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Kaposi's sarcoma and its associated herpesvirus

Key Points

  • Kaposi's sarcoma herpesvirus (KSHV; also known as human herpesvirus 8 (HHV8)) is the causative agent of Kaposi's sarcoma (KS) and certain lymphoproliferations, and its seroepidemiology correlates with the global incidence of KS.

  • KS is the most common neoplasm in untreated HIV-infected individuals, and also occurs in other states of immunosuppression, including after an organ transplant.

  • KSHV is transmitted through saliva and replicates in oropharyngeal cells.

  • Unlike most cancer cells, KS tumour cells are not fully transformed, do not show autonomous growth, and remain dependent on exogenous cytokines for in vitro growth.

  • KS starts as a proliferation of endothelial-type cells, with an early onset inflammatory and abnormal leaky blood vessel expansion.

  • KSHV is present in the vast majority of KS tumour cells (that is, spindle cells), expressing the latent viral proteins, including viral cyclin, viral FLICE inhibitory protein, latency-associated nuclear antigen (LANA) and a group of viral microRNAs.

  • A proportion of cells in KS lesions seem to undergo lytic replication, expressing lytic viral proteins including K1, viral interleukin-6, viral BCL-2, viral G protein-coupled receptor, K15 and viral chemokines.

  • KSHV latent genes drive cell proliferation and prevent apoptosis; whereas KSHV lytic genes could further contribute to KS tumorigenesis by triggering host signalling cascades that lead to cytokine and growth factor secretion.

  • Biological insights into KSHV oncogenesis are leading to promising rational therapeutic approaches.

Abstract

Kaposi's sarcoma (KS) is the most common cancer in HIV-infected untreated individuals. Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 (HHV8)) is the infectious cause of this neoplasm. In this Review we describe the epidemiology of KS and KSHV, and the insights into the remarkable mechanisms through which KSHV can induce KS that have been gained in the past 16 years. KSHV latent transcripts, such as latency-associated nuclear antigen (LANA), viral cyclin, viral FLIP and viral-encoded microRNAs, drive cell proliferation and prevent apoptosis, whereas KSHV lytic proteins, such as viral G protein-coupled receptor, K1 and virally encoded cytokines (viral interleukin-6 and viral chemokines) further contribute to the unique angioproliferative and inflammatory KS lesions through a mechanism called paracrine neoplasia.

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Figure 1: Geographical prevalence of KS and seroprevalence of KSHV.
Figure 2: Cellular heterogeneity in KS.
Figure 3: Proposed mechanism of KSHV-induced sarcoma.
Figure 4: Mouse model of KSHV-induced KS.

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Acknowledgements

E.A.M. is supported by US National Institutes of Health grants CA75918 and CA136387, and C.B. by Cancer Research UK, the Medical Research Council and the University College London and University College London Hopsitals Comprehensive Biomedical Research Centre.

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Mesri, E., Cesarman, E. & Boshoff, C. Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer 10, 707–719 (2010). https://doi.org/10.1038/nrc2888

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