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Shabangu MM, Blumenthal MJ, Sass DT, Lang DM, Schafer G, Franz T. Endothelial Cells Stably Infected with Recombinant Kaposi's Sarcoma-Associated Herpesvirus Display Distinct Viscoelastic and Morphological Properties. Cell Mol Bioeng 2025; 18:123-135. [PMID: 40290109 PMCID: PMC12018662 DOI: 10.1007/s12195-025-00848-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 04/05/2025] [Indexed: 04/30/2025] Open
Abstract
Purpose Kaposi's sarcoma-associated herpesvirus (KSHV) is a γ-herpesvirus that has a tropism for endothelial cells and leads to the development of Kaposi's sarcoma, especially in people living with HIV. The present study aimed to quantify morphological and mechanical changes in endothelial cells after infection with KSHV to assess their potential as diagnostic and therapeutic markers. Methods Vascular (HuARLT2) and lymphatic endothelial cells (LEC) were infected with recombinant KSHV (rKSHV) by spinoculation, establishing stable infections (HuARLT2-rKSHV and LEC-rKSHV). Cellular changes were assessed using mitochondria-tracking microrheology and morphometric analysis. Results rKSHV infection increased cellular deformability, indicated by higher mitochondrial mean squared displacement (MSD) for short lag times. Specifically, MSD at τ = 0.19 s was 49.4% and 42.2% higher in HuARLT2-rKSHV and LEC-rKSHV, respectively, compared to uninfected controls. There were 23.9% and 36.7% decreases in the MSD power law exponents for HuARLT2-rKSHV and LEC-rKSHV, respectively, indicating increased cytosolic viscosity associated with rKSHV infection. Infected cells displayed a marked spindloid phenotype with an increase in aspect ratio (29.7%) and decreases in roundness (26.1%) and circularity (25.7%) in HuARLT2-rKSHV, with similar changes observed in LEC-rKSHV. Conclusions The quantification of distinct KSHV-induced morpho-mechanical changes in endothelial cells demonstrates the potential of these changes as diagnostic markers and therapeutic targets.
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Affiliation(s)
- Majahonkhe M. Shabangu
- Biomedical Engineering Research Centre, Division of Biomedical Engineering, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925 South Africa
- International Centre for Genetic Engineering and Biotechnology, Observatory, Cape Town, 7925 South Africa
- Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925 South Africa
| | - Melissa J. Blumenthal
- International Centre for Genetic Engineering and Biotechnology, Observatory, Cape Town, 7925 South Africa
- Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925 South Africa
- Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925 South Africa
| | - Danielle T. Sass
- Biomedical Engineering Research Centre, Division of Biomedical Engineering, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925 South Africa
| | - Dirk M. Lang
- Division of Physiological Sciences, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925 South Africa
| | - Georgia Schafer
- International Centre for Genetic Engineering and Biotechnology, Observatory, Cape Town, 7925 South Africa
- Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925 South Africa
- Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925 South Africa
| | - Thomas Franz
- Biomedical Engineering Research Centre, Division of Biomedical Engineering, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925 South Africa
- Bioengineering Science Research Group, Faculty of Engineering and Physical Sciences, University of Southampton, Southampton, UK
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Basu R, Boguszewski CL, Kopchick JJ. Growth Hormone Action as a Target in Cancer: Significance, Mechanisms, and Possible Therapies. Endocr Rev 2025; 46:224-280. [PMID: 39657053 DOI: 10.1210/endrev/bnae030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 08/29/2024] [Accepted: 12/03/2024] [Indexed: 12/17/2024]
Abstract
Growth hormone (GH) is a pituitary-derived endocrine hormone required for normal postnatal growth and development. Hypo- or hypersecretion of endocrine GH results in 2 pathologic conditions, namely GH deficiency (GHD) and acromegaly. Additionally, GH is also produced in nonpituitary and tumoral tissues, where it acts rather as a cellular growth factor with an autocrine/paracrine mode of action. An increasingly persuasive and large body of evidence over the last 70 years concurs that GH action is implicit in escalating several cancer-associated events, locally and systemically. This pleiotropy of GH's effects is puzzling, but the association with cancer risk automatically raises a concern for patients with acromegaly and for individuals treated with GH. By careful assessment of the available knowledge on the fundamental concepts of cancer, suggestions from epidemiological and clinical studies, and the evidence from specific reports, in this review we aimed to help clarify the distinction of endocrine vs autocrine/paracrine GH in promoting cancer and to reconcile the discrepancies between experimental and clinical data. Along this discourse, we critically weigh the targetability of GH action in cancer-first by detailing the molecular mechanisms which posit GH as a critical node in tumor circuitry; and second, by enumerating the currently available therapeutic options targeting GH action. On the basis of our discussion, we infer that a targeted intervention on GH action in the appropriate patient population can benefit a sizable subset of current cancer prognoses.
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Affiliation(s)
- Reetobrata Basu
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine (OU-HCOM), Athens, OH 45701, USA
- Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine (OU-HCOM), Athens, OH 45701, USA
| | - Cesar L Boguszewski
- SEMPR, Endocrine Division, Department of Internal Medicine, Federal University of Parana, Curitiba 80060-900, Brazil
| | - John J Kopchick
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine (OU-HCOM), Athens, OH 45701, USA
- Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine (OU-HCOM), Athens, OH 45701, USA
- Molecular and Cellular Biology Program, Ohio University, Athens, OH 45701, USA
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Mouna K, Fourat A, Vayza M, Nesrine BS, Amel EK, Sirine B, Ahlem B, Asma F, Jamel K, Habib S, Jameleddine Z. An Isolated Kaposi's Sarcoma of the Tongue in an HIV-Negative Patient. Am J Med 2025; 138:436-438. [PMID: 39617113 DOI: 10.1016/j.amjmed.2024.11.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 02/14/2025]
Affiliation(s)
- Korbi Mouna
- Dermatology Department, Fattouma Bourguiba University Hospital, University of Monastir, Monastir, Tunisia.
| | - Amor Fourat
- Dermatology Department, Fattouma Bourguiba University Hospital, University of Monastir, Monastir, Tunisia
| | - Mahmoud Vayza
- Dermatology Department, Fattouma Bourguiba University Hospital, University of Monastir, Monastir, Tunisia
| | - Ben Salah Nesrine
- Dermatology Department, Fattouma Bourguiba University Hospital, University of Monastir, Monastir, Tunisia
| | - El Korbi Amel
- Otolaryngology Department, Fattouma Bourguiba University Hospital, Monastir, Tunisia
| | - Bchir Sirine
- Nephrology Department, Fattouma Bourguiba University Hospital, Monastir, Tunisia
| | - Bellalah Ahlem
- Anatomopathology Department, Fattouma Bourguiba University Hospital, Monastir, Tunisia
| | - Felfoul Asma
- Radiotherapy Department, Fattouma Bourguiba University Hospital, University of Monastir, Monastir, Tunisia
| | - Koubaa Jamel
- Otolaryngology Department, Fattouma Bourguiba University Hospital, Monastir, Tunisia
| | - Skhiri Habib
- Nephrology Department, Fattouma Bourguiba University Hospital, Monastir, Tunisia
| | - Zili Jameleddine
- Dermatology Department, Fattouma Bourguiba University Hospital, University of Monastir, Monastir, Tunisia
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Losay VA, Damania B. Unraveling the Kaposi Sarcoma-Associated Herpesvirus (KSHV) Lifecycle: An Overview of Latency, Lytic Replication, and KSHV-Associated Diseases. Viruses 2025; 17:177. [PMID: 40006930 PMCID: PMC11860327 DOI: 10.3390/v17020177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/18/2025] [Accepted: 01/23/2025] [Indexed: 02/27/2025] Open
Abstract
Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus and the etiological agent of several diseases. These include the malignancies Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD), as well as the inflammatory disorder KSHV inflammatory cytokine syndrome (KICS). The KSHV lifecycle is characterized by two phases: a default latent phase and a lytic replication cycle. During latency, the virus persists as an episome within host cells, expressing a limited subset of viral genes to evade immune surveillance while promoting cellular transformation. The lytic phase, triggered by various stimuli, results in the expression of the full viral genome, production of infectious virions, and modulation of the tumor microenvironment. Both phases of the KSHV lifecycle play crucial roles in driving viral pathogenesis, influencing oncogenesis and immune evasion. This review dives into the intricate world of the KSHV lifecycle, focusing on the molecular mechanisms that drive its latent and lytic phases, their roles in disease progression, and current therapeutic strategies.
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Affiliation(s)
- Victor A. Losay
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA;
- Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA;
- Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Microbiology & Immunology, University of North Carolina, Chapel Hill, NC 27599, USA
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Mutchler AL, Zhong J, Yang HC, Zhao S, Crescenzi R, Taylor S, Rao RL, Shelton EL, Kirabo A, Kon V. ET-3/ETBR Mediates Na +-Activated Immune Signaling and Kidney Lymphatic Dynamics. Circ Res 2025; 136:194-208. [PMID: 39676651 PMCID: PMC11800760 DOI: 10.1161/circresaha.124.324890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 11/14/2024] [Accepted: 12/02/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND Lymphatic collecting vessels in the kidney are critical in clearing interstitial fluid, macromolecules, and infiltrating immune cells. Dysfunction of the lymphatic vessels can disrupt this process and exacerbate injury-associated inflammation in many disease conditions. We previously found that sodium accumulates within the kidney interstitium during proteinuric kidney injury and elevated sodium environments stimulate isolevuglandin production in antigen-presenting cells, stimulating T cells, and modulating inflammatory responses. In the present study, we investigated whether proteinuric injury increases production of isolevuglandin-adduct formation in antigen-presenting cells, their effects on lymphatic endothelial cells (LECs), and the role of the ET-3 (endothelin-3)/ETBR (endothelin type B receptor) on lymphatic vessel function. METHODS We used a mouse model of nephrotoxin-induced proteinuric injury to show that proteinuric injury expanded the kidney lymphatic network and to immunophenotype the infiltrating immune cells. To determine mechanisms, we analyzed the interaction of migratory immune cells and LECs using an in vitro transwell migration assay, bulk RNA sequencing, and flow cytometric analysis. To determine the effect of ET-3/ETBR axis on lymphatic vessel contractility, we analyzed microdissected lymphangions utilizing a vessel perfusion chamber. RESULTS We found that animals with proteinuric injury have increased kidney lymphangiogenesis, isolevuglandin-producing dendritic cells, and IFN (interferon)-γ-producing CD4+T cells. The sodium avid environment present in kidney injury enhances the interaction between LECs and migratory antigen-presenting cells and LEC production of isolevuglandin-adducts. Elevated sodium environment-induced isolevuglandin-adduct formation facilitates the ET-3/ETBR communication between LECs and dendritic cells. In addition, the ET-3/ETBR axis modulates lymphatic collecting vessel pumping dynamics. CONCLUSIONS These findings reveal a novel mechanism linking the isolevuglandin-mediated ET-3/ETBR axis with LECs and infiltrating dendritic cells. ET-3/ETBR signaling in lymphatic vessel dynamics is a novel pathogenic component and a possible therapeutic target in kidney disease.
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Affiliation(s)
- Ashley L. Mutchler
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jianyong Zhong
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Hai-Chun Yang
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Shilin Zhao
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Rachelle Crescenzi
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA
- Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Shannon Taylor
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA
| | - Roy L. Rao
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Elaine L. Shelton
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Annet Kirabo
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Valentina Kon
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Fabian R, Rosato G, Stewart JP, Kipar A. Bovine Gammaherpesvirus 6 Tropism in the Natural Host. Viruses 2024; 16:1730. [PMID: 39599845 PMCID: PMC11598913 DOI: 10.3390/v16111730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 10/31/2024] [Accepted: 11/02/2024] [Indexed: 11/29/2024] Open
Abstract
Bovine gammaherpesvirus 6 (BoHV-6) is endemic in cattle in Europe, with a high prevalence. There is evidence that the virus is a commensal and not associated with disease processes. For other gammaherpesviruses, it is known that they have a rather specific target cell spectrum, generally including B cells and, at least in the early phase of infection, the epithelium of the respiratory tract. In a previous study we detected BoHV-6 by quantitative PCR for the gB gene sequence of BoHV-6 in lung, bronchial lymph nodes, spleen and tongue with variable loads, suggesting cells in these tissues as target cells. In the present study, formalin-fixed, paraffin embedded samples of the same tissues from 10 cattle, with high overall BoHV-6 copy numbers, were examined by RNA in situ hybridization for BoHV-6 ORF73. This revealed extremely limited viral ORF73 transcription. A signal was only detected in individual lymphocytes within lymphatic follicles in bronchial lymph nodes, and within very rare alveolar epithelial cells and interstitial cells in the lungs, without any evidence of pathological changes in the tissues. No signal was detected in the spleen or in the oral mucosa of the tongue. The results are consistent with previous findings with other gammaherpesviruses, murine herpesvirus-68, ovine herpesvirus-2 and/or Epstein-Barr virus. They provide further evidence that BoHV-6 is without any consequence to the host and can indeed represent a commensal in cattle.
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Affiliation(s)
- Rosalie Fabian
- Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland; (R.F.); (G.R.)
| | - Giuliana Rosato
- Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland; (R.F.); (G.R.)
| | - James P. Stewart
- Department of Infection Biology & Microbiomes, University of Liverpool, Liverpool L3 3RF, UK;
| | - Anja Kipar
- Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland; (R.F.); (G.R.)
- Department of Infection Biology & Microbiomes, University of Liverpool, Liverpool L3 3RF, UK;
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Li X, Ohler ZW, Day A, Bassel L, Grosskopf A, Afsari B, Tagawa T, Custer W, Mangusan R, Lurain K, Yarchoan R, Ziegelbauer J, Ramaswami R, Krug LT. Mapping herpesvirus-driven impacts on the cellular milieu and transcriptional profile of Kaposi sarcoma in patient-derived mouse models. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.27.615429. [PMID: 39386738 PMCID: PMC11463583 DOI: 10.1101/2024.09.27.615429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
Kaposi sarcoma (KS) is defined by aberrant angiogenesis driven by Kaposi sarcoma herpesvirus (KSHV)-infected spindle cells with endothelial characteristics. KS research is hindered by rapid loss of KSHV infection upon explant culture of tumor cells. Here, we establish patient-derived KS xenografts (PDXs) upon orthotopic implantation of cutaneous KS biopsies in immunodeficient mice. KS tumors were maintained in 27/28 PDX until experimental endpoint, up to 272 days in the first passage of recipient mice. KSHV latency associated nuclear antigen (LANA)+ endothelial cell density increased by a mean 4.3-fold in 14/15 PDX analyzed by IHC at passage 1 compared to respective input biopsies, regardless of implantation variables and clinical features of patients. The Ki-67 proliferation marker colocalized with LANA more frequently in PDXs. Spatial transcriptome analysis revealed increased expression of viral transcripts from latent and lytic gene classes in the PDX. The expanded KSHV+ regions of the PDX maintained signature gene expression of KS tumors, with enrichment in pathways associated with angiogenesis and endothelium development. Cells with characteristics of tumor-associated fibroblasts derived from PDX were propagated for 15 passages. These fibroblast-like cells were permissive for de novo KSHV infection, and one lineage produced CXCL12, a cancer-promoting chemokine. Spatial analysis revealed that fibroblasts are a likely source of CXCL12 signaling to CXCR4 that was upregulated in KS regions. The reproducible expansion of KSHV-infected endothelial cells in PDX from multiple donors and recapitulation of a KS tumor gene signature supports the application of patient-derived KS mouse models for studies of pathogenesis and novel therapies.
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Affiliation(s)
- Xiaofan Li
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Zoë Weaver Ohler
- Center for Advanced Preclinical Research, Center for Cancer Research, National Cancer Institute; Frederick, MD
| | - Amanda Day
- Center for Advanced Preclinical Research, Center for Cancer Research, National Cancer Institute; Frederick, MD
| | - Laura Bassel
- Center for Advanced Preclinical Research, Center for Cancer Research, National Cancer Institute; Frederick, MD
| | - Anna Grosskopf
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Bahman Afsari
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Takanobu Tagawa
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Wendi Custer
- Center for Advanced Preclinical Research, Center for Cancer Research, National Cancer Institute; Frederick, MD
| | - Ralph Mangusan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Kathryn Lurain
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Joseph Ziegelbauer
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Ramya Ramaswami
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
| | - Laurie T. Krug
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute; Bethesda, MD
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Moorad R, Kasonkanji E, Gumulira J, Gondwe Y, Dewey M, Pan Y, Peng A, Pluta LJ, Kudowa E, Nyasosela R, Tomoka T, Tweya H, Heller T, Gugsa S, Phiri S, Moore DT, Damania B, Painschab M, Hosseinipour MC, Dittmer DP. A prospective cohort study identifies two types of HIV+ Kaposi Sarcoma lesions: proliferative and inflammatory. Int J Cancer 2023; 153:2082-2092. [PMID: 37602960 PMCID: PMC11074775 DOI: 10.1002/ijc.34689] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/15/2023] [Accepted: 06/29/2023] [Indexed: 08/22/2023]
Abstract
Kaposi sarcoma (KS) is the most common cancer in people living with HIV (PLWH) in many countries where KS-associated herpesvirus is endemic. Treatment has changed little in 20 years, but the disease presentation has. This prospective cohort study enrolled 122 human immunodeficiency virus (HIV) positive KS patients between 2017 and 2019 in Malawi. Participants were treated with bleomycin, vincristine and combination antiretroviral therapy, the local standard of care. One-year overall survival was 61%, and progression-free survival was 58%. The 48-week complete response rate was 35%. RNAseq (n = 78) differentiated two types of KS lesions, those with marked endothelial characteristics and those enriched in inflammatory transcripts. This suggests that different KS lesions are in different disease states consistent with the known heterogeneous clinical response to treatment. In contrast to earlier cohorts, the plasma HIV viral load of KS patients in our study was highly variable. A total of 25% of participants had no detectable HIV; all had detectable KSHV viral load. Our study affirms that many KS cases today develop in PLWH with well-controlled HIV infection and that different KS lesions have differing molecular compositions. Further studies are needed to develop predictive biomarkers for this disease.
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Affiliation(s)
- Razia Moorad
- Lineberger Comprehensive Cancer Centre, School of Medicine, University of North Carolina at Chapel Hill; Chapel Hill, USA
- Department of Immunology and Microbiology, University of North Carolina at Chapel Hill; Chapel Hill, USA
| | | | | | | | | | - Yue Pan
- Lineberger Comprehensive Cancer Centre, School of Medicine, University of North Carolina at Chapel Hill; Chapel Hill, USA
- Department of Biostatistics, The University of North Carolina at Chapel Hill; Chapel Hill
| | - Alice Peng
- Lineberger Comprehensive Cancer Centre, School of Medicine, University of North Carolina at Chapel Hill; Chapel Hill, USA
| | - Linda J. Pluta
- Lineberger Comprehensive Cancer Centre, School of Medicine, University of North Carolina at Chapel Hill; Chapel Hill, USA
| | - Evaristar Kudowa
- Department of Immunology and Microbiology, University of North Carolina at Chapel Hill; Chapel Hill, USA
| | | | | | | | | | | | | | - Dominic T Moore
- Lineberger Comprehensive Cancer Centre, School of Medicine, University of North Carolina at Chapel Hill; Chapel Hill, USA
| | - Blossom Damania
- Lineberger Comprehensive Cancer Centre, School of Medicine, University of North Carolina at Chapel Hill; Chapel Hill, USA
- Department of Immunology and Microbiology, University of North Carolina at Chapel Hill; Chapel Hill, USA
- Institute for Global Health and Infectious Diseases, University of North Carolina at Chapel Hill; Chapel Hill, USA
| | - Matthew Painschab
- Lineberger Comprehensive Cancer Centre, School of Medicine, University of North Carolina at Chapel Hill; Chapel Hill, USA
- UNC Project Malawi, Lilongwe, Malawi
| | - Mina C. Hosseinipour
- Lineberger Comprehensive Cancer Centre, School of Medicine, University of North Carolina at Chapel Hill; Chapel Hill, USA
- UNC Project Malawi, Lilongwe, Malawi
- Institute for Global Health and Infectious Diseases, University of North Carolina at Chapel Hill; Chapel Hill, USA
| | - Dirk P. Dittmer
- Lineberger Comprehensive Cancer Centre, School of Medicine, University of North Carolina at Chapel Hill; Chapel Hill, USA
- Department of Immunology and Microbiology, University of North Carolina at Chapel Hill; Chapel Hill, USA
- Institute for Global Health and Infectious Diseases, University of North Carolina at Chapel Hill; Chapel Hill, USA
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Qian B, Qian Y, Xiao P, Guo L. Prognostic analysis of cutaneous Kaposi sarcoma based on a competing risk model. Sci Rep 2023; 13:17572. [PMID: 37845261 PMCID: PMC10579376 DOI: 10.1038/s41598-023-44800-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 10/12/2023] [Indexed: 10/18/2023] Open
Abstract
The data regarding the prognosis of cutaneous Kaposi sarcoma (KS) was limited. The current study aimed to explore the risk factors and develop a predictive model for the prognosis of cutaneous KS patients. Data were extracted from Surveillance, Epidemiology, and End Results database from 2000 to 2018 and randomly divided into training and validation cohort. The Kaplan-Meier analysis, cumulative incidence function based on the competing risk model and Fine-Gray multivariable regression model was used to identify the prognostic factors and then construct a 5-, 10-, and 15-year KS-specific death (KSSD) nomogram for patients. The concordance index (C-index), area under the curve (AUC) of operating characteristics and calibration plots were used to evaluate the performance of the model. The clinical utility of the model was measured by decision curve analysis (DCA). In 2257 cutaneous KS patients identified from database, the overall median survival time was about 13 years. Radiotherapy (p = 0.013) and surgery (p < 0.001) could lower the KSSD, while chemotherapy (p = 0.042) and surgery (p < 0.001) could increase the overall survival (OS) of patients with metastatic and localized lesions, respectively. Race, number of lesions, surgery, extent of disease, year of diagnosis and age were identified as risk factors associated with cutaneous KS-specific survival. Performance of the nomogram was validated by calibration and discrimination, with C-index values of 0.709 and AUC for 5-, 10-, and 15-year-KSSD of 0.739, 0.728 and 0.725 respectively. DCA indicated that the nomogram had good net benefits in clinical scenarios. Using a competing-risk model, this study firstly identified the prognostic factors, and constructed a validated nomogram to provide individualized assessment and reliable prognostic prediction for cutaneous KS patients.
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Affiliation(s)
- Bei Qian
- Department of Thyroid and Breast Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Ying Qian
- Department of Pharmacy, Jingzhou Hospital, Yangtze University, Jingzhou, 434020, Hubei, China
| | - Peng Xiao
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Liang Guo
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
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Lucas CJ, Sheridan RM, Reynoso GV, Davenport BJ, McCarthy MK, Martin A, Hesselberth JR, Hickman HD, Tamburini BAJ, Morrison TE. Chikungunya virus infection disrupts lymph node lymphatic endothelial cell composition and function via MARCO. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.12.561615. [PMID: 37873393 PMCID: PMC10592756 DOI: 10.1101/2023.10.12.561615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Infection with chikungunya virus (CHIKV) causes disruption of draining lymph node (dLN) organization, including paracortical relocalization of B cells, loss of the B cell-T cell border, and lymphocyte depletion that is associated with infiltration of the LN with inflammatory myeloid cells. Here, we find that during the first 24 h of infection, CHIKV RNA accumulates in MARCO-expressing lymphatic endothelial cells (LECs) in both the floor and medullary LN sinuses. The accumulation of viral RNA in the LN was associated with a switch to an antiviral and inflammatory gene expression program across LN stromal cells, and this inflammatory response, including recruitment of myeloid cells to the LN, was accelerated by CHIKV-MARCO interactions. As CHIKV infection progressed, both floor and medullary LECs diminished in number, suggesting further functional impairment of the LN by infection. Consistent with this idea, we find that antigen acquisition by LECs, a key function of LN LECs during infection and immunization, was reduced during pathogenic CHIKV infection.
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11
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Damania B, Dittmer DP. Today's Kaposi sarcoma is not the same as it was 40 years ago, or is it? J Med Virol 2023; 95:e28773. [PMID: 37212317 PMCID: PMC10266714 DOI: 10.1002/jmv.28773] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/20/2023] [Accepted: 04/22/2023] [Indexed: 05/23/2023]
Abstract
This review will provide an overview of the notion that Kaposi sarcoma (KS) is a disease that manifests under diverse and divergent circumstances. We begin with a historical introduction of KS and KS-associated herpesvirus (KSHV), highlight the diversity of clinical presentations of KS, summarize what we know about the cell of origin for this tumor, explore KSHV viral load as a potential biomarker for acute KSHV infections and KS-associated complications, and discuss immune modulators that impact KSHV infection, KSHV persistence, and KS disease.
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Affiliation(s)
- Blossom Damania
- Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, 450 West Drive CB#7295, Rm 12-048, Chapel Hill, NC 27599
| | - Dirk P. Dittmer
- Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, 450 West Drive CB#7295, Rm 12-048, Chapel Hill, NC 27599
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12
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Dorothea M, Xie J, Yiu SPT, Chiang AKS. Contribution of Epstein–Barr Virus Lytic Proteins to Cancer Hallmarks and Implications from Other Oncoviruses. Cancers (Basel) 2023; 15:cancers15072120. [PMID: 37046781 PMCID: PMC10093119 DOI: 10.3390/cancers15072120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/27/2023] [Accepted: 03/31/2023] [Indexed: 04/05/2023] Open
Abstract
Epstein–Barr virus (EBV) is a prevalent human gamma-herpesvirus that infects the majority of the adult population worldwide and is associated with several lymphoid and epithelial malignancies. EBV displays a biphasic life cycle, namely, latent and lytic replication cycles, expressing a diversity of viral proteins. Among the EBV proteins being expressed during both latent and lytic cycles, the oncogenic roles of EBV lytic proteins are largely uncharacterized. In this review, the established contributions of EBV lytic proteins in tumorigenesis are summarized according to the cancer hallmarks displayed. We further postulate the oncogenic properties of several EBV lytic proteins by comparing the evolutionary conserved oncogenic mechanisms in other herpesviruses and oncoviruses.
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Affiliation(s)
- Mike Dorothea
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Jia Xie
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Stephanie Pei Tung Yiu
- Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA
- Harvard Graduate Program in Virology, Boston, MA 02115, USA
| | - Alan Kwok Shing Chiang
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
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13
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Doodnauth AV, Zhou J, Sivarajah S, Xavier HE, McFarlane SI. Kaposi Sarcoma: A Rare Presentation of Elephantiasis Nostras Verrucosa. Cureus 2023; 15:e37339. [PMID: 37182020 PMCID: PMC10169094 DOI: 10.7759/cureus.37339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2023] [Indexed: 05/16/2023] Open
Abstract
Although a low-grade vascular tumor, Kaposi sarcoma (KS) can have mucosal, and visceral involvement. Additionally, disfiguring disseminated lesions can be seen in patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). KS may cause lymphatic obstruction leading to chronic lymphedema that further contributes to progressive cutaneous hypertrophy and severe disfigurement in the form of non-filarial elephantiasis nostras verrucosa (ENV). This report highlights a case of a 33-year-old male with AIDS who presented in acute respiratory distress with bilateral lower extremity nodular lesions. We confirmed a diagnosis of KS with overlying ENV via a multi-disciplinary approach. Collaboratively, we optimized our patient and observed adequate treatment response and overall improvement in clinical status. Our report emphasizes the importance of a multi-disciplinary approach in recognizing a rare presentation of ENV. Recognition of the disease and understanding the extent of the disease are crucial in preventing irreversible disease progression and allowing for maximum response.
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Affiliation(s)
| | - Jordan Zhou
- Internal Medicine, Downstate Health Sciences University, Brooklyn, USA
| | - Sigogini Sivarajah
- Internal Medicine, Downstate Health Sciences University, St. George's University, Brooklyn, USA
| | - Hannah E Xavier
- Internal Medicine, Downstate Health Sciences University, St. George's University, Brooklyn, USA
| | - Samy I McFarlane
- Internal Medicine, Downstate Health Sciences University, Brooklyn, USA
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14
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Naipauer J, Mesri EA. The Kaposi's sarcoma progenitor enigma: KSHV-induced MEndT-EndMT axis. Trends Mol Med 2023; 29:188-200. [PMID: 36635149 PMCID: PMC9957928 DOI: 10.1016/j.molmed.2022.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/02/2022] [Accepted: 12/13/2022] [Indexed: 01/11/2023]
Abstract
Endothelial-to-mesenchymal transition has been described in tumors as a source of mesenchymal stroma, while the reverse process has been proposed in tumor vasculogenesis and angiogenesis. A human oncogenic virus, Kaposi's sarcoma herpes virus (KSHV), can regulate both processes in order to transit through this transition 'boulevard' when infecting KS oncogenic progenitor cells. Endothelial or mesenchymal circulating progenitor cells can serve as KS oncogenic progenitors recruited by inflammatory cytokines because KSHV can reprogram one into the other through endothelial-to-mesenchymal and mesenchymal-to-endothelial transitions. Through these novel insights, the identity of the potential oncogenic progenitor of KS is revealed while gaining knowledge of the biology of the mesenchymal-endothelial differentiation axis and pointing to this axis as a therapeutic target in KS.
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Affiliation(s)
- Julian Naipauer
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina; Tumor Biology Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA; University of Miami- Center for AIDS Research (UM-CFAR)/Sylvester Comprehensive Cancer Center (CCC) Argentina Consortium for Research and Training in Virally Induced AIDS-Malignancies, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Center for AIDS Research, Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Enrique A Mesri
- Tumor Biology Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA; University of Miami- Center for AIDS Research (UM-CFAR)/Sylvester Comprehensive Cancer Center (CCC) Argentina Consortium for Research and Training in Virally Induced AIDS-Malignancies, University of Miami Miller School of Medicine, Miami, FL, USA; Miami Center for AIDS Research, Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
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15
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Endemic Kaposi's Sarcoma. Cancers (Basel) 2023; 15:cancers15030872. [PMID: 36765830 PMCID: PMC9913747 DOI: 10.3390/cancers15030872] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 02/01/2023] Open
Abstract
Kaposi's sarcoma (KS) is a common neoplasm in Eastern and central Africa reflecting the spread of human gammaherpesvirus-8 (HHV-8), now considered a necessary causal agent for the development of KS. The endemic KS subtype can follow an aggressive clinical course with ulcerative skin lesions with soft tissue invasion or even bone or visceral involvement. In the latter cases, a thorough imaging work-up and better follow-up schedules are warranted. As KS is a chronic disease, the therapeutic goal is to obtain sustainable remission in cutaneous and visceral lesions and a good quality of life. Watchful monitoring may be sufficient in localized cutaneous forms. Potential therapeutic modalities for symptomatic advanced KS include systemic chemotherapies, immunomodulators, immune checkpoint inhibitors, and antiangiogenic drugs.
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16
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Tuohinto K, DiMaio TA, Kiss EA, Laakkonen P, Saharinen P, Karnezis T, Lagunoff M, Ojala PM. KSHV infection of endothelial precursor cells with lymphatic characteristics as a novel model for translational Kaposi's sarcoma studies. PLoS Pathog 2023; 19:e1010753. [PMID: 36689549 PMCID: PMC9894539 DOI: 10.1371/journal.ppat.1010753] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 02/02/2023] [Accepted: 01/11/2023] [Indexed: 01/24/2023] Open
Abstract
Kaposi's sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), a hyperplasia consisting of enlarged malformed vasculature and spindle-shaped cells, the main proliferative component of KS. While spindle cells express markers of lymphatic and blood endothelium, the origin of spindle cells is unknown. Endothelial precursor cells have been proposed as the source of spindle cells. We previously identified two types of circulating endothelial colony forming cells (ECFCs), ones that expressed markers of blood endothelium and ones that expressed markers of lymphatic endothelium. Here we examined both blood and lymphatic ECFCs infected with KSHV. Lymphatic ECFCs are significantly more susceptible to KSHV infection than the blood ECFCs and maintain the viral episomes during passage in culture while the blood ECFCs lose the viral episome. Only the KSHV-infected lymphatic ECFCs (K-ECFCLY) grew to small multicellular colonies in soft agar whereas the infected blood ECFCs and all uninfected ECFCs failed to proliferate. The K-ECFCLYs express high levels of SOX18, which supported the maintenance of high copy number of KSHV genomes. When implanted subcutaneously into NSG mice, the K-ECFCLYs persisted in vivo and recapitulated the phenotype of KS tumor cells with high number of viral genome copies and spindling morphology. These spindle cell hallmarks were significantly reduced when mice were treated with SOX18 inhibitor, SM4. These data suggest that KSHV-infected lymphatic ECFCs can be utilized as a KSHV infection model for in vivo translational studies to test novel inhibitors representing potential treatment modalities for KS.
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Affiliation(s)
- Krista Tuohinto
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Terri A DiMaio
- Department of Microbiology, University of Washington, Seattle, WA, United States of America
| | - Elina A Kiss
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Pirjo Laakkonen
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Laboratory Animal Center, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Pipsa Saharinen
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
| | - Tara Karnezis
- Gertrude Biomedical Pty Ltd., Melbourne, Victoria, Australia
| | - Michael Lagunoff
- Department of Microbiology, University of Washington, Seattle, WA, United States of America
| | - Päivi M Ojala
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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17
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Histologic Variants of Kaposi Sarcoma in the Gastrointestinal Tract: A Contemporary Multi-institutional Clinicopathologic Analysis of 46 Cases. Am J Surg Pathol 2022; 46:1500-1506. [PMID: 35973011 DOI: 10.1097/pas.0000000000001937] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Kaposi sarcoma (KS) can pose diagnostic challenges in biopsy specimens. Multiple histologic variants of cutaneous KS have been described; however, the histomorphologic spectrum of gastrointestinal (GI) KS has not been systematically studied. This large series comprehensively evaluated 46 cases of KS involving the GI tract and identified 7 histomorphologic variants, some that have not been previously described. Five of them are inconspicuous but have unique morphologic patterns, including lymphangioma/lymphangiectatic-like (n=17), mucosal hemorrhage/telangiectatic-like (n=17), mucosal inflammation-like (n=15), granulation tissue-like (n=13), and mucosal prolapse-like (n=4) variants. These variants can be easily misdiagnosed or misinterpreted on routine examination if KS is not considered, and if the immunohistochemical stain for human herpesvirus-8 is not performed. The other 2 morphologic variants present as spindle cell proliferations and are the GI stromal tumor-like (n=8) and inflammatory myofibroblastic tumor-like (n=2). These variants raise a broad differential diagnosis of spindle cell tumors of the GI tract and could pose diagnostic challenges. In summary, GI KS lesions exhibit variable, often unconventional histomorphologic patterns. KS should be included in the differential diagnosis even if features of conventional KS are not seen, particularly in limited biopsies in immunocompromised patients, such as those with human immunodeficiency virus infection. Although the clinical significance of these morphologic variants is yet to be determined, they are nonetheless important from a diagnostic standpoint. Misdiagnosis and delay in appropriate management can be avoided by recognizing the morphologic diversity of GI KS and appropriately utilizing the human herpesvirus-8 immunohistochemical stain.
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18
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Rusu-Zota G, Manole OM, Galeș C, Porumb-Andrese E, Obadă O, Mocanu CV. Kaposi Sarcoma, a Trifecta of Pathogenic Mechanisms. Diagnostics (Basel) 2022; 12:1242. [PMID: 35626397 PMCID: PMC9140574 DOI: 10.3390/diagnostics12051242] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/29/2022] [Accepted: 05/13/2022] [Indexed: 01/10/2023] Open
Abstract
Kaposi's sarcoma is a rare disease with four known variants: classic, epidemic, endemic and iatrogenic (transplant-related), all caused by an oncogenic virus named Human Herpes Virus 8. The viral infection in itself, along with the oncogenic properties of HHV8 and with immune system dysfunction, forms the grounds on which Kaposi's Sarcoma may develop. Infection with HHV8 occurs through saliva via close contacts, blood, blood products, solid organ donation and, rarely, vertical transmission. Chronic inflammation and oncogenesis are promoted by a mix of viral genes that directly promote cell survival and transformation or interfere with the regular cell cycle and cell signaling (of particular note: LANA-1, v-IL6, vBCL-2, vIAP, vIRF3, vGPCR, gB, K1, K8.1, K15). The most common development sites for Kaposi's sarcoma are the skin, mucocutaneous zones, lymph nodes and visceral organs, but it can also rarely appear in the musculoskeletal system, urinary system, endocrine organs, heart or eye. Histopathologically, spindle cell proliferation with slit-like vascular spaces, plasma cell and lymphocyte infiltrate are characteristic. The clinical presentation is heterogenic depending on the variant; some patients have indolent disease and others have aggressive disease. The treatment options include highly active antiretroviral therapy, surgery, radiation therapy, chemotherapy, and immunotherapy. A literature search was carried out using the MEDLINE/PubMed, SCOPUS and Google Scholar databases with a combination of keywords with the aim to provide critical, concise, and comprehensive insights into advances in the pathogenic mechanism of Kaposi's sarcoma.
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Affiliation(s)
- Gabriela Rusu-Zota
- Department of Pharmacology, Clinical Pharmacology and Algesiology, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa” Iasi, 700115 Iasi, Romania;
| | - Oana Mădălina Manole
- Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa” Iasi, 700115 Iasi, Romania
| | - Cristina Galeș
- Department of Histology, University of Medicine and Pharmacy “Grigore T. Popa” Iasi, 700115 Iasi, Romania;
| | - Elena Porumb-Andrese
- Department of Dermatology, University of Medicine and Pharmacy “Grigore T. Popa” Iasi, 700115 Iasi, Romania;
| | - Otilia Obadă
- Department of Ophthalmology, University of Medicine and Pharmacy “Grigore T. Popa” Iasi, 700115 Iasi, Romania;
| | - Cezar Valentin Mocanu
- Department of Anatomical Pathology, University of Medicine and Pharmacy “Grigore T. Popa” Iasi, 700115 Iasi, Romania;
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19
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Goerdt LV, Schneider SW, Booken N. Kutane Angiosarkome: molekulare Pathogenese und neue therapeutische Ansätze. J Dtsch Dermatol Ges 2022; 20:429-444. [PMID: 35446507 DOI: 10.1111/ddg.14694_g] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 11/16/2021] [Indexed: 12/27/2022]
Abstract
Das kutane Angiosarkom (CAS) ist ein hochaggressiver maligner Tumor mit schlechter Prognose. Das primäre, spontane CAS (pCAS) und das sekundäre, mit einer Bestrahlung oder einem Lymphödem assoziierte CAS (sCAS) unterscheiden sich klinisch sowie molekular. Die Amplifikation/Überexpression von Myc ist ein charakteristisches, wenn auch nicht ausschließliches Merkmal von sCAS, während der Verlust von TP53 selektiv bei pCAS vorkommt. Detaillierte molekulare Analysen mit modernen Multi-Omics-Ansätzen haben gezeigt, dass sowohl pCAS als auch sCAS eine erhebliche molekulare Heterogenität aufweisen. Die betroffenen Gene und ihre molekularen Regulatoren sind mögliche therapeutische Zielstrukturen. Darüber hinaus kann das pCAS in Cluster mit hoher Mutationsrate und/oder ausgeprägten Entzündungssignaturen eingeteilt werden, die als Grundlage für die künftige Stratifizierung von pCAS-Patienten in immuntherapeutischen klinischen Studien dienen können. Während die Aufklärung der der Erkrankung zugrunde liegenden molekularen Veränderungen zügig voranschreitet, verläuft die Entwicklung daraus abgeleiteter neuer Therapien für das CAS jedoch bisher eher langsam. Dennoch wurden einige über die Standardtherapien wie Operation und Radiochemotherapie hinausgehende klinische Studien zu neuen Behandlungsmöglichkeiten initiiert. Dazu gehören zielgerichtete Therapien gegen VEGF und VEGFR1-3 wie Bevacizumab und Pazopanib, sowie β-Adrenozeptorenblocker wie Propranolol. Derzeit werden auch Immuntherapien entwickelt, unter anderem unter Verwendung der Immuncheckpoint-Inhibitoren Pembrolizumab und Nivolumab sowie des Anti-RANKL-Antikörper Denosumab.
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Affiliation(s)
- Lea V Goerdt
- Klinik für Dermatologie und Venerologie, Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg.,Asklepios Campus Hamburg, medizinische Fakultät, Semmelweis Universität Budapest, Hamburg
| | - Stefan W Schneider
- Klinik für Dermatologie und Venerologie, Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg
| | - Nina Booken
- Klinik für Dermatologie und Venerologie, Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg
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20
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Goerdt LV, Schneider SW, Booken N. Cutaneous Angiosarcomas: Molecular Pathogenesis Guides Novel Therapeutic Approaches. J Dtsch Dermatol Ges 2022; 20:429-443. [PMID: 35218306 DOI: 10.1111/ddg.14694] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 11/16/2021] [Indexed: 12/12/2022]
Abstract
Cutaneous angiosarcoma (CAS) is a highly aggressive cancer with a poor prognosis. Primary, spontaneous CAS (pCAS) and secondary, post-irradiation- or lymphedema-associated CAS (sCAS) are clinically, but also molecularly distinct. Myc amplification/overexpression is a characteristic, although not exclusive feature of sCAS, while loss of TP53 selectively occurs in pCAS. Detailed molecular analyses with modern multi-omics approaches have revealed that both pCAS and sCAS exhibit considerable molecular heterogeneity. Affected genes and their molecular regulators including a plethora of microRNAs may serve as future drug targets. Furthermore, pCAS could be subdivided into clusters with high tumor mutational burden and/or high tumor inflammation signatures providing a rationale for the stratification of pCAS patients in future immunotherapeutic clinical studies. Development of novel treatment regimens guided by these molecular alterations, however, cannot fully keep up with the pace of their discovery due to the low incidence of the disease. Nevertheless, beyond conventional surgery and chemoradiotherapy, clinical trials investigating novel treatment options have been initiated including targeted therapies against VEGF and VEGFR1-3 such as bevacizumab and pazopanib, and β-adrenoreceptor blockers such as propranolol. Finally, immunotherapies are being developed including immune checkpoint inhibitors pembrolizumab and nivolumab as well as anti-RANKL antibody denosumab.
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Affiliation(s)
- Lea V Goerdt
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.,Asklepios Campus Hamburg, Medical Faculty, Semmelweis University Budapest, Hamburg, Germany
| | - Stefan W Schneider
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
| | - Nina Booken
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
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21
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Jary A, Veyri M, Gothland A, Leducq V, Calvez V, Marcelin AG. Kaposi's Sarcoma-Associated Herpesvirus, the Etiological Agent of All Epidemiological Forms of Kaposi's Sarcoma. Cancers (Basel) 2021; 13:cancers13246208. [PMID: 34944828 PMCID: PMC8699694 DOI: 10.3390/cancers13246208] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/30/2021] [Accepted: 12/07/2021] [Indexed: 01/08/2023] Open
Abstract
Simple Summary Kaposi’s sarcoma-associated herpesvirus (KSHV) is one of the seven oncogenic viruses currently recognized by the International Agency for Research on Cancer. Its presence for Kaposi’s sarcoma development is essential and knowledge on the oncogenic process has increased since its discovery in 1994. However, some uncertainties remain to be clarified, in particular on the exact routes of transmission and disparities in KSHV seroprevalence and the prevalence of Kaposi’s sarcoma worldwide. Here, we summarized the current data on the KSHV viral particle’s structure, its genome, the replication, its seroprevalence, the viral diversity and the lytic and latent oncogenesis proteins involved in Kaposi’s sarcoma. Lastly, we reported the environmental, immunological and viral factors possibly associated with KSHV transmission that could also play a role in the development of Kaposi’s sarcoma. Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is an oncogenic virus belonging to the Herpesviridae family. The viral particle is composed of a double-stranded DNA harboring 90 open reading frames, incorporated in an icosahedral capsid and enveloped. The viral cycle is divided in the following two states: a short lytic phase, and a latency phase that leads to a persistent infection in target cells and the expression of a small number of genes, including LANA-1, v-FLIP and v-cyclin. The seroprevalence and risk factors of infection differ around the world, and saliva seems to play a major role in viral transmission. KSHV is found in all epidemiological forms of Kaposi’s sarcoma including classic, endemic, iatrogenic, epidemic and non-epidemic forms. In a Kaposi’s sarcoma lesion, KSHV is mainly in a latent state; however, a small proportion of viral particles (<5%) are in a replicative state and are reported to be potentially involved in the proliferation of neighboring cells, suggesting they have crucial roles in the process of tumorigenesis. KSHV encodes oncogenic proteins (LANA-1, v-FLIP, v-cyclin, v-GPCR, v-IL6, v-CCL, v-MIP, v-IRF, etc.) that can modulate cellular pathways in order to induce the characteristics found in all cancer, including the inhibition of apoptosis, cells’ proliferation stimulation, angiogenesis, inflammation and immune escape, and, therefore, are involved in the development of Kaposi’s sarcoma.
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Affiliation(s)
- Aude Jary
- Service de Virologie, Hôpital Pitié-Salpêtrière, AP-HP, Institut Pierre Louis d’Épidémiologie et de Santé Publique (iPLESP), INSERM, Sorbonne Université, 75013 Paris, France; (A.G.); (V.L.); (V.C.); (A.-G.M.)
- Correspondence: ; Tel.: +33-1-4217-7401
| | - Marianne Veyri
- Service d’Oncologie Médicale, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, AP-HP, Institut Pierre Louis d’Épidémiologie et de Santé Publique (iPLESP), INSERM, Sorbonne Université, 75013 Paris, France;
| | - Adélie Gothland
- Service de Virologie, Hôpital Pitié-Salpêtrière, AP-HP, Institut Pierre Louis d’Épidémiologie et de Santé Publique (iPLESP), INSERM, Sorbonne Université, 75013 Paris, France; (A.G.); (V.L.); (V.C.); (A.-G.M.)
| | - Valentin Leducq
- Service de Virologie, Hôpital Pitié-Salpêtrière, AP-HP, Institut Pierre Louis d’Épidémiologie et de Santé Publique (iPLESP), INSERM, Sorbonne Université, 75013 Paris, France; (A.G.); (V.L.); (V.C.); (A.-G.M.)
| | - Vincent Calvez
- Service de Virologie, Hôpital Pitié-Salpêtrière, AP-HP, Institut Pierre Louis d’Épidémiologie et de Santé Publique (iPLESP), INSERM, Sorbonne Université, 75013 Paris, France; (A.G.); (V.L.); (V.C.); (A.-G.M.)
| | - Anne-Geneviève Marcelin
- Service de Virologie, Hôpital Pitié-Salpêtrière, AP-HP, Institut Pierre Louis d’Épidémiologie et de Santé Publique (iPLESP), INSERM, Sorbonne Université, 75013 Paris, France; (A.G.); (V.L.); (V.C.); (A.-G.M.)
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22
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Gaglia MM. Kaposi's sarcoma-associated herpesvirus at 27. Tumour Virus Res 2021; 12:200223. [PMID: 34153523 PMCID: PMC8250455 DOI: 10.1016/j.tvr.2021.200223] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 06/16/2021] [Accepted: 06/17/2021] [Indexed: 01/25/2023] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) was discovered 27 years ago and its link to several pathologies - Kaposi's sarcoma, primary effusion lymphoma, and the B cell variant of Multicentric Castleman disease - is now well established. However, many questions remain about how KSHV causes tumors. Here, I will review studies from the last few years (primarily 2019-2021) that report new information about KSHV biology and tumorigenesis, including new results about KSHV proteins implicated in tumorigenesis, genetic and environmental variability in KSHV-related tumor development, and potential vulnerabilities of KSHV-caused tumors that could be novel therapeutic targets.
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Affiliation(s)
- Marta Maria Gaglia
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, 02111, USA.
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23
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Moura Silva H, Kitoko JZ, Queiroz CP, Kroehling L, Matheis F, Yang KL, Reis BS, Ren-Fielding C, Littman DR, Bozza MT, Mucida D, Lafaille JJ. c-MAF-dependent perivascular macrophages regulate diet-induced metabolic syndrome. Sci Immunol 2021; 6:eabg7506. [PMID: 34597123 DOI: 10.1126/sciimmunol.abg7506] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Hernandez Moura Silva
- Kimmel Center for Biology and Medicine at the Skirball Institute; New York University School of Medicine, New York, NY 10016, USA
| | - Jamil Zola Kitoko
- Kimmel Center for Biology and Medicine at the Skirball Institute; New York University School of Medicine, New York, NY 10016, USA.,Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Camila Pereira Queiroz
- Kimmel Center for Biology and Medicine at the Skirball Institute; New York University School of Medicine, New York, NY 10016, USA.,Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas. Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil
| | - Lina Kroehling
- Kimmel Center for Biology and Medicine at the Skirball Institute; New York University School of Medicine, New York, NY 10016, USA
| | - Fanny Matheis
- Laboratory of Mucosal Immunology, Rockefeller University, New York, NY 10065, USA
| | - Katharine Lu Yang
- Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - Bernardo S Reis
- Laboratory of Mucosal Immunology, Rockefeller University, New York, NY 10065, USA
| | | | - Dan R Littman
- Kimmel Center for Biology and Medicine at the Skirball Institute; New York University School of Medicine, New York, NY 10016, USA.,Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.,Howard Hughes Medical Institute, New York, NY 10016, USA
| | - Marcelo Torres Bozza
- Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil
| | - Daniel Mucida
- Laboratory of Mucosal Immunology, Rockefeller University, New York, NY 10065, USA
| | - Juan J Lafaille
- Kimmel Center for Biology and Medicine at the Skirball Institute; New York University School of Medicine, New York, NY 10016, USA.,Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
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24
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Ding Y, Chen W, Lu Z, Wang Y, Yuan Y. Kaposi's sarcoma-associated herpesvirus promotes mesenchymal-to-endothelial transition by resolving the bivalent chromatin of PROX1 gene. PLoS Pathog 2021; 17:e1009847. [PMID: 34492084 PMCID: PMC8448337 DOI: 10.1371/journal.ppat.1009847] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 09/17/2021] [Accepted: 07/27/2021] [Indexed: 01/05/2023] Open
Abstract
Increasing evidence suggests that Kaposi’s sarcoma (KS) arises from Kaposi’s sarcoma-associated herpesvirus (KSHV)-infected mesenchymal stem cells (MSCs) through mesenchymal-to-endothelial transition (MEndT). KSHV infection promotes MSC differentiation of endothelial lineage and acquisition of tumorigeneic phenotypes. To understand how KSHV induces MEndT and transforms MSCs to KS cells, we investigated the mechanism underlying KSHV-mediated MSC endothelial lineage differentiation. Like embryonic stem cells, MSC differentiation and fate determination are under epigenetic control. Prospero homeobox 1 (PROX1) is a master regulator that controls lymphatic vessel development and endothelial differentiation. We found that the PROX1 gene in MSCs harbors a distinctive bivalent epigenetic signature consisting of both active marker H3K4me3 and repressive marker H3K27me3, which poises expression of the genes, allowing timely activation upon differentiation signals or environmental stimuli. KSHV infection effectively resolves the bivalent chromatin by decreasing H3K27me3 and increasing H3K4me3 to activate the PROX1 gene. vIL-6 signaling leads to the recruitment of MLL2 and SET1 complexes to the PROX1 promoter to increase H3K4me3, and the vGPCR-VEGF-A axis is responsible for removing PRC2 from the promoter to reduce H3K27me3. Therefore, through a dual signaling process, KSHV activates PROX1 gene expression and initiates MEndT, which renders MSC tumorigenic features including angiogenesis, invasion and migration. Numerous parallelisms between development and cancer led to the concept that cancer is a development problem over the past 50 years. As our knowledge of epigenetic regulation is advancing, the similarities between development and cancer are becoming more apparent, providing further support to the theory. KSHV infection of mesenchymal stem cells (MSCs) may result in Kaposi’s sarcoma (KS) through mesenchymal-to-endothelial transition (MEndT), a process resembling endothelial differentiation during development. KSHV initiates MEndT by activating the homeobox gene PROX1, a master regulator of the lymphatic endothelial cell differentiation, at the epigenetic level. Here we found that the PROX1 gene resides in bivalent domain chromatin in MSCs and KSHV infection resolves it through a dual signaling process to activates the PROX1 gene, which initiates MEndT and confers MSC KS-like phenotypes. The significance of this study is two-fold. First, the study elucidated the mechanism underlying KSHV-mediated MEndT and KS development at the transcription level. Second, KSHV uses two independent pathways to elevate activating histone modification and decrease repressive marker, respectively, to resolved bivalent chromatin, revealing a two-factor-authentication mechanism in the epigenetic regulation, which may grant a more efficient and accurate response to activate a gene in bivalent chromatin.
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Affiliation(s)
- Yao Ding
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Weikang Chen
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhengzhou Lu
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yan Wang
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yan Yuan
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
- Department of Basic and Translational Sciences, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania
- * E-mail:
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25
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Ducoli L, Detmar M. Beyond PROX1: transcriptional, epigenetic, and noncoding RNA regulation of lymphatic identity and function. Dev Cell 2021; 56:406-426. [PMID: 33621491 DOI: 10.1016/j.devcel.2021.01.018] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 12/08/2020] [Accepted: 01/25/2021] [Indexed: 12/11/2022]
Abstract
The lymphatic vascular system acts as the major transportation highway of tissue fluids, and its activation or impairment is associated with a wide range of diseases. There has been increasing interest in understanding the mechanisms that control lymphatic vessel formation (lymphangiogenesis) and function in development and disease. Here, we discuss recent insights into new players whose identification has contributed to deciphering the lymphatic regulatory code. We reveal how lymphatic endothelial cells, the building blocks of lymphatic vessels, utilize their transcriptional, post-transcriptional, and epigenetic portfolio to commit to and maintain their vascular lineage identity and function, with a particular focus on development.
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Affiliation(s)
- Luca Ducoli
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland; Molecular Life Sciences PhD Program, Swiss Federal Institute of Technology and University of Zürich, Zurich, Switzerland
| | - Michael Detmar
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.
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26
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Venkateswaran N, Ramos JC, Cohen AK, Alvarez OP, Cohen NK, Galor A, Karp CL. Spotlight on ocular Kaposi’s sarcoma: an update on the presentation, diagnosis, and management options. EXPERT REVIEW OF OPHTHALMOLOGY 2021; 16:477-489. [DOI: 10.1080/17469899.2021.1962294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
| | - Juan C. Ramos
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Adam K. Cohen
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Osmel P. Alvarez
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Noah K. Cohen
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Anat Galor
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Surgical Services, Miami Veterans Affairs Hospital, Miami, FL, USA
| | - Carol L. Karp
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
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27
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Shao Y, Saredy J, Xu K, Sun Y, Saaoud F, Drummer C, Lu Y, Luo JJ, Lopez-Pastrana J, Choi ET, Jiang X, Wang H, Yang X. Endothelial Immunity Trained by Coronavirus Infections, DAMP Stimulations and Regulated by Anti-Oxidant NRF2 May Contribute to Inflammations, Myelopoiesis, COVID-19 Cytokine Storms and Thromboembolism. Front Immunol 2021; 12:653110. [PMID: 34248940 PMCID: PMC8269631 DOI: 10.3389/fimmu.2021.653110] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 05/12/2021] [Indexed: 12/13/2022] Open
Abstract
To characterize transcriptomic changes in endothelial cells (ECs) infected by coronaviruses, and stimulated by DAMPs, the expressions of 1311 innate immune regulatomic genes (IGs) were examined in 28 EC microarray datasets with 7 monocyte datasets as controls. We made the following findings: The majority of IGs are upregulated in the first 12 hours post-infection (PI), and maintained until 48 hours PI in human microvascular EC infected by middle east respiratory syndrome-coronavirus (MERS-CoV) (an EC model for COVID-19). The expressions of IGs are modulated in 21 human EC transcriptomic datasets by various PAMPs/DAMPs, including LPS, LPC, shear stress, hyperlipidemia and oxLDL. Upregulation of many IGs such as nucleic acid sensors are shared between ECs infected by MERS-CoV and those stimulated by PAMPs and DAMPs. Human heart EC and mouse aortic EC express all four types of coronavirus receptors such as ANPEP, CEACAM1, ACE2, DPP4 and virus entry facilitator TMPRSS2 (heart EC); most of coronavirus replication-transcription protein complexes are expressed in HMEC, which contribute to viremia, thromboembolism, and cardiovascular comorbidities of COVID-19. ECs have novel trained immunity (TI), in which subsequent inflammation is enhanced. Upregulated proinflammatory cytokines such as TNFα, IL6, CSF1 and CSF3 and TI marker IL-32 as well as TI metabolic enzymes and epigenetic enzymes indicate TI function in HMEC infected by MERS-CoV, which may drive cytokine storms. Upregulated CSF1 and CSF3 demonstrate a novel function of ECs in promoting myelopoiesis. Mechanistically, the ER stress and ROS, together with decreased mitochondrial OXPHOS complexes, facilitate a proinflammatory response and TI. Additionally, an increase of the regulators of mitotic catastrophe cell death, apoptosis, ferroptosis, inflammasomes-driven pyroptosis in ECs infected with MERS-CoV and the upregulation of pro-thrombogenic factors increase thromboembolism potential. Finally, NRF2-suppressed ROS regulate innate immune responses, TI, thrombosis, EC inflammation and death. These transcriptomic results provide novel insights on the roles of ECs in coronavirus infections such as COVID-19, cardiovascular diseases (CVD), inflammation, transplantation, autoimmune disease and cancers.
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Affiliation(s)
- Ying Shao
- Centers of Cardiovascular Research, Inflammation, Translational & Clinical Lung Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Jason Saredy
- Metabolic Disease Research, Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Keman Xu
- Centers of Cardiovascular Research, Inflammation, Translational & Clinical Lung Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Yu Sun
- Centers of Cardiovascular Research, Inflammation, Translational & Clinical Lung Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Fatma Saaoud
- Centers of Cardiovascular Research, Inflammation, Translational & Clinical Lung Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Charles Drummer
- Centers of Cardiovascular Research, Inflammation, Translational & Clinical Lung Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Yifan Lu
- Centers of Cardiovascular Research, Inflammation, Translational & Clinical Lung Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Jin J Luo
- Neurology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Jahaira Lopez-Pastrana
- Psychiatry and Behavioral Science, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Eric T Choi
- Surgery, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Xiaohua Jiang
- Centers of Cardiovascular Research, Inflammation, Translational & Clinical Lung Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States.,Metabolic Disease Research, Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Hong Wang
- Metabolic Disease Research, Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
| | - Xiaofeng Yang
- Centers of Cardiovascular Research, Inflammation, Translational & Clinical Lung Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States.,Metabolic Disease Research, Thrombosis Research, Departments of Pharmacology, Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States
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28
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Neuropilin 1 Regulation of Vascular Permeability Signaling. Biomolecules 2021; 11:biom11050666. [PMID: 33947161 PMCID: PMC8146136 DOI: 10.3390/biom11050666] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 04/24/2021] [Accepted: 04/28/2021] [Indexed: 12/18/2022] Open
Abstract
The vascular endothelium acts as a selective barrier to regulate macromolecule exchange between the blood and tissues. However, the integrity of the endothelium barrier is compromised in an array of pathological settings, including ischemic disease and cancer, which are the leading causes of death worldwide. The resulting vascular hyperpermeability to plasma molecules as well as leukocytes then leads to tissue damaging edema formation and inflammation. The vascular endothelial growth factor A (VEGFA) is a potent permeability factor, and therefore a desirable target for impeding vascular hyperpermeability. However, VEGFA also promotes angiogenesis, the growth of new blood vessels, which is required for reperfusion of ischemic tissues. Moreover, edema increases interstitial pressure in poorly perfused tumors, thereby affecting the delivery of therapeutics, which could be counteracted by stimulating the growth of new functional blood vessels. Thus, targets must be identified to accurately modulate the barrier function of blood vessels without affecting angiogenesis, as well as to develop more effective pro- or anti-angiogenic therapies. Recent studies have shown that the VEGFA co-receptor neuropilin 1 (NRP1) could be playing a fundamental role in steering VEGFA-induced responses of vascular endothelial cells towards angiogenesis or vascular permeability. Moreover, NRP1 is involved in mediating permeability signals induced by ligands other than VEGFA. This review therefore focuses on current knowledge on the role of NRP1 in the regulation of vascular permeability signaling in the endothelium to provide an up-to-date landscape of the current knowledge in this field.
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29
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Tutaeva VV, Bobin AN, Ovsiannikova MR, Bulgakova MV, Kuchma YM, Kryukov EV, Rukavitsyn OA. Disseminated form of the Kaposi sarcoma in HIV-negative patient associated with Hodgkin's lymphoma. Oxf Med Case Reports 2020; 2020:omaa069. [PMID: 32995025 PMCID: PMC7507874 DOI: 10.1093/omcr/omaa069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 06/30/2020] [Indexed: 11/26/2022] Open
Abstract
We report a case of a 35-year-old, non-HIV-infected male diagnosed simultaneously with a disseminated form of Kaposi’s sarcoma (KS; skin, stomach and colon are involved) and Hodgkin’s lymphoma. There is no sign of changes in the immune status, but three herpes viruses were detected in the patient’s blood (EBV, HHV6 and HHV8). He received ABVD chemotherapy and achieved complete metabolic remission for Hodgkin’s lymphoma. Moreover, the signs of the disseminated KS were resolved. Our observations indicate that a combination of distinct types of viruses may play an important role in triggering the development of angio- and lymphoproliferative disorders in the same person. In addition, treatment with chemotherapy cycles, which included doxorubicin and vinblastine, led to the stable remission of both diseases.
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Affiliation(s)
- V V Tutaeva
- Department of Hematology, the Main Military Clinical Hospital named after N.N. Burdenko, Moscow, Russia
| | - A N Bobin
- Department of Pathology, the Main Military Clinical Hospital named after N.N. Burdenko, Moscow, Russia
| | - M R Ovsiannikova
- Department of Pathology, the Main Military Clinical Hospital named after N.N. Burdenko, Moscow, Russia
| | - M V Bulgakova
- Department of Radiology, the Main Military Clinical Hospital named after N.N. Burdenko, Moscow, Russia
| | - Y M Kuchma
- Department of Hematology, the Main Military Clinical Hospital named after N.N. Burdenko, Moscow, Russia
| | - E V Kryukov
- The Main Military Clinical Hospital named after N.N. Burdenko, Moscow, Russia
| | - O A Rukavitsyn
- Department of Hematology, the Main Military Clinical Hospital named after N.N. Burdenko, Moscow, Russia
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30
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DiMaio TA, Vogt DT, Lagunoff M. KSHV requires vCyclin to overcome replicative senescence in primary human lymphatic endothelial cells. PLoS Pathog 2020; 16:e1008634. [PMID: 32555637 PMCID: PMC7326280 DOI: 10.1371/journal.ppat.1008634] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 06/30/2020] [Accepted: 05/14/2020] [Indexed: 12/13/2022] Open
Abstract
Kaposi's Sarcoma Herpesvirus (KSHV) is present in the main tumor cells of Kaposi's Sarcoma (KS), the spindle cells, which are of endothelial origin. KSHV is also associated with two B-cell lymphomas, Primary Effusion Lymphoma (PEL) and Multicentric Castleman's Disease. In KS and PEL, KSHV is primarily latent in the infected cells, expressing only a few genes. Although KSHV infection is required for KS and PEL, it is unclear how latent gene expression contributes to their formation. Proliferation of cancer cells occurs despite multiple checkpoints intended to prevent dysregulated cell growth. The first of these checkpoints, caused by shortening of telomeres, results in replicative senescence, where cells are metabolically active, but no longer divide. We found that human dermal lymphatic endothelial cells (LECs) are more susceptible to KSHV infection than their blood-specific endothelial cell counterparts and maintain KSHV latency to higher levels during passage. Importantly, KSHV infection of human LECs but not human BECs promotes their continued proliferation beyond this first checkpoint of replicative senescence. The latently expressed viral cyclin homolog is essential for KSHV-induced bypass of senescence in LECs. These data suggest that LECs may be an important reservoir for KSHV infection and may play a role during KS tumor development and that the viral cyclin is a critical oncogene for this process.
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Affiliation(s)
- Terri A. DiMaio
- Department of Microbiology, University of Washington, Seattle, Washington, United States of America
| | - Daniel T. Vogt
- Department of Microbiology, University of Washington, Seattle, Washington, United States of America
| | - Michael Lagunoff
- Department of Microbiology, University of Washington, Seattle, Washington, United States of America
- * E-mail:
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31
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Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication Is Independent of Anaphase-Promoting Complex Activity. J Virol 2020; 94:JVI.02079-19. [PMID: 32295923 PMCID: PMC7307157 DOI: 10.1128/jvi.02079-19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 04/12/2020] [Indexed: 11/20/2022] Open
Abstract
The anaphase-promoting complex, or cyclosome (APC/C), is a large E3 ubiquitin ligase composed of 14 subunits. The activity of APC/C oscillates during the cell cycle to ensure a timely transition through each phase by promoting the degradation of important cell cycle regulators. Of the human herpesviruses, cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) both impair the activity of APC/C during their lytic replication cycle through virus-encoded protein kinases. Here, we addressed whether the oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) deregulates the activity of APC/C during the lytic replication cycle. To this end, we used the well-characterized iSLK.219 cell model of KSHV infection and established a new infection model of primary lymphatic endothelial cells (LECs) infected with a lytically replicating KSHV BAC16 mutant. In contrast to those of EBV and HCMV, the KSHV lytic cycle occurs while the APC/C is active. Moreover, interfering with the activity of APC/C did not lead to major changes in the production of infectious virus. We further investigated whether rereplication stress induced by the unscheduled activation of the APC/C-CDH1 complex affects the number and integrity of KSHV viral episomes. Deep sequencing of the viral episomes and host chromosomes in iSLK.219 cells revealed that, while distinct regions in the cellular chromosomes were severely affected by rereplication stress, the integrity of the viral episomes remained unaltered.IMPORTANCE DNA viruses have evolved complex strategies to gain control over the cell cycle. Several of them target APC/C, a key cellular machinery that controls the timely progression of the cell cycle, by either blocking or enhancing its activity. Here, we investigated the activity of APC/C during the lytic replication cycle of KSHV and found that, in contrast to that of KSHV's close relatives EBV and HCMV, KSHV lytic replication occurs while the APC/C is active. Perturbing APC/C activity by depleting a core protein or the adaptor proteins of the catalytic domain, and hence interfering with normal cell-cycle progression, did not affect virus replication. This suggests that KSHV has evolved to replicate independently of the activity of APC/C and in various cell cycle conditions.
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32
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Gramolelli S, Elbasani E, Tuohinto K, Nurminen V, Günther T, Kallinen RE, Kaijalainen SP, Diaz R, Grundhoff A, Haglund C, Ziegelbauer JM, Pellinen T, Bower M, Francois M, Ojala PM. Oncogenic Herpesvirus Engages Endothelial Transcription Factors SOX18 and PROX1 to Increase Viral Genome Copies and Virus Production. Cancer Res 2020; 80:3116-3129. [PMID: 32518203 DOI: 10.1158/0008-5472.can-19-3103] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 02/13/2020] [Accepted: 06/04/2020] [Indexed: 11/16/2022]
Abstract
Kaposi sarcoma is a tumor caused by Kaposi sarcoma herpesvirus (KSHV) infection and is thought to originate from lymphatic endothelial cells (LEC). While KSHV establishes latency in virtually all susceptible cell types, LECs support spontaneous expression of oncogenic lytic genes, high viral genome copies, and release of infectious virus. It remains unknown the contribution of spontaneous virus production to the expansion of KSHV-infected tumor cells and the cellular factors that render the lymphatic environment unique to KSHV life cycle. We show here that expansion of the infected cell population, observed in LECs, but not in blood endothelial cells, is dependent on the spontaneous virus production from infected LECs. The drivers of lymphatic endothelium development, SOX18 and PROX1, regulated different steps of the KSHV life cycle. SOX18 enhanced the number of intracellular viral genome copies and bound to the viral origins of replication. Genetic depletion or chemical inhibition of SOX18 caused a decrease of KSHV genome copy numbers. PROX1 interacted with ORF50, the viral initiator of lytic replication, and bound to the KSHV genome in the promoter region of ORF50, increasing its transactivation activity and KSHV spontaneous lytic gene expression and infectious virus release. In Kaposi sarcoma tumors, SOX18 and PROX1 expression correlated with latent and lytic KSHV protein expression. These results demonstrate the importance of two key transcriptional drivers of LEC fate in the regulation of the tumorigenic KSHV life cycle. Moreover, they introduce molecular targeting of SOX18 as a potential novel therapeutic avenue in Kaposi sarcoma. SIGNIFICANCE: SOX18 and PROX1, central regulators of lymphatic development, are key factors for KSHV genome maintenance and lytic cycle in lymphatic endothelial cells, supporting Kaposi sarcoma tumorigenesis and representing attractive therapeutic targets.
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Affiliation(s)
- Silvia Gramolelli
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Endrit Elbasani
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Krista Tuohinto
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Veijo Nurminen
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Thomas Günther
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Riikka E Kallinen
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Seppo P Kaijalainen
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Raquel Diaz
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Adam Grundhoff
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Caj Haglund
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Joseph M Ziegelbauer
- HIV and AIDS Malignancy Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Teijo Pellinen
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
| | - Mark Bower
- National Centre for HIV Malignancy, Chelsea & Westminster Hospital, London, United Kingdom
| | - Mathias Francois
- The David Richmond Program for Cardio-Vascular Research: Gene Regulation and Editing, The Centenary Institute, The University of Sydney, Camperdown, Australia
| | - Päivi M Ojala
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. .,Department of Infectious Diseases, Imperial College London, Medical School Building, St. Mary's Campus, London, United Kingdom
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Eason AB, Sin SH, Shah M, Yuan H, Phillips DJ, Droste M, Shamshiev A, Dittmer DP. DLX1008 (brolucizumab), a single-chain anti-VEGF-A antibody fragment with low picomolar affinity, leads to tumor involution in an in vivo model of Kaposi Sarcoma. PLoS One 2020; 15:e0233116. [PMID: 32407363 PMCID: PMC7224538 DOI: 10.1371/journal.pone.0233116] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 04/28/2020] [Indexed: 12/17/2022] Open
Abstract
Kaposi Sarcoma (KS) is among the most angiogenic cancers in humans and an AIDS-defining condition. KS-associated herpesvirus (KSHV) is necessary for KS development, as is vascular endothelial growth factor (VEGF-A). DLX1008 is a novel anti-VEGF-A antibody single-chain variable fragment (scFv) with low picomolar affinity for VEGF-A. In vivo imaging techniques were used to establish the efficacy of DLX1008 and to establish the mechanism of action; this included non-invasive imaging by ultrasound and optical fluorescence, verified by post-mortem histochemistry. The results showed that DLX1008 was efficacious in a KS mouse model. The NSG mouse xenografts suffered massive internal necrosis or involution, consistent with a lack of blood supply. We found that imaging by ultrasound was superior to external caliper measurements in the validation of the angiogenesis inhibitor DLX1008. Further development of DLX1008 against VEGF-dependent sarcomas is warranted.
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Affiliation(s)
- Anthony B. Eason
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Sang-Hoon Sin
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Mohsin Shah
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
| | - Hong Yuan
- Biomedical Research Imaging Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
| | | | | | | | - Dirk P. Dittmer
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
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Abstract
The etiopathogenesis of severe periodontitis includes herpesvirus-bacteria coinfection. This article evaluates the pathogenicity of herpesviruses (cytomegalovirus and Epstein-Barr virus) and periodontopathic bacteria (Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis) and coinfection of these infectious agents in the initiation and progression of periodontitis. Cytomegalovirus and A. actinomycetemcomitans/P. gingivalis exercise synergistic pathogenicity in the development of localized ("aggressive") juvenile periodontitis. Cytomegalovirus and Epstein-Barr virus are associated with P. gingivalis in adult types of periodontitis. Periodontal herpesviruses that enter the general circulation may also contribute to disease development in various organ systems. A 2-way interaction is likely to occur between periodontal herpesviruses and periodontopathic bacteria, with herpesviruses promoting bacterial upgrowth, and bacterial factors reactivating latent herpesviruses. Bacterial-induced gingivitis may facilitate herpesvirus colonization of the periodontium, and herpesvirus infections may impede the antibacterial host defense and alter periodontal cells to predispose for bacterial adherence and invasion. Herpesvirus-bacteria synergistic interactions, are likely to comprise an important pathogenic determinant of aggressive periodontitis. However, mechanistic investigations into the molecular and cellular interaction between periodontal herpesviruses and bacteria are still scarce. Herpesvirus-bacteria coinfection studies may yield significant new discoveries of pathogenic determinants, and drug and vaccine targets to minimize or prevent periodontitis and periodontitis-related systemic diseases.
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Affiliation(s)
- Casey Chen
- Division of Periodontology, Diagnostic Sciences & Dental Hygiene, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA
| | - Pinghui Feng
- Section of Infection and Immunity, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA
| | - Jørgen Slots
- Division of Periodontology, Diagnostic Sciences & Dental Hygiene, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA
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PDGFRA defines the mesenchymal stem cell Kaposi's sarcoma progenitors by enabling KSHV oncogenesis in an angiogenic environment. PLoS Pathog 2019; 15:e1008221. [PMID: 31881074 PMCID: PMC6980685 DOI: 10.1371/journal.ppat.1008221] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 01/24/2020] [Accepted: 11/15/2019] [Indexed: 11/19/2022] Open
Abstract
Kaposi's sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (Pα(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis. This is because growth in KS-like conditions generates a de-repressed KSHV epigenome allowing oncogenic KSHV gene expression in infected Pα(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected Pα(+)S MSCs to overcome KSHV-driven oncogene-induced senescence and cell cycle arrest via a PDGFRA-signaling mechanism; thus identifying PDGFRA not only as a phenotypic determinant for KS-progenitors but also as a critical enabler for viral oncogenesis.
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Dollery SJ. Towards Understanding KSHV Fusion and Entry. Viruses 2019; 11:E1073. [PMID: 31752107 PMCID: PMC6893419 DOI: 10.3390/v11111073] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 11/10/2019] [Accepted: 11/14/2019] [Indexed: 02/06/2023] Open
Abstract
How viruses enter cells is of critical importance to pathogenesis in the host and for treatment strategies. Over the last several years, the herpesvirus field has made numerous and thoroughly fascinating discoveries about the entry of alpha-, beta-, and gamma-herpesviruses, giving rise to knowledge of entry at the amino acid level and the realization that, in some cases, researchers had overlooked whole sets of molecules essential for entry into critical cell types. Herpesviruses come equipped with multiple envelope glycoproteins which have several roles in many aspects of infection. For herpesvirus entry, it is usual that a collective of glycoproteins is involved in attachment to the cell surface, specific interactions then take place between viral glycoproteins and host cell receptors, and then molecular interactions and triggers occur, ultimately leading to viral envelope fusion with the host cell membrane. The fact that there are multiple cell and virus molecules involved with the build-up to fusion enhances the diversity and specificity of target cell types, the cellular entry pathways the virus commandeers, and the final triggers of fusion. This review will examine discoveries relating to how Kaposi's sarcoma-associated herpesvirus (KSHV) encounters and binds to critical cell types, how cells internalize the virus, and how the fusion may occur between the viral membrane and the host cell membrane. Particular focus is given to viral glycoproteins and what is known about their mechanisms of action.
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Rivera-Soto R, Damania B. Modulation of Angiogenic Processes by the Human Gammaherpesviruses, Epstein-Barr Virus and Kaposi's Sarcoma-Associated Herpesvirus. Front Microbiol 2019; 10:1544. [PMID: 31354653 PMCID: PMC6640166 DOI: 10.3389/fmicb.2019.01544] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 06/20/2019] [Indexed: 12/25/2022] Open
Abstract
Angiogenesis is the biological process by which new blood vessels are formed from pre-existing vessels. It is considered one of the classic hallmarks of cancer, as pathological angiogenesis provides oxygen and essential nutrients to growing tumors. Two of the seven known human oncoviruses, Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), belong to the Gammaherpesvirinae subfamily. Both viruses are associated with several malignancies including lymphomas, nasopharyngeal carcinomas, and Kaposi’s sarcoma. The viral genomes code for a plethora of viral factors, including proteins and non-coding RNAs, some of which have been shown to deregulate angiogenic pathways and promote tumor growth. In this review, we discuss the ability of both viruses to modulate the pro-angiogenic process.
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Affiliation(s)
- Ricardo Rivera-Soto
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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Lee KB, Lee KS, Lee HS. Tumor-Associated Protein Profiles in Kaposi Sarcoma and Mimicking Vascular Tumors, and Their Pathological Implications. Int J Mol Sci 2019; 20:ijms20133142. [PMID: 31252633 PMCID: PMC6651042 DOI: 10.3390/ijms20133142] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 06/14/2019] [Accepted: 06/26/2019] [Indexed: 12/11/2022] Open
Abstract
We investigated protein profiles specific to vascular lesions mimicking Kaposi sarcoma (KS), based on stepwise morphogenesis progression of KS. We surveyed 26 tumor-associated proteins in 130 cases, comprising 39 benign vascular lesions (BG), 14 hemangioendotheliomas (HE), 37 KS, and 40 angiosarcomas (AS), by immunohistochemistry. The dominant proteins in KS were HHV8, lymphatic markers, Rb, phosphorylated Rb, VEGF, and galectin-3. Aberrant expression of p53, inactivation of cell cycle inhibitors, loss of beta-catenin, and increased VEGFR1 were more frequent in AS. HE had the lowest Ki-67 index, and the inactivation rates of cell cycle inhibitors in HE were between those of AS and BG/KS. Protein expression patterns in BG and KS were similar. Clustering analysis showed that the 130 cases were divided into three clusters: AS-rich, BG-rich, and KS-rich clusters. The AS-rich cluster was characterized by high caveolin-1 positivity, abnormal p53, high Ki-67 index, and inactivated p27. The KS-rich cluster shared the features of KS, and the BG-rich group had high positive expression rates of galectin-3 and low bcl2 expression. In conclusion, although the rate was different, AS and HE tended to have less cell cycle marker expression than KS, and features of BG and activated KS cell signaling were similar.
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MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Child
- Child, Preschool
- Diagnosis, Differential
- Female
- Galectin 3/blood
- Galectin 3/genetics
- Galectin 3/metabolism
- Gene Expression Regulation, Neoplastic
- Hemangioma/blood
- Hemangioma/genetics
- Hemangioma/pathology
- Humans
- Male
- Middle Aged
- Proto-Oncogene Proteins c-bcl-2/blood
- Proto-Oncogene Proteins c-bcl-2/genetics
- Proto-Oncogene Proteins c-bcl-2/metabolism
- Sarcoma, Kaposi/blood
- Sarcoma, Kaposi/genetics
- Sarcoma, Kaposi/pathology
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Affiliation(s)
- Kyoung Bun Lee
- Department of Pathology, Seoul National University Hospital, Seoul 110-799, Korea
| | - Kyu Sang Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam 463-707, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam 463-707, Korea.
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He M, Cheng F, da Silva SR, Tan B, Sorel O, Gruffaz M, Li T, Gao SJ. Molecular Biology of KSHV in Relation to HIV/AIDS-Associated Oncogenesis. Cancer Treat Res 2019; 177:23-62. [PMID: 30523620 DOI: 10.1007/978-3-030-03502-0_2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Discovered in 1994, Kaposi's sarcoma-associated herpesvirus (KSHV) has been associated with four human malignancies including Kaposi's sarcoma, primary effusion lymphoma, a subset of multicentric Castleman's disease, and KSHV inflammatory cytokine syndrome. These malignancies mostly occur in immunocompromised patients including patients with acquired immunodeficiency syndrome and often cause significant mortality because of the lack of effective therapies. Significant progresses have been made to understand the molecular basis of KSHV infection and KSHV-induced oncogenesis in the last two decades. This chapter provides an update on the recent advancements focusing on the molecular events of KSHV primary infection, the mechanisms regulating KSHV life cycle, innate and adaptive immunity, mechanism of KSHV-induced tumorigenesis and inflammation, and metabolic reprogramming in KSHV infection and KSHV-transformed cells.
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Affiliation(s)
- Meilan He
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Fan Cheng
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Suzane Ramos da Silva
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Brandon Tan
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Océane Sorel
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Marion Gruffaz
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Tingting Li
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Shou-Jiang Gao
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, USA.
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40
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Lazăr DC, Avram MF, Romoșan I, Văcariu V, Goldiș A, Cornianu M. Malignant hepatic vascular tumors in adults: Characteristics, diagnostic difficulties and current management. World J Clin Oncol 2019; 10:110-135. [PMID: 30949442 PMCID: PMC6441663 DOI: 10.5306/wjco.v10.i3.110] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 02/23/2019] [Accepted: 03/12/2019] [Indexed: 02/06/2023] Open
Abstract
Malignant vascular tumors of the liver include rare primary hepatic mesenchymal tumors developed in the background of a normal liver parenchyma. Most of them are detected incidentally by the increased use of performing imaging techniques. Their diagnosis is challenging, involving clinical and imaging criteria, with final confirmation by histology and immunohistochemistry. Surgery represents the mainstay of treatment. Liver transplantation (LT) has improved substantially the prognosis of hepatic epithelioid hemangioendothelioma (HEHE), with 5-year patient survival rates of up to 81%, based on the European Liver Intestine Transplantation Association-European Liver Transplant Registry study. Unfortunately, the results of surgery and LT are dismal in cases of hepatic angiosarcoma (HAS). Due to the disappointing results of very short survival periods of approximately 6-7 mo after LT, because of tumor recurrence and rapid progression of the disease, HAS is considered an absolute contraindication to LT. Recurrences after surgical resection are high in cases of HEHE and invariably present in cases of HAS. The discovery of reliable prognostic markers and the elaboration of prognostic scores following LT are needed to provide the best therapeutic choice for each patient. Studies on a few patients have demonstrated the stabilization of the disease in a proportion of patients with hepatic vascular tumors using novel targeted antiangiogenic agents, cytokines or immunotherapy. These new approaches, alone or in combination with other therapeutic modalities, such as surgery and classical chemotherapy, need further investigation to assess their role in prolonging patient survival. Personalized therapeutic algorithms according to the histopathological features, behavior, molecular biology and genetics of the tumors should be elaborated in the near future for the management of patients diagnosed with primary malignant vascular tumors of the liver.
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Affiliation(s)
- Daniela Cornelia Lazăr
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Romania
| | - Mihaela Flavia Avram
- Department of Surgery X, 1st Surgery Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Romania
| | - Ioan Romoșan
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Romania
| | - Violetta Văcariu
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Romania
| | - Adrian Goldiș
- Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Romania
| | - Mărioara Cornianu
- Department of Pathology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Romania
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41
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McNamara RP, Chugh PE, Bailey A, Costantini LM, Ma Z, Bigi R, Cheves A, Eason AB, Landis JT, Host KM, Xiong J, Griffith JD, Damania B, Dittmer DP. Extracellular vesicles from Kaposi Sarcoma-associated herpesvirus lymphoma induce long-term endothelial cell reprogramming. PLoS Pathog 2019; 15:e1007536. [PMID: 30716130 PMCID: PMC6361468 DOI: 10.1371/journal.ppat.1007536] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 12/17/2018] [Indexed: 01/08/2023] Open
Abstract
Extracellular signaling is a mechanism that higher eukaryotes have evolved to facilitate organismal homeostasis. Recent years have seen an emerging interest in the role of secreted microvesicles, termed extracellular vesicles (EV) or exosomes in this signaling network. EV contents can be modified by the cell in response to stimuli, allowing them to relay information to neighboring cells, influencing their physiology. Here we show that the tumor virus Kaposi's Sarcoma-associated herpesvirus (KSHV) hijacks this signaling pathway to induce cell proliferation, migration, and transcriptome reprogramming in cells not infected with the virus. KSHV-EV activates the canonical MEK/ERK pathway, while not alerting innate immune regulators, allowing the virus to exert these changes without cellular pathogen recognition. Collectively, we propose that KSHV establishes a niche favorable for viral spread and cell transformation through cell-derived vesicles, all while avoiding detection.
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Affiliation(s)
- Ryan P McNamara
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Pauline E Chugh
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- Q2 Solutions-EA Genomics, Morrisville, North Carolina
| | - Aubrey Bailey
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Lindsey M Costantini
- Department of Biological and Biomedical Sciences, North Carolina Central University, Durham, North Carolina
| | - Zhe Ma
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Rachele Bigi
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Avery Cheves
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Anthony B Eason
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Justin T Landis
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kurtis M Host
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Jie Xiong
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Jack D Griffith
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Blossom Damania
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Dirk P Dittmer
- Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Dittmer DP, Damania B. Kaposi's Sarcoma-Associated Herpesvirus (KSHV)-Associated Disease in the AIDS Patient: An Update. Cancer Treat Res 2019; 177:63-80. [PMID: 30523621 PMCID: PMC7201581 DOI: 10.1007/978-3-030-03502-0_3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2023]
Abstract
In this book chapter, we review the current knowledge of the biology and pathogenesis of Kaposi's sarcomaassociated herpesvirus (KSHV). We describe the lifecycle of KSHV, the cancers associated with this virus, as well as current treatment modalities.
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Affiliation(s)
- Dirk P Dittmer
- Department of Microbiology & Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, CB #7295, NC, 27599, Chapel Hill, USA
| | - Blossom Damania
- Department of Microbiology & Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, CB #7295, NC, 27599, Chapel Hill, USA.
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Pathological Features of Kaposi's Sarcoma-Associated Herpesvirus Infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1045:357-376. [PMID: 29896675 DOI: 10.1007/978-981-10-7230-7_16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV, human herpesvirus 8, or HHV-8) was firstly discovered in Kaposi's sarcoma tissue derived from patients with acquired immune deficiency syndrome. KSHV infection is associated with malignancies and certain inflammatory conditions. In addition to Kaposi's sarcoma, KSHV has been detected in primary effusion lymphoma, KSHV-associated lymphoma, and some cases of multicentric Castleman disease (MCD). Recently, KSHV inflammatory cytokine syndrome (KICS) was also defined as a KSHV-associated disease. In KSHV-associated malignancies, such as Kaposi's sarcoma and lymphoma, KSHV latently infects almost all tumor cells, and lytic proteins are rarely expressed. A high titer of KSHV is detected in the sera of patients with MCD and KICS, and the expression of lytic proteins such as ORF50, vIL-6, and vMIP-I and vMIP-II is frequently observed in the lesions of patients with these diseases. Immunohistochemistry of LANA-1 is an important diagnostic tool for KSHV infection. However, much of the pathogenesis of KSHV remains to be elucidated, especially regarding oncogenesis. Some viral proteins have been shown to have transforming activity in mammalian cells; however, these proteins are not expressed in latently KSHV-infected cells. KSHV encodes homologs of cellular proteins in its genome such as cyclin D, G-protein coupled protein, interleukin-6, and macrophage inflammatory protein-1 and -2. Molecular mimicry by these viral proteins may contribute to the establishment of microenvironments suitable for tumor growth. In this review, the virus pathogenesis is discussed based on pathological and experimental findings and clinical aspects.
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Abstract
RNA modifications have generated much interest in the virology field, as recent works have shown that many viruses harbor these marks and modify cellular marks. The most abundant mRNA modification in eukaryotic cells, N6-methyladenosine (m6A), has been examined extensively at the genome-wide scale in both cellular and viral contexts. This Gem discusses the role of m6A in gene regulation and describes recent advancements in Kaposi's sarcoma-associated herpesvirus (KSHV) and simian virus 40 (SV40) research. We provide insights into future research related to m6A in DNA viruses.
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Affiliation(s)
- Brandon Tan
- Department of Systems Biology, City of Hope, Monrovia, California, USA
| | - Shou-Jiang Gao
- UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Laboratory of Human Virology and Oncology, Shantou University Medical College, Shantou, Guangdong, People's Republic of China
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Zhu X, Chen Y, Zhu W, Ji M, Xu J, Guo Y, Gao F, Gu W, Yang X, Zhang C. Oroxylin A inhibits Kaposi's sarcoma-associated herpes virus (KSHV) vIL-6-mediated lymphatic reprogramming of vascular endothelial cells through modulating PPARγ/Prox1 axis. J Med Virol 2018; 91:463-472. [PMID: 30318784 DOI: 10.1002/jmv.25337] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 10/08/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND PURPOSE Kaposi's sarcoma-associated herpes virus (KSHV) vIL-6 is sufficient to induce lymphatic reprogramming of vascular endothelial cells, which is a key event in Kaposi's sarcoma (KS) development. This study was aimed to investigate the effect of Chinese herb oroxylin A on lymphatic reprogramming and neovascularization by KSHV vIL-6 in vitro and in vivo. METHODS The lymphatic-phenotype endothelial cell line was generated by lentiviral KSHV vIL-6 infection. Cell viability and apoptosis were determined by MTT assay or flow cytometry with annexin V/propidium iodide staining. Migration, invasion, and neovascularization of the vIL-6-expressing lymphatic-phenotype endothelial cells were determined by wound healing assay, transwell chamber assay, microtubule formation assay, and chick chorioallantoic membrane assay, respectively. Quantitative polymerase chain reaction and Western blot analysis were used to test the expression of Prox1, VEGFR3, podoplanin, LYVE-1, and PPARγ in cells. Co-localization of Prox1 and PPARγ was determined by immunofluorescence. Ubiquitination of Prox1 was detected by in vivo ubiquitination assay. RESULTS The lymphatic-phenotype endothelial cell line expressing KSHV vIL-6 was successfully generated. Oroxylin A induced cellular invasion abrogation, apoptosis induction, and neovascularization inhibition of the vIL-6-expressing endothelial cells. Mechanically, oroxylin A elevated PPARγ expression, which in turn interacted with and facilitated Prox1 to undergo ubiquitinational degradation, and subsequently leads to VEGFR3, LYVE-1, and podoplanin reduction. CONCLUSION Through modulating PPARγ/Prox1 axis, oroxylin A inhibits lymphatic reprogramming and neovascularization of KSHV vIL-6. Thus, oroxylin A may serve as a candidate for the treatment of KS as well as other aggressive angiomas.
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Affiliation(s)
- Xiaofei Zhu
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yun Chen
- Department of Gynecology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenqiang Zhu
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Mingde Ji
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jing Xu
- Department of Respiratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuanyuan Guo
- Department of Biochemistry, Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Gao
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wanjian Gu
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xuewen Yang
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Chunbing Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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Konradt C, Hunter CA. Pathogen interactions with endothelial cells and the induction of innate and adaptive immunity. Eur J Immunol 2018; 48:1607-1620. [PMID: 30160302 DOI: 10.1002/eji.201646789] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 07/24/2018] [Accepted: 08/23/2018] [Indexed: 12/28/2022]
Abstract
There are over 10 trillion endothelial cells (EC) that line the vasculature of the human body. These cells not only have specialized functions in the maintenance of homeostasis within the circulation and various tissues but they also have a major role in immune function. EC also represent an important replicative niche for a subset of viral, bacterial, and parasitic organisms that are present in the blood or lymph; however, there are major gaps in our knowledge regarding how pathogens interact with EC and how this influences disease outcome. In this article, we review the literature on EC-pathogen interactions and their role in innate and adaptive mechanisms of resistance to infection and highlight opportunities to address prominent knowledge gaps.
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Affiliation(s)
- Christoph Konradt
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christopher A Hunter
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
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47
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Ma W, Oliver G. Lymphatic Endothelial Cell Plasticity in Development and Disease. Physiology (Bethesda) 2018; 32:444-452. [PMID: 29021364 DOI: 10.1152/physiol.00015.2017] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 07/17/2017] [Accepted: 07/17/2017] [Indexed: 11/22/2022] Open
Abstract
The lymphatic vasculature is crucial for maintaining tissue-fluid homeostasis, providing immune surveillance and mediating lipid absorption. The lymphatic vasculature is tightly associated with the blood vasculature, although it exhibits distinct morphological and functional features. Endothelial cells (ECs) lineage fate specification is determined during embryonic development; however, accumulating evidence suggests that differentiated ECs exhibit remarkable heterogeneity and plasticity. In this review, we provide an overview of the molecular mechanisms promoting lymphatic cell fate specification in the mammalian embryo. We also summarize available data suggesting that lymphatic EC fate is reprogrammable in normal and pathological settings. We further discuss the possible advantages of cell fate manipulation to treat certain disorders associated with lymphatic dysfunction.
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Affiliation(s)
- Wanshu Ma
- Center for Vascular & Developmental Biology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Guillermo Oliver
- Center for Vascular & Developmental Biology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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48
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Tan B, Gao SJ. RNA epitranscriptomics: Regulation of infection of RNA and DNA viruses by N 6 -methyladenosine (m 6 A). Rev Med Virol 2018; 28:e1983. [PMID: 29698584 PMCID: PMC6339815 DOI: 10.1002/rmv.1983] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 03/24/2018] [Accepted: 03/29/2018] [Indexed: 02/05/2023]
Abstract
N6 -methyladenosine (m6 A) was discovered 4 decades ago. However, the functions of m6 A and the cellular machinery that regulates its changes have just been revealed in the last few years. m6 A is an abundant internal mRNA modification on cellular RNA and is implicated in diverse cellular functions. Recent works have demonstrated the presence of m6 A in the genomes of RNA viruses and transcripts of a DNA virus with either a proviral or antiviral role. Here, we first summarize what is known about the m6 A "writers," "erasers," "readers," and "antireaders" as well as the role of m6 A in mRNA metabolism. We then review how the replications of numerous viruses are enhanced and restricted by m6 A with emphasis on the oncogenic DNA virus, Kaposi sarcoma-associated herpesvirus (KSHV), whose m6 A epitranscriptome was recently mapped. In the context of KSHV, m6 A and the reader protein YTHDF2 acts as an antiviral mechanism during viral lytic replication. During viral latency, KSHV alters m6 A on genes that are implicated in cellular transformation and viral latency. Lastly, we discuss future studies that are important to further delineate the functions of m6 A in KSHV latent and lytic replication and KSHV-induced oncogenesis.
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Affiliation(s)
- Brandon Tan
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Shou-Jiang Gao
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
- Laboratory of Human Virology and Oncology, Shantou University Medical College, Shantou, Guangdong, People's Republic of China
- Department of Microbiology, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
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Vangipuram R, Tyring SK. Epidemiology of Kaposi sarcoma: review and description of the nonepidemic variant. Int J Dermatol 2018; 58:538-542. [DOI: 10.1111/ijd.14080] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 05/10/2018] [Accepted: 05/16/2018] [Indexed: 12/23/2022]
Affiliation(s)
- Ramya Vangipuram
- Department of Dermatology University of Texas Health Sciences Center at Houston Houston TX USA
- Center for Clinical Studies Houston TX USA
| | - Stephen K. Tyring
- Department of Dermatology University of Texas Health Sciences Center at Houston Houston TX USA
- Center for Clinical Studies Houston TX USA
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50
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Mariggiò G, Koch S, Schulz TF. Kaposi sarcoma herpesvirus pathogenesis. Philos Trans R Soc Lond B Biol Sci 2018; 372:rstb.2016.0275. [PMID: 28893942 PMCID: PMC5597742 DOI: 10.1098/rstb.2016.0275] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2017] [Indexed: 12/15/2022] Open
Abstract
Kaposi sarcoma herpesvirus (KSHV), taxonomical name human gammaherpesvirus 8, is a phylogenetically old human virus that co-evolved with human populations, but is now only common (seroprevalence greater than 10%) in sub-Saharan Africa, around the Mediterranean Sea, parts of South America and in a few ethnic communities. KSHV causes three human malignancies, Kaposi sarcoma, primary effusion lymphoma, and many cases of the plasmablastic form of multicentric Castleman's disease (MCD) as well as occasional cases of plasmablastic lymphoma arising from MCD; it has also been linked to rare cases of bone marrow failure and hepatitis. As it has colonized humans physiologically for many thousand years, cofactors are needed to allow it to unfold its pathogenic potential. In most cases, these include immune defects of genetic, iatrogenic or infectious origin, and inflammation appears to play an important role in disease development. Our much improved understanding of its life cycle and its role in pathogenesis should now allow us to develop new therapeutic strategies directed against key viral proteins or intracellular pathways that are crucial for virus replication or persistence. Likewise, its limited (for a herpesvirus) distribution and transmission should offer an opportunity for the development and use of a vaccine to prevent transmission. This article is part of the themed issue ‘Human oncogenic viruses’.
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Affiliation(s)
- Giuseppe Mariggiò
- Institute of Virology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany.,German Centre for Infection Research, Hannover-Braunschweig site, Hannover, Germany
| | - Sandra Koch
- Institute of Virology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany.,German Centre for Infection Research, Hannover-Braunschweig site, Hannover, Germany
| | - Thomas F Schulz
- Institute of Virology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany .,German Centre for Infection Research, Hannover-Braunschweig site, Hannover, Germany
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