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Kaposi Sarcoma Pathogenesis: A Triad of Viral Infection, Oncogenesis and Chronic Inflammation

Kaposi Sarcoma Pathogenesis: A Triad of Viral Infection, Oncogenesis and Chronic Inflammation

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iMedPub Journals
2010Vol.1No. 2:2
doi: 10:3823/409
Kaposi Sarcoma Pathogenesis: A Triad o Viral Inection, Oncogenesis andChronic Inammation
Janet L. Douglas
, Jean K. Gustin
, Ashlee V. Moses
*, Bruce J. Dezube
, and Liron Pantanowitz
1 Vaccine and Gene Therapy Institute, Oregon Health Sciences University, Beaverton, OR2 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA3 Department o Pathology, University o Pittsburgh Medical Center, Pittsburgh, PA*Corresponding authorAshlee V. MosesVGTI-Oregon Health & Science University505 NW 185th Ave. Beaverton, OR 97006Phone: 503-418-2712 mosesa@ohsu.edu
Kaposi sarcoma (KS) is characterized by angioprolierative mul-tiocal tumors o the skin, mucosa and less requently the visce-ra. A close inspection o KS lesions reveals that they are largelycomprised o cells o endothelial origin with a unique spindledmorphology, and these are accompanied by a variable chronicinammatory inltrate. From an epidemiological standpoint,our dierent orms o KS are recognized: Classic (sporadic), Ari-can (endemic), acquired immune deciency syndrome (AIDS)-associated (epidemic), and Transplant or immunosuppression-associated (iatrogenic) KS (Table 1). Although these variousorms o KS have dierent environmental and immunologicalcomponents, the development o each depends upon prior in-ection with KSHV. However, KSHV inection alone is insucientor the development o KS. For most cases o AIDS and Trans-plant KS it is well established that in addition to inection withKSHV, some orm o immunodeciency is also necessary ordisease progression. However, several natural history studies
© Under License o Creative Commons Attribution 3.0 License This article is available rom:http://www.transbiomedicine.com
indicate that additional actors may contribute to the develop-ment o KS in asymptomatic KSHV-inected persons. For exam-ple, not all AIDS patients develop KS even in the ace o pro-ound immunosuppression, only a minority o KSHV-inectedtransplant recipients develop iatrogenic KS, and people withclassic or endemic KS are not typically immunosuppressed [1,2]. The co-actors involved in classic and endemic KS have yet tobe denitively elucidated. Various environmental and geneticactors have been implicated, as well as age, sex and malnutri-tion. The association o KS with the Koebner phenomenon, acondition where lesions initiate or recur at inammatory sites o injury or trauma [3] and the recrudescent KS (KS are) seen withthe immune constitution inammatory syndrome (IRIS) [4] su-ggest that inammation plays a contributing role in oncogene-sis. Progression o KS disease likely depends on a complex andas yet incompletely understood interplay between KSHV andthe host immune system that allows or the establishment o a tumor-promoting environment. Like all herpesviruses, KSHVestablishes a lie-long inection in the host that depends upon
Kaposi sarcoma (KS) is a complex cancer that arises rom the initial inection o an appropriate endothelial or progenitorcell by Kaposi Sarcoma Herpesvirus/Human Herpesvirus-8 (KSHV/HHV8). However, the majority o KS cases occur wheninected patients also suer rom some coincident orm o immune deregulation, providing a avorable microenviron-ment or tumor development. Cellular hallmarks o KS progression include both the hyper-prolieration o KSHV-inect-ed cells and the inltration o immune modulatory cells into KS lesions, which together result in chronic inammation,the induction o angiogenesis and tumor growth. This review describes the current understanding o the interactionsbetween KSHV and host responses that result in this unusual cancer, along with existing treatments and prospects oruture therapeutic approaches.
iMedPub Journals
2010Vol.1No. 2:1
doi: 10:3823/408
virus-encoded immune evasion genes and genes that inuen-ce cellular prolieration, survival, migration, angiogenesis andcytokine/chemokine production. The host responds to persis-tent viral inection with its own chronic inammatory response,thereby acilitating events that, particularly in the context o immunosuppression, could drive viral oncogenesis. Understan-ding the dynamic relationship between host and viral actorsthat drives KS oncogenesis is central to mounting eective stra-tegies to prevent or ameliorate tumor development. In addition,deciphering KS pathogenesis will enhance our understandingo novel virus-induced mechanisms o tumorigenesis. There isa growing appreciation o the role that chronic inammationplays in cancer development, and KS oers a unique opportu-nity to explore this topic.
© Under License o Creative Commons Attribution 3.0 License This article is available rom:http://www.transbiomedicine.com
Historical Perspective
In the late 19th century, Moritz Kaposi rst described KS as a rareand relatively indolent disease o the lower extremities (classicKS). Throughout the 20th century, endemic KS was recognizedin parts o Arica and the Middle East as a common cancer o children and adults. For example, in the pre-AIDS era, endemicKS in central Arica comprised up to 9% o malignant tumors inmales [5]. Today, KS is the most prevalent malignancy amongAIDS patients worldwide, and it has become the most commoncancer in several sub-Saharan Arican countries where KSHV isendemic and HIV is widespread. Compared to the other ormso KS, AIDS-associated KS is an aggressive disease typically ma-niesting with disseminated and even visceral involvement, andhas an untreated median survival o less than 2 years. KS occursin AIDS patients who have not had highly active antiretroviraltherapy (HAART) around 20,000x more oten than in the gene-ral population [6]. In areas where highly active antiretroviraltherapy (HAART) is widely available, there has been a dramaticdecline in KS incidence. However, access to HAART is not uni-versal, and this has led to a KS epidemic in many parts o Ari-ca, along with the resultant potential or disease re-emergenceelsewhere. KSHV-seropositive individuals with other orms o immunodeciency (genetic, iatrogenic, idiopathic) are also atincreased risk (~500x greater than the general population) orKS development [6]. In addition to KS, KSHV is also involved intwo AIDS-associated B-cell cancers, primary eusion lymphoma(PEL), and the plasma cell variant o multicentric Castleman’s di-sease (MCD). KSHV seroprevalence varies geographically anddemographically, and both sexual and non-sexual routes o transmission have been proposed. In the USA, prevalence ran-ges rom approximately 5% among random blood donors to ashigh as 80% among groups o homosexual men [7]. In sub-Sa-haran Arica, where KS was endemic prior to the AIDS epidemic,seroprevalence ranges rom 30-100% [8].
KSHV Biology
KSHV is a g-herpesvirus in the Rhadinovirus genus encodingapproximately 87 open reading rames (ORFs), 15 o whichhave no homologues in the other human herpesviruses. Likemost herpesviruses, KSHV has two major modes o replication.In the lytic phase, entry, uncoating, and nuclear import are o-llowed by a coordinated sequence o viral transcription, DNAreplication, and assembly, ollowed by the nal release o nas-cent virions. KSHV can also undergo a “latent” lie cycle whereonly a small subset o viral genes is expressed. Here, ater entryand translocation to the nucleus, the viral DNA circularizes, andmultiple copies are maintained as episomes attached to thehost chromosome via the viral latency associated nuclear anti-gen (Lana-1). Viral genomes are then replicated at roughly thesame rate as the host chromosome, such that each daughter Table 1. KS clinical presentationClassic (sporadic) KSPrimarily aects older non-HIV inected men o Mediterra-nean and Jewish originPatients present with multiocal mucocutaneous lesions,typically as violaceous lesions on the legs, but may inre-quently present solely with KS o the mucosa, genitalia andgastrointestinal tract [118]Visceral and lung involvement portends a poor prognosisArican (endemic) KSCauses lymphadenopathy in young males, but maniests inadults with deeply ulcerating tumors o the lower extremityPresently, it is dicult to dierentiate between true endemicKS and AIDS-associated KSAIDS-related (epidemic) KSMay cause minimal disease or maniest with widespreadlesions resulting in signicant morbidity and mortalitySkin lesions vary rom small papules to large plaques andexophytic or ungating nodulesLymphedema may be extensive and disproportionate to theextent o the cutaneous diseaseExtracutaneous disease is common, and typically involvesthe oral cavity, gastrointestinal tract, lymph nodes, and lungs Transplant (iatrogenic) KSKSHV inection can be associated with atal KS in this setting
iMedPub Journals
2010Vol.1No. 2:1
doi: 10:3823/408 
© Under License o Creative Commons Attribution 3.0 License This article is available rom:http://www.transbiomedicine.com
cell receives several copies o the viral genome at cell division.Most cells in both KS lesions and KSHV-inected cultures are la-tently inected, with lytic replication occurring in only a subseto inected cells. However, as discussed elsewhere and summa-rized in Table 2, it appears that both phases o the virus lie cycleplay signicant roles in the pathogenesis o KS.
KS Pathology
Well-developed KS lesions (Figure 1) are comprised o spindled-shaped tumor cells, abnormal vessels, and a variable chronicinammatory inltrate. Various histological variants (e.g. ana-plastic KS, pyogenic-granuloma like KS, lymphangioma-like KS,amongst others) exist, that may mimic other vascular lesions [9,10]. A premalignant stage o KS (so-called lymphedematousKS or KS in-situ) has been described in the setting o chroniclymphedema [11]. Chronic lymphedema results in local immu-ne incompetence that, when coupled with lymphangiogenesis
ORF73 (Lana-1)LatentXXORF72 (vCyc)LatentXX XORF71 (vFlip)LatentXK12 (Kaposin A)Latent/TPA Indu-cibleXORF74 (vGPCR)Lytic earlyX XXK1Lytic early andlatent*XXXXXK9 (vIRF1)Lytic early XXXK11/11.1 (vIRF2)Lytic XK10.5/10.6 (vIRF3Lana-2)Latent XXORF45 (tegument)Immediate Early XORF50 (RTA)Immediate Early XK2 (vIL-6)Lytic early andlatent*XXXORF4 (KCP)Lytic late XK3 (MIR1)Immediate Early XK5 (MIR2)Immediate Early XK8 (KbZIP)Immediate Early XK7 (vIAP)Lytic late XORF16 (vBcl-2)Lytic early XK6, K4, K4.1 (vCCL-1,-2,-3)Immediate Early XXKaposin BLatent/TPA Indu-cible?miRK1-12LatentXXXXX
KSHV inducedprotein
 c-KitCellularXPDGF-RCellularX XRDC1 (CXCR7)CellularX XXIL-6Cellular XXMMPsCellular XXAng-2 Cellular XHIF1a, HIF1bCellular XCox-2CellularXXX
KSHV encodedprotein or miRNAExpression Type[119]
    O   n   c   o   g   e   n    i   c    A   n   t    i  -    A   p   o   p   t   o   t    i   c    I   m   m   u   n   e    M   o    d   u    l   a   t   o   r   y    P   r   o  -    i   n    f   a   m   m   a   t   o   r   y    A   n   g    i   o   g   e   n    i   c
 Table 2. KSHV-encoded and KSHV-induced proteins involvedin KS pathogenesis
* Recent evidence suggests that K1 and vIL-6 mRNAs can also be detected latently [120]Figure 1. KS plaques o the lower extremity

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