mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis.

Feb 2013

Roy D, Sin SH, Lucas AS, Venkataramanan R, Wang L, Eason A, Chavakula V, Tamburro KM, Hilton IB, Damania B,Dittmer DP.

Source

Lineberger Comprehensive Cancer Center, UNC Chapel Hill.

Abstract

Kaposi's Sarcoma (KS) originates from endothelial cells and it is one of the most overt angiogenic tumors. In Sub-Saharan Africa, where HIV and the Kaposi Sarcoma-associated Herpes Virus (KSHV) are endemic, KS is the most common cancer overall, but model systems for disease study are insufficient. Here we report the development of a novel mouse model of KS where KSHV is retained stably and tumors are elicited rapidly. Tumor growth was sensitive to specific allosteric inhibitors (rapamycin, CCI-779, RAD001) of the pivotal cell growth regulator mTOR. Inhibition of tumor growth was durable up to 130 days and reversible. mTOR blockade reduced VEGF secretion and formation of tumor vasculature. Together, the results demonstrated that mTOR inhibitors exert a direct anti-KS effect by inhibiting angiogenesis and paracrine effectors, suggesting their application as a new treatment modality for KS and other cancers of endothelial origin.

Full Text

Cancer Research

Do we still need chemotherapy for AIDS-associated Kaposi's sarcoma?

Feb 2013

Pria AD, Hayward K, Bower M.

Source

National Centre for HIV Malignancy, Chelsea & Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK.

Abstract

The widespread introduction of effective combination antiretroviral therapy (cART) has had a major influence on the epidemiology and natural history of AIDS-associated Kaposi's sarcoma (AIDS-KS). cART has reduced the incidence of AIDS-KS, and it has been shown to be an effective treatment for early-stage KS. So with the widespread availability of cART, is systemic chemotherapy still required for AIDS-KS? Two indications appear to remain: advanced-stage AIDS-KS and patients who have progressive KS despite effective cART including immune reconstitution inflammatory syndrome KS.

Expert Reviews

Kaposi sarcoma.

Radu O, Pantanowitz L.

Source

From the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Abstract

Kaposi sarcoma (KS) is a low-grade vascular tumor associated with Kaposi sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8) infection. Kaposi sarcoma lesions predominantly present at mucocutaneous sites, but may involve all organs and anatomic locations. Recognized epidemiologic-clinical forms of KS include classic, African (endemic), AIDS-associated (epidemic), and iatrogenic KS. New clinical manifestations have been described, such as antiretroviral therapy-related KS regression or flares. Kaposi sarcoma lesions evolve from early (patch stage) macules into plaques (plaque stage) that grow into larger nodules (tumor stage). Newer histologic variants include anaplastic, hyperkeratotic, lymphangioma-like, bullous, telangiectatic, ecchymotic, keloidal, pyogenic granuloma-like, micronodular, intravascular, glomeruloid and pigmented KS, as well as KS with sarcoidlike granulomas and KS with myoid nodules. Latency-associated nuclear antigen (HHV8) is the most specific immunohistochemical marker available to help distinguish KS from its mimics. Since KS remains one of the most common AIDS-defining malignancies, it is important that pathologists be able to recognize KS and its contemporary manifestations.

Archives of Pathology and Laboratory Medicine

Nationwide registry-based analysis of cancer clustering detects strong familial occurrence of kaposi sarcoma.

2013

Kaasinen E, Aavikko M, Vahteristo P, Patama T, Li Y, Saarinen S, Kilpivaara O, Pitkänen E, Knekt P, Laaksonen M, Artama M, Lehtonen R, Aaltonen LA, Pukkala E.

Source

Genome-Scale Biology Research Program, and Department of Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland ; Haartman Institute, University of Helsinki, Helsinki, Finland.

Abstract

Many cancer predisposition syndromes are rare or have incomplete penetrance, and traditional epidemiological tools are not well suited for their detection. Here we have used an approach that employs the entire population based data in the Finnish Cancer Registry (FCR) for analyzing familial aggregation of all types of cancer, in order to find evidence for previously unrecognized cancer susceptibility conditions. We performed a systematic clustering of 878,593 patients in FCR based on family name at birth, municipality of birth, and tumor type, diagnosed between years 1952 and 2011. We also estimated the familial occurrence of the tumor types using cluster score that reflects the proportion of patients belonging to the most significant clusters compared to all patients in Finland. The clustering effort identified 25,910 birth name-municipality based clusters representing 183 different tumor types characterized by topography and morphology. We produced information about familial occurrence of hundreds of tumor types, and many of the tumor types with high cluster score represented known cancer syndromes. Unexpectedly, Kaposi sarcoma (KS) also produced a very high score. We verified from population records that many of the KS patients forming the clusters were indeed close relatives, and identified one family with five affected individuals in two generations and several families with two first degree relatives. Our approach is unique in enabling systematic examination of a national epidemiological database to derive evidence of aberrant familial aggregation of all tumor types, both common and rare. It allowed effortless identification of families displaying features of both known as well as potentially novel cancer predisposition conditions, including striking familial aggregation of KS. Further work with high-throughput methods should elucidate the molecular basis of the potentially novel predisposition conditions found in this study. 

PubMed

Late post transplant HIV infection with BK viremia and allograft tuberculosis in a renal transplant recipient with Kaposi sarcoma.

Sep 2012

Viswanathan V, Kandasamy V, Reddy YN, Reddy YN, Kurien A, Mathew M, Abraham G.

Source

Department of Medicine and Tanker Foundation, Madras Medical Mission, Chennai, India.

Abstract

In this report, we discuss a case of a 51-year-old African renal transplant who presented with metastatic Kaposi sarcoma1 year after transplant. The Kaposi sarcoma was treated with a switch of immunosuppressants and chemotherapy. Six years after transplant, he presented with chronic allograft nephropathy, allograft tuberculosis, BK viremia, and was diagnosed to have contracted HIV infection.

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PubMedCentral - Indian Journal of Nephrology

Microscopic diversity in oral Kaposi sarcoma.

Feb 2013

Bunn BK, Carvalho Mde V, Louw M, Vargas PA, van Heerden WF.

Source

Oral Pathologist, Department of Oral Pathology and Oral Biology, School of Dentistry, Faculty of Health Sciences, University of Pretoria, South Africa.

Abstract

Kaposi sarcoma is the most common HIV-associated neoplasm, frequently presenting with oral mucosal involvement. This retrospective study aimed to assess and highlight the histomorphological spectrum of oral Kaposi sarcoma. A total of 135 cases diagnosed between 1990 and 2011 were retrieved from the archives of the Oral and Dental Hospital of the University of Pretoria, South Africa. Following histologic review, each case was placed into 1 of 7 categories based on the predominant pattern of growth. These histologic divisions included lesions designated as solid, lymphangioma-like, telangiectatic, desmoplastic, lymphangiectatic, ecchymotic, and anaplastic. The presence of coexistent pathology was identified in 25 cases, largely represented by superimposed candidiasis. Concomitant cytomegalovirus and non-necrotizing granulomatous inflammation were also observed. Although the prognostic significance of these variants is yet to be determined, the appreciation and recognition of such morphologic diversity remains essential in distinguishing these lesions from possible mimickers.

Science Direct

Complete Response to Second Line Paclitaxel Every 2 Weeks of Eyelid Kaposi Sarcoma: A Case Report.

Dec 2012

Brunetti AE, Attilio G, Vito L, Carla M, Angela S, Ilaria M, Nicola S.

Source

*Scientific Direction, †Hematology Unit, ‡Medical and Experimental Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy.

Abstract

A 77-year-old male patient presented to our attention with violaceous nodular lesions on the skin of his hands and lower extremities. Clinical and histologic examination supported the diagnosis of Kaposi sarcoma. A first-line systemic chemotherapy based on liposomal doxorubicin at a dosage of 40 mg/m every 3 weeks for 5 cycles was carried out, resulting in partial resolution of skin lesions. However, 1 year later, a relapse of the disease in the lower limbs and a new lesion of the left eyelid were found, therefore the patient began a second-line therapy with 100 mg/m paclitaxel every 2 weeks. After 8 cycles of therapy, we observed a complete remission of eyelid tumor and a partial response of lower limbs lesions up to 6 months of follow up. In conclusion, eyelid Kaposi sarcoma was successfully treated with paclitaxel every 2 weeks, obtaining a complete response.

Lippincott

Kaposi's sarcoma in pregnancy after initiation of highly active antiretroviral therapy: a manifestation of immune reconstitution syndrome.

Dec 2012

Adeyemo A, Wood C, Govind A.

Source

Department of Obstetrics and Gynaecology.

Abstract

A case of Kaposi's sarcoma (KS) presenting as an immune reconstitution inflammatory syndrome in pregnancy with conservative management is reported. Successful outcomes for mother and baby were achieved. HIV was diagnosed at antenatal booking and highly active antiretroviral therapy commenced at 20 weeks. Multiple lymphadenopathies developed two months later. Excision biopsy of a node confirmed KS. In the absence of advanced disease, she was managed conservatively until delivery. The placenta showed no evidence of KS or human herpes virus 8 (HHV-8). The baby had negative HIV and HHV-8 polymerase chain reaction tests at zero, six and 12 weeks of life. Six months postpartum, the KS had regressed and HHV-8 viral load was undetectable.

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Int Journal of STD & AIDS

Simultaneous lymph node involvement by Castleman disease and Kaposi sarcoma.

2011

Pinto LW, Nunes EP.

Source

Instituto de Pesquisa Clínica Evandro Chagas (IPE), Fiocruz Rio de Janeiro (RJ), Brazil.

Abstract

Both multicentric Castleman disease and Kaposi sarcoma are more frequently observed in HIV infected patients. The coexistence of these Human herpes virus 8 related lesions, in the same tissue, has been observed, but literature reports are scant. On the other hand, the expression of HHV-8-LANA-1 is easily demonstrable by immunohistochemistry. This has been shown to be a powerful tool for the diagnosis of these entities. The aim of this report is to communicate our experience with a case of multicentric Castleman disease occurring in the setting of HIV infection, which demonstrated microscopic Kaposi sarcoma in the same lymph node during the pathological work-up.

PubMed

Kaposi's sarcoma: a computational approach through protein-protein interaction and gene regulatory networks analysis.

Dec 2012

Zaman A, Rahaman MH, Razzaque S.

Source

Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, 1000, Bangladesh, aubhishek@gmail.com.

Abstract

Interactomic data for Kaposi's Sarcoma Associated Herpes virus (KSHV)-the causative agent of vascular origin tumor called Kaposi's sarcoma-is relatively modest to date. The objective of this study was to assign functions to the previously uncharacterized ORFs in the virus using computational approaches and subsequently fit them to the host interactome landscape on protein, gene, and cellular level. On the basis of expression data, predicted RNA interference data, reported experimental data, and sequence based functional annotation we also tried to hypothesize the ORFs role in lytic and latent cycle during viral infection. We studied 17 previously uncharacterized ORFs in KSHV and the host-virus interplay seems to work in three major functional pathways-cell division, transport, metabolic and enzymatic in general. Studying the host-virus crosstalk for lytic phase predicts ORF 10 and ORF 11 as a predicted virus hub whereas PCNA is predicted as a host hub. On the other hand, ORF31 has been predicted as a latent phase inducible protein. KSHV invests a lion's share of its coding potential to suppress host immune response; various inflammatory mediators such as IFN-γ, TNF, IL-6, and IL-8 are negatively regulated by the ORFs while Il-10 secretion is stimulated in contrast. Although, like any other computational prediction, the study requires further validation, keeping into account the reproducibility and vast sample size of the systems biology approach the study allows us to propose an integrated network for host-virus interaction with good confidence. We hope that the study, in the long run, would help us identify effective dug against potential molecular targets.

SpringerLink

Cannabidiol inhibits growth and induces programmed cell death in kaposi sarcoma-associated herpesvirus-infected endothelium.

Jul 2012

Maor Y, Yu J, Kuzontkoski PM, Dezube BJ, Zhang X, Groopman JE.

Source

Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Abstract

Kaposi sarcoma is the most common neoplasm caused by Kaposi sarcoma-associated herpesvirus (KSHV). It is prevalent among the elderly in the Mediterranean, inhabitants of sub-Saharan Africa, and immunocompromised individuals such as organ transplant recipients and AIDS patients. Current treatments for Kaposi sarcoma can inhibit tumor growth but are not able to eliminate KSHV from the host. When the host's immune system weakens, KSHV begins to replicate again, and active tumor growth ensues. New therapeutic approaches are needed. Cannabidiol (CBD), a plant-derived cannabinoid, exhibits promising antitumor effects without inducing psychoactive side effects. CBD is emerging as a novel therapeutic for various disorders, including cancer. In this study, we investigated the effects of CBD both on the infection of endothelial cells (ECs) by KSHV and on the growth and apoptosis of KSHV-infected ECs, an in vitro model for the transformation of normal endothelium to Kaposi sarcoma. While CBD did not affect the efficiency with which KSHV infected ECs, it reduced proliferation and induced apoptosis in those infected by the virus. CBD inhibited the expression of KSHV viral G protein-coupled receptor (vGPCR), its agonist, the chemokine growth-regulated protein α (GRO-α), vascular endothelial growth factor receptor 3 (VEGFR-3), and the VEGFR-3 ligand, vascular endothelial growth factor C (VEGF-C). This suggests a potential mechanism by which CBD exerts its effects on KSHV-infected endothelium and supports the further examination of CBD as a novel targeted agent for the treatment of Kaposi sarcoma.

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NIH / Genes and Cancer

Human Herpesvirus 8 (HHV8) Sequentially Shapes the NK Cell Repertoire during the Course of Asymptomatic Infection and Kaposi Sarcoma

Jan 2012

Stéphanie Dupuy, Marion Lambert, David Zucman, Siméon-Pierre Choukem,^3,¤ Sara Tognarelli,¹ Cécile Pages, Céleste Lebbé, and Sophie Caillat-Zucma

Abstract

The contribution of innate immunity to immunosurveillance of the oncogenic Human Herpes Virus 8 (HHV8) has not been studied in depth. We investigated NK cell phenotype and function in 70 HHV8-infected subjects, either asymptomatic carriers or having developed Kaposi's sarcoma (KS). Our results revealed substantial alterations of the NK cell receptor repertoire in healthy HHV8 carriers, with reduced expression of NKp30, NKp46 and CD161 receptors. In addition, down-modulation of the activating NKG2D receptor, associated with impaired NK-cell lytic capacity, was observed in patients with active KS. Resolution of KS after treatment was accompanied with restoration of NKG2D levels and NK cell activity. HHV8-latently infected endothelial cells overexpressed ligands of several NK cell receptors, including NKG2D ligands. The strong expression of NKG2D ligands by tumor cells was confirmed in situ by immunohistochemical staining of KS biopsies. However, no tumor-infiltrating NK cells were detected, suggesting a defect in NK cell homing or survival in the KS microenvironment. Among the known KS-derived immunoregulatory factors, we identified prostaglandin E2 (PGE2) as a critical element responsible for the down-modulation of NKG2D expression on resting NK cells. Moreover, PGE2 prevented up-regulation of the NKG2D and NKp30 receptors on IL-15-activated NK cells, and inhibited the IL-15-induced proliferation and survival of NK cells. Altogether, our observations are consistent with distinct immunoevasion mechanisms that allow HHV8 to escape NK cell responses stepwise, first at early stages of infection to facilitate the maintenance of viral latency, and later to promote tumor cell growth through suppression of NKG2D-mediated functions. Importantly, our results provide additional support to the use of PGE2 inhibitors as an attractive approach to treat aggressive KS, as they could restore activation and survival of tumoricidal NK cells.

Complete Text:

NIH/PLOS

Opposing Regulation of PROX1 by Interleukin-3 Receptor and NOTCH Directs Differential Host Cell Fate Reprogramming by Kaposi Sarcoma Herpes Virus

June 2012

Jaehyuk Yoo,^#1 Ha Neul Lee,^#1 Inho Choi,¹ Dongwon Choi,¹ Hee Kyoung Chung,¹ Kyu Eui Kim,¹Sunju Lee,¹ Berenice Aguilar,¹ Jinjoo Kang,¹ Eunkyung Park,¹ Yong Suk Lee,¹ Yong-Sun Maeng,¹Nam Yoon Kim,¹ Chester J. Koh,² and Young-Kwon Hong^1,*

^Abstract

^{Lymphatic endothelial cells (LECs) are differentiated from blood vascular endothelial cells (BECs) during embryogenesis and this physiological cell fate specification is controlled by PROX1, the master regulator for lymphatic development. When Kaposi sarcoma herpes virus (KSHV) infects host cells, it activates the otherwise silenced embryonic endothelial differentiation program and reprograms their cell fates. Interestingly, previous studies demonstrated that KSHV drives BECs to acquire a partial lymphatic phenotype by upregulating PROX1 (forward reprogramming), but stimulates LECs to regain some BEC-signature genes by downregulating PROX1 (reverse reprogramming). Despite the significance of this KSHV-induced bidirectional cell fate reprogramming in KS pathogenesis, its underlying molecular mechanism remains undefined. Here, we report that IL3 receptor alpha (IL3Rα) and NOTCH play integral roles in the host cell type-specific regulation of PROX1 by KSHV. In BECs, KSHV upregulates IL3Rα and phosphorylates STAT5, which binds and activates the PROX1 promoter. In LECs, however, PROX1 was rather downregulated by KSHV-induced NOTCH signal via HEY1, which binds and represses the PROX1 promoter. Moreover, PROX1 was found to be required to maintain HEY1 expression in LECs, establishing a reciprocal regulation between PROX1 and HEY1. Upon co-activation of IL3Rα and NOTCH, PROX1 was upregulated in BECs, but downregulated in LECs. Together, our study provides the molecular mechanism underlying the cell type-specific endothelial fate reprogramming by KSHV.}

^{Author Summary}

^{Kaposi's sarcoma (KS) is one of the most common neoplasms in HIV-positive individuals and organ transplant recipients. KS-associated herpes virus (KSHV), also known as human herpes virus (HHV)-8, has been identified as the causative agent and infects endothelial cells to form KS. Importantly, we and others have discovered that when KSHV infects endothelial cells of blood vessels, it reprograms host cells to resemble endothelial cells in lymphatic vessels. On the other hand, when KSHV infects endothelial cells in lymphatic vessels, the virus directs the host cells to partially obtain the phenotypes of blood vessel endothelial cells. These host cell reprogramming represent abnormal pathological processes, which are not as complete as the physiological process occurring during embryonic development. Currently, it is not clear how and why this cancer causing virus modifies the fate of its host cells. In this study, we aimed to dissect the molecular mechanism underlying the virus-induced host cell fate reprogramming and found two important cellular signaling pathways, interleukin-3 and Notch, playing key roles in the pathological events. Our current study provides a better understanding of KS tumorigenesis with a potential implication in a new KS therapy.}

Full Text Article

NIH-PLOS One

Variable clinical presentations of Classic Kaposi Sarcoma in Turkish patients

March 2012

Ilknur Altunay, Asli Kucukunal,^* Gulsen Tukenmez Demirci, and Bilge Ates

Abstract

Key Words: HHV-8, HIV, Kaposi sarcoma, skin cancer

Background

Kaposi sarcoma (KS) is a vascular neoplasm with multicentric cutanenous and extracutaneous involvements, which was first described by Moriz Kaposi in 1872. Since then, different epidemiological clinical and histopathological variants of this neoplasm have been identified. Classic Kaposi sarcoma (CKS) is one of four main clinico-epidemiologiologic variants. characteristics of the disease.

Materials and Methods

Four Turkish inpatients with CKS were evaluated in the study. All medical history and clinical data were noted. A screening immunodeficiency workup were performed for all patients. HHV-8 immunofluorescence testing on the specimens and ELISA test for human immunodeficiency virus (HIV 1 and 2) were performed. Pulmonary X ray graphies and computurized tomography (CT) scan were applied. Stage of the tumor was determined, in each case, according to the classification system proposed by Brambilla et al in 2003.

Results

All patients are positive for HHV-8. They were all immunocompetent and negative for HIV1 and HIV2. The first patient was unusual for morphological presentation of several verrucoid lesions that was evaluated as verrucoid KS. He was considered stage IB CKS. The patient 2 was a young man and the course of KS seemed unexpectedly aggressive for CKS. His clinical appearence seemed us to be a patient with AIDSassociated KS. The patient was evaluated as stage IVB CKS. Our third patient had also prominent lymphedema associated with bluish discoloration on the toes and fingers, suggesting a diagnosis of peripheral vascular disorder. He was diagnosed as stage IIIB CKS. The fourth case was interesting for very extensive lesions involving big sized plaques and also the existence of mucosal lesion. The patient was diagnosed as stage IVB CKS.

Conclusions

It seems that the reports of exceptional cases of KS are accumulating. Data from various cases should be collected and perhaps, novel clinical classifications should be considered. 

Full Text Article

NIH - Journal of Dermatological Case Reports