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Hofmann AT, Slezak P, Neumann S, Ferguson J, Redl H, Mittermayr R. Ischemia Impaired Wound Healing Model in the Rat—Demonstrating Its Ability to Test Proangiogenic Factors. Biomedicines 2023; 11:biomedicines11041043. [PMID: 37189661 DOI: 10.3390/biomedicines11041043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/13/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
Chronic wounds remain a serious clinical problem with insufficient therapeutic approaches. In this study we investigated the dose dependency of rhVEGF165 in fibrin sealant in both ischemic and non-ischemic excision wounds using our recently developed impaired-wound healing model. An abdominal flap was harvested from the rat with unilateral ligation of the epigastric bundle and consequent unilateral flap ischemia. Two excisional wounds were set in the ischemic and non-ischemic area. Wounds were treated with three different rhVEGF165 doses (10, 50 and 100 ng) mixed with fibrin or fibrin alone. Control animals received no therapy. Laser Doppler imaging (LDI) and immunohistochemistry were performed to verify ischemia and angiogenesis. Wound size was monitored with computed planimetric analysis. LDI revealed insufficient tissue perfusion in all groups. Planimetric analysis showed slower wound healing in the ischemic area in all groups. Wound healing was fastest with fibrin treatment—irrespective of tissue vitality. Lower dose VEGF (10 and 50 ng) led to faster wound healing compared to high-dose VEGF. Immunohistochemistry showed the highest vessel numbers in low-dose VEGF groups. In our previously established model, different rhVEGF165 treatments led to dose-dependent differences in angiogenesis and wound healing, but the fastest wound closure was achieved with fibrin matrix alone.
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2
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Abstract
Angiogenesis, or the growth of new blood vessels from the preexisting vasculature, is a visible and important component of wound repair. When tissue damage occurs, disruption of the vasculature structure leads to hypoxia. The restoration of normoxia is essential for appropriate and durable tissue repair. Angiogenesis in wounds is regulated by endogenous proangiogenic mediators, which cause rapid growth of a new vascular bed that is much denser than that of normal tissue. Such rapid growth of the capillary bed results in capillaries that are abnormal, and the newly formed vessels are tortuous, dilated, and immature. During wound resolution, this substantial neocapillary bed is pruned back to normal density with attendant maturation. Many poorly healing wounds, including nonhealing ulcers and scars, exhibit an aberrant angiogenic response. The fine-tuning of capillary regrowth in wounds is an area of significant therapeutic potential.
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Affiliation(s)
- Chen Han
- Center for Wound Healing and Tissue Regeneration, Colleges of Dentistry and Medicine, University of Illinois Chicago, Chicago, Illinois 60612, USA
| | - May Barakat
- Center for Wound Healing and Tissue Regeneration, Colleges of Dentistry and Medicine, University of Illinois Chicago, Chicago, Illinois 60612, USA
| | - Luisa A DiPietro
- Center for Wound Healing and Tissue Regeneration, Colleges of Dentistry and Medicine, University of Illinois Chicago, Chicago, Illinois 60612, USA
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3
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Liu YH, Brunner LM, Rebling J, Ben-Yehuda Greenwald M, Werner S, Detmar M, Razansky D. Non-invasive longitudinal imaging of VEGF-induced microvascular alterations in skin wounds. Theranostics 2022; 12:558-573. [PMID: 34976201 PMCID: PMC8692907 DOI: 10.7150/thno.65287] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 10/03/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Microcirculation is essential for skin homeostasis and repair. A variety of growth factors have been identified as important regulators of wound healing. However, direct observation and longitudinal monitoring of skin remodeling in an unperturbed in vivo environment remains challenging. Methods: We report on non-invasive longitudinal imaging of the wound healing process in transgenic mice overexpressing vascular endothelial growth factor A (VEGF-A) in keratinocytes by means of large-scale optoacoustic microscopy (LSOM). This rapid, label-free, high throughput intravital microscopy method averts the use of dorsal skin-fold chambers, allowing for fully non-invasive repeated imaging of intact wounds with capillary resolution over field-of-view spanning several centimeters. Results: We observed VEGF-driven enhancement of dermal vascularization in ears, dorsal skin and healing wounds and quantified the hemoglobin content, fill fraction, vessel diameter and tortuosity. The in vivo findings were further corroborated by detailed side-by-side classical histological whole-mount vascular stainings and pan-endothelial CD31 immunofluorescence. Conclusion: The new approach is suitable for supplementing or replacing the cumbersome histological procedures in a broad range of skin regeneration and tissue engineering applications.
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Raina N, Rani R, Gupta M. Angiogenesis: Aspects in wound healing. ENDOTHELIAL SIGNALING IN VASCULAR DYSFUNCTION AND DISEASE 2021:77-90. [DOI: 10.1016/b978-0-12-816196-8.00010-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Chakroborty D, Goswami S, Basu S, Sarkar C. Catecholamines in the regulation of angiogenesis in cutaneous wound healing. FASEB J 2020; 34:14093-14102. [PMID: 32949437 DOI: 10.1096/fj.202001701r] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 08/04/2020] [Accepted: 08/24/2020] [Indexed: 12/13/2022]
Abstract
Angiogenesis involves the formation of new blood vessels from preexisting ones, and it is an essential step during cutaneous wound healing, which supports cells at the wound site with nutrition and oxygen. Impaired angiogenesis in the wound tissues results in delayed wound closure and healing. Among the regulators of angiogenesis, the role of catecholamines (epinephrine, norepinephrine, and dopamine) is of interest due to their diverse roles in the process of wound healing. While both norepinephrine and epinephrine mostly inhibit the angiogenic process in cutaneous wounds, dopamine, the other member of the catecholamine family, has interesting and contradictory roles in the regulation of angiogenesis in the wound beds, depending on the type of dopamine receptor involved. The stimulation of dopamine D2 receptors negatively regulates the angiogenic process in normal dermal wounds and thereby delays healing, whereas the stimulation of dopamine D1 receptors promotes angiogenesis and expedites healing in diabetic wounds. Importantly, catecholamines also play important roles in other pathological conditions, and specific agonists and antagonists of catecholamines are available for the treatment of some disorders. Therefore, such drugs may be utilized for the management of angiogenesis to promote the healing of dermal wounds. This review provides a broad overview of the angiogenic process during cutaneous wound healing and the regulatory roles played by catecholamines during the process.
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Affiliation(s)
| | - Sandeep Goswami
- Department of Pathology, Ohio State University, Columbus, OH, USA
| | - Sujit Basu
- Department of Pathology, Ohio State University, Columbus, OH, USA.,Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.,Department of Medical Oncology, Ohio State University, Columbus, OH, USA
| | - Chandrani Sarkar
- Department of Pathology, Ohio State University, Columbus, OH, USA.,Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
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Ma D, Chen L, Shi J, Zhao Y, Vasani S, Chen K, Romana‐Souza B, Henkin J, DiPietro LA. Pigment epithelium‐derived factor attenuates angiogenesis and collagen deposition in hypertrophic scars. Wound Repair Regen 2020; 28:684-695. [DOI: 10.1111/wrr.12828] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 04/28/2020] [Accepted: 05/05/2020] [Indexed: 12/15/2022]
Affiliation(s)
- Da Ma
- Guangdong Provincial Key Laboratory of Stomatology, Stomatological Hospital Guanghua School of Stomatology, SunYat‐sen University Guangzhou Guangdong China
| | - Lin Chen
- Center for Wound Healing and Tissue Regeneration, College of Dentistry University of Illinois at Chicago Chicago Illinois USA
| | - Junhe Shi
- Center for Wound Healing and Tissue Regeneration, College of Dentistry University of Illinois at Chicago Chicago Illinois USA
| | - Yan Zhao
- Center for Wound Healing and Tissue Regeneration, College of Dentistry University of Illinois at Chicago Chicago Illinois USA
| | - Shruti Vasani
- Center for Wound Healing and Tissue Regeneration, College of Dentistry University of Illinois at Chicago Chicago Illinois USA
| | - Kevin Chen
- Center for Wound Healing and Tissue Regeneration, College of Dentistry University of Illinois at Chicago Chicago Illinois USA
| | - Bruna Romana‐Souza
- Tissue Repair Laboratory State University of Rio de Janeiro Rio de Janeiro Brazil
| | - Jack Henkin
- Center for Developmental Therapeutics and Department of Chemistry Northwestern University Evanston Illinois USA
| | - Luisa A. DiPietro
- Center for Wound Healing and Tissue Regeneration, College of Dentistry University of Illinois at Chicago Chicago Illinois USA
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7
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Bläsius FM, Link BC, Beeres FJP, Iselin LD, Leu BM, Gueorguiev B, Klos K, Ganse B, Nebelung S, Modabber A, Eschbach D, Weber CD, Horst K, Knobe M. Impact of surgical procedures on soft tissue microcirculation in calcaneal fractures: A prospective longitudinal cohort study. Injury 2019; 50:2332-2338. [PMID: 31630780 DOI: 10.1016/j.injury.2019.10.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 09/10/2019] [Accepted: 10/02/2019] [Indexed: 02/02/2023]
Abstract
PURPOSE Wound healing complications are a major concern after open reduction and internal fixation (ORIF) in patients with calcaneal fractures. Microcirculation is known to play a key role in bone and soft tissue healing. The present study aimed to characterize and contrast the dynamics of changes in microcirculation comparing two different surgical procedures: A) ORIF and B) a minimally invasive approach (MIA). METHODS Blood flow (BF[AU]), oxygen saturation (sO2[%]) and relative amount of haemoglobin (rHb[AU]) were measured at two depths (2 mm and 8 mm) non-invasively by spectrophotometry (Micro-Lightguide O2C®, LEA Medizintechnik, Giessen, Germany) before surgery and every 24 h after surgery for a duration of six days. A linear mixed model (LMM) was used to analyse longitudinal data and repeated measurements. RESULTS Nineteen patients (44 years, range 21.9-71.0 years) were enrolled in the study. Surgical treatment consisted of ORIF (n = =15) and MIA (n = =9). The postoperative BF and sO2 at the 2 mm and 8 mm depths were higher in the ORIF group (BF: p < 0.001, p = =0.003; sO2: p = =0.001, p = =0.011). The BF at the 2 mm and 8 mm depths increased after surgery (2 mm: p = =0.003, 8 mm: p = =0.001) in both groups. This increase did not correlate with the surgical technique. sO2 and rHb values at the 8 mm depth decreased after surgery (sO2: p = =0.008, rHb: p < 0.001) in both groups, whereas sO2 at the 2 mm depth increased after surgery (p = =0.003). Furthermore, the surgical technique correlated with the postsurgical course of sO2 values at the 2 mm depth (p = =0.042). CONCLUSIONS The spectrophotometry results were in line with the generally accepted phases of soft tissue wound healing. Postsurgical changes in microcirculation are predominantly independent of surgical techniques and may be primarily determined by wound and fracture healing. Future studies should focus on the potential of spectrophotometry to monitor wound healing after surgery. Moreover, studies with longer observation periods are needed in order to examine the changes in microcirculation during all wound-healing phases.
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Affiliation(s)
- Felix M Bläsius
- Department of Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, D-52074 Aachen, Germany.
| | - Björn-Christian Link
- Department of Orthopaedic and Trauma Surgery, Lucerne Cantonal Hospital, Switzerland.
| | - Frank J P Beeres
- Department of Orthopaedic and Trauma Surgery, Lucerne Cantonal Hospital, Switzerland.
| | - Lukas D Iselin
- Department of Orthopaedic and Trauma Surgery, Lucerne Cantonal Hospital, Switzerland.
| | - Benjamin Moritz Leu
- Department of Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, D-52074 Aachen, Germany.
| | | | - Kajetan Klos
- Department of Foot and Ankle Surgery, Catholic Hospital Mainz, Germany.
| | - Bergita Ganse
- Research Centre for Musculoskeletal Science & Sports Medicine, Faculty of Science and Engineering, School of Healthcare Science, Manchester Metropolitan University, Manchester, United Kingdom.
| | - Sven Nebelung
- Department of Radiology, University Hospital RWTH Aachen, Germany.
| | - Ali Modabber
- Department of Oral and Maxillofacial Surgery, University Hospital RWTH Aachen, Germany.
| | - Daphne Eschbach
- Center for Orthopaedics and Trauma Surgery, University Hospital Giessen and Marburg GmbH, Germany.
| | - Christian David Weber
- Department of Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, D-52074 Aachen, Germany.
| | - Klemens Horst
- Department of Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, D-52074 Aachen, Germany.
| | - Matthias Knobe
- Department of Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, D-52074 Aachen, Germany; Department of Orthopaedic and Trauma Surgery, Lucerne Cantonal Hospital, Switzerland.
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Nyakas M, Aamdal E, Jacobsen KD, Guren TK, Aamdal S, Hagene KT, Brunsvig P, Yndestad A, Halvorsen B, Tasken KA, Aukrust P, Maelandsmo GM, Ueland T. Prognostic biomarkers for immunotherapy with ipilimumab in metastatic melanoma. Clin Exp Immunol 2019; 197:74-82. [PMID: 30821848 PMCID: PMC6591141 DOI: 10.1111/cei.13283] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2019] [Indexed: 12/23/2022] Open
Abstract
New therapies, including the anti‐cytotoxic T lymphocyte antigen (CTLA)‐4 antibody, ipilimumab, is approved for metastatic melanoma. Prognostic biomarkers need to be identified, because the treatment has serious side effects. Serum samples were obtained before and during treatment from 56 patients with metastatic or unresectable malignant melanoma, receiving treatment with ipilimumab in a national Phase IV study (NCT0268196). Expression of a panel of 17 inflammatory‐related markers reflecting different pathways including extracellular matrix remodeling and fibrosis, vascular inflammation and monocyte/macrophage activation were measured at baseline and the second and/or third course of treatment with ipilimumab. Six candidate proteins [endostatin, osteoprotegerin (OPG), C‐reactive protein (CRP), pulmonary and activation‐regulated chemokine (PARC), growth differentiation factor 15 (GDF15) and galectin‐3 binding‐protein (Gal3BP)] were persistently higher in non‐survivors. In particular, high Gal3BP and endostatin levels were also independently associated with poor 2‐year survival after adjusting for lactate dehydrogenase, M‐stage and number of organs affected. A 1 standard deviation increase in endostatin gave 1·74 times [95% confidence interval (CI) = 1·10–2·78, P = 0·019] and for Gal3BP 1·52 times (95% CI = 1·01–2·29, P = 0·047) higher risk of death in the adjusted model. Endostatin and Gal3BP may represent prognostic biomarkers for patients on ipilimumab treatment in metastatic melanoma and should be further evaluated. Owing to the non‐placebo design, we could only relate our findings to prognosis during ipilimumab treatment.
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Affiliation(s)
- M Nyakas
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - E Aamdal
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - K D Jacobsen
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - T K Guren
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - S Aamdal
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - K T Hagene
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - P Brunsvig
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - A Yndestad
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway
| | - B Halvorsen
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway
| | - K A Tasken
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - P Aukrust
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway.,K. G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway
| | - G M Maelandsmo
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.,Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
| | - T Ueland
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,K. G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway
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9
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Ricard-Blum S, Vallet SD. Fragments generated upon extracellular matrix remodeling: Biological regulators and potential drugs. Matrix Biol 2017; 75-76:170-189. [PMID: 29133183 DOI: 10.1016/j.matbio.2017.11.005] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 11/05/2017] [Accepted: 11/07/2017] [Indexed: 12/13/2022]
Abstract
The remodeling of the extracellular matrix (ECM) by several protease families releases a number of bioactive fragments, which regulate numerous biological processes such as autophagy, angiogenesis, adipogenesis, fibrosis, tumor growth, metastasis and wound healing. We review here the proteases which generate bioactive ECM fragments, their ECM substrates, the major bioactive ECM fragments, together with their biological properties and their receptors. The translation of ECM fragments into drugs is challenging and would take advantage of an integrative approach to optimize the design of pre-clinical and clinical studies. This could be done by building the contextualized interaction network of the ECM fragment repertoire including their parent proteins, remodeling proteinases, and their receptors, and by using mathematical disease models.
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Affiliation(s)
- Sylvie Ricard-Blum
- Univ Lyon, University Claude Bernard Lyon 1, CNRS, INSA Lyon, CPE, Institute of Molecular and Supramolecular Chemistry and Biochemistry, UMR 5246, F-69622 Villeurbanne cedex, France.
| | - Sylvain D Vallet
- Univ Lyon, University Claude Bernard Lyon 1, CNRS, INSA Lyon, CPE, Institute of Molecular and Supramolecular Chemistry and Biochemistry, UMR 5246, F-69622 Villeurbanne cedex, France.
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Zheng Z, Xu PP, Wang L, Zhao HJ, Weng XQ, Zhong HJ, Qu B, Xiong J, Zhao Y, Wang XF, Janin A, Zhao WL. MiR21 sensitized B-lymphoma cells to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017. [PMID: 28637496 PMCID: PMC5480196 DOI: 10.1186/s13046-017-0551-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND MicroRNAs (miRs) are involved in tumor progression by regulating tumor cells and tumor microenvironment. MiR21 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological impact on tumor microenvironment remains unclear. METHODS MiR21 was assessed by quantitative RT-PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR21 on lymphoma progression and tumor angiogenesis was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model. RESULTS Serum miR21 was significantly elevated in patients and associated with advanced disease stage, International Prognostic Index indicating intermediate-high and high-risk, and increased tumor angiogenesis. When co-cultured with immune cells and endothelial cells, miR21-overexpressing B-lymphoma cells were resistant to chemotherapeutic agents, but sensitive to Bcl-2 inhibitor ABT-199, irrespective of Bcl-2 expression on lymphoma cells. In both co-culture systems of Bcl-2positive and Bcl-2negative B-lymphoma cells, miR21 induced inducible co-stimulator (ICOS) expression on regulatory T (Treg) cells. Through crosstalking with Treg cells by ICOS ligand (ICOSL), endothelial cells were activated, resulting in stimulation of Bcl-2 expression and vessel formation. ABT-199 directly targeted Bcl-2 on endothelial cells, induced endothelial cell apoptosis and inhibited tumor angiogenesis. In a murine xenograft model established with subcutaneous injection of B-lymphoma cells, ABT-199 particularly retarded the growth of miR21-overexpressing tumors, consistent with the induction of endothelial cell apoptosis and inhibition of tumor angiogenesis. CONCLUSIONS As a serum oncogenic biomarker of B-cell lymphoma, miR21 indicated B-lymphoma cell sensitivity to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells.
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Affiliation(s)
- Zhong Zheng
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China
| | - Peng-Peng Xu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China.,Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China
| | - Li Wang
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China.,Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China
| | - Hui-Jin Zhao
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China
| | - Xiang-Qin Weng
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China
| | - Hui-Juan Zhong
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China
| | - Bin Qu
- Department of Laboratory Medicine, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Xiong
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China
| | - Yan Zhao
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China
| | - Xue-Feng Wang
- Department of Laboratory Medicine, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Anne Janin
- Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.,U1165 Inserm/Université Paris 7, Hôpital Saint Louis, Paris, France
| | - Wei-Li Zhao
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China. .,Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China.
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11
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Szpaderska AM, Walsh CG, Steinberg MJ, DiPietro LA. Distinct Patterns of Angiogenesis in Oral and Skin Wounds. J Dent Res 2016; 84:309-14. [PMID: 15790734 DOI: 10.1177/154405910508400403] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Clinical observation suggests that oral mucosal wounds heal faster than skin; however, little is known about the site-specific differences. Since fetal skin wounds heal rapidly, but are less vascular than adult wounds, we hypothesized that less robust wound angiogenesis might be observed in healing oral mucosa. This study investigated angiogenesis in equivalent-size oral and skin murine wounds. Change in wound bed vascularity was significantly lower in oral wounds than in skin. Also, vascular endothelial growth factor (VEGF) levels were less in oral than cutaneous wounds. Because keratinocytes are a prominent source of VEGF in wounds, we compared VEGF production by oral and epidermal keratinocytes in vitro. Significantly higher levels of VEGF protein and mRNA were observed in epidermal keratinocytes than in oral keratinocytes after 18 hrs of hypoxia. This study demonstrates distinct angiogenesis patterns in oral and skin wounds and intrinsic site-specific differences in VEGF production by keratinocytes.
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Affiliation(s)
- A M Szpaderska
- Burn and Shock Trauma Institute, Loyola University Medical Center, Maywood, IL 60153, USA
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12
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DiPietro LA. Angiogenesis and wound repair: when enough is enough. J Leukoc Biol 2016; 100:979-984. [PMID: 27406995 DOI: 10.1189/jlb.4mr0316-102r] [Citation(s) in RCA: 395] [Impact Index Per Article: 43.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 06/17/2016] [Indexed: 12/14/2022] Open
Abstract
All animals heal, and the ability to heal is requisite for human health. One aspect of repair that has always been considered to be essential for adequate healing is the creation of a new vasculature via angiogenesis. As adult skin wounds heal, a period of rapid and robust capillary growth creates a vascular bed that has many fold more capillaries than does normal tissue. Over time, most of the newly formed capillaries regress, resulting in a final vascular density similar to that of normal skin. Certainly, new capillaries are necessary to bring nutrients, immune cells, and oxygen to healing wounds. Yet, the presumed functional importance of an overabundance of capillaries has recently been challenged, creating questions about whether excess capillary growth is truly necessary for healing. In particular, studies of wounds that heal exceptionally quickly and with less scar formation, such as those in fetal skin and oral mucosa, show that these tissues heal with a reduced angiogenic burst composed of more mature vessels that provide better oxygenation. The level of angiogenesis in wounds often correlates with the inflammatory response, largely because inflammatory cells produce an abundance of proangiogenic mediators. Both the selective reduction of inflammation and the selective reduction of angiogenesis have now been suggested as ways to improve scarring. These concepts link excessive inflammation and the production of a dense but poorly perfused capillary bed to inferior healing outcomes.
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Affiliation(s)
- Luisa A DiPietro
- Center for Wound Healing and Tissue Regeneration, University of Illinois at Chicago, Chicago, Illinois
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13
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Boron promotes streptozotocin-induced diabetic wound healing: roles in cell proliferation and migration, growth factor expression, and inflammation. Mol Cell Biochem 2016; 417:119-33. [PMID: 27206737 DOI: 10.1007/s11010-016-2719-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 05/13/2016] [Indexed: 12/26/2022]
Abstract
Acute wounds do not generally require professional treatment modalities and heal in a predictable fashion, but chronic wounds are mainly accompanied with infection and prolonged inflammation, leading to healing impairments and continuous tissue degradation. Although a vast amount of products have been introduced in the market, claiming to provide a better optimization of local and systemic conditions of patients, they do not meet the expectations due to being expensive and not easily accessible, requiring wound care facilities, having patient-specific response, low efficiency, and severe side-effects. In this sense, developing new, safe, self-applicable, effective, and cheap wound care products with broad-range antimicrobial activity is still an attractive area of international research. In the present work, boron derivatives [boric acid and sodium pentaborate pentahydrate (NaB)] were evaluated for their antimicrobial activity, proliferation, migratory, angiogenesis, gene, and growth factor expression promoting effects on dermal cells in vitro. In addition, boron-containing hydrogel formulation was examined for its wound healing promoting potential using full-thickness wound model in streptozotocin-induced diabetic rats. The results revealed that while both boron compounds significantly increased proliferation, migration, vital growth factor, and gene expression levels of dermal cells along with displaying remarkable antimicrobial effects against bacteria, yeast, and fungi, NaB displayed greater antimicrobial properties as well as gene and growth factor expression inductive effects. Animal studies proved that NaB-containing gel formulation enhanced wound healing rate of diabetic animals and histopathological scores. Overall data suggest a potential promising therapeutic option for the management of chronic wounds but further studies are highly warranted to determine signaling pathways and target metabolisms in which boron is involved to elucidate the limitations and extend its use in clinics.
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Johnson KE, Wilgus TA. Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair. Adv Wound Care (New Rochelle) 2014; 3:647-661. [PMID: 25302139 DOI: 10.1089/wound.2013.0517] [Citation(s) in RCA: 611] [Impact Index Per Article: 55.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Accepted: 01/21/2014] [Indexed: 12/12/2022] Open
Abstract
Significance: Angiogenesis, the growth of new blood vessels from existing vessels, is an important aspect of the repair process. Restoration of blood flow to damaged tissues provides oxygen and nutrients required to support the growth and function of reparative cells. Vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic growth factors in the skin, and the amount of VEGF present in a wound can significantly impact healing. Recent Advances: The activity of VEGF was once considered to be specific for endothelial cells lining the inside of blood vessels, partly because VEGF receptor (VEGFR) expression was believed to be restricted to endothelial cells. It is now known, however, that VEGFRs can be expressed by a variety of other cell types involved in wound repair. For example, keratinocytes and macrophages, which both carry out important functions during wound healing, express VEGFRs and are capable of responding directly to VEGF. Critical Issues: The mechanisms by which VEGF promotes angiogenesis are well established. Recent studies, however, indicate that VEGF can directly affect the activity of several nonendothelial cell types present in the skin. The implications of these extra-angiogenic effects of VEGF on wound repair are not yet known, but they suggest that this growth factor may play a more complex role during wound healing than previously believed. Future Directions: Despite the large number of studies focusing on VEGF and wound healing, it is clear that the current knowledge of how VEGF contributes to the repair of skin wounds is incomplete. Further research is needed to obtain a more comprehensive understanding of VEGF activities during the wound healing process.
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Affiliation(s)
- Kelly E. Johnson
- Department of Pathology, College of Medicine, The Ohio State University, Columbus, Ohio
- Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio
| | - Traci A. Wilgus
- Department of Pathology, College of Medicine, The Ohio State University, Columbus, Ohio
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Chakraborty N, Gautam A, Muhie S, Miller SA, Jett M, Hammamieh R. An integrated omics analysis: impact of microgravity on host response to lipopolysaccharide in vitro. BMC Genomics 2014; 15:659. [PMID: 25102863 PMCID: PMC4287545 DOI: 10.1186/1471-2164-15-659] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 07/30/2014] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Microgravity facilitates the opportunistic infections by augmenting the pathogenic virulence and suppressing the host resistance. Hence the extraterrestrial infections may activate potentially novel bionetworks different from the terrestrial equivalent, which could only be probed by investigating the host-pathogen relationship with a minimum of terrestrial bias. RESULTS We customized a cell culture module to expose human endothelial cells to lipopolysaccharide (LPS). The assay was carried out onboard the STS-135 spaceflight, and a concurrent ground study constituted the baseline. Transcriptomic investigation revealed a possible immune blunting in microgravity suppressing in particular Lbp, MyD88 and MD-2, which encode proteins responsible for early LPS uptake. Certain cytokines, such as IL-6 and IL-8, surged in response to LPS insult in microgravity, as suggested by the proteomics study. Contrasting proteomic expressions of B2M, TIMP-1 and VEGRs suggested impaired pro-survival adaptation and healing mechanisms. Differential expression of miR-200a and miR-146b suggested the susceptibility of hosts in spaceflight to oxidative stress and further underscored the influence of microgravity on the immunity. CONCLUSIONS A molecular interpretation explaining the etiology of the microgravitational impact on the host-pathogen relationship elucidated comprehensive immune blunting of the host cells responding to LPS challenges. Longer LPS exposure prompted a delayed host response, potentially ineffectual in preventing pathogens from opportunistic invasion. Significant consequences include the subsequent failure in recruiting the growth factors and a debilitated apoptosis. Follow up studies with larger sample size are warranted.
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Affiliation(s)
- Nabarun Chakraborty
- US Army Center for Environmental Health Research Fort Detrick, 568 Doughten Drive, Fort Detrick, MD 21702-5010 USA
| | - Aarti Gautam
- US Army Center for Environmental Health Research Fort Detrick, 568 Doughten Drive, Fort Detrick, MD 21702-5010 USA
| | - Seid Muhie
- US Army Center for Environmental Health Research Fort Detrick, 568 Doughten Drive, Fort Detrick, MD 21702-5010 USA
| | - Stacy-Ann Miller
- US Army Center for Environmental Health Research Fort Detrick, 568 Doughten Drive, Fort Detrick, MD 21702-5010 USA
| | - Marti Jett
- US Army Center for Environmental Health Research Fort Detrick, 568 Doughten Drive, Fort Detrick, MD 21702-5010 USA
| | - Rasha Hammamieh
- US Army Center for Environmental Health Research Fort Detrick, 568 Doughten Drive, Fort Detrick, MD 21702-5010 USA
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Ricard-Blum S, Salza R. Matricryptins and matrikines: biologically active fragments of the extracellular matrix. Exp Dermatol 2014; 23:457-63. [DOI: 10.1111/exd.12435] [Citation(s) in RCA: 119] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2014] [Indexed: 12/21/2022]
Affiliation(s)
- Sylvie Ricard-Blum
- Institut de Biologie et Chimie des Protéines; UMR 5086 CNRS; Université Lyon 1; Lyon Cedex 07 France
| | - Romain Salza
- Institut de Biologie et Chimie des Protéines; UMR 5086 CNRS; Université Lyon 1; Lyon Cedex 07 France
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Burger RA, Brady MF, Bookman MA, Monk BJ, Walker JL, Homesley HD, Fowler J, Greer BE, Boente M, Fleming GF, Lim PC, Rubin SC, Katsumata N, Liang SX. Risk factors for GI adverse events in a phase III randomized trial of bevacizumab in first-line therapy of advanced ovarian cancer: A Gynecologic Oncology Group Study. J Clin Oncol 2014; 32:1210-7. [PMID: 24637999 PMCID: PMC3986384 DOI: 10.1200/jco.2013.53.6524] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
PURPOSE To evaluate risk factors for GI adverse events (AEs) within a phase III trial of bevacizumab in first-line ovarian cancer therapy. PATIENTS AND METHODS Women with previously untreated advanced disease after surgery were randomly allocated to six cycles of platinum-taxane chemotherapy plus placebo cycles (C)2 to C22 (R1); chemotherapy plus bevacizumab C2 to C6 plus placebo C7 to C22 (R2); or chemotherapy plus bevacizumab C2 to C22 (R3). Patients were evaluated for history or on-study development of potential risk factors for GI AEs defined as grade ≥ 2 perforation, fistula, necrosis, or hemorrhage. RESULTS Of 1,873 patients enrolled, 1,759 (94%) were evaluable, and 2.8% (50 of 1,759) experienced a GI AE: 10 of 587 (1.7%, R1), 20 of 587 (3.4%, R2), and 20 of 585 (3.4%, R3). Univariable analyses indicated that previous treatment of inflammatory bowel disease (IBD; P = .005) and small bowel resection (SBR; P = .032) or large bowel resection (LBR; P = .012) at primary surgery were significantly associated with a GI AE. The multivariable estimated relative odds of a GI AE were 13.4 (95% CI, 3.44 to 52.3; P < .001) for IBD; 2.05 (95% CI, 1.09 to 3.88; P = .026) for LBR; 1.95 (95% CI, 0.894 to 4.25; P = .093) for SBR; and 2.15 for bevacizumab exposure (aggregated 95% CI, 1.05 to 4.40; P = .036). CONCLUSION History of treatment for IBD, and bowel resection at primary surgery, increase the odds of GI AEs in patients receiving first-line platinum-taxane chemotherapy for advanced ovarian cancer. After accounting for these risk factors, concurrent bevacizumab doubles the odds of a GI AE, but is not appreciably increased by continuation beyond chemotherapy.
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Affiliation(s)
- Robert A. Burger
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
| | - Mark F. Brady
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
| | - Michael A. Bookman
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
| | - Bradley J. Monk
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
| | - Joan L. Walker
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
| | - Howard D. Homesley
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
| | - Jeffrey Fowler
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
| | - Benjamin E. Greer
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
| | - Matthew Boente
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
| | - Gini F. Fleming
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
| | - Peter C. Lim
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
| | - Stephen C. Rubin
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
| | - Noriyuki Katsumata
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
| | - Sharon X. Liang
- Robert A. Burger, Fox Chase Cancer Center, Philadelphia, PA; Mark F. Brady, GOG Statistical and Data Center, Buffalo, NY; Michael A. Bookman, Arizona Cancer Center, Tucson, AZ; Bradley J. Monk, University of California at Irvine, Orange, CA; Joan L. Walker, University of Oklahoma, Oklahoma City, OK; Howard D. Homesley, Wake Forest University Medical Center, Winston-Salem, NC; Jeffrey Fowler, Ohio State University, Columbus, OH; Benjamin E. Greer, University of Washington Medical Center, Seattle, WA; Matthew Boente, Minnesota Oncology Hematology, Minneapolis, MN; Gini F. Fleming, University of Chicago, Chicago, IL; Peter C. Lim, Center of Hope at Renown Regional Medical Center, Reno, NV; Stephen C. Rubin, University of Pennsylvania Cancer Center, Philadelphia, PA; Noriyuki Katsumata, Saitama Medical University/International Medical Center–GOG Japan, Saitama, Japan; and Sharon X. Liang, North Shore University Hospital, Manhasset, NY
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Johnson A, DiPietro LA. Apoptosis and angiogenesis: an evolving mechanism for fibrosis. FASEB J 2013; 27:3893-901. [PMID: 23783074 PMCID: PMC4046186 DOI: 10.1096/fj.12-214189] [Citation(s) in RCA: 122] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 05/28/2013] [Indexed: 12/11/2022]
Abstract
Fibrosis, seen in the liver, lung, heart, kidney, and skin, is a significant global disease burden. Currently, therapeutic treatment is limited, and the number of cases continues to grow. Apoptosis has been identified as a potential initiator and propagator of fibrosis. This review specifically examines the correlation between the presence of apoptotic cells and their effect on fibroblast phenotype and collagen metabolism in several different experimental models of fibrosis. Fibrosis in these models is generally preceded by robust angiogenesis and vascular regression, suggesting that the vascular apoptotic burden may be important to fibrotic outcomes. This review considers the emerging evidence that angiogenesis or vascular regression contributes to fibrosis and identifies initial vascular outgrowth or vascular apoptotic cell presence as possible regulators of fibrosis. A further understanding of the cellular mechanisms of fibrosis may suggest novel methods for the reduction of the fibrotic response and promotion of regeneration.
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Affiliation(s)
- Ariel Johnson
- 1University of Illinois at Chicago, College of Dentistry, Center for Wound Healing and Tissue Regeneration (MC 859), 801 S. Paulina, Rm. 401B, Chicago, IL 60612-7211, USA.
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Abstract
PURPOSE OF REVIEW One well described feature of wound healing is the ingrowth of new capillaries or angiogenesis. At its peak, the capillary content in healing wounds may reach three or more times that of normal uninjured tissue. This new vasculature is required to restore oxygenation and allow the growth of new tissue to fill the wound space. This review examines the assumption that a capillary content in excess of normal density is essential for adequate healing. RECENT FINDINGS The regulation of wound angiogenesis has been demonstrated to involve both proangiogenic and antiangiogenic stimuli, with the level of capillary growth reliant upon both sets of factors. Several studies now show that normal skin wounds heal adequately even when the angiogenic response is artificially reduced. In normal skin, a reduction of capillary growth to a level consistent with normal tissue does not affect wound closure and may even lead to highly favorable long term healing outcomes. SUMMARY The angiogenic response in normal wounds may exceed what is needed for optimal repair.
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Jia H, Li Y, Zhao T, Li X, Hu J, Yin D, Guo B, Kopecko DJ, Zhao X, Zhang L, Xu DQ. Antitumor effects of Stat3-siRNA and endostatin combined therapies, delivered by attenuated Salmonella, on orthotopically implanted hepatocarcinoma. Cancer Immunol Immunother 2012; 61:1977-87. [PMID: 22527247 PMCID: PMC11028561 DOI: 10.1007/s00262-012-1256-y] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 03/27/2012] [Indexed: 01/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive carcinomas. Limited therapeutic options, mainly due to a fragmented genetic understanding of HCC, and major HCC resistance to conventional chemotherapy are the key reasons for a poor prognosis. Thus, new effective treatments are urgent and gene therapy may be a novel option. Signal transducer and activator of transcription 3 (Stat3) is a highly studied member of the STAT family. Inhibition of Stat3 signaling has been found to suppress tumor growth and improve survival, providing a molecular target for cancer therapy. Furthermore, HCC is a hypervascular tumor and angiogenesis plays a crucial role in tumor growth and metastasis. Thus, anti-angiogenic therapy, combined with inhibition of Stat3, may be an effective approach to combat HCC. We tested the effect that the combination therapy consisting of endostatin (a powerful angiogenesis inhibitor) and Stat3-specific small interfering RNA, using a DNA vector delivered by attenuated S. typhimurium, on an orthotopic HCC model in C57BL/6 mice. Although antitumor effects were observed with either single therapeutic treatment, the combination therapy provided superior antitumor effects. Correlated with this finding, the combination treatment resulted in significant alteration of Stat3 and endostatin levels and that of the downstream gene VEGF, decreased cell proliferation, induced cell apoptosis and inhibited angiogenesis. Importantly, combined treatment also elicited immune system regulation of various immune cells and cytokines. This study has provided a novel cancer gene therapeutic approach.
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Affiliation(s)
- Huijie Jia
- Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune College of Medicine, Jilin University, Changchun, 130021 People’s Republic of China
| | - Yang Li
- Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune College of Medicine, Jilin University, Changchun, 130021 People’s Republic of China
| | - Tiesuo Zhao
- Department of Immunology, Norman Bethune Medical School, Jilin University, Changchun, People’s Republic of China
| | - Xin Li
- Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune College of Medicine, Jilin University, Changchun, 130021 People’s Republic of China
| | - Jiadi Hu
- Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, MD USA
| | - Di Yin
- Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune College of Medicine, Jilin University, Changchun, 130021 People’s Republic of China
| | - Baofeng Guo
- Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune College of Medicine, Jilin University, Changchun, 130021 People’s Republic of China
| | - Dennis J. Kopecko
- Laboratory of Enteric and Sexually Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD USA
| | - Xuejian Zhao
- Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune College of Medicine, Jilin University, Changchun, 130021 People’s Republic of China
| | - Ling Zhang
- Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune College of Medicine, Jilin University, Changchun, 130021 People’s Republic of China
| | - De Qi Xu
- New Vaccine National Engineering Research Center, Beijing three-room South 4 hospital, Chaoyang District, Beijing, 100024 People’s Republic of China
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Desjardins A, Sampson JH. Avastin: more questions than answers. . . J Neurosurg 2011; 116:336-40; discussion 340. [PMID: 22035270 DOI: 10.3171/2011.8.jns111107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Oikonomou KA, Kapsoritakis AN, Kapsoritaki AI, Manolakis AC, Tiaka EK, Tsiopoulos FD, Tsiompanidis IA, Potamianos SP. Angiogenin, angiopoietin-1, angiopoietin-2, and endostatin serum levels in inflammatory bowel disease. Inflamm Bowel Dis 2011; 17:963-70. [PMID: 20629092 DOI: 10.1002/ibd.21410] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND Angiogenesis is a complex process, involving a great number of mediators. It is implicated in the pathogenesis of numerous diseases, holding a critical role in inflammatory bowel disease (IBD). The objective of this study was to assess serum levels of angiogenin, angiopoietin-1, angiopoietin-2, and endostatin in IBD patients. METHODS Measurement of all angiogenesis mediators was performed with a commercially available enzyme-linked immunosorbent assay. Fifty-two patients with ulcerative colitis (UC), 59 with Crohn's disease (CD), and 55 healthy controls (HC) were included in the study. The values were analyzed with regard to disease and patients characteristics. RESULTS Angiogenin levels were significantly higher in IBD patients compared to HC (P < 0.001) and in UC and CD smoker patients compared to nonsmokers (P = 0.0121 and P = 0.005, respectively). Angiogenin levels were lower in UC patients receiving 5-aminosalicylate (5-ASA) alone, compared to those receiving combined therapy (P = 0.0478). Angiopoietin-1 levels were significantly lower in IBD patients compared to HC (P < 0.0001) and increased in smokers compared to nonsmoker UC patients (P = 0.0085). IBD patients demonstrated increased angiopoietin-2 levels compared to HC (P = 0.0131), while CD patients with disease restricted to the colon had significantly lower levels compared to other disease locations (P < 0.0001). Higher endostatin levels were recorded in UC patients with extensive colitis. CONCLUSIONS Elevated serum angiogenin and angiopoietin-2 levels and lower serum angiopoietin-1 levels were shown in IBD patients, as well as a different pattern of angiogenic factor alterations related to location, treatment, smoking habits and gender.
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23
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Jung HJ, Lim CJ. The antiangiogenic and antinociceptive activities of n-propyl gallate. Phytother Res 2011; 25:1570-3. [PMID: 21442671 DOI: 10.1002/ptr.3452] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2010] [Revised: 02/01/2011] [Accepted: 02/01/2011] [Indexed: 11/09/2022]
Abstract
n-Propyl gallate dose-dependently displayed an inhibitory effect on chick chorioallantoic membrane (CAM) angiogenesis. It markedly increased the endostatin level in both isolated CAM tissues and human umbilical vein endothelial cells (HUVECs). n-Propyl gallate was also able to enhance the endostatin mRNA level in HUVECs. Antinociceptive activity of n-propyl gallate was assessed using an acetic acid-induced writhing test in mice. In brief, n-propyl gallate possesses antiangiogenic activity via up-regulation of endostatin.
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Affiliation(s)
- H-J Jung
- College of Pharmacy, Sookmyung Women's University, Seoul, Korea
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24
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Seppinen L, Pihlajaniemi T. The multiple functions of collagen XVIII in development and disease. Matrix Biol 2011; 30:83-92. [DOI: 10.1016/j.matbio.2010.11.001] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2010] [Revised: 11/19/2010] [Accepted: 11/22/2010] [Indexed: 12/11/2022]
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25
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Therapeutic efficacy of recombinant human endostatin combined with chemotherapeutics in mice-transplanted tumors. Eur J Pharmacol 2009; 617:23-7. [PMID: 19615993 DOI: 10.1016/j.ejphar.2009.07.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2008] [Revised: 07/01/2009] [Accepted: 07/06/2009] [Indexed: 11/21/2022]
Abstract
Endostatin is an endogenous inhibitor of angiogenesis and has been shown to exhibit potent inhibitory activity in certain mice tumor models. In this study, a treatment strategy of combining recombinant human endostatin (rhEndostatin) and chemotherapeutics was implemented to evaluate the therapeutic efficacy of rhEndostatin against solid tumors. The antitumor effect of rhEndostatin in combination with several chemotherapeutic drugs, e.g., 5-fluorouracil, cyclophosphamide, methotrexate, and mitomycin C, on human QGY liver tumor and mice H22 liver tumor was compared with that of rhEndostatin treatment alone. The results showed that the combination of rhEndostatin and chemotherapeutic drugs resulted in a more potent inhibition of tumor growth. The potential advantages of rhEndostatin plus tumor chemotherapy provide a basis for further clinical trials of rhEndostatin.
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26
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Duan WR, Patyna S, Kuhlmann MA, Li S, Blomme EAG. A Multitargeted Receptor Tyrosine Kinase Inhibitor, SU6668, Does Not Affect the Healing of Cutaneous Full-Thickness Incisional Wounds in SKH-1 Mice. J INVEST SURG 2009; 19:245-54. [PMID: 16835139 DOI: 10.1080/08941930600778248] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Disturbances of angiogenesis have been suggested to result in the impaired healing of skin wounds. Using a murine incisional wound model, we evaluated the effects of SU6668, an inhibitor of the receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF), on the healing of skin wounds. Mice were administered vehicle, SU6668 (100 or 400 mg/kg/day, b.i.d.), or dexamethasone (1 mg/kg/day, b.i.d.), and wound healing was monitored histologically and using a tensiometer. SU6668 at a fully efficacious dose of 100 mg/kg/day had no significant effect on the healing process, while at a supratherapeutic dose of 400 mg/kg/day, there were subtle transient histologic changes and slight decreases in tensile strength, suggesting a slight delay in the wound healing process. In conclusion, these data indicate that inhibition of the receptors for VEGF, PDGF, and FGF at levels necessary to inhibit tumor growth in mouse xenograft models does not affect the healing of incisional wounds in mice. Redundant pathways likely compensate for inhibition of VEGF, PDGF, and FGF signaling pathways in the skin healing process.
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27
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Thomay AA, Daley JM, Sabo E, Worth PJ, Shelton LJ, Harty MW, Reichner JS, Albina JE. Disruption of interleukin-1 signaling improves the quality of wound healing. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 174:2129-36. [PMID: 19389930 DOI: 10.2353/ajpath.2009.080765] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In this study, we investigated the role of interleukin (IL)-1 signaling in wound healing. IL-1 receptor type I (IL-1R) knockout (KO) mice showed reduced fibrosis in both cutaneous and deep tissue wounds, which was accompanied by a reduction in inflammatory cellular infiltration in cutaneous but not in deep tissue wounds. There were no differences in either total collagenolytic activity or in the expression of selected matrix metalloproteinases or tissue inhibitors of metalloproteinases between the wound fluids from wild-type or IL-1R KO mice. However, wound fluids from IL-1R KO mice contained lower levels of IL-6 compared with wild-type controls. In addition, the infusion of IL-6 into wounds in IL-1R KO mice did not increase fibrosis. Skin wounds in IL-1R KO animals had lower levels of collagen and improved restoration of normal skin architecture compared with skin wounds in wild-type mice. However, neither the tensile strength of incisional skin wounds nor the rate of closure of excisional wounds differed between IL-1R KO and wild-type animals. The reduced fibrotic response in wounds from IL-1R KO mice could be reproduced by the administration of an IL-1R antagonist. These findings suggest that pharmacological interference with IL-1 signaling could have therapeutic value in the prevention of hypertrophic scarring and in the treatment of fibrotic diseases.
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Affiliation(s)
- Alan A Thomay
- Division of Surgical Research, Rhode Island Hospital, NAB 216, 593 Eddy St., Providence, RI 02903, USA
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28
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Seppinen L, Sormunen R, Soini Y, Elamaa H, Heljasvaara R, Pihlajaniemi T. Lack of collagen XVIII accelerates cutaneous wound healing, while overexpression of its endostatin domain leads to delayed healing. Matrix Biol 2008; 27:535-46. [PMID: 18455382 DOI: 10.1016/j.matbio.2008.03.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2007] [Revised: 03/11/2008] [Accepted: 03/14/2008] [Indexed: 11/25/2022]
Abstract
Endostatin, the C-terminal fragment of collagen XVIII, is known to suppress tumour growth and angiogenesis by inhibiting endothelial cell proliferation and migration. We have previously shown that endostatin and its precursor are important for the structural organization of basement membranes (BM). The aim of this study was to investigate cutaneous wound healing in mice overexpressing endostatin in keratinocytes (ES-tg) and in mice lacking collagen XVIII (Col18a1(-/-)). Excisional wounds were made on the dorsal skin of mice, the wound areas were measured and the wounds were collected for further analyses after 3, 6 or 14 days. The healing of the wounds was delayed in the ES-tg mice and accelerated in the Col18a1(-/-) mice, and the vascularisation rate was accelerated in the Col18a1(-/-) mice, but not affected in the ES-tg mice. Abnormal capillaries with swollen endothelial cells and narrowed lumens were observed in the wounds of the ES-tg mice. In these mice also the formation of the epidermal BM was delayed, and the structure of the epidermal and capillary BMs was more disorganised. Moreover, detachment of the epidermis from the granulation tissue was observed in half (n=10) of the 6-day-old ES-tg wounds, but in none of the controls, suggesting an increased fragility of the epidermal-dermal junction in the presence of an excess of endostatin.
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Affiliation(s)
- Lotta Seppinen
- Biocenter Oulu, Collagen Research Unit, University of Oulu, Oulu, Finland
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29
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Lesional expression of the endogenous angiogenesis inhibitor endostatin/collagen XVIII following traumatic brain injury (TBI). Exp Neurol 2007; 208:228-37. [DOI: 10.1016/j.expneurol.2007.07.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2007] [Revised: 07/23/2007] [Accepted: 07/25/2007] [Indexed: 11/17/2022]
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30
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Mueller CA, Conrad S, Schluesener HJ, Pietsch T, Schwab JM. Spinal cord injury-induced expression of the antiangiogenic endostatin/collagen XVIII in areas of vascular remodelling. J Neurosurg Spine 2007; 7:205-14. [PMID: 17688061 DOI: 10.3171/spi-07/08/205] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECT Spinal cord injury (SCI) induces the disruption of neural and vascular structures. In contrast to the emerging knowledge of mechanisms regulating the onset of the postinjury angiogenic response, little is known about counterregulatory signals. METHODS Using immunohistochemical methods, the authors investigated the expression of the endogenous angiogenic inhibitor endostatin/collagen XVIII during the tissue remodeling response to SCI. RESULTS After SCI, endostatin/collagen XVIII+ cells accumulated at the lesion site, in pannecrotic regions (especially in areas of cavity formation), at the lesion margin/areas of ongoing secondary damage, and in perivascular Virchow-Robin spaces. In remote areas (> 0.75 cm from the epicenter) a more modest accumulation of endostatin/collagen XVIII+ cells was observed, especially in areas of pronounced Wallerian degeneration. The numbers of endostatin/collagen XVIII+ cells reached their maximum on Day 7 after SCI. The cell numbers remained elevated in both, the lesion and remote regions, compared with control spinal cords for 4 weeks afterwards. In addition to being predominantly confined to ED1+-activated microglia/macrophages within the pannecrotic lesion core, endostatin/collagen XVIII expression was frequently detected by the endothelium/vessel walls. Numbers of lesional endostatin/collagen XVIII+ endothelium/vessel walls were found to increase early by Day 1 postinjury, reaching their maximum on Day 3 and declining subsequently to enhanced (above control) levels 30 days after SCI. CONCLUSIONS The authors detected that in comparison to the early expression of neoangiogenic factors, there was a postponed lesional expression of the antiangiogenic endostatin/collagen XVIII. Furthermore, the expression of endostatin/collagen XVIII was localized to areas of neovascular pruning and retraction (cavity formation). The expression of endostatin/collagen XVIII by macrophages in a "late" activated phagocytic mode suggests that this factor plays a role in counteracting the preceding "early" neoangiogenic response after SCI.
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Affiliation(s)
- Christian A Mueller
- Institute of Brain Research, University of Tübingen Medical School, Tübingen, Germany.
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31
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Zhang ZY, Zhang Z, Fauser U, Artelt M, Burnet M, Schluesener HJ. Dexamethasone transiently attenuates up-regulation of endostatin/collagen XVIII following traumatic brain injury. Neuroscience 2007; 147:720-6. [PMID: 17560042 DOI: 10.1016/j.neuroscience.2007.04.052] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2007] [Revised: 04/16/2007] [Accepted: 04/16/2007] [Indexed: 12/28/2022]
Abstract
Endostatin/collagen XVIII is a specific inhibitor of endothelial proliferation and migration in vitro. It has also been shown to have anti-angiogenic activity and tumor growth inhibitory activity in vivo and in vitro. Here we studied expression of endostatin/collagen XVIII in a rat traumatic brain injury (TBI) model, focusing on the early phase. A significant up-regulation of endostatin/collagen XVIII in TBI began as early as 24 h post-TBI. Double-staining experiment revealed that the major resource of endostatin/collagen XVIII(+) cells in our TBI rat model was a subpopulation of reactivated microglia/macrophages. Our data further showed that dexamethasone attenuated up-regulation of endostatin/collagen XVIII expression at days 1 and 2, but not at day 4, post-TBI, indicating that dexamethasone might possess an early and transient influence to the angiogenesis following TBI.
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Affiliation(s)
- Z-Y Zhang
- Institute of Brain Research, University of Tuebingen, Tuebingen, Germany
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32
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Lai LJ, Xiao X, Wu JH. Inhibition of corneal neovascularization with endostatin delivered by adeno-associated viral (AAV) vector in a mouse corneal injury model. J Biomed Sci 2007; 14:313-22. [PMID: 17373573 DOI: 10.1007/s11373-007-9153-7] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2006] [Accepted: 01/31/2007] [Indexed: 11/29/2022] Open
Abstract
The use of a recombinant adeno-associated viral (rAAV) vector carrying endostatin gene as an anti-angiogenesis strategy to treat corneal neovascularization in a mouse model was evaluated. Subconjunctival injection of recombinant endostatin-AAV was used to examine the inhibition of corneal neovascularization induced by silver nitrate cauterization in mice. The results showed that gene expression in corneal tissue was observed as early as 4 days after gene transfer and stably lasted for over 8 months with minimal immune reaction. Subconjunctival injection of a high-titer rAAV-endostatin successfully inhibited neovascularization. Immunohistchemistry staining of CD 31 and endostatin showed that the treatment significantly inhibits angiogenesis in cornea. We concluded that the rAAV was capable of directly delivering genes to the ocular surface epithelium by way of subconjunctival injection and was able to deliver sustained, high levels of gene expression in vivo to inhibit angiogenesis.
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Affiliation(s)
- Li-Ju Lai
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei San, Tao Yuan, 333, Taiwan
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33
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Chiang B, Essick E, Ehringer W, Murphree S, Hauck MA, Li M, Chien S. Enhancing skin wound healing by direct delivery of intracellular adenosine triphosphate. Am J Surg 2007; 193:213-8. [PMID: 17236849 PMCID: PMC1850226 DOI: 10.1016/j.amjsurg.2006.08.069] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2006] [Revised: 07/28/2006] [Accepted: 08/02/2006] [Indexed: 01/09/2023]
Abstract
BACKGROUND A new intracellular adenosine triphosphate (ATP) delivery technique has been developed and was tested for skin wound care. METHODS Eleven pairs of adult nude mice were used. ATP-vesicles were applied in 11 mice, and another 11 mice were treated with lipid vesicles only. RESULTS The group treated with ATP-encapsulated fusogenic small, unilamellar lipid vesicles healed faster than the group treated with only lipid vesicles. Histologic study indicated better developed granular tissue and re-epithelialization in the study group, and wound tissue vascular endothelial growth factor expressions were also higher in ATP-vesicles treated mice. CONCLUSIONS This intracellular ATP delivery system may provide a new hope for wound healing as well as the treatment of medical conditions in which ischemia is involved.
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Affiliation(s)
- Benjamin Chiang
- Department of Surgery, University of Louisville, Louisville, KY 40202, USA
| | - Eric Essick
- Department of Physiology, University of Louisville, Louisville, KY 40202, USA
| | - William Ehringer
- Department of Physiology, University of Louisville, Louisville, KY 40202, USA
| | - Sidney Murphree
- Department of Pathology, University of Louisville, Louisville, KY 40202, USA
| | - Mary Anne Hauck
- Department of Surgery, University of Louisville, Louisville, KY 40202, USA
| | - Ming Li
- Department of Surgery, University of Louisville, Louisville, KY 40202, USA
| | - Sufan Chien
- Department of Surgery, University of Louisville, Louisville, KY 40202, USA
- *Corresponding and reprint author: Sufan Chien, MD, Department of Surgery, University of Louisville, Louisville, KY 40202, Telephone: 502-852-4418, Fax: 502-852-1795,
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Tanabe K, Maeshima Y, Ichinose K, Kitayama H, Takazawa Y, Hirokoshi K, Kinomura M, Sugiyama H, Makino H. Endostatin peptide, an inhibitor of angiogenesis, prevents the progression of peritoneal sclerosis in a mouse experimental model. Kidney Int 2006; 71:227-38. [PMID: 17191085 DOI: 10.1038/sj.ki.5002040] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Peritoneal sclerosis is a major and serious complication in patients on long-term continuous ambulatory peritoneal dialysis (PD). The involvement of angiogenesis and proangiogenic factors such as vascular endothelial growth factor (VEGF)-A in progressing peritoneal sclerosis has been reported. We previously reported the therapeutic efficacy of endostatin peptide, a potent inhibitor of angiogenesis derived from type XVIII collagen, in a mouse diabetic nephropathy model. Here, we examined the therapeutic effect of endostatin peptide in preventing progression in a mouse peritoneal sclerosis model. Male ICR mice received intraperitoneal injections of chlorhexidine gluconate (CG) every other day to induce peritoneal sclerosis. Endostatin peptide (1 or 4 mg/kg/day) was administered via subcutaneously implanted osmotic minipumps. Peritoneal sclerosis (day 24) was significantly suppressed by endostatin peptide in a dose-dependent manner. Peritoneal accumulation of type III collagen was significantly suppressed by endostatin peptide. Increase in the number of CD31(+) blood vessels, F4/80(+) monocyte/macrophage accumulation, and 5-bromodeoxyuridine(+) proliferating cells was significantly inhibited by endostatin peptide. Increase in peritoneal expression of VEGF-A, profibrotic transforming growth factor-beta1, and alpha-smooth muscle actin was suppressed by endostatin peptide. Immunoreactivity for endogenous endostatin (whole molecule) and endostatin receptor alpha5beta1-integrin was increased and colocalized to CD31(+) blood vessels in the thickened peritonea of CG-injected mice. These results demonstrate the potential use of antiangiogenic endostatin peptide as a novel therapeutic agent in preventing peritoneal sclerosis, a severe complication in patients undergoing long-term PD.
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Affiliation(s)
- K Tanabe
- Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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35
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Prevention of Intra-abdominal Adhesions Using the Antiangiogenic COX-2 Inhibitor Celecoxib. Ann Surg 2006. [DOI: 10.1097/00000658-200608000-00030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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36
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Schaffhauser B, Veikkola T, Strittmatter K, Antoniadis H, Alitalo K, Christofori G. Moderate antiangiogenic activity by local, transgenic expression of endostatin in Rip1Tag2 transgenic mice. J Leukoc Biol 2006; 80:669-76. [PMID: 16793908 DOI: 10.1189/jlb.1105644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Many previous reports have demonstrated that systemic administration of endostatin (ES), a proteolytic cleavage product of collagen type XVIII and an endogenous angiogenesis inhibitor, represses tumor angiogenesis in different preclinical tumor models with varying efficacy. For example, systemic delivery of recombinant ES to rat insulin promoter 1 (Rip1)T-antigen 2 (Tag2)-transgenic mice, a mouse model of pancreatic beta-cell carcinogenesis, has repressed tumor angiogenesis efficiently and with it, tumor growth. Here, we report that the transgenic expression of ES in Rip1ES-transgenic mice only interferes moderately with tumor growth in Rip1Tag2;Rip1ES double-transgenic mice. Tumor incidence is not reduced by the local expression of ES, and tumor outgrowth and progression to tumor malignancy are only retarded slightly. A significant effect of local ES expression on tumor angiogenesis is only apparent during the early stages of tumor development, where less angiogenic hyperplastic lesions are observed. Although efficiently produced and secreted by transgenic beta cells, locally expressed ES appears to be sequestered in the microenvironment, and its systemic levels are not increased. The results indicate that the antiangiogenic functions of ES critically depend on the mode of delivery and the site of expression: although its systemic application represses tumor angiogenesis and tumor growth efficiently, locally expressed ES appears to be less effective, and hence, additional mechanisms of solubilization or activation of latent ES seem to be required. These results have important implications about the modes of delivery used in antiangiogenic, therapeutic strategies, which are based on the antiangiogenic activities of ES.
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MESH Headings
- Angiogenesis Inhibitors/biosynthesis
- Angiogenesis Inhibitors/genetics
- Angiogenesis Inhibitors/pharmacology
- Animals
- Antigens, Polyomavirus Transforming/genetics
- Carcinoma, Islet Cell/blood supply
- Carcinoma, Islet Cell/genetics
- Carcinoma, Islet Cell/metabolism
- Cell Proliferation
- Crosses, Genetic
- Disease Models, Animal
- Disease Progression
- Endostatins/biosynthesis
- Endostatins/genetics
- Endostatins/pharmacology
- Female
- Humans
- Insulin/genetics
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Neoplasms, Experimental/blood supply
- Neoplasms, Experimental/genetics
- Neoplasms, Experimental/metabolism
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/pathology
- Pancreas/blood supply
- Pancreas/pathology
- Pancreatic Neoplasms/blood supply
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Rats
- Transgenes
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Affiliation(s)
- Birgit Schaffhauser
- Department of Clinical-Biological Sciences, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland
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37
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Schmidt A, Wenzel D, Thorey I, Sasaki T, Hescheler J, Timpl R, Addicks K, Werner S, Fleischmann BK, Bloch W. Endostatin influences endothelial morphology via the activated ERK1/2-kinase endothelial morphology and signal transduction. Microvasc Res 2006; 71:152-62. [PMID: 16650878 DOI: 10.1016/j.mvr.2006.01.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2005] [Revised: 01/02/2006] [Accepted: 01/07/2006] [Indexed: 11/28/2022]
Abstract
Endostatin, the proteolytic fragment of collagen XVIII, is known to be a potent inhibitor of angiogenesis. However, to date, only limited knowledge exists with regard to the effects of endostatin on vessel morphology and the underlying signaling pathway. The aim of the present work was therefore to determine the impact of endostatin and its collagen XV analogue restin on vessel development during wound healing and embryonic angio- and vasculogenesis. Time lapse experiments and electron microscopy demonstrate similar morphological changes evoked by endostatin and the ERK1/2-kinase inhibitor PD98059. Furthermore, we show that ERK1/2 phosphorylation, a crucial signaling event in vascular morphogenesis, is regulated by endostatin via the protein phosphatase 2A PP2A. These findings provide new insight into a key signaling pathway of vascular remodeling evoked by a matrix-derived factor.
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Affiliation(s)
- Annette Schmidt
- Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Germany
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38
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Michaels J, Dobryansky M, Galiano RD, Bhatt KA, Ashinoff R, Ceradini DJ, Gurtner GC. Topical vascular endothelial growth factor reverses delayed wound healing secondary to angiogenesis inhibitor administration. Wound Repair Regen 2006; 13:506-12. [PMID: 16176459 DOI: 10.1111/j.1067-1927.2005.00071.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The prevention of new blood vessel growth is an increasingly attractive strategy to limit tumor growth. However, it remains unclear whether anti-angiogenesis approaches will impair wound healing, a process thought to be angiogenesis dependent. Results of previous studies differ as to whether angiogenesis inhibitors delay wound healing. We evaluated whether endostatin at tumor-inhibiting doses delayed excisional wound closure. C57/BL6J mice were treated with endostatin or phosphate-buffered solution 3 days prior to the creation of two full-thickness wounds on the dorsum. Endostatin was administered daily until wound closure was complete. A third group received endostatin, but also had daily topical vascular endothelial growth factor applied locally to the wound. Wound area was measured daily and the wounds were analyzed for granulation tissue formation, epithelial gap, and wound vascularity. Endostatin-treated mice showed a significant delay in wound healing. Granulation tissue formation and wound vascularity were significantly decreased, but reepithelialization was not effected. Topical vascular endothelial growth factor application to wounds in endostatin-treated mice resulted in increased granulation tissue formation, increased wound vascularity, and wound closure approaching that of control mice. This study shows that the angiogenesis inhibitor endostatin delays wound healing and that topical vascular endothelial growth factor is effective in counteracting this effect.
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Affiliation(s)
- Joseph Michaels
- Laboratory of Microvascular Research and Vascular Tissue Engineering, Institute of Reconstructive Plastic Surgery, New York University Medical Center, New York 10016, USA
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39
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Ichinose K, Maeshima Y, Yamamoto Y, Kitayama H, Takazawa Y, Hirokoshi K, Sugiyama H, Yamasaki Y, Eguchi K, Makino H. Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model. Diabetes 2005; 54:2891-903. [PMID: 16186390 DOI: 10.2337/diabetes.54.10.2891] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Diabetic nephropathy is one of the major microvascular complications in diabetes and is the leading cause of end-stage renal disease worldwide. Among various factors, angiogenesis-associated factors such as vascular endothelial growth factor (VEGF)-A and angiopoietin (Ang)-2 are involved in the development of diabetic nephropathy. We previously reported the therapeutic efficacy of antiangiogenic tumstatin peptide in the early diabetic nephropathy model. Here, we examine the effect of endostatin peptide, a potent inhibitor of angiogenesis derived from type XVIII collagen, in preventing progression in the type 1 diabetic nephropathy mouse model. Endostatin peptide did not affect hyperglycemia induced by streptozotocin (STZ). Glomerular hypertrophy, hyperfiltration, and albuminuria were significantly suppressed by endostatin peptide (5 mg/kg) in STZ-induced diabetic mice. Glomerular mesangial matrix expansion, the increase of glomerular type IV collagen, endothelial area (CD31(+)), and F4/80(+) monocyte/macrophage accumulation were significantly inhibited by endostatin peptide. Increase in the renal expression of VEGF-A, flk-1, Ang-2, an antagonist of angiopoietin-1, transforming growth factor-beta1, interleukin-6, and monocyte chemoattractant protein-1 was inhibited by endostatin peptide in diabetic mice. Decrease of nephrin mRNA and protein in diabetic mice was suppressed by treatment with endostatin peptide. The level of endostatin in the renal cortex and sera was increased in diabetic mice. Endogenous renal levels of endostatin were decreased in endostatin peptide-treated groups in parallel with VEGF-A. Although serum levels of endostatin were decreased in the low-dose endostatin-peptide group, high-dose administration resulted in elevated serum levels of endostatin. These results demonstrate the potential use of antiangiogenic endostatin peptide as a novel therapeutic agent in diabetic nephropathy.
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Affiliation(s)
- Kunihiro Ichinose
- Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan
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Scappaticci FA, Fehrenbacher L, Cartwright T, Hainsworth JD, Heim W, Berlin J, Kabbinavar F, Novotny W, Sarkar S, Hurwitz H. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 2005; 91:173-80. [PMID: 16118771 DOI: 10.1002/jso.20301] [Citation(s) in RCA: 388] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Bevacizumab (Avastin; rhuMab VEGF), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), significantly prolongs survival when added to intravenous 5-fluorouracil-based chemotherapy in first-line metastatic colorectal cancer (CRC) treatment. Because antiangiogenic agents might inhibit wound healing, we assessed postoperative wound healing complications in two randomized trials of 5 mg/kg bevacizumab in CRC treatment. METHODS We assessed the wound healing complications in patients who: (1) underwent cancer surgery 28-60 days before study treatment and (2) underwent major surgery during study treatment. Cases were reviewed for wound healing complications occurring < or = 60 days after surgery. RESULTS With cancer surgery 28-60 days before study treatment, wound healing complications occurred in 3/230 (1.3%) bevacizumab-treated patients and 1/194 (0.5%) control patients. With major surgery during study treatment, 10/75 bevacizumab-treated patients (13%) and 1/29 control patients (3.4%) had wound healing complications. Bevacizumab-treated patients experienced complications with surgery < or = 30 and 31-60 days after the last dose. CONCLUSIONS Bevacizumab administered in combination with 5-fluorouracil/leucovorin-based chemotherapy 28-60 days after primary cancer surgery caused no increased risk of wound healing complications compared with chemotherapy alone. While wound healing complications were increased in patients who had major surgery during bevacizumab therapy, the majority of bevacizumab-treated patients experienced no complications.
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Wickström SA, Alitalo K, Keski-Oja J. Endostatin signaling and regulation of endothelial cell-matrix interactions. Adv Cancer Res 2005; 94:197-229. [PMID: 16096002 DOI: 10.1016/s0065-230x(05)94005-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The growth and survival of a malignant tumor are dependent on the formation and maintenance of its own microvasculature, a process termed angiogenesis. Inhibition of this phenomenon is an emerging strategy in cancer therapy. The extracellular matrix surrounding the vascular endothelial cells contains cryptic protein domains, which are exposed by changes in the proteolytic homeostasis of the tumor microenvironment. These fragments transmit local signals, which regulate vascular endothelial cell proliferation and migration. Endostatin, the proteolytic fragment of collagen type XVIII, is a potent inhibitor of tumor angiogenesis in various mouse models and is currently in clinical trials for therapeutic use in human cancer. Multiple cell surface receptors have been described for endostatin, but the signals transmitted by these receptors resulting in the inhibition of angiogenesis have so far been poorly characterized. Studies on the effects of endostatin on cultured endothelial cells suggest that the antimigratory and antiproliferative properties of this molecule are the major mechanisms underlying its antiangiogenic potential. These effects may be a consequence of endostatin modulation of endothelial cell-matrix interactions and pericellular proteolysis.
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Affiliation(s)
- Sara A Wickström
- Department of Pathology, Haartman Institute, University of Helsinki, Biomedicum Helsinki and Helsinki University Hospital, FIN-00014 Helsinki, Finland
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Ko J, Ross J, Awad H, Hurwitz H, Klitzman B. The effects of ZD6474, an inhibitor of VEGF signaling, on cutaneous wound healing in mice. J Surg Res 2005; 129:251-9. [PMID: 16140331 DOI: 10.1016/j.jss.2005.05.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2005] [Revised: 05/03/2005] [Accepted: 05/05/2005] [Indexed: 10/25/2022]
Abstract
BACKGROUND ZD6474 is an inhibitor of the VEGFR-2 receptor tyrosine kinase with additional activity against EGFR-1 receptor tyrosine kinases that has been shown to inhibit tumor growth and wound-induced neovascularization in pre-clinical studies and phase I clinical trials. The purpose of this study was to determine the effects of ZD6474 on breaking strength in a murine model of cutaneous wound healing. MATERIALS AND METHODS Balb/C mice were given ZD6474 (50 or 100 mg/kg p.o.) or vehicle starting 7 days before wounding. Two full-thickness incisions were made in each mouse and closed using suture. On post-wounding day 7 or 28, laser Doppler blood flow measurements were made, and the breaking strength of the wounded skin was determined. Microvessel density measurements were performed using computer image analysis of CD31-stained sections. RESULTS Compared with controls, mice treated with ZD6474 showed a significantly reduced dose-dependent decline in breaking strength, both at POD 7 (P < 0.001) and at POD 28 (P < 0.005). Histologically, the ZD6474-treated mice showed a qualitative reduction in the degree of fibrosis and epithelial proliferation at the wound site, but no significant difference was noted between the 50 mg/kg and 100 mg/kg ZD6474-treated groups. Also, microvessel density measurements demonstrated no significant difference between groups. CONCLUSION In a murine model of wound healing, ZD6474 treatment did not prevent wound healing, but was associated with a reduced skin breaking strength compared with vehicle-treated controls at both 7 and 28 days post-wounding. These observations may have clinical relevance for the perioperative management of patients treated with inhibitors of angiogenesis.
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Affiliation(s)
- Jason Ko
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
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Davidoff AM, Ng CYC, Zhang Y, Streck CJ, Mabry SJ, Barton SH, Baudino T, Zhou J, Kerbel RS, Vanin EF, Nathwani AC. Careful decoy receptor titering is required to inhibit tumor angiogenesis while avoiding adversely altering VEGF bioavailability. Mol Ther 2005; 11:300-10. [PMID: 15668142 DOI: 10.1016/j.ymthe.2004.09.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2003] [Accepted: 09/15/2004] [Indexed: 01/16/2023] Open
Abstract
To inhibit tumor-induced angiogenesis, the VEGF signaling pathway was targeted using AAV vectors encoding a VEGF decoy receptor, a truncated, soluble form of the murine VEGF receptor-2 (tsFlk-1). This approach initially had significant anti-neuroblastoma efficacy in murine xenograft models of local and metastatic disease, but when higher circulating levels of tsFlk-1 were established, tumor growth was more aggressive than even in control mice. Part of the mechanism for this apparent tumor resistance was increased human VEGF expression by the tumor cells. However, further investigation revealed that although a greater amount of VEGF could be bound by higher levels of tsFlk-1, more VEGF also existed in an unbound state and was, therefore, available to support angiogenesis. This novel, tumor-independent mechanism for resistance to antiangiogenic strategies suggests that careful titering of angiogenesis inhibitors may be required to achieve maximal antitumor efficacy and avoid therapy resistance mediated, in part, by ligand bioavailability. This has important implications for therapeutic strategies that use decoy receptors and other agents, such as antibodies, to bind angiogenic factors, in an attempt to inhibit tumor neovascularization.
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Affiliation(s)
- Andrew M Davidoff
- Department of Surgery St. Jude Children's Research Hospital, Memphis, TN 38105, USA
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Smith E, Hoffman R. Multiple fragments related to angiostatin and endostatin in fluid from venous leg ulcers. Wound Repair Regen 2005; 13:148-57. [PMID: 15828939 DOI: 10.1111/j.1067-1927.2005.130205.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
To investigate whether compromised angiogenesis could contribute to the impaired healing of venous leg ulcers, we have analyzed fluids from venous leg ulcers for the presence of the angiogenesis inhibitors angiostatin and endostatin. Multiple fragments related to angiostatin were detected by Western blot analysis. One angiostatin fragment was identified by mass spectrometry as plasminogen kringle domains 1-3 containing amino acids 82-343 of plasminogen, and a fraction containing this fragment inhibited tubule formation of human umbilical vein endothelial cells in a Matrigel assay. The leg ulcer fluids also contained endogenous endostatin (20 kDa) as well as higher molecular weight endostatin-related proteins. The concentrations of endostatin in the wound fluids, which ranged from 12.8 to 65.5 ng/ml, were higher than the concentration in human serum (7.7 ng/ml). Most of the endostatin in leg ulcer fluid appeared to be bound to the proteoglycan glypican-1. These data suggest that anti-angiogenic activity is present at the site of venous leg ulcers, and at least in the case of angiostatin, is biologically active.
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Affiliation(s)
- Ewen Smith
- Department of Biosciences, University of Hertfordshire, Hatfield, Hertfordshire, United Kingdom
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Mikler JR, Theoret CL, High JC. Effects of topical elk velvet antler on cutaneous wound healing in streptozotocin-induced diabetic rats. J Altern Complement Med 2005; 10:835-40. [PMID: 15650473 DOI: 10.1089/acm.2004.10.835] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVE Wound repair is a finely orchestrated process involving cellular, molecular, physiologic, and biochemical interactions that restore the integrity of damaged tissue. Cyclic replacement of deer antlers requires rapid regenerative growth, in many ways analogous to that encountered during tissue repair. Molecular mechanisms regulating these processes are not fully understood, but it is increasingly apparent that growth factors are important mediators. Previous studies have shown that elk velvet antler (EVA) contains various growth factors and that a water-soluble extract stimulates dermal fibroblast growth in vitro. DESIGN The efficacy of EVA water-soluble extract on wound healing in streptozotocin-induced diabetic rats was EVAluated using a full-thickness cutaneous wound model. Animals were randomly selected to receive topical application of either control or EVA gel. Daily photographs of the wounds served to measure the rate of wound closure. Wound-edge biopsies obtained on postoperative days 2 and 10 allowed histologic evaluation and measurement of transforming growth factor-beta 1 (TGF-beta (1)) concentrations by enzyme-linked immunoabsorbent assay. RESULTS Wounds treated with the EVA topical gel were significantly smaller by postoperative day 6. TGF- beta (1) protein expression was not different in EVA-treated wounds compared to control wounds. CONCLUSIONS This study indicates that topical treatment with an EVA water-soluble extract accelerates repair of cutaneous wounds in diabetic rats. Further studies are warranted to reveal the mechanisms involved in EVA enhancement of wound closure and to determine if this compound is an economical pharmacologic agent in the treatment of normal and compromised wounds.
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Affiliation(s)
- John R Mikler
- Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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Schmidt A, Sommer F, Reiner M, Klotz T, Engelmann U, Addicks K, Bloch W. Differential endostatin binding to bladder, prostate and kidney tumour vessels. BJU Int 2005; 95:174-9. [PMID: 15638918 DOI: 10.1111/j.1464-410x.2005.05272.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVES To define the anti-angiogenic mechanism and causes of the heterogeneous influence of endostatin, one of a group of matrix-derived inhibitors of tumour angiogenesis of increasing significance in tumour treatment, on various tissue types. MATERIALS AND METHODS Variations in the binding behaviour of endostatin with vessels were assessed in different tumours (bladder, prostate and kidney) and compared with benign tissue vessels. Biotinylated endostatin was used and detected using extravidin CY3 and extravidin-gold immunolabelling. RESULTS There were significant differences in the number of vessels showing endostatin binding among benign and malignant bladder, prostate and kidney tissues. While there was distinct endostatin binding on a mean (sd) of 94.2 (3.0)% bladder and 73.8 (19.5)% prostate tumour vessels, there was less binding, at 11.32 (3.9)%, on kidney tumour vessels. There was less binding to vessels of benign bladder, prostate and kidney tissue, at 2.0 (1.5), 1.7 (1.7) and 1.5 (1.7)%, respectively. At the ultrastructural level, different binding sites were detected both inside and outside the endothelial cells. CONCLUSION Endostatin binds more to all tumour tissues than to benign tissue, but the degree of binding in malignant kidney tissue was significantly less than that in malignant prostate and bladder tissues. These divergent vascular endostatin-binding patterns could be responsible for a tumour type-dependent anti-angiogenic effect attributable to endostatin. Such selective behaviour would have therapeutic consequences for future anti-angiogenic therapy, in which different kinds of tumours could be further classified into those responding to endostatin or not.
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Affiliation(s)
- Annette Schmidt
- Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Carl-Diem-Weg 6, 50933 Cologne, Germany
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Berger AC, Wang XQ, Zalatoris A, Cenna J, Watson JC. A murine model of ex vivo angiogenesis using aortic disks grown in fibrin clot☆. Microvasc Res 2004; 68:179-87. [PMID: 15501237 DOI: 10.1016/j.mvr.2004.05.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2004] [Indexed: 12/01/2022]
Abstract
The rat aortic ring model is well utilized for evaluation of angiogenesis. We report here an alternative assay employing an ex vivo mouse aorta angiogenesis model that can be extensively manipulated and serially evaluated using digital-assisted image analysis. Mouse aortas were harvested, cut into 2-mm disks, and cultured in fibrin matrix with growth media. Radial vascular outgrowths arose from the cut edge of the aortic disk and were digitally photographed and serially quantified. A variety of culture conditions were evaluated to determine their ability to alter angiogenesis in this model. Vessel outgrowth became apparent on day 3 and continued through day 10 with linear growth occurring between days 3 and 6. Increasing concentrations of serum from 0% to 40% resulted in stimulation of angiogenesis after day 3. Suramin and endostatin dramatically inhibited angiogenesis, which was more profound when applied at day 0 than when linear growth could be identified (day 3). Cells isolated from vessel outgrowths were predominantly endothelial in origin by immunocytochemistry and FACS analysis. We demonstrate that angiogenesis in an ex vivo murine model can be easily quantified using digital image analysis, responds appropriately to stimulation and inhibition, and exhibits differential results based on time of inhibitor administration. Antiangiogenic agents may be most effective if administered before development of accelerated vessel growth.
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Affiliation(s)
- Adam C Berger
- Division of Surgical Research, Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
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Jansen M, de Witt Hamer PC, Witmer AN, Troost D, van Noorden CJF. Current perspectives on antiangiogenesis strategies in the treatment of malignant gliomas. ACTA ACUST UNITED AC 2004; 45:143-63. [PMID: 15210301 DOI: 10.1016/j.brainresrev.2004.03.001] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2004] [Indexed: 01/12/2023]
Abstract
Progressive tumor growth depends on angiogenesis to sustain metabolic needs of tumor cells, thus providing a potential target for cancer therapy. Malignant gliomas have retained their dismal prognosis despite aggressive multimodal conventional therapeutic approaches, illustrating the need for novel therapeutic strategies. Gliomas are a suitable tumor type for probing angiogenesis inhibition as their proliferation is characterized by a prominent proliferative vascular component. In the present review, we discuss the current status and future directions of angiogenesis inhibition in gliomas. We focus on recently developed approaches inducing an antiangiogenic response such as targeted gene delivery, protein tyrosine kinase inhibitors and encapsulated producer cells. Although several of these modalities have shown promising results on their own, the true potential of these novel approaches lies in their combined use with radiotherapy or 'metronomically scheduled' chemotherapy. A combined approach potentially counteracts the selective pressure on hypoxia-resistant malignant tumor cells, circumvents endothelial resistance induced by local cytoprotective responses and enhances the delivery of cytotoxic agents by normalizing vascular physiology. Surrogate markers of angiogenesis currently under study may provide accurate assessment of response in individual patients. Future research on endothelial markers expressed on tumor-associated vasculature as well as endothelial responses to cytotoxic treatment will provide new avenues for molecularly targeted therapy in malignant gliomas.
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Affiliation(s)
- Marnix Jansen
- Department of Pathology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
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Varma MR, Moaveni DM, Dewyer NA, Varga AJ, Deatrick KB, Kunkel SL, Upchurch GR, Wakefield TW, Henke PK. Deep vein thrombosis resolution is not accelerated with increased neovascularization. J Vasc Surg 2004; 40:536-42. [PMID: 15337885 DOI: 10.1016/j.jvs.2004.05.023] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
INTRODUCTION Deep venous thrombosis (DVT) resolution involves fibrinolysis, neovascularization, and fibrosis. We hypothesized that promoting neovascularization would accelerate DVT resolution. METHODS A rat model of stasis DVT was produced with proximal ligation of the inferior vena cava (IVC) and all visible tributaries. One microg of interferon inducible protein (IP-10; angiostatic chemokine), basic fibroblast growth factor (bFGF; pro-angiogenic cytokine), epithelial neutrophil activating protein (ENA-78; pro-angiogenic chemokine), or saline solution control was injected into the IVC after ligation, and then via tail vein injection daily until sacrifice at either 4 or 8 days. Peripheral blood counts were measured, and thrombus weight was recorded at sacrifice. Laser Doppler in vivo imaging was used to estimate post-thrombotic IVC blood flow. Immunohistologic assessment of the thrombosed IVC for polymorphonuclear neutrophils (PMNs), monocytes (ED-1), and laminin (neovascular channels) was performed or the thrombus was separated from the IVC and assayed for keratinocyte cytokine (KC), monocyte chemotactic protein-1 (MCP-1), bFGF with enzyme-linked immunosorbent assay (ELISA), and total collagen with a direct colorimetric assay. RESULTS Peripheral blood and intrathrombus PMNs and monocytes were not significantly different in the treated or control rats. There were no differences in any measure at 4 days. At 8 days, thrombus neovascularity, but not weight or collagen content, was increased in rats treated with bFGF or ENA-78 compared with control rats (17.6 +/- 0.93, 16.2 +/- 0.97 vs 13.2 +/- 0.79; channels/5 high-power fields (hpf; n = 6-10; P <.05). Post DVT IVC blood flow was significantly increased in bFGF-treated rats but not in rats treated with IP-10 or ENA-78, as compared with control rats. Rats treated with ENA-78 had increased intrathrombus bFGF compared with control rats (85 +/- 27 pg/mg protein vs 20 +/- 6 pg/mg protein; n = 6; P <.05), but other mediators were not significantly different in treated rats compared with control rats. CONCLUSION Pro-angiogenic compounds increase thrombus neovascularization, but this does not correlate with smaller or less fibrotic DVT. Mechanisms other than neovascularization may be more important to hasten DVT dissolution. Clinical relevance Improved therapy for deep venous thrombosis (DVT) will ideally increase the rate of thrombus dissolution and eliminate the bleeding risks of anticoagulation. This study evaluated promoting DVT neovascularization with angiogenic chemokines, and, while successful by experimental measures, this did not translate into smaller DVT. Solely promoting thrombus neovascularization will not likely speed resolution.
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Affiliation(s)
- Manu R Varma
- Department of Surgery, University of Michigan Medical School, Ann Arbor, USA
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Streck CJ, Zhou J, Ng CY, Zhang Y, Nathwani AC, Davidoff AM. Longterm recombinant adeno-associated, virus-mediated, liver-generated expression of an angiogenesis inhibitor improves survival in mice with disseminated neuroblastoma. J Am Coll Surg 2004; 199:78-86. [PMID: 15217634 DOI: 10.1016/j.jamcollsurg.2004.02.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2003] [Revised: 02/06/2004] [Accepted: 02/06/2004] [Indexed: 01/29/2023]
Abstract
BACKGROUND A gene therapy-mediated approach to the delivery of antiangiogenic agents using adeno-associated virus (AAV) vectors has a number of advantages including the potential for sustained expression. The purpose of this study was to attempt to restrict the growth of disseminated neuroblastoma through delivery of a truncated, soluble form of the vascular endothelial growth factor receptor-2 (VEGFR-2 fetal liver kinase [Flk]-1), a decoy receptor for VEGF. STUDY DESIGN Mice underwent portal vein injection of vector, either AAV-CAGG-tsFlk-1 or control vector. Subsequent truncated soluble fetal liver kinase-1 (tsFlk-1) expression was confirmed and quantified by ELISA. After 8 weeks, mice were given human neuroblastoma cells through the tail vein to establish disseminated disease and were sacrificed after 40 days. The weight of liver metastasis was measured. Intrahepatic tumor microvessel density and levels of apoptosis were determined. Survival was assessed in a second cohort of mice. RESULTS After intraportal injection of AAV-CAGG-tsFlk-1, high-level, stable transgene expression was generated. Sera from these mice inhibited endothelial cell activation in vitro and Matrigel plug (BD Biosciences) neovascularization in vivo, suggesting that a systemic state of angiogenesis inhibition had been established. After neuroblastoma injection, mice expressing tsFlk-1 had a smaller tumor burden in the liver when sacrificed, as compared with control mice. The decrease in tumor weight in the liver correlated with lower intratumoral microvessel density and higher levels of tumor cell apoptosis in the tsFlk-1-treated tumors, supporting the hypothesis that decreased angiogenesis had occurred. In a second cohort of mice, survival of tsFlk-1-expressing mice after tumor cell challenge was longer than in control mice. CONCLUSIONS Longterm in vivo expression of a functional VEGF inhibitor was established using an AAV-mediated gene therapy approach, and it demonstrated antiangiogenic and anticancer efficacy in a murine model of disseminated neuroblastoma.
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Affiliation(s)
- Christian J Streck
- Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, USA
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