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Kaposi's sarcoma (KS) is an endothelial tumor causally linked to Kaposi's sarcoma herpesvirus (KSHV) infection. At early stages of KS, inflammation and aberrant neoangiogenesis are predominant, while at late stages the disease is characterized by the proliferation of KSHV-infected spindle cells (SC). Since KSHV infection modifies the endothelial cell (EC) identity, the origin of SCs remains elusive. Yet, pieces of evidence indicate the lymphatic origin. KSHV-infected ECs display increased proliferative, angiogenic and migratory capacities which account for KS oncogenesis. Here we propose a model in which KSHV reprograms the EC identity, induces DNA damage and establishes a dysregulated gene expression program involving interplay of latent and lytic genes allowing continuous reinfection of ECs attracted to the tumor by the secretion of virus-induced cellular factors., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Kaposi's sarcoma (KS) is an unusual neoplasm characterized by extensive neoangiogenesis, infiltrates of inflammatory cells and atypically differentiated spindle cells of endothelial origin. KS is caused by an oncogenic γ-herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus-8 (HHV-8). Several KSHV proteins can subvert multiple cellular angiogenic, mitogenic and inflammatory pathways. Here, we discuss the KSHV encoded membrane proteins vGPCR, K1 and K15, with a particular emphasis on their activation of cellular signaling pathways and their role in the development of specific features of KS., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Herpesviruses can establish latent infections in the host with severely limited viral gene expression. Kaposi's Sarcoma-associated herpesvirus (KSHV) is found predominantly in the latent state in the main KS tumor cell, a cell of endothelial origin. While many viruses alter host cell metabolism during productive infection, latent KSHV infection of endothelial cells activates metabolic pathways that are activated in many cancer cells. Inhibition of these major metabolic pathways leads to apoptotic cell death of the latently infected cells. The study of KSHV activation of metabolism may lead to novel therapeutic options for eliminating latent infection of gamma-herpesviruses and could also lead to a deeper mechanistic understanding of how to target cancer cell metabolism., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A woman in her 30s presented with recurrent low-grade fever and cough (onset, 1 week). She reported occasional night sweats and weight loss of approximately 20 pounds over the past 4 months. She denied nausea, vomiting, diarrhea, or any urinary complaints. Her past medical history was significant for chronic hepatitis C and HIV infection, the latter diagnosed in 2001. She was noncompliant with highly active antiretroviral therapy for more than 4 years and had pneumocystis pneumonia 2 years prior to this presentation. She had a 10-pack per year smoking history and reported active use of cocaine and heroin. The patient denied any occupational exposures., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Kaposi sarcoma (KS) is associated with human herpesvirus (HHV)-8 and is dependent on the induction of vascular endothelial growth factors (VEGFs). VEGF regulates genes that provide arterial or venous identity to endothelial cells, such as the induction of EphrinB2, which phenotypically defines arterial endothelial cells and pericytes, and represses EphB4, which defines venous endothelial cells. We conducted a comprehensive analysis of the Eph receptor tyrosine kinases to determine which members are expressed and therefore contribute to KS pathogenesis. We demonstrated limited Eph/Ephrin expression; notably, the only ligand highly expressed is EphrinB2. We next studied the biologic effects of blocking EphrinB2 using the extracellular domain of EphB4 fused with human serum albumin (sEphB4-HSA). sEphB4-HSA inhibited migration and invasion of the KS cells in vitro in response to various growth factors. Finally, we determined the biologic effects of combining sEphB4-HSA and an antibody to VEGF. sEphB4-HSA was more active than the VEGF antibody, and combination of the 2 had at least additive activity. sEphB4-HSA reduced blood vessel density, pericyte recruitment, vessel perfusion, and increased hypoxia, with an associated increase in VEGF and DLL4 expression. The combination of sEphB4-HSA and VEGF antibody is a rational treatment combination for further investigation.

Background: Acquired immune deficiency syndrome related Kaposi's sarcoma (AIDS-KS) remains a significant cause of morbidity and mortality. We describe for the first time a proportion of patients with AIDS-KS who presented with no evidence of cutaneous disease., Patients and Methods: From our cohort of 5932 individuals infected with the human immunodeficiency virus (HIV-1) treated in the HAART era, 319 were identified with KS. Of these, 11 patients (5.4%) were diagnosed with KS without the presence of any cutaneous disease. We compared their survival, clinical, immunological and virological characteristics to other individuals with KS., Results: There were no statistically significant differences in survival, CD4 count or HIV viral load at KS presentation. We observed that tumour-associated oedema (P = 0.046) and non-oral gastrointestinal KS (P = 0.042) were significantly more common in patients with non-cutaneous KS. Only one case of non-cutaneous KS was observed prior to the era of highly active anti-retroviral therapy (HAART)., Conclusions: Non-cutaneous KS is a recognisable condition; patients should be treated with the standard of care as their prognosis is not inferior. This is likely to reflect a strong immune response, in the era of HAART.

In the present study, we evaluated whether motility of Kaposi's sarcoma (KS) cells induced by platelet-activating factor (PAF) is dependent on the regulation of adherens junctions components. The results obtained indicate that PAF dose and time dependently reduced the endogenous expression of the main components of the adherens junctions: VE-cadherin, alpha-catenin, and beta-catenin. In addition, PAF initiated events that directly or indirectly up-regulated both the tyrosine and serine/threonine phosphorylation pathways, and both types of phosphorylation of beta-catenin were involved in the motility of KS cells. This motility was abrogated by addition of the tyrosine kinase inhibitor genistein, suggesting that this phosphorylation is an important signal responsible for breaking down the adherens junctions and diminishing the ability of neighboring cells to interact. Furthermore, immunofluorescence analysis showed that beta-catenin and VE-cadherin staining changed from a uniform distribution along the membrane of controls to a diffuse pattern with gap formation in PAF-treated KS cells. In conclusion, the data presented here indicate that PAF induces tumor cell motility by altering cell-cell adhesion through beta-catenin phosphorylation.

The prevalence of Kaposi's sarcoma (KS) after renal transplantation varies greatly depending on geographic and ethnic backgrounds. Out of 1400 live-donor kidney transplantation, 50 patients developed malignancy in our center. Kaposi's sarcoma was diagnosed in 24 patients (48%). Twenty patients were males and the main age of the patients was 29.8 +/- 11.1 years. They developed KS at a mean interval of 33.9 +/- 27.2 months, and the main duration of follow up was 62.2 +/- 50.7 months. Nineteen patients were cyclosporinee treated while four patients were azathioprine-based. Cutaneous KS was diagnosed in 20 patients, visceral in one, and three patients had both lesions. We found that the frequency of HLA-A1, -A2 and -DR5 were significantly common in KS patients. Titrated reduction of immunosuppression was initially tried in all patients. Bleomycin injection and superficial irradiation was tried in some cases. Response to therapeutic modalities was good in cutaneous form of KS. Twelve patients died (50%), two of them with functioning graft. We conclude that KS is the most common malignancy after kidney transplantation in our locality. Patients on cyclosporine are more prone to develop KS, and certain HLA-antigens may predispose to this. Early diagnosis and interference carry a favorable outcome.

Endomucin is an endothelial sialomucin that was recently identified with the help of monoclonal antibodies raised against mouse endothelial cells. Cloning of human endomucin allowed us to generate monoclonal antibodies against soluble recombinant forms of human endomucin. In this study, we investigated the expression of this novel molecule in human skin under different conditions, using the monoclonal antibodies. In normal human skin, endomucin was detected for the monoclonal antibody L6H10 by immunoblotting, and immunohistologic analysis of wax-embedded sections revealed that this glycoprotein is expressed on capillaries, venules, and lymphatic vessels. Interestingly, staining of arterial endothelium was either weak or focal using the monoclonal antibodies against endomucin. In situ hybridization of normal human skin confirmed the expression pattern on the messenger RNA level obtained above. We further analyzed the expression of endomucin in skin biopsy specimens from patients with inflammatory skin diseases, such as atopic dermatitis, psoriasis, lichen planus, cutaneous lupus erythematosus, and T cell lymphoma as well as with vascular skin tumors, such as hemangioma, pyogenic granuloma, angiolipoma, Kaposi's sarcoma, and angiosarcoma. We found endomucin expressed on the endothelium of each tissue, concluding that this novel molecule is a new endothelial-specific marker in the study of normal and diseased human skin.

Kaposi's sarcoma-associated herpesvirus (KSHV) is present in all epidemiologic forms of Kaposi's sarcoma (KS). The KSHV genome contains several open reading frames which are potentially implicated in the development of KS. Some are unique to KSHV; others are homologous to cellular genes. The putative role of these genes in the genesis of KS is discussed.

All forms of Kaposi's sarcoma (KS) are characterized by spindle cell proliferation, angiogenesis, inflammatory cell infiltration, and edema. We have previously reported that spindle cells of primary KS lesions and KS-derived spindle cell cultures express high levels of basic fibroblast growth factor (bFGF), which is promoted by the inflammatory cytokines identified in these lesions. These cytokines, namely, tumor necrosis factor, interleukin-1, and interferon-gamma, induce production and release of bFGF, which stimulates angiogenesis and spindle cell growth in an autocrine fashion. Here we show that both AIDS-KS and classical KS lesions co-express vascular endothelial growth factor (VEGF) and bFGF. VEGF production by KS cells is promoted synergistically by inflammatory cytokines present in conditioned media from activated T cells and in KS lesions. KS cells show synthesis of VEGF isoforms that are mitogenic to endothelial cells but not to KS spindle cells, suggesting a prevailing paracrine effect of this cytokine. This may be due to the level of expression of the flt-1-VEGF receptor that is down-regulated in KS cells as compared with endothelial cells. KS-derived bFGF and VEGF synergize in inducing endothelial cell growth as shown by studies using both neutralizing antibodies and antisense oligodeoxynucleotides directed against these cytokines. In addition, VEGF and bFGF synergize to induce angiogenic KS-like lesions in nude mice and vascular permeability and edema in guinea pigs. These results indicate that inflammatory cytokines present in KS lesions stimulate the production of bFGF and VEGF, which, in turn, cooperate to induce angiogenesis, edema, and KS lesion formation.

Abundant vasculature with increased permeability is a prominent histological feature of Kaposi's sarcoma (KS), a multifocal, cytokine-regulated tumor. Here we report on the role of vascular endothelial growth factor (VEGF) in AIDS-KS angiogenesis and vascular permeability. We demonstrate that different cytokines, which were previously shown to be active in KS development, modulate VEGF expression in KS spindle cells and cooperate with VEGF on the functional level. Northern blot analysis as well as studies on single cells using in situ hybridization revealed that VEGF expression in cultivated AIDS-KS spindle cells is up-regulated by platelet-derived growth factor-B and interleukin-1 beta. Western blot and enzyme-linked immunosorbent assay analysis of cell culture supernatants demonstrated that the VEGF protein is secreted by stimulated AIDS-KS spindle cells in sufficiently high amounts to activate proliferation of human dermal microvascular endothelial cells. Basic fibroblast growth factor did not increase VEGF expression but acted synergistically with VEGF in the induction of angiogenic KS-like lesions in a mouse model in vivo. Angiogenesis and cellularity of KS-like lesions were clearly increased when both factors were injected simultaneously into the flanks of mice, compared with separate injection of each factor. A comparable angiogenic reaction as obtained by simultaneous injection of basic fibroblast growth factor and VEGF was observed when cell culture supernatants of AIDS-KS spindle cells were used for these experiments. Finally, analysis of primary human AIDS-KS lesions revealed that high amounts of VEGF mRNA and protein were present in KS spindle cells in vivo. These data provide evidence that VEGF, in concert with platelet-derived growth factor-B, interleukin-1 beta, and basic fibroblast growth factor, is a key mediator of angiogenesis and vascular permeability in KS lesions in vivo.

Scatter factor (hepatocyte growth factor) is a mesenchyme-derived cytokine that stimulates motility, proliferation, and morphogenesis of epithelia. These responses are transduced through the c-met protooncogene product, a transmembrane tyrosine kinase that functions as the SF receptor. SF is a potent angiogenic molecule, and its angiogenic activity is mediated primarily through direct actions on endothelial cells. These include stimulation of cell motility, proliferation, protease production, invasion, and organization into capillary-like tubes. SF is chronically overexpressed in tumors, suggesting that it may function as a tumor angiogenesis factor. SF production in tumors may be due, in part, to an abnormal tumor-stroma interaction, in which the tumor cells secrete factors (SF-IFs) that stimulate SF production by tumor-associated stromal cells. Studies suggest a link between tumor suppressors (antioncogenes) and inhibition of angiogenesis. We hypothesize that tumor suppressor gene mutations may contribute to the activation of an SF-IF-->SF-->c-met pathway, leading to an invasive and angiogenic tumor phenotype. Modulation of this pathway may, ultimately, provide clinically useful methods of enhancing or inhibiting angiogenesis.

Secretion of angiogenesis inhibitors and stimulators is modulated during in vitro differentiation of embryonic chick growth plate chondrocytes. Supernatants from dedifferentiated cells undergoing maturation to hypertrophic chondrocytes in suspension progressively inhibited vascular cell random migration and invasion of basement membrane matrix by endothelial cells. Maximal inhibition was exhibited by conditioned medium from hypertrophic chondrocytes. The same medium also repressed vascular cell migration induced by highly angiogenic Kaposi's sarcoma cell supernatants and prevented formation of an anastomosed network of tube-like structures by endothelial cells plated on matrigel. On the contrary, when the suspension culture of hypertrophic chondrocytes was supplemented with ascorbic acid, a condition leading to the formation of a mineralized tissue similar to calcified cartilage, a dramatic switch to production of angiogenic activity was observed. Medium conditioned by osteoblast-like cells derived from hypertrophic chondrocytes also induced vascular cell migration and invasion of basement membrane matrix. The presence of angiogenic activity in the conditioned medium was assessed also by an in vivo assay in mice using reconstituted basement membrane associated with heparin. Therefore, interactions of chondrocytes with their extracellular matrix are an absolute requirement for the expression of angiogenic activities by hypertrophic chondrocytes at late developmental stages.

Dermal dendrocytes represent a population of resident cells of the dermis identified recently by virtue of the immunohistochemical expression of the coagulation factor XIIIa (fXIIIa). These dendritic cells of bone-marrow origin bear particular histoenzymatic and immunohistochemical features, some of which are shared with antigen-presenting cells; however, they are clearly distinct from epidermal Langerhans cells. Dermal dendrocytes could act as macrophages, antigen-presenting cells or participate in the homeostasis of macromolecules of the dermis. These cells give rise to some cutaneous tumours and seem involved in inflammatory dermatoses where they act by means of cytokine production; they could even represent targets of HIV infection. Future functional studies will hopefully lead to a better understanding of their precise role in normal and diseased skin, which remains presently partly speculative.

This article has reviewed the disease process and oral manifestations of AIDS. Specifically, dentists should review the medical history and perform an overall health assessment for all dental patients before treatment is rendered. Attention should be directed to the prodromal signs and symptoms of AIDS. If dental treatment of a patient with AIDS is required, strict infection control guidelines are mandatory.

Kaposi's sarcoma has many unusual features: for example, the pronounced male preponderance; its appearance in "crops" rather than as primary tumour with metastases; a substantial rate of spontaneous remission; the predictability of involved sites; the lack of aneuploidy; and the strong association with immunodeficiency. These features and other evidence suggest that it is not a malignant neoplasm but a benign, potentially controllable and reversible hyperplasia.

We describe a 29-year-old homosexual man with acquired immunodeficiency syndrome who developed pericardial effusion and tamponade. Pericardiocentesis resulted in clinical improvement. All diagnostic tests on pericardial fluid were negative. At autopsy, extensive plaques and nodules of Kaposi's sarcoma were found studding the epicardium, and no other cause of effusion was found. To our knowledge there has been no previous case of Kaposi's sarcoma associated with pericardial effusion and tamponade reported in patients with AIDS. Kaposi's sarcoma should be considered in the differential diagnosis of pericardial effusion in these patients.