostatin gene therapy and B7H3-mediated immunotherapy. J Hepatol 2007; 46:98-106. [PMID: 17109987 DOI: 10.1016/j.jhep.2006.07.031] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2006] [Revised: 06/19/2006] [Accepted: 07/13/2006] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS B7H3 immunogene therapy is able to completely eradicate tumors when combined with an anti-vascular agent. The aim of this study was to determine whether vasostatin, a potent anti-angiogenic agent, could synergize with B7H3-mediated immunotherapy to combat hepatocellular carcinoma (HCC). METHODS Vasostatin and B7H3 expression plasmids were constructed, and the in vitro and in vivo expression and anti-angiogenic activity of recombinant vasostatin were measured. The anti-tumor activities of B7H3 and vasostatin alone and in combination were assessed using single and multiple H22 tumor models. RESULTS Gene transfer of vasostatin inhibited the proliferation of aortic endothelial cells, and angiogenesis in the chorioallantoic membrane assay. Subcutaneous H22 tumors established in BALB/c mice were completely eradicated in response to intratumoral injection of B7H3-expressing plasmids followed 24h later by vasostatin-expressing plasmids. In contrast, neither vasostatin nor B7H3 monotherapy was effective. Gene transfer of vasostatin inhibited tumor angiogenesis and enhanced infiltration of NK cells, whereas B7H3 therapy activated CD8+ and NK cells and increased their infiltration into tumors, and enhanced the levels of circulating IFN-gamma. B7H3 and vasostatin combination gene therapy was effective in combating a systemic challenge of parental H22 cells, and caused the complete regression of multiple distant tumor nodules. CONCLUSIONS Combining vasostatin anti-angiogenic therapy with B7H3-mediated immunotherapy warrants investigation as a therapeutic strategy to combat HCC, and other malignancies.
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Affiliation(s)
- Lixin Ma
- The Hepatosplenic Surgery Center of Heilongjiang Province/Department of General Surgery, The First Clinical College of Harbin Medical University, Harbin 150001, China
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