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KSHV/HHV-8 and HIV infection in Kaposi's sarcoma development

KSHV/HHV-8 and HIV infection in Kaposi's sarcoma development Kaposi's sarcoma (KS) is a highly and abnormally vascularized tumor-like lesion affecting the skin, lymphnodes and viscera, which develops from early inflammatory stages of patch/plaque to late, nodular tumors composed predominant of spindle cells (SC). These SC are infected with the Kaposi's sarcoma-associated herpesvirus or human herpesvirus-8 (KSHV/HHV-8). KS is promoted during HIV infection by various angiogenic and pro-inflammatory factors including HIV-Tat. The latency associated nuclear antigen type 1 (LANA-1) protein is well expressed in SC, highly immunogenic and considered important in the generation and maintenance of HHV-8 associated malignancies. Various studies favour an endothelial origin of the KS SC, expressing "mixed" lymphatic and vascular endothelial cell markers, possibly representing hybrid phenotypes of endothelial cells (EC). A significant number of SC during KS development are apparently not HHV8 infected, which heterogeneity in viral permissiveness may indicate that non-infected SC may continuously be recruited in to the lesion from progenitor cells and locally triggered to develop permissiveness to HHV8 infection. In the present study various aspects of KS pathogenesis are discussed, focusing on the histopathological as well as cytogenetic and molecular genetic changes in KS. Background a) Classical or sporadic KS (CKS), originally described [1] Kaposi's sarcoma as a slow growing, indolent tumor mostly developing in Kaposi's sarcoma first described by Moritz Kaposi in 1872 the extremities of elderly males of eastern and Mediterra- as "idiopathic multiple pigmented sarcomas of the skin" nean Europe. b) Endemic KS (EKS), predominant in east- [1] is an angioproliferative, tumour-like lesion usually ern and central sub-Saharan Africa before the AIDS developing in the skin [2], and eventually disseminating epidemic and clinically similar to CKS, but also seen in a to multiple cutaneous sites, viscera and lymph nodes. Pre- more fulminant and fatal form in children. The childhood viously a rare disease, it is now a global health care and EKS is often lymphoglandular with or without skin clinical problem because of its association with the HIV involvement. c) Acquired immunodeficiency syndrome pandemic [3] and other immunosuppressed states[4]. (AIDS)-associated KS (AKS), the most frequent tumor of human immunodeficiency virus type I (HIV-l) infection Four clinically different KS forms are now recognized [5]: Page 1 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 and the most aggressive and rapidly growing form of KS in LANA-1 AIDS, with early dissemination in the skin and viscera. The latency associated nuclear antigen type 1 (LANA-1) protein is a well expressed and highly immunogenic, d) Iatrogenic KS (IKS), seen in drug related immunosup- latent nuclear antigen of HHV-8 considered important in pressed patients, e.g. transplant patients, emphasizing the the generation and maintenance of HHV-8 associated importance of immune disturbance as a co-factor in the malignancies [17] by its cell cycle regulation in competing pathogenesis of IKS and AKS, and possibly also EKS. with E2F for binding of hypophosphorylated pRb thus freeing E2F to activate gene transcription involved in cell In spite of the clear clinical differences the histopathology cycle progression [18] (Fig 1). E2F activity can also trigger of the various KS forms is essentially the same, with char- apoptosis via the p53 pathway but LANA-1 interacts with acteristic changes related to stage in the development of p53, repressing its gene transcriptional activity and ability the KS tumor[6]. to induce apoptosis (Fig 1). Therefore the inhibition of p53 by LANA-1 allows latent HHV-8 to promote cell cycle The epidemiology of AKS led to the discovery of a novel progression whilst inhibiting apoptosis [19]. Oncogenic herpes virus [7], which subsequently was shown to be viruses often block cell differentiation during tumor associated with all clinico-epidemiological forms of KS development by the stabilization of beta-catenin which [8]. The virus was rapidly characterised as a KS associated also appears to be promoted by LANA [20]. herpes virus (KSHV) and classified as human herpes virus type 8 (HHV-8). It was soon recognized to also be associ- The LANA-1 antigen is well detectable by immunohisto- ated with some rare types of lymphomas in AIDS patients, chemistry also in routinely formalin fixed paraffin embed- namely primary effusion lymphoma or body-cavity- ded biopsies. It is expressed by most SC in both early and based-lymphoma (PEL/BCBL) and Castleman's disease late stage lesions of all different clinical KS forms (AKS, (MCD)[9]. EKS, CKS and IKS) [8,21] and therefore used as a diagnos- tic marker in suspected HHV-8 related lesions and also for Human herpesvirus type 8 (HHV-8) serology of LANA-1 antibodies in patients by immunocy- Human herpesvirus 8 or Kaposi's sarcoma associated her- tochemistry that gives a characteristic speckled nuclear pesvirus (HHV-8/KSHV) was recognized to be a novel staining on HHV-8 infected BCBL cells. Several studies gamma-2 herpesvirus of the rhadinovirus genus closely have shown an increase in LANA-1 positive cells during related to the human gamma -1 herpesvirus, Epstein-Barr progression of KS lesions [22,23] allowing quantification virus (EBV) [10]. and phenotyping of these cells in KS lesions. A number of viral glycoproteins have been characterized Pathogenesis of KS shown to bind to cell surface heparan sulfate [11] and the HHV-8 is the most recently identified human oncogenic cell receptor integrin α3β1, respectively, thereby mediat- herpesvirus [24] expressing candidate viral oncogenes ing virus entry through endocytosis [12]. In the KS lesion which constitutively activate growth-signalling pathways HHV-8 is predominantly found in the so called tumor [13,25]. The pathogenesis of KS is however still unclear spindle (SC) cells in KS but was also in some lym- and appears complex, involving various mechanisms phocytes, monocytes and keratinocytes [13]. The virus dependent on both viral and cellular activities related to replicates in either a lytic or predominantly in the latent inflammation and angiogenesis promoted by endothelial form as closed circular episomal DNA [14] within the growth factors (β-FGF, PDGF, VEGF) including HIV-Tat as nucleus of KS tumor cells (SC) and B cells of MCD and well as cell proliferation and anti-apoptosis (vBCL2) other infected mononuclear cells [15]. It has been shown [2,13,26,27]. Characteristic for HHV-8 is the high hom- that the episomal viral DNA is tethered to metaphase ology of several viral and cellular genes suggesting viral chromosomes and copied in tandem with host cell DNA genes were pirated from host chromosomes during viral during cell division [16]. Latent viral specific genes well evolution. Some of these genes are involved in down demonstrated in infected KS SC are the latent nuclear anti- modulating the host immune responsiveness to target, gen (LANA-1), viral cyclin (v-cyclin), v-FLIP and kaposin infected cells and modulate cell proliferation, cell differ- a small membrane protein, which are all adjacent in the entiation and angiogenesis [13], including genes as vBcl- genome [16]. Lytic virus expression is most frequent in 2, vIL-8R, vMIPs, vIL-6, and the D type viral cyclin MCD, moderate in KS and relatively rare in PEL cells. Common viral genes found during lytic expression The HHV-8 infected cells escape immune response target- include K1 transmembrane protein, v-GCR, v-IRF, v-IL-6 ing by down regulation of surface MHC mediated by two and v-MIP [15]. transmembrane proteins, MIR1 and MIR2 [28] (Fig 1), which promote MHC endocytosis, and lysosomal degra- dation (Fig 1). Downregulation of MHC I and its acces- Page 2 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 HH Figure 1 V-8 gene expression (pathogenesis) during SC development and tumor growth HHV-8 gene expression (pathogenesis) during SC development and tumor growth. sory immune receptors poses the risk of initiating a early to late stage KS lesions, [30,31]. Thus viral exploita- natural killer (NK) cell response by initiating apoptosis tion of these two anti-apoptotic pathways contributes to through Fas (CD95/Apo-1) in cells lacking appropriate the tumor-like growth and progression of the KS lesion. MHC I expression. However, HHV-8 can inhibit NK- mediated killing through expression of the anti apoptotic V-cyclin binds with cyclin dependent kinases (CDK6), v-FLICE-inhibitory proteins (v-FLIPs) [28]. V-FLIP which which complex phosphorylates pRb, releasing a transcrip- acts as a dominant inhibitor of receptor-activated apopto- tion factor (E2F), which activates the transcription of S- sis by binding to Fas-associated death domain protein and phase genes (Fig 1). However, unlike cellular cyclin, vCy- caspase 8 (FLICE) [29]. This prevents activated caspase clin-CDK6 complexes are resistant to CDK inhibitory pro- recruitment into the death-inducing signaling complex teins, which may lead to unregulated cell cycle (Fig 1). progression and transformation and thereby promote tumor development [32]. HHV-8 v-FLIP shares with c-FLIPs the ability to activate NF-κB [28] which is essential for the growth and survival Kaposin, the latency gene represents a potential viral of the cell. Our studies on KS biopsies have shown that oncogene and is characterized as a transforming gene apoptosis clearly decreases during development of early to [33], although little is known about its role in deregulat- late nodular KS lesions [30], and that the expression of ing cell signalling [34]. It is present in three (A, B, C) iso- anti-apoptotic v-FLIP and cellular Bcl-2 increase from forms [35] of which Kaposin B is expressed by all HHV-8 Page 3 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 infected cells and can activate the p38-MK2 pathway [36] Histogenesis of KS (Fig 1) and block the degradation of the messenger RNAs The histopathology of KS is characterized by an early infil- transcribing various cytokines necessary for cell survival, tration of mononuclear inflammatory cells, formation of hence increasing their translation [36]. The Kaposin gene small, irregular, endothelial lined slits around new blood also encodes several microRNAs (miRNA), which may vessels (angiogenesis) and extravasation of erythrocytes regulate gene expression by binding to complementary [2] with accumulation of hemosiderin pigments. KS at messenger RNAs [37]. Two of these HHV-8 miRNAs are early stages appears to reflect a predominantly reactive cell expressed by SC at all KS stages [37] and may contribute proliferation of polyclonal nature that may regress, but to tumorigenic transformation of infected cells [33], and usually progresses to a nodular possibly clonal tumor therefore of therapeutic interest [37]. [2,46]. Pathognomonic for KS development from early patch/plaque to late nodular tumor lesions is the The KSHV miRNAs are expressed from what appears to be increased appearance of bundles of morphological spin- a single genetic locus that largely coincides with an 4-kb dle cells (SC) expressing CD34 (hematopoietic stem cell noncoding sequence located between the KSHV v-cyclin and vascular endothelial marker). At the late nodular KS and K12 Kaposin genes, both of which are also expressed stage there is less inflammatory cell infiltration, mostly in latently infected cells. Computer analysis of potential around the boaders of the dense, nodular accumulation of mRNA targets for these viral miRNAs identified a number SC bundles which skin lesions may later ulcerate. Unlike of interesting candidate genes, including several mRNAs typical metastatic cancers, KS often appears early as a mul- previously shown to be downregulated in KSHV-infected ticentric tumour, with each lesion arising de novo by a cells. It appears that these viral miRNAs play a critical role localized small patch and of SC [47]. in the establishment and or maintenance of KSHV latent infection and hence, in KSHV-induced oncogenesis [38]. Most SC are positive for CD34 and LANA but a consider- able number of CD34+ SC are LANA- at all AKS/EKS HHV-8 also encodes a G-protein-coupled receptor stages [22,23]. This apparent heterogeneity in viral per- (vGCR) homolog to the human angiogenic, chemokine missiveness of CD34+ SC seems less compatible with a interleukin-8 receptor (IL-8R, CCR1 and CXCR2) [39] (Fig clonal CD34+ SC proliferation and virus transfer but SC are 1). Angiogenic responses induced by vGCR are mediated appears to indicate that also non-infected CD34 by upregulation of vascular endothelial growth factor continuously recruited from progenitor cells and locally (VEGF) [40]. The constitutive activity of vGCR could triggered to develop permissiveness to HHV-8 infection therefore have a role for VEGF expression by SC during the [22,23]. Furthermore cells belonging to the non-cycling development of early stage KS lesions [41]. Furthermore SC (Ki67-) population showed a clear increase during the vGCR dependent expression of autocrine and para- development from patch/plaque (median 13.5%) to nod- crine growth factors (bFGF, VEGF,) promotes the angio- ular stage (median 40.3%) [22], also supporting the con- genesis and edema [26,42] seen in KS patients. It was also cept of continuous recruitment of CD34+ cells to the shown [43] that viral envelop glycoprotein gB can activate lesion. KS spindle-like cells have been shown to develop the VEGFR-3 receptor and trigger receptor signalling on in cultures of peripheral blood of HIV infected patients the surface of microvascular endothelial cells, thereby with KS or at high risk for developing KS [48]. Further- modulating cell migration and proliferation. VEGFR-3 more recent studies show that endothelial cells or their expression and activation may also enhance HHV-8 infec- precursors residing in donor kidneys may contribute to tion and participate in HHV-8 mediated transformation post-renal transplant KS indicated by the finding that KS [43] and thereby appears to be an important factor in the SC in the female recipient kidney had a male (donor) pathogenesis of Kaposi's sarcoma. karyotype and that KS SC expressed the donor HLA anti- gen [49]. These findings appear to indicate that KS SC The Kaposi sarcoma herpesvirus (KSHV) also encodes and/or their progenitors can be recruited during develop- multiple proteins that disrupt host antiviral responses, ment of KS lesion. including four viral proteins that have homology to the interferon regulatory factor (IRF) family of transcription Characteristic spindle cells (SC) express various "mixed" factors. At least three of the KSHV vIRFs (vIRFs 1–3) alter (LEC and VEC) endothelial phenotypic cell markers pos- responses to cellular IRFs and to interferons (IFNs). The sibly representing hybrid phenotypes of endothelial cells vIRFs also affect other important regulatory proteins in at different maturation stages. It has been recurrently the cell, including responses to transforming growth fac- debated whether SC are vascular (VEC) or lymphatic tor beta (TGF-beta) and the tumor suppressor protein p53 (LEC) in origin or derive from mesenchymal progenitor [44]. K7/vIAP (inhibitor of apoptosis protein) is another cells [50-52], although most studies by immunohisto- antiapoptotic factor homologous to the cellular protein chemistry have revealed that SC express lymphatic mark- survivin [45]. ers, such as D2-40 [53], LYVE-1 [50] and VEGFR-3 [51]. Page 4 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 Also studies by gene expression microarray show that KS tions and deletions in the short arm of chromosome 3 at neoplastic cells are closely related to lymphatic endothe- region 3p14. These KS cell lines also exhibit loss of heter- lial cells (LEC) but coexpressing some blood vascular ozygosity of loci at region 3p14-ter. The chromosome 3 endothelial cell (VEC) markers [54]. Furthermore HHV-8 alterations observed were suggested to contribute to the can infect both LEC and VEC in vitro and infected LEC neoplastic process in KS [57] but other cytogenetic studies had a higher HHV-8 genome copy number than VEC[54]. on the KS-IMM cell line (IKS) [56] showed gains in In-vitro infection of CD34+ human dermal microvascular 1q10→qter, 7p10→pter, 7q22→qter, 8p11→qter, endothelial cells (HDMEC) with HHV-8 resulted in the 14pter→q22 but no changes in chromosome 3 [56]. upregulation of LEC markers such as LYVE-1 in the These aberrations are compatible with the notion that ini- infected HDMEC [55]. tially KS may develop as a reactive polyclonal cell prolifer- ation associated with chromosome instability, followed In our study all LANA+ cells were LYVE-1+ (lymphatic by acquisition of clonal chromosome changes in later endothelial markers) in early and late KS and the HHV-8 stages [56]. However, the significance in KS pathogenesis infection (LANA) appeared better correlated to LYVE-1 of aberrations on established KS cell lines should be than to CD34 expression [23]. LANA+/CD34-cells were related to finding that such cell lines when established more frequent in early as compared to late lesions and did usually loose their HHV-8 episomes and possibly may not express a leucocytic phenotype (CD3, CD20, CD45, represent only a minor KS cell population. CD68) [22], but most expressed lymphatic endothelial (LEC) markers such as LYVE-1, VEGFR-3 and D2-40, sug- The chromosomal instability suggested by the studies on gesting that resident LECs represent an early target of pri- cell lines may lead to cell apoptotis via the p53 path- mary HHV-8 infection [23]. This is also supported by way[58]. However, HHV-8 LANA binds to p53repressing other findings [54] that infected LECs have a higher HHV- its ability to induce apoptosis [59]. Furthermore telomer- 8 genome copy number than VECs. Obviously a high viral ase activity has been found to be upregulated in KS [60], copy number may result in an efficient maintenance and which may immortalise the infected cell leading to propagation of episomal HHV-8 DNA in dividing and increased tumor cell survival. migrating LECs. Furthermore in-vitro activation of VEGFR-3 by HHV-8 has been shown to increase endothe- Previous, CGH studies of formalin fixed paraffin embed- lial cell migration and to enhance cell susceptibility to ded KS biopsies revealed a recurrent gain at 11q13 [61], HHV-8 infection and transformation [43]. Hence, the which also amplifies two known oncogenes, FGF4 and activation of VEGFR-3 in LANA+/VEGFR-3+ SC observed INT2, residing at 11q13 suggesting a possible role of during KS development will probably promote an HHV-8 in the amplification and activation of genomic increased endothelial cell migration (recruitment) and oncogenes [61]. transformation to tumor SC including formation of path- ological vascular slits. Loss of chromosome Y was observed in most AKS and EKS cases recently studied by us [62] and interestingly it was Cell proliferation is relatively low in KS as shown by our the only aberration observed in early KS. Late stage (nod- previous studies on proliferation related protein Ki67 ular) KS had beside loss of chromosome Y, also recurrent expression and DNA flow cytometry [30]. The frequency deletions on chromosomes 16 and 17. Deletion of chro- of proliferating (Ki67+) cells usually decreased during mosome Y was also reported by previous studies on short development from early to late KS lesions, consistent with term cultures of primary KS tumor cells and established the notion that KS growth from a early reactive lesion to a KS cell lines [56]. EKS showed often more chromosomal nodular tumor depends not only on SC division but also abnormalities than AKS [62], which might indicate that on decreased apoptosis [30] and progenitor recruitment genomic instability could be a more important factor in [22,23]. No significant difference in cell proliferation was the development of EKS than AKS. Most likely AKS devel- observed between nodular AKS and EKS [22]. These find- opment is also promoted by various cytokines and growth ings could therefore indicate that the usually more spread factors produced by the HIV infection and the dysregu- and aggressive growth of the AKS tumors may reflect a lated and compromised state of host immune response. higher rate of SC progenitor recruitment compared to the Loss of the Y chromosome and encoded male specific more indolent EKS lesions. minor histocompatibility antigens (HY antigen) has been shown to be linked to haematological relapse in acute Cytogenesis of KS lymphoblastic leukemia due to immune escape mecha- Reports on cytogenetic and molecular genetic changes in nisms [63]. The HY antigens are presented at the cell sur- KS are few [56]. Studies from KS cell lines, KS Y-1 (AKS face with the major histocompatibility complex (MHC) derived) and KS SLK (IKS derived) revealed loss of copies and together also processed intracellularly [64]. However, of chromosomes 14 and 21 and non-random transloca- no studies have previously indicated a deficiency of HY Page 5 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 Salaam, Tanzania and The ethical committee, Karolinska Hospital (Dnr 01- antigen in KS tumors, which loss of the Y chromosome in 096). We declare no conflict of interest. our studies suggests as of possible importance in KS pathogenesis. References 1. Kaposi M: Idiopathisches multiples pigment sarcoma de Haut. HIV pathogenesis in KS Arch Dermatol Syphil 1872, 4(265):. There seems to be a cross talk between HIV-1 and HHV-8 2. Biberfeld P, Ensoli B, Sturzl M, Schulz TF: Kaposi sarcoma-associ- ated herpesvirus/human herpesvirus 8, cytokines, growth as recent studies have shown that HIV-1 replication stim- factors and HIV in pathogenesis of Kaposi's sarcoma. Curr ulates HHV-8 production in PEL cell lines and peripheral Opin Infect Dis 1998, 11(2):97-105. 3. Amir H, Kaaya EE, Manji KP, Kwesigabo G, Biberfeld P: Kaposi's sar- blood mononuclear cells from KS patients, possibly due coma before and during a human immunodeficiency virus to the activating functions of HIV-Tat [65, 66] ORF50, the epidemic in Tanzanian children. Pediatr Infect Dis J 2001, major transactivator of HHV-8 lytic cycle can also induce 20(5):518-521. 4. Lessan-Pezeshki M, Einollahi B, Khatami MR, Mahdavi M: Kidney increased levels of HIV replication by interacting synergis- transplantation and Kaposi's sarcoma: review of 2050 recip- tically with HIV-1 Tat leading to increased cell susceptibil- ients. Transplant Proc 2001, 33(5):2818. 5. Biberfeld P, Lebbe C, Tschachler E, Luppi M: Human herpesvirus- ity to HIV infection and transient permissiveness to HIV 8 and HIV. In: Viral co-infections in HIV Impact and manag- replication [67]. ment:. In Lalezari J, Moyle G Volume Chapter 4. Remedica; 2002:63-91. 6. Kaaya EE, Parravicini C, Sundelin B, Mgaya E, Kitinya J, Lema L, Luande The increased incidence of KS in patients with AIDS was J, Biberfeld P: Spindle cell ploidy and proliferation in endemic also shown to be related to effects of the HIV-1 Tat protein and epidemic African Kaposi's sarcoma. Eur J Cancer 1992, by stimulation of proliferation and anti-apoptosis of 28A(11):1890-1894. 7. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, infected spindle cells (SC) and also activation of HHV-8 Moore PS: Identification of herpesvirus-like DNA sequences thus increasing SC viral load and expression of various in AIDS-associated Kaposi's sarcoma. Science 1994, 266(5192):1865-1869. viral genes with oncogenic potential (vGCR, vBCL2, and 8. Schalling M, Ekman M, Kaaya EE, Linde A, Biberfeld P: A role for a vIRF1, see above) [65]. Thus, Tat promotes tumorigenesis new herpes virus (KSHV) in different forms of Kaposi's sar- of endothelial cells, both via stimulation of vascular coma. Nat Med 1995, 1(7):707-708. 9. Gaidano G, Castanos-Velez E, Biberfeld P: Lymphoid disorders endothelial growth factors, anti-apoptotic activity and associated with HHV-8/KSHV infection: facts and conten- HHV-8 replication. Notably, the functional activity of Tat tions. Med Oncol 1999, 16(1):8-12. 10. Viejo-Borbolla A, Ottinger M, Schulz TF: Human Herpesvirus 8: protein in the pathogenesis of AKS clearly involves an Biology and Role in the Pathogenesis of Kaposi's Sarcoma intercellular signalling cascade which is inhibited by anti- and Other AIDS-related Malignancies. Curr Infect Dis Rep 2003, bodies to HIV-Tat epitopes [68, 69]. 5(2):169-175. 11. Wang FZ, Akula SM, Pramod NP, Zeng L, Chandran B: Human her- pesvirus 8 envelope glycoprotein K8.1A interaction with the Recently we have found differences in SC viral load target cells involves heparan sulfate. J Virol 2001, between oral and cutaneous KS lesion also suggesting pos- 75(16):7517-7527. 12. Akula SM, Naranatt PP, Walia NS, Wang FZ, Fegley B, Chandran B: sible differences of Tat expression in these lesions [70]. Kaposi's sarcoma-associated herpesvirus (human herpesvi- rus 8) infection of human fibroblast cells occurs through endocytosis. J Virol 2003, 77(14):7978-7990. In summary the concept of oncogenesis related to infec- 13. Hengge UR, Ruzicka T, Tyring SK, Stuschke M, Roggendorf M, tion is particularly well exemplified by the herpes virus Schwartz RA, Seeber S: Update on Kaposi's sarcoma and other HHV-8 and retrovirus HIV-1 associated Kaposi's sarcoma, HHV8 associated diseases. Part 2: pathogenesis, Castle- man's disease, and pleural effusion lymphoma. Lancet Infect Dis which develops due to the effects of various host-cells and 2002, 2(6):344-352. viral factors elicited during infection affecting cell prolifer- 14. Renne R, Lagunoff M, Zhong W, Ganem D: The size and confor- ation, cell escape from apoptosis and dysregulation of mation of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) DNA in infected cells and virions. J Virol 1996, host immune responses. 70(11):8151-8154. 15. Schulz TF: Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8): epidemiology and pathogenesis. J Antimicrob Acknowledgements Chemother 2000, 45 Suppl T3:15-27. These studies were supported by Swedish Cancer Society, Cancer Society 16. Szekely L, Kiss C, Mattsson K, Kashuba E, Pokrovskaja K, Juhasz A, of Stockholm, Karolinska Institutet research fund and Swedish International Holmvall P, Klein G: Human herpesvirus-8-encoded LNA-1 Development Agency (Sida), Department of Research Cooperation accumulates in heterochromatin- associated nuclear bodies. J Gen Virol 1999, 80 ( Pt 11):2889-2900. (SAREC). 17. Komatsu T, Ballestas ME, Barbera AJ, Kaye KM: The KSHV latency- associated nuclear antigen: a multifunctional protein. Front Drs. L. Lema, and B. Kalyanyama of the Muhimbili University College, Drs. Biosci 2002, 7:d726-30. J. Luande, T. Ngoma, M. Diwani of Ocean Road Cancer Institute (ORCI), 18. Radkov SA, Kellam P, Boshoff C: The latent nuclear antigen of Dar-Es-Salaam, Tanzania provided the biopsies. The technical assistance of Kaposi sarcoma-associated herpesvirus targets the retino- blastoma-E2F pathway and with the oncogene Hras trans- A. Magogo and V. Nelson from Muhimbili University College, Dar-Es- forms primary rat cells. Nat Med 2000, 6(10):1121-1127. Salaam, Tanzania is highly appreciated. 19. Jenner RG, Boshoff C: The molecular pathology of Kaposi's sar- coma-associated herpesvirus. Biochim Biophys Acta 2002, The ethical clearance was obtained from Ministry of Health (MoH), and the 1602(1):1-22. 20. Boshoff C: Kaposi virus scores cancer coup. Nat Med 2003, Muhimbili University College of Health Sciences (MUCHS) in Dar Es 9(3):261-262. Page 6 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 21. Katano H, Sato Y, Kurata T, Mori S, Sata T: High expression of naling effects in primary effusion lymphoma cells. J Virol 2003, HHV-8-encoded ORF73 protein in spindle-shaped cells of 77(1):57-67. Kaposi's sarcoma. Am J Pathol 1999, 155(1):47-52. 41. Choi J, Means RE, Damania B, Jung JU: Molecular piracy of 22. Pyakurel P, Massambu C, Castanos-Velez E, Ericsson S, Kaaya E, Bib- Kaposi's sarcoma associated herpesvirus. Cytokine Growth Fac- erfeld P, Heiden T: Human Herpesvirus 8/Kaposi Sarcoma Her- tor Rev 2001, 12(2-3):245-257. pesvirus Cell Association During Evolution of Kaposi 42. Samaniego F, Markham PD, Gendelman R, Watanabe Y, Kao V, Kow- Sarcoma. J Acquir Immune Defic Syndr 2004, 36(2):678-683. alski K, Sonnabend JA, Pintus A, Gallo RC, Ensoli B: Vascular 23. Pyakurel P, Pak F, Mwakigonja AR, Kaaya E, Heiden T, Biberfeld P: endothelial growth factor and basic fibroblast growth factor Lymphatic and vascular origin of Kaposi's sarcoma spindle present in Kaposi's sarcoma (KS) are induced by inflamma- cells during tumor development. Int J Cancer 2006, tory cytokines and synergize to promote vascular permea- 119(6):1262-1267. bility and KS lesion development. Am J Pathol 1998, 24. Verma SC, Lan K, Robertson E: Structure and function of 152(6):1433-1443. latency-associated nuclear antigen. Curr Top Microbiol Immunol 43. Zhang X, Wang JF, Chandran B, Persaud K, Pytowski B, Fingeroth J, 2007, 312:101-136. Groopman JE: KSHV activation of VEGFR-3 alters endothelial 25. Boshoff C, Weiss R: AIDS-related malignancies. Nat Rev Cancer function and enhances infection. J Biol Chem 2005. 2002, 2(5):373-382. 44. Offermann MK: Kaposi sarcoma herpesvirus-encoded inter- 26. Biberfeld P EB Sturzl M, and Schulz TF.: Kaposi's sarcoma associ- feron regulator factors. Curr Top Microbiol Immunol 2007, ated herpesvirus/human herpesvirus 8, cytokine growth fac- 312:185-209. tos and HIV in pathogenesis of Kaposi's sarcoma. Curr Opin Inf 45. Wang HW, Sharp TV, Koumi A, Koentges G, Boshoff C: Character- Dis 1998, 11(97):105. ization of an anti-apoptotic glycoprotein encoded by 27. Dalgleish AG, O'Byrne KJ: Chronic immune activation and Kaposi's sarcoma-associated herpesvirus which resembles a inflammation in the pathogenesis of AIDS and cancer. Adv spliced variant of human survivin. EMBO J 2002, Cancer Res 2002, 84:231-276. 21(11):2602-2615. 28. Moore PS, Chang Y: Kaposi's sarcoma-associated herpesvirus 46. Kondo Y, Izumi T, Yanagawa T, Kanda H, Katano H, Sata T: Sponta- immunoevasion and tumorigenesis: two sides of the same neously regressed Kaposi's sarcoma and human herpesvirus coin? Annu Rev Microbiol 2003, 57:609-639. 8 infection in a human immunodeficiency virus-negative 29. Belanger C, Gravel A, Tomoiu A, Janelle ME, Gosselin J, Tremblay MJ, patient. Pathol Int 2000, 50(4):340-346. Flamand L: Human herpesvirus 8 viral FLICE-inhibitory pro- 47. Ensoli B, Sgadari C, Barillari G, Sirianni MC, Sturzl M, Monini P: Biol- tein inhibits Fas-mediated apoptosis through binding and ogy of Kaposi's sarcoma. Eur J Cancer 2001, 37(10):1251-1269. prevention of procaspase-8 maturation. J Hum Virol 2001, 48. Browning PJ, Sechler JM, Kaplan M, Washington RH, Gendelman R, 4(2):62-73. Yarchoan R, Ensoli B, Gallo RC: Identification and culture of 30. Kaaya E, Castanos-Velez E, Heiden T, Ekman M, Catrina AI, Kitinya J, Kaposi's sarcoma-like spindle cells from the peripheral blood Andersson L, Biberfeld P: Proliferation and apoptosis in the evo- of human immunodeficiency virus-1-infected individuals and lution of endemic and acquired immunodeficiency syn- normal controls. Blood 1994, 84(8):2711-2720. drome-related Kaposi's sarcoma. Med Oncol 2000, 49. Barozzi P, Luppi M, Facchetti F, Mecucci C, Alu M, Sarid R, Rasini V, 17(4):325-332. Ravazzini L, Rossi E, Festa S, Crescenzi B, Wolf DG, Schulz TF, Torelli 31. Sturzl M, Hohenadl C, Zietz C, Castanos-Velez E, Wunderlich A, G: Post-transplant Kaposi sarcoma originates from the seed- Ascherl G, Biberfeld P, Monini P, Browning PJ, Ensoli B: Expression ing of donor-derived progenitors. Nat Med 2003, 9(5):554-561. of K13/v-FLIP gene of human herpesvirus 8 and apoptosis in 50. Carroll PA, Brazeau E, Lagunoff M: Kaposi's sarcoma-associated Kaposi's sarcoma spindle cells. J Natl Cancer Inst 1999, herpesvirus infection of blood endothelial cells induces lym- 91(20):1725-1733. phatic differentiation. Virology 2004, 328(1):7-18. 32. Verma SC, Robertson ES: Molecular biology and pathogenesis of 51. Jussila L, Valtola R, Partanen TA, Salven P, Heikkila P, Matikainen MT, Kaposi sarcoma-associated herpesvirus. FEMS Microbiol Lett Renkonen R, Kaipainen A, Detmar M, Tschachler E, Alitalo R, Alitalo 2003, 222(2):155-163. K: Lymphatic endothelium and Kaposi's sarcoma spindle 33. Muralidhar S, Pumfery AM, Hassani M, Sadaie MR, Kishishita M, Brady cells detected by antibodies against the vascular endothelial JN, Doniger J, Medveczky P, Rosenthal LJ: Identification of kaposin growth factor receptor-3. Cancer Res 1998, 58(8):1599-1604. (open reading frame K12) as a human herpesvirus 8 52. Masood R, Xia G, Smith DL, Scalia P, Still JG, Tulpule A, Gill PS: (Kaposi's sarcoma-associated herpesvirus) transforming Ephrin B2 expression in Kaposi's sarcoma is induced by gene. J Virol 1998, 72(6):4980-4988. human herpes virus type 8: phenotype switch from venous to 34. Direkze S, Laman H: Regulation of growth signalling and cell arterial endothelium. Blood 2004. cycle by Kaposi's sarcoma-associated herpesvirus genes. Int J 53. Kahn HJ, Bailey D, Marks A: Monoclonal antibody D2-40, a new Exp Pathol 2004, 85(6):305-319. marker of lymphatic endothelium, reacts with Kaposi's sar- 35. Sadler R, Wu L, Forghani B, Renne R, Zhong W, Herndier B, Ganem coma and a subset of angiosarcomas. Mod Pathol 2002, D: A complex translational program generates multiple 15(4):434-440. novel proteins from the latently expressed kaposin (K12) 54. Wang HW, Trotter MW, Lagos D, Bourboulia D, Henderson S, Mak- locus of Kaposi's sarcoma-associated herpesvirus. J Virol 1999, inen T, Elliman S, Flanagan AM, Alitalo K, Boshoff C: Kaposi sar- 73(7):5722-5730. coma herpesvirus-induced cellular reprogramming 36. McCormick C, Ganem D: The kaposin B protein of KSHV acti- contributes to the lymphatic endothelial gene expression in vates the p38/MK2 pathway and stabilizes cytokine mRNAs. Kaposi sarcoma. Nat Genet 2004, 36(7):687-693. Science 2005, 307(5710):739-741. 55. Hong YK, Foreman K, Shin JW, Hirakawa S, Curry CL, Sage DR, 37. Pfeffer S, Sewer A, Lagos-Quintana M, Sheridan R, Sander C, Grasser Libermann T, Dezube BJ, Fingeroth JD, Detmar M: Lymphatic FA, van Dyk LF, Ho CK, Shuman S, Chien M, Russo JJ, Ju J, Randall G, reprogramming of blood vascular endothelium by Kaposi Lindenbach BD, Rice CM, Simon V, Ho DD, Zavolan M, Tuschl T: sarcoma-associated herpesvirus. Nat Genet 2004, Identification of microRNAs of the herpesvirus family. Nat 36(7):683-685. Methods 2005, 2(4):269-276. 56. Casalone R, Albini A, Righi R, Granata P, Toniolo A: Nonrandom 38. Cai X, Lu S, Zhang Z, Gonzalez CM, Damania B, Cullen BR: Kaposi's chromosome changes in Kaposi sarcoma: cytogenetic and sarcoma-associated herpesvirus expresses an array of viral FISH results in a new cell line (KS-IMM) and literature microRNAs in latently infected cells. Proc Natl Acad Sci U S A review. Cancer Genet Cytogenet 2001, 124(1):16-19. 2005, 102(15):5570-5575. 57. Popescu NC, Zimonjic DB, Leventon-Kriss S, Bryant JL, Lunardi- 39. Yen-Moore A, Hudnall SD, Rady PL, Wagner RF Jr., Moore TO, Iskandar Y, Gallo RC: Deletion and translocation involving Memar O, Hughes TK, Tyring SK: Differential expression of the chromosome 3 (p14) in two tumorigenic Kaposi's sarcoma HHV-8 vGCR cellular homolog gene in AIDS-associated and cell lines. J Natl Cancer Inst 1996, 88(7):450-455. classic Kaposi's sarcoma: potential role of HIV-1 Tat. Virology 58. Artandi SE, Attardi LD: Pathways connecting telomeres and 2000, 267(2):247-251. p53 in senescence, apoptosis, and cancer. Biochem Biophys Res 40. Cannon M, Philpott NJ, Cesarman E: The Kaposi's sarcoma-asso- Commun 2005, 331(3):881-890. ciated herpesvirus G protein-coupled receptor has broad sig- Page 7 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 59. Friborg J Jr., Kong W, Hottiger MO, Nabel GJ: p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 1999, 402(6764):889-894. 60. Chen Z, Smith KJ, Skelton HG 3rd, Barrett TL, Greenway HT Jr., Lo SC: Telomerase activity in Kaposi's sarcoma, squamous cell carcinoma, and basal cell carcinoma. Exp Biol Med (Maywood) 2001, 226(8):753-757. 61. Kiuru-Kuhlefelt S, Sarlomo-Rikala M, Larramendy ML, Soderlund M, Hedman K, Miettinen M, Knuutila S: FGF4 and INT2 oncogenes are amplified and expressed in Kaposi's sarcoma. Mod Pathol 2000, 13(4):433-437. 62. Pyakurel P, Montag U, Castaños-Vélez E, Kaaya E, Christensson B, Tönnies H, Biberfeld P, Heiden T: CGH of microdissected Kaposi’s sarcoma lesions reveals recurrent loss of chromo- some Y in early and additional chromosomal changes in late tumor stages. AIDS 2006, 20(14):1805-1812. 63. Wolff D, Knopp A, Weirich V, Steiner B, Junghanss C, Casper J, Fre- und M: Loss of the GVL effect by loss of the Y-chromosome as putative mechanism of immune escape in ALL. Bone Mar- row Transplant 2005, 35(1):101-102. 64. Rotzschke O, Falk K, Wallny HJ, Faath S, Rammensee HG: Charac- terization of naturally occurring minor histocompatibility peptides including H-4 and H-Y. Science 1990, 249(4966):283-287. 65. Harrington W Jr., Sieczkowski L, Sosa C, Chan-a-Sue S, Cai JP, Cabral L, Wood C: Activation of HHV-8 by HIV-1 tat. Lancet 1997, 349(9054):774-775. 66. Varthakavi V, Smith RM, Deng H, Sun R, Spearman P: Human immunodeficiency virus type-1 activates lytic cycle replica- tion of Kaposi's sarcoma-associated herpesvirus through induction of KSHV Rta. Virology 2002, 297(2):270-280. 67. Caselli E, Galvan M, Cassai E, Di Luca D: Transient expression of human herpesvirus-8 (Kaposi's sarcoma-associated herpes- virus) ORF50 enhances HIV-1 replication. Intervirology 2003, 46(3):141-149. 68. Demirhan I, Chandra A, Hasselmayer O, Biberfeld P, Chandra P: Detection of distinct patterns of anti-tat antibodies in HIV- infected individuals with or without Kaposi's sarcoma. J Acquir Immune Defic Syndr 1999, 22(4):364-368. 69. Demirhan I, Chandra A, Hasselmayer O, Chandra P: Intercellular traffic of human immunodeficiency virus type 1 transactiva- tor protein defined by monoclonal antibodies. In FEBS Lett Vol- ume 445. Issue 1 Netherlands ; 1999:53-56. 70. Pak F, Mwakigonja AR, Kokhaei P, Hosseinzadeh N, Pyakurel P, Kaaya E, Bogdanovic G, Selivanova G, Biberfeld P: Kaposi`s sarcoma her- pesvirus load in biopsies of cutaneous and oral KS lesions. European Journal of Cancer . Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 8 of 8 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Infectious Agents and Cancer Springer Journals

KSHV/HHV-8 and HIV infection in Kaposi's sarcoma development

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Springer Journals
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Copyright © 2007 by Pyakurel et al; licensee BioMed Central Ltd.
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Biomedicine; Cancer Research; Infectious Diseases; Oncology
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1750-9378
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10.1186/1750-9378-2-4
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17270056
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Abstract

Kaposi's sarcoma (KS) is a highly and abnormally vascularized tumor-like lesion affecting the skin, lymphnodes and viscera, which develops from early inflammatory stages of patch/plaque to late, nodular tumors composed predominant of spindle cells (SC). These SC are infected with the Kaposi's sarcoma-associated herpesvirus or human herpesvirus-8 (KSHV/HHV-8). KS is promoted during HIV infection by various angiogenic and pro-inflammatory factors including HIV-Tat. The latency associated nuclear antigen type 1 (LANA-1) protein is well expressed in SC, highly immunogenic and considered important in the generation and maintenance of HHV-8 associated malignancies. Various studies favour an endothelial origin of the KS SC, expressing "mixed" lymphatic and vascular endothelial cell markers, possibly representing hybrid phenotypes of endothelial cells (EC). A significant number of SC during KS development are apparently not HHV8 infected, which heterogeneity in viral permissiveness may indicate that non-infected SC may continuously be recruited in to the lesion from progenitor cells and locally triggered to develop permissiveness to HHV8 infection. In the present study various aspects of KS pathogenesis are discussed, focusing on the histopathological as well as cytogenetic and molecular genetic changes in KS. Background a) Classical or sporadic KS (CKS), originally described [1] Kaposi's sarcoma as a slow growing, indolent tumor mostly developing in Kaposi's sarcoma first described by Moritz Kaposi in 1872 the extremities of elderly males of eastern and Mediterra- as "idiopathic multiple pigmented sarcomas of the skin" nean Europe. b) Endemic KS (EKS), predominant in east- [1] is an angioproliferative, tumour-like lesion usually ern and central sub-Saharan Africa before the AIDS developing in the skin [2], and eventually disseminating epidemic and clinically similar to CKS, but also seen in a to multiple cutaneous sites, viscera and lymph nodes. Pre- more fulminant and fatal form in children. The childhood viously a rare disease, it is now a global health care and EKS is often lymphoglandular with or without skin clinical problem because of its association with the HIV involvement. c) Acquired immunodeficiency syndrome pandemic [3] and other immunosuppressed states[4]. (AIDS)-associated KS (AKS), the most frequent tumor of human immunodeficiency virus type I (HIV-l) infection Four clinically different KS forms are now recognized [5]: Page 1 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 and the most aggressive and rapidly growing form of KS in LANA-1 AIDS, with early dissemination in the skin and viscera. The latency associated nuclear antigen type 1 (LANA-1) protein is a well expressed and highly immunogenic, d) Iatrogenic KS (IKS), seen in drug related immunosup- latent nuclear antigen of HHV-8 considered important in pressed patients, e.g. transplant patients, emphasizing the the generation and maintenance of HHV-8 associated importance of immune disturbance as a co-factor in the malignancies [17] by its cell cycle regulation in competing pathogenesis of IKS and AKS, and possibly also EKS. with E2F for binding of hypophosphorylated pRb thus freeing E2F to activate gene transcription involved in cell In spite of the clear clinical differences the histopathology cycle progression [18] (Fig 1). E2F activity can also trigger of the various KS forms is essentially the same, with char- apoptosis via the p53 pathway but LANA-1 interacts with acteristic changes related to stage in the development of p53, repressing its gene transcriptional activity and ability the KS tumor[6]. to induce apoptosis (Fig 1). Therefore the inhibition of p53 by LANA-1 allows latent HHV-8 to promote cell cycle The epidemiology of AKS led to the discovery of a novel progression whilst inhibiting apoptosis [19]. Oncogenic herpes virus [7], which subsequently was shown to be viruses often block cell differentiation during tumor associated with all clinico-epidemiological forms of KS development by the stabilization of beta-catenin which [8]. The virus was rapidly characterised as a KS associated also appears to be promoted by LANA [20]. herpes virus (KSHV) and classified as human herpes virus type 8 (HHV-8). It was soon recognized to also be associ- The LANA-1 antigen is well detectable by immunohisto- ated with some rare types of lymphomas in AIDS patients, chemistry also in routinely formalin fixed paraffin embed- namely primary effusion lymphoma or body-cavity- ded biopsies. It is expressed by most SC in both early and based-lymphoma (PEL/BCBL) and Castleman's disease late stage lesions of all different clinical KS forms (AKS, (MCD)[9]. EKS, CKS and IKS) [8,21] and therefore used as a diagnos- tic marker in suspected HHV-8 related lesions and also for Human herpesvirus type 8 (HHV-8) serology of LANA-1 antibodies in patients by immunocy- Human herpesvirus 8 or Kaposi's sarcoma associated her- tochemistry that gives a characteristic speckled nuclear pesvirus (HHV-8/KSHV) was recognized to be a novel staining on HHV-8 infected BCBL cells. Several studies gamma-2 herpesvirus of the rhadinovirus genus closely have shown an increase in LANA-1 positive cells during related to the human gamma -1 herpesvirus, Epstein-Barr progression of KS lesions [22,23] allowing quantification virus (EBV) [10]. and phenotyping of these cells in KS lesions. A number of viral glycoproteins have been characterized Pathogenesis of KS shown to bind to cell surface heparan sulfate [11] and the HHV-8 is the most recently identified human oncogenic cell receptor integrin α3β1, respectively, thereby mediat- herpesvirus [24] expressing candidate viral oncogenes ing virus entry through endocytosis [12]. In the KS lesion which constitutively activate growth-signalling pathways HHV-8 is predominantly found in the so called tumor [13,25]. The pathogenesis of KS is however still unclear spindle (SC) cells in KS but was also in some lym- and appears complex, involving various mechanisms phocytes, monocytes and keratinocytes [13]. The virus dependent on both viral and cellular activities related to replicates in either a lytic or predominantly in the latent inflammation and angiogenesis promoted by endothelial form as closed circular episomal DNA [14] within the growth factors (β-FGF, PDGF, VEGF) including HIV-Tat as nucleus of KS tumor cells (SC) and B cells of MCD and well as cell proliferation and anti-apoptosis (vBCL2) other infected mononuclear cells [15]. It has been shown [2,13,26,27]. Characteristic for HHV-8 is the high hom- that the episomal viral DNA is tethered to metaphase ology of several viral and cellular genes suggesting viral chromosomes and copied in tandem with host cell DNA genes were pirated from host chromosomes during viral during cell division [16]. Latent viral specific genes well evolution. Some of these genes are involved in down demonstrated in infected KS SC are the latent nuclear anti- modulating the host immune responsiveness to target, gen (LANA-1), viral cyclin (v-cyclin), v-FLIP and kaposin infected cells and modulate cell proliferation, cell differ- a small membrane protein, which are all adjacent in the entiation and angiogenesis [13], including genes as vBcl- genome [16]. Lytic virus expression is most frequent in 2, vIL-8R, vMIPs, vIL-6, and the D type viral cyclin MCD, moderate in KS and relatively rare in PEL cells. Common viral genes found during lytic expression The HHV-8 infected cells escape immune response target- include K1 transmembrane protein, v-GCR, v-IRF, v-IL-6 ing by down regulation of surface MHC mediated by two and v-MIP [15]. transmembrane proteins, MIR1 and MIR2 [28] (Fig 1), which promote MHC endocytosis, and lysosomal degra- dation (Fig 1). Downregulation of MHC I and its acces- Page 2 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 HH Figure 1 V-8 gene expression (pathogenesis) during SC development and tumor growth HHV-8 gene expression (pathogenesis) during SC development and tumor growth. sory immune receptors poses the risk of initiating a early to late stage KS lesions, [30,31]. Thus viral exploita- natural killer (NK) cell response by initiating apoptosis tion of these two anti-apoptotic pathways contributes to through Fas (CD95/Apo-1) in cells lacking appropriate the tumor-like growth and progression of the KS lesion. MHC I expression. However, HHV-8 can inhibit NK- mediated killing through expression of the anti apoptotic V-cyclin binds with cyclin dependent kinases (CDK6), v-FLICE-inhibitory proteins (v-FLIPs) [28]. V-FLIP which which complex phosphorylates pRb, releasing a transcrip- acts as a dominant inhibitor of receptor-activated apopto- tion factor (E2F), which activates the transcription of S- sis by binding to Fas-associated death domain protein and phase genes (Fig 1). However, unlike cellular cyclin, vCy- caspase 8 (FLICE) [29]. This prevents activated caspase clin-CDK6 complexes are resistant to CDK inhibitory pro- recruitment into the death-inducing signaling complex teins, which may lead to unregulated cell cycle (Fig 1). progression and transformation and thereby promote tumor development [32]. HHV-8 v-FLIP shares with c-FLIPs the ability to activate NF-κB [28] which is essential for the growth and survival Kaposin, the latency gene represents a potential viral of the cell. Our studies on KS biopsies have shown that oncogene and is characterized as a transforming gene apoptosis clearly decreases during development of early to [33], although little is known about its role in deregulat- late nodular KS lesions [30], and that the expression of ing cell signalling [34]. It is present in three (A, B, C) iso- anti-apoptotic v-FLIP and cellular Bcl-2 increase from forms [35] of which Kaposin B is expressed by all HHV-8 Page 3 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 infected cells and can activate the p38-MK2 pathway [36] Histogenesis of KS (Fig 1) and block the degradation of the messenger RNAs The histopathology of KS is characterized by an early infil- transcribing various cytokines necessary for cell survival, tration of mononuclear inflammatory cells, formation of hence increasing their translation [36]. The Kaposin gene small, irregular, endothelial lined slits around new blood also encodes several microRNAs (miRNA), which may vessels (angiogenesis) and extravasation of erythrocytes regulate gene expression by binding to complementary [2] with accumulation of hemosiderin pigments. KS at messenger RNAs [37]. Two of these HHV-8 miRNAs are early stages appears to reflect a predominantly reactive cell expressed by SC at all KS stages [37] and may contribute proliferation of polyclonal nature that may regress, but to tumorigenic transformation of infected cells [33], and usually progresses to a nodular possibly clonal tumor therefore of therapeutic interest [37]. [2,46]. Pathognomonic for KS development from early patch/plaque to late nodular tumor lesions is the The KSHV miRNAs are expressed from what appears to be increased appearance of bundles of morphological spin- a single genetic locus that largely coincides with an 4-kb dle cells (SC) expressing CD34 (hematopoietic stem cell noncoding sequence located between the KSHV v-cyclin and vascular endothelial marker). At the late nodular KS and K12 Kaposin genes, both of which are also expressed stage there is less inflammatory cell infiltration, mostly in latently infected cells. Computer analysis of potential around the boaders of the dense, nodular accumulation of mRNA targets for these viral miRNAs identified a number SC bundles which skin lesions may later ulcerate. Unlike of interesting candidate genes, including several mRNAs typical metastatic cancers, KS often appears early as a mul- previously shown to be downregulated in KSHV-infected ticentric tumour, with each lesion arising de novo by a cells. It appears that these viral miRNAs play a critical role localized small patch and of SC [47]. in the establishment and or maintenance of KSHV latent infection and hence, in KSHV-induced oncogenesis [38]. Most SC are positive for CD34 and LANA but a consider- able number of CD34+ SC are LANA- at all AKS/EKS HHV-8 also encodes a G-protein-coupled receptor stages [22,23]. This apparent heterogeneity in viral per- (vGCR) homolog to the human angiogenic, chemokine missiveness of CD34+ SC seems less compatible with a interleukin-8 receptor (IL-8R, CCR1 and CXCR2) [39] (Fig clonal CD34+ SC proliferation and virus transfer but SC are 1). Angiogenic responses induced by vGCR are mediated appears to indicate that also non-infected CD34 by upregulation of vascular endothelial growth factor continuously recruited from progenitor cells and locally (VEGF) [40]. The constitutive activity of vGCR could triggered to develop permissiveness to HHV-8 infection therefore have a role for VEGF expression by SC during the [22,23]. Furthermore cells belonging to the non-cycling development of early stage KS lesions [41]. Furthermore SC (Ki67-) population showed a clear increase during the vGCR dependent expression of autocrine and para- development from patch/plaque (median 13.5%) to nod- crine growth factors (bFGF, VEGF,) promotes the angio- ular stage (median 40.3%) [22], also supporting the con- genesis and edema [26,42] seen in KS patients. It was also cept of continuous recruitment of CD34+ cells to the shown [43] that viral envelop glycoprotein gB can activate lesion. KS spindle-like cells have been shown to develop the VEGFR-3 receptor and trigger receptor signalling on in cultures of peripheral blood of HIV infected patients the surface of microvascular endothelial cells, thereby with KS or at high risk for developing KS [48]. Further- modulating cell migration and proliferation. VEGFR-3 more recent studies show that endothelial cells or their expression and activation may also enhance HHV-8 infec- precursors residing in donor kidneys may contribute to tion and participate in HHV-8 mediated transformation post-renal transplant KS indicated by the finding that KS [43] and thereby appears to be an important factor in the SC in the female recipient kidney had a male (donor) pathogenesis of Kaposi's sarcoma. karyotype and that KS SC expressed the donor HLA anti- gen [49]. These findings appear to indicate that KS SC The Kaposi sarcoma herpesvirus (KSHV) also encodes and/or their progenitors can be recruited during develop- multiple proteins that disrupt host antiviral responses, ment of KS lesion. including four viral proteins that have homology to the interferon regulatory factor (IRF) family of transcription Characteristic spindle cells (SC) express various "mixed" factors. At least three of the KSHV vIRFs (vIRFs 1–3) alter (LEC and VEC) endothelial phenotypic cell markers pos- responses to cellular IRFs and to interferons (IFNs). The sibly representing hybrid phenotypes of endothelial cells vIRFs also affect other important regulatory proteins in at different maturation stages. It has been recurrently the cell, including responses to transforming growth fac- debated whether SC are vascular (VEC) or lymphatic tor beta (TGF-beta) and the tumor suppressor protein p53 (LEC) in origin or derive from mesenchymal progenitor [44]. K7/vIAP (inhibitor of apoptosis protein) is another cells [50-52], although most studies by immunohisto- antiapoptotic factor homologous to the cellular protein chemistry have revealed that SC express lymphatic mark- survivin [45]. ers, such as D2-40 [53], LYVE-1 [50] and VEGFR-3 [51]. Page 4 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 Also studies by gene expression microarray show that KS tions and deletions in the short arm of chromosome 3 at neoplastic cells are closely related to lymphatic endothe- region 3p14. These KS cell lines also exhibit loss of heter- lial cells (LEC) but coexpressing some blood vascular ozygosity of loci at region 3p14-ter. The chromosome 3 endothelial cell (VEC) markers [54]. Furthermore HHV-8 alterations observed were suggested to contribute to the can infect both LEC and VEC in vitro and infected LEC neoplastic process in KS [57] but other cytogenetic studies had a higher HHV-8 genome copy number than VEC[54]. on the KS-IMM cell line (IKS) [56] showed gains in In-vitro infection of CD34+ human dermal microvascular 1q10→qter, 7p10→pter, 7q22→qter, 8p11→qter, endothelial cells (HDMEC) with HHV-8 resulted in the 14pter→q22 but no changes in chromosome 3 [56]. upregulation of LEC markers such as LYVE-1 in the These aberrations are compatible with the notion that ini- infected HDMEC [55]. tially KS may develop as a reactive polyclonal cell prolifer- ation associated with chromosome instability, followed In our study all LANA+ cells were LYVE-1+ (lymphatic by acquisition of clonal chromosome changes in later endothelial markers) in early and late KS and the HHV-8 stages [56]. However, the significance in KS pathogenesis infection (LANA) appeared better correlated to LYVE-1 of aberrations on established KS cell lines should be than to CD34 expression [23]. LANA+/CD34-cells were related to finding that such cell lines when established more frequent in early as compared to late lesions and did usually loose their HHV-8 episomes and possibly may not express a leucocytic phenotype (CD3, CD20, CD45, represent only a minor KS cell population. CD68) [22], but most expressed lymphatic endothelial (LEC) markers such as LYVE-1, VEGFR-3 and D2-40, sug- The chromosomal instability suggested by the studies on gesting that resident LECs represent an early target of pri- cell lines may lead to cell apoptotis via the p53 path- mary HHV-8 infection [23]. This is also supported by way[58]. However, HHV-8 LANA binds to p53repressing other findings [54] that infected LECs have a higher HHV- its ability to induce apoptosis [59]. Furthermore telomer- 8 genome copy number than VECs. Obviously a high viral ase activity has been found to be upregulated in KS [60], copy number may result in an efficient maintenance and which may immortalise the infected cell leading to propagation of episomal HHV-8 DNA in dividing and increased tumor cell survival. migrating LECs. Furthermore in-vitro activation of VEGFR-3 by HHV-8 has been shown to increase endothe- Previous, CGH studies of formalin fixed paraffin embed- lial cell migration and to enhance cell susceptibility to ded KS biopsies revealed a recurrent gain at 11q13 [61], HHV-8 infection and transformation [43]. Hence, the which also amplifies two known oncogenes, FGF4 and activation of VEGFR-3 in LANA+/VEGFR-3+ SC observed INT2, residing at 11q13 suggesting a possible role of during KS development will probably promote an HHV-8 in the amplification and activation of genomic increased endothelial cell migration (recruitment) and oncogenes [61]. transformation to tumor SC including formation of path- ological vascular slits. Loss of chromosome Y was observed in most AKS and EKS cases recently studied by us [62] and interestingly it was Cell proliferation is relatively low in KS as shown by our the only aberration observed in early KS. Late stage (nod- previous studies on proliferation related protein Ki67 ular) KS had beside loss of chromosome Y, also recurrent expression and DNA flow cytometry [30]. The frequency deletions on chromosomes 16 and 17. Deletion of chro- of proliferating (Ki67+) cells usually decreased during mosome Y was also reported by previous studies on short development from early to late KS lesions, consistent with term cultures of primary KS tumor cells and established the notion that KS growth from a early reactive lesion to a KS cell lines [56]. EKS showed often more chromosomal nodular tumor depends not only on SC division but also abnormalities than AKS [62], which might indicate that on decreased apoptosis [30] and progenitor recruitment genomic instability could be a more important factor in [22,23]. No significant difference in cell proliferation was the development of EKS than AKS. Most likely AKS devel- observed between nodular AKS and EKS [22]. These find- opment is also promoted by various cytokines and growth ings could therefore indicate that the usually more spread factors produced by the HIV infection and the dysregu- and aggressive growth of the AKS tumors may reflect a lated and compromised state of host immune response. higher rate of SC progenitor recruitment compared to the Loss of the Y chromosome and encoded male specific more indolent EKS lesions. minor histocompatibility antigens (HY antigen) has been shown to be linked to haematological relapse in acute Cytogenesis of KS lymphoblastic leukemia due to immune escape mecha- Reports on cytogenetic and molecular genetic changes in nisms [63]. The HY antigens are presented at the cell sur- KS are few [56]. Studies from KS cell lines, KS Y-1 (AKS face with the major histocompatibility complex (MHC) derived) and KS SLK (IKS derived) revealed loss of copies and together also processed intracellularly [64]. However, of chromosomes 14 and 21 and non-random transloca- no studies have previously indicated a deficiency of HY Page 5 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 Salaam, Tanzania and The ethical committee, Karolinska Hospital (Dnr 01- antigen in KS tumors, which loss of the Y chromosome in 096). We declare no conflict of interest. our studies suggests as of possible importance in KS pathogenesis. References 1. Kaposi M: Idiopathisches multiples pigment sarcoma de Haut. HIV pathogenesis in KS Arch Dermatol Syphil 1872, 4(265):. There seems to be a cross talk between HIV-1 and HHV-8 2. Biberfeld P, Ensoli B, Sturzl M, Schulz TF: Kaposi sarcoma-associ- ated herpesvirus/human herpesvirus 8, cytokines, growth as recent studies have shown that HIV-1 replication stim- factors and HIV in pathogenesis of Kaposi's sarcoma. Curr ulates HHV-8 production in PEL cell lines and peripheral Opin Infect Dis 1998, 11(2):97-105. 3. Amir H, Kaaya EE, Manji KP, Kwesigabo G, Biberfeld P: Kaposi's sar- blood mononuclear cells from KS patients, possibly due coma before and during a human immunodeficiency virus to the activating functions of HIV-Tat [65, 66] ORF50, the epidemic in Tanzanian children. Pediatr Infect Dis J 2001, major transactivator of HHV-8 lytic cycle can also induce 20(5):518-521. 4. Lessan-Pezeshki M, Einollahi B, Khatami MR, Mahdavi M: Kidney increased levels of HIV replication by interacting synergis- transplantation and Kaposi's sarcoma: review of 2050 recip- tically with HIV-1 Tat leading to increased cell susceptibil- ients. Transplant Proc 2001, 33(5):2818. 5. Biberfeld P, Lebbe C, Tschachler E, Luppi M: Human herpesvirus- ity to HIV infection and transient permissiveness to HIV 8 and HIV. In: Viral co-infections in HIV Impact and manag- replication [67]. ment:. In Lalezari J, Moyle G Volume Chapter 4. Remedica; 2002:63-91. 6. Kaaya EE, Parravicini C, Sundelin B, Mgaya E, Kitinya J, Lema L, Luande The increased incidence of KS in patients with AIDS was J, Biberfeld P: Spindle cell ploidy and proliferation in endemic also shown to be related to effects of the HIV-1 Tat protein and epidemic African Kaposi's sarcoma. Eur J Cancer 1992, by stimulation of proliferation and anti-apoptosis of 28A(11):1890-1894. 7. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, infected spindle cells (SC) and also activation of HHV-8 Moore PS: Identification of herpesvirus-like DNA sequences thus increasing SC viral load and expression of various in AIDS-associated Kaposi's sarcoma. Science 1994, 266(5192):1865-1869. viral genes with oncogenic potential (vGCR, vBCL2, and 8. Schalling M, Ekman M, Kaaya EE, Linde A, Biberfeld P: A role for a vIRF1, see above) [65]. Thus, Tat promotes tumorigenesis new herpes virus (KSHV) in different forms of Kaposi's sar- of endothelial cells, both via stimulation of vascular coma. Nat Med 1995, 1(7):707-708. 9. Gaidano G, Castanos-Velez E, Biberfeld P: Lymphoid disorders endothelial growth factors, anti-apoptotic activity and associated with HHV-8/KSHV infection: facts and conten- HHV-8 replication. Notably, the functional activity of Tat tions. Med Oncol 1999, 16(1):8-12. 10. Viejo-Borbolla A, Ottinger M, Schulz TF: Human Herpesvirus 8: protein in the pathogenesis of AKS clearly involves an Biology and Role in the Pathogenesis of Kaposi's Sarcoma intercellular signalling cascade which is inhibited by anti- and Other AIDS-related Malignancies. Curr Infect Dis Rep 2003, bodies to HIV-Tat epitopes [68, 69]. 5(2):169-175. 11. Wang FZ, Akula SM, Pramod NP, Zeng L, Chandran B: Human her- pesvirus 8 envelope glycoprotein K8.1A interaction with the Recently we have found differences in SC viral load target cells involves heparan sulfate. J Virol 2001, between oral and cutaneous KS lesion also suggesting pos- 75(16):7517-7527. 12. Akula SM, Naranatt PP, Walia NS, Wang FZ, Fegley B, Chandran B: sible differences of Tat expression in these lesions [70]. Kaposi's sarcoma-associated herpesvirus (human herpesvi- rus 8) infection of human fibroblast cells occurs through endocytosis. J Virol 2003, 77(14):7978-7990. In summary the concept of oncogenesis related to infec- 13. Hengge UR, Ruzicka T, Tyring SK, Stuschke M, Roggendorf M, tion is particularly well exemplified by the herpes virus Schwartz RA, Seeber S: Update on Kaposi's sarcoma and other HHV-8 and retrovirus HIV-1 associated Kaposi's sarcoma, HHV8 associated diseases. Part 2: pathogenesis, Castle- man's disease, and pleural effusion lymphoma. Lancet Infect Dis which develops due to the effects of various host-cells and 2002, 2(6):344-352. viral factors elicited during infection affecting cell prolifer- 14. Renne R, Lagunoff M, Zhong W, Ganem D: The size and confor- ation, cell escape from apoptosis and dysregulation of mation of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) DNA in infected cells and virions. J Virol 1996, host immune responses. 70(11):8151-8154. 15. Schulz TF: Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8): epidemiology and pathogenesis. J Antimicrob Acknowledgements Chemother 2000, 45 Suppl T3:15-27. These studies were supported by Swedish Cancer Society, Cancer Society 16. Szekely L, Kiss C, Mattsson K, Kashuba E, Pokrovskaja K, Juhasz A, of Stockholm, Karolinska Institutet research fund and Swedish International Holmvall P, Klein G: Human herpesvirus-8-encoded LNA-1 Development Agency (Sida), Department of Research Cooperation accumulates in heterochromatin- associated nuclear bodies. J Gen Virol 1999, 80 ( Pt 11):2889-2900. (SAREC). 17. Komatsu T, Ballestas ME, Barbera AJ, Kaye KM: The KSHV latency- associated nuclear antigen: a multifunctional protein. Front Drs. L. Lema, and B. Kalyanyama of the Muhimbili University College, Drs. Biosci 2002, 7:d726-30. J. Luande, T. Ngoma, M. Diwani of Ocean Road Cancer Institute (ORCI), 18. Radkov SA, Kellam P, Boshoff C: The latent nuclear antigen of Dar-Es-Salaam, Tanzania provided the biopsies. The technical assistance of Kaposi sarcoma-associated herpesvirus targets the retino- blastoma-E2F pathway and with the oncogene Hras trans- A. Magogo and V. Nelson from Muhimbili University College, Dar-Es- forms primary rat cells. Nat Med 2000, 6(10):1121-1127. Salaam, Tanzania is highly appreciated. 19. Jenner RG, Boshoff C: The molecular pathology of Kaposi's sar- coma-associated herpesvirus. Biochim Biophys Acta 2002, The ethical clearance was obtained from Ministry of Health (MoH), and the 1602(1):1-22. 20. Boshoff C: Kaposi virus scores cancer coup. Nat Med 2003, Muhimbili University College of Health Sciences (MUCHS) in Dar Es 9(3):261-262. Page 6 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 21. Katano H, Sato Y, Kurata T, Mori S, Sata T: High expression of naling effects in primary effusion lymphoma cells. J Virol 2003, HHV-8-encoded ORF73 protein in spindle-shaped cells of 77(1):57-67. Kaposi's sarcoma. Am J Pathol 1999, 155(1):47-52. 41. Choi J, Means RE, Damania B, Jung JU: Molecular piracy of 22. Pyakurel P, Massambu C, Castanos-Velez E, Ericsson S, Kaaya E, Bib- Kaposi's sarcoma associated herpesvirus. Cytokine Growth Fac- erfeld P, Heiden T: Human Herpesvirus 8/Kaposi Sarcoma Her- tor Rev 2001, 12(2-3):245-257. pesvirus Cell Association During Evolution of Kaposi 42. Samaniego F, Markham PD, Gendelman R, Watanabe Y, Kao V, Kow- Sarcoma. J Acquir Immune Defic Syndr 2004, 36(2):678-683. alski K, Sonnabend JA, Pintus A, Gallo RC, Ensoli B: Vascular 23. Pyakurel P, Pak F, Mwakigonja AR, Kaaya E, Heiden T, Biberfeld P: endothelial growth factor and basic fibroblast growth factor Lymphatic and vascular origin of Kaposi's sarcoma spindle present in Kaposi's sarcoma (KS) are induced by inflamma- cells during tumor development. Int J Cancer 2006, tory cytokines and synergize to promote vascular permea- 119(6):1262-1267. bility and KS lesion development. Am J Pathol 1998, 24. Verma SC, Lan K, Robertson E: Structure and function of 152(6):1433-1443. latency-associated nuclear antigen. Curr Top Microbiol Immunol 43. Zhang X, Wang JF, Chandran B, Persaud K, Pytowski B, Fingeroth J, 2007, 312:101-136. Groopman JE: KSHV activation of VEGFR-3 alters endothelial 25. Boshoff C, Weiss R: AIDS-related malignancies. Nat Rev Cancer function and enhances infection. J Biol Chem 2005. 2002, 2(5):373-382. 44. Offermann MK: Kaposi sarcoma herpesvirus-encoded inter- 26. Biberfeld P EB Sturzl M, and Schulz TF.: Kaposi's sarcoma associ- feron regulator factors. Curr Top Microbiol Immunol 2007, ated herpesvirus/human herpesvirus 8, cytokine growth fac- 312:185-209. tos and HIV in pathogenesis of Kaposi's sarcoma. Curr Opin Inf 45. Wang HW, Sharp TV, Koumi A, Koentges G, Boshoff C: Character- Dis 1998, 11(97):105. ization of an anti-apoptotic glycoprotein encoded by 27. Dalgleish AG, O'Byrne KJ: Chronic immune activation and Kaposi's sarcoma-associated herpesvirus which resembles a inflammation in the pathogenesis of AIDS and cancer. Adv spliced variant of human survivin. EMBO J 2002, Cancer Res 2002, 84:231-276. 21(11):2602-2615. 28. Moore PS, Chang Y: Kaposi's sarcoma-associated herpesvirus 46. Kondo Y, Izumi T, Yanagawa T, Kanda H, Katano H, Sata T: Sponta- immunoevasion and tumorigenesis: two sides of the same neously regressed Kaposi's sarcoma and human herpesvirus coin? Annu Rev Microbiol 2003, 57:609-639. 8 infection in a human immunodeficiency virus-negative 29. Belanger C, Gravel A, Tomoiu A, Janelle ME, Gosselin J, Tremblay MJ, patient. Pathol Int 2000, 50(4):340-346. Flamand L: Human herpesvirus 8 viral FLICE-inhibitory pro- 47. Ensoli B, Sgadari C, Barillari G, Sirianni MC, Sturzl M, Monini P: Biol- tein inhibits Fas-mediated apoptosis through binding and ogy of Kaposi's sarcoma. Eur J Cancer 2001, 37(10):1251-1269. prevention of procaspase-8 maturation. J Hum Virol 2001, 48. Browning PJ, Sechler JM, Kaplan M, Washington RH, Gendelman R, 4(2):62-73. Yarchoan R, Ensoli B, Gallo RC: Identification and culture of 30. Kaaya E, Castanos-Velez E, Heiden T, Ekman M, Catrina AI, Kitinya J, Kaposi's sarcoma-like spindle cells from the peripheral blood Andersson L, Biberfeld P: Proliferation and apoptosis in the evo- of human immunodeficiency virus-1-infected individuals and lution of endemic and acquired immunodeficiency syn- normal controls. Blood 1994, 84(8):2711-2720. drome-related Kaposi's sarcoma. Med Oncol 2000, 49. Barozzi P, Luppi M, Facchetti F, Mecucci C, Alu M, Sarid R, Rasini V, 17(4):325-332. Ravazzini L, Rossi E, Festa S, Crescenzi B, Wolf DG, Schulz TF, Torelli 31. Sturzl M, Hohenadl C, Zietz C, Castanos-Velez E, Wunderlich A, G: Post-transplant Kaposi sarcoma originates from the seed- Ascherl G, Biberfeld P, Monini P, Browning PJ, Ensoli B: Expression ing of donor-derived progenitors. Nat Med 2003, 9(5):554-561. of K13/v-FLIP gene of human herpesvirus 8 and apoptosis in 50. Carroll PA, Brazeau E, Lagunoff M: Kaposi's sarcoma-associated Kaposi's sarcoma spindle cells. J Natl Cancer Inst 1999, herpesvirus infection of blood endothelial cells induces lym- 91(20):1725-1733. phatic differentiation. Virology 2004, 328(1):7-18. 32. Verma SC, Robertson ES: Molecular biology and pathogenesis of 51. Jussila L, Valtola R, Partanen TA, Salven P, Heikkila P, Matikainen MT, Kaposi sarcoma-associated herpesvirus. FEMS Microbiol Lett Renkonen R, Kaipainen A, Detmar M, Tschachler E, Alitalo R, Alitalo 2003, 222(2):155-163. K: Lymphatic endothelium and Kaposi's sarcoma spindle 33. Muralidhar S, Pumfery AM, Hassani M, Sadaie MR, Kishishita M, Brady cells detected by antibodies against the vascular endothelial JN, Doniger J, Medveczky P, Rosenthal LJ: Identification of kaposin growth factor receptor-3. Cancer Res 1998, 58(8):1599-1604. (open reading frame K12) as a human herpesvirus 8 52. Masood R, Xia G, Smith DL, Scalia P, Still JG, Tulpule A, Gill PS: (Kaposi's sarcoma-associated herpesvirus) transforming Ephrin B2 expression in Kaposi's sarcoma is induced by gene. J Virol 1998, 72(6):4980-4988. human herpes virus type 8: phenotype switch from venous to 34. Direkze S, Laman H: Regulation of growth signalling and cell arterial endothelium. Blood 2004. cycle by Kaposi's sarcoma-associated herpesvirus genes. Int J 53. Kahn HJ, Bailey D, Marks A: Monoclonal antibody D2-40, a new Exp Pathol 2004, 85(6):305-319. marker of lymphatic endothelium, reacts with Kaposi's sar- 35. Sadler R, Wu L, Forghani B, Renne R, Zhong W, Herndier B, Ganem coma and a subset of angiosarcomas. Mod Pathol 2002, D: A complex translational program generates multiple 15(4):434-440. novel proteins from the latently expressed kaposin (K12) 54. Wang HW, Trotter MW, Lagos D, Bourboulia D, Henderson S, Mak- locus of Kaposi's sarcoma-associated herpesvirus. J Virol 1999, inen T, Elliman S, Flanagan AM, Alitalo K, Boshoff C: Kaposi sar- 73(7):5722-5730. coma herpesvirus-induced cellular reprogramming 36. McCormick C, Ganem D: The kaposin B protein of KSHV acti- contributes to the lymphatic endothelial gene expression in vates the p38/MK2 pathway and stabilizes cytokine mRNAs. Kaposi sarcoma. Nat Genet 2004, 36(7):687-693. Science 2005, 307(5710):739-741. 55. Hong YK, Foreman K, Shin JW, Hirakawa S, Curry CL, Sage DR, 37. Pfeffer S, Sewer A, Lagos-Quintana M, Sheridan R, Sander C, Grasser Libermann T, Dezube BJ, Fingeroth JD, Detmar M: Lymphatic FA, van Dyk LF, Ho CK, Shuman S, Chien M, Russo JJ, Ju J, Randall G, reprogramming of blood vascular endothelium by Kaposi Lindenbach BD, Rice CM, Simon V, Ho DD, Zavolan M, Tuschl T: sarcoma-associated herpesvirus. Nat Genet 2004, Identification of microRNAs of the herpesvirus family. Nat 36(7):683-685. Methods 2005, 2(4):269-276. 56. Casalone R, Albini A, Righi R, Granata P, Toniolo A: Nonrandom 38. Cai X, Lu S, Zhang Z, Gonzalez CM, Damania B, Cullen BR: Kaposi's chromosome changes in Kaposi sarcoma: cytogenetic and sarcoma-associated herpesvirus expresses an array of viral FISH results in a new cell line (KS-IMM) and literature microRNAs in latently infected cells. Proc Natl Acad Sci U S A review. Cancer Genet Cytogenet 2001, 124(1):16-19. 2005, 102(15):5570-5575. 57. Popescu NC, Zimonjic DB, Leventon-Kriss S, Bryant JL, Lunardi- 39. Yen-Moore A, Hudnall SD, Rady PL, Wagner RF Jr., Moore TO, Iskandar Y, Gallo RC: Deletion and translocation involving Memar O, Hughes TK, Tyring SK: Differential expression of the chromosome 3 (p14) in two tumorigenic Kaposi's sarcoma HHV-8 vGCR cellular homolog gene in AIDS-associated and cell lines. J Natl Cancer Inst 1996, 88(7):450-455. classic Kaposi's sarcoma: potential role of HIV-1 Tat. Virology 58. Artandi SE, Attardi LD: Pathways connecting telomeres and 2000, 267(2):247-251. p53 in senescence, apoptosis, and cancer. Biochem Biophys Res 40. Cannon M, Philpott NJ, Cesarman E: The Kaposi's sarcoma-asso- Commun 2005, 331(3):881-890. ciated herpesvirus G protein-coupled receptor has broad sig- Page 7 of 8 (page number not for citation purposes) Infectious Agents and Cancer 2007, 2:4 http://www.infectagentscancer.com/content/2/1/4 59. Friborg J Jr., Kong W, Hottiger MO, Nabel GJ: p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 1999, 402(6764):889-894. 60. Chen Z, Smith KJ, Skelton HG 3rd, Barrett TL, Greenway HT Jr., Lo SC: Telomerase activity in Kaposi's sarcoma, squamous cell carcinoma, and basal cell carcinoma. Exp Biol Med (Maywood) 2001, 226(8):753-757. 61. Kiuru-Kuhlefelt S, Sarlomo-Rikala M, Larramendy ML, Soderlund M, Hedman K, Miettinen M, Knuutila S: FGF4 and INT2 oncogenes are amplified and expressed in Kaposi's sarcoma. Mod Pathol 2000, 13(4):433-437. 62. Pyakurel P, Montag U, Castaños-Vélez E, Kaaya E, Christensson B, Tönnies H, Biberfeld P, Heiden T: CGH of microdissected Kaposi’s sarcoma lesions reveals recurrent loss of chromo- some Y in early and additional chromosomal changes in late tumor stages. AIDS 2006, 20(14):1805-1812. 63. Wolff D, Knopp A, Weirich V, Steiner B, Junghanss C, Casper J, Fre- und M: Loss of the GVL effect by loss of the Y-chromosome as putative mechanism of immune escape in ALL. Bone Mar- row Transplant 2005, 35(1):101-102. 64. Rotzschke O, Falk K, Wallny HJ, Faath S, Rammensee HG: Charac- terization of naturally occurring minor histocompatibility peptides including H-4 and H-Y. Science 1990, 249(4966):283-287. 65. Harrington W Jr., Sieczkowski L, Sosa C, Chan-a-Sue S, Cai JP, Cabral L, Wood C: Activation of HHV-8 by HIV-1 tat. Lancet 1997, 349(9054):774-775. 66. Varthakavi V, Smith RM, Deng H, Sun R, Spearman P: Human immunodeficiency virus type-1 activates lytic cycle replica- tion of Kaposi's sarcoma-associated herpesvirus through induction of KSHV Rta. Virology 2002, 297(2):270-280. 67. Caselli E, Galvan M, Cassai E, Di Luca D: Transient expression of human herpesvirus-8 (Kaposi's sarcoma-associated herpes- virus) ORF50 enhances HIV-1 replication. Intervirology 2003, 46(3):141-149. 68. Demirhan I, Chandra A, Hasselmayer O, Biberfeld P, Chandra P: Detection of distinct patterns of anti-tat antibodies in HIV- infected individuals with or without Kaposi's sarcoma. J Acquir Immune Defic Syndr 1999, 22(4):364-368. 69. Demirhan I, Chandra A, Hasselmayer O, Chandra P: Intercellular traffic of human immunodeficiency virus type 1 transactiva- tor protein defined by monoclonal antibodies. In FEBS Lett Vol- ume 445. Issue 1 Netherlands ; 1999:53-56. 70. Pak F, Mwakigonja AR, Kokhaei P, Hosseinzadeh N, Pyakurel P, Kaaya E, Bogdanovic G, Selivanova G, Biberfeld P: Kaposi`s sarcoma her- pesvirus load in biopsies of cutaneous and oral KS lesions. European Journal of Cancer . Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 8 of 8 (page number not for citation purposes)

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