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Review
. 2016 Jul 20;8(7):198.
doi: 10.3390/v8070198.

KSHV-Mediated Angiogenesis in Tumor Progression

Pravinkumar Purushothaman  1 , Timsy Uppal  2 , Roni Sarkar  3 , Subhash C Verma  4
Affiliations
Review

KSHV-Mediated Angiogenesis in Tumor Progression

Pravinkumar Purushothaman et al. Viruses. .

Abstract

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), is a malignant human oncovirus belonging to the gamma herpesvirus family. HHV-8 is closely linked to the pathogenesis of Kaposi's sarcoma (KS) and two other B-cell lymphoproliferative diseases: primary effusion lymphoma (PEL) and a plasmablastic variant of multicentric Castleman's disease (MCD). KS is an invasive tumor of endothelial cells most commonly found in untreated HIV-AIDS or immuno-compromised individuals. KS tumors are highly vascularized and have abnormal, excessive neo-angiogenesis, inflammation, and proliferation of infected endothelial cells. KSHV directly induces angiogenesis in an autocrine and paracrine fashion through a complex interplay of various viral and cellular pro-angiogenic and inflammatory factors. KS is believed to originate due to a combination of KSHV's efficient strategies for evading host immune systems and several pro-angiogenic and pro-inflammatory stimuli. In addition, KSHV infection of endothelial cells produces a wide array of viral oncoproteins with transforming capabilities that regulate multiple host-signaling pathways involved in the activation of angiogenesis. It is likely that the cellular-signaling pathways of angiogenesis and lymph-angiogenesis modulate the rate of tumorigenesis induction by KSHV. This review summarizes the current knowledge on regulating KSHV-mediated angiogenesis by integrating the findings reported thus far on the roles of host and viral genes in oncogenesis, recent developments in cell-culture/animal-model systems, and various anti-angiogenic therapies for treating KSHV-related lymphoproliferative disorders.

Keywords: KSHV; Kaposi’s sarcoma; Kaposi’s sarcoma-associated herpesvirus; angiogenesis; lymphangiogenesis; oncogenesis; oncoproteins.

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Figures

Figure 1
Figure 1
Schematic representation of Kaposi’s sarcoma-associated herpesvirus (KSHV)-induced transformation of B-cells and endothelial cells. KSHV infection activates the expression of multiple viral as well as cellular autocrine and paracrine factors to modulate numerous signaling pathways in order to to promote KSHV-mediated angiogenesis.
Figure 2
Figure 2
Schematic representation of KSHV-mediated activation of angiogenic signaling pathways. Signaling pathways that are regulated by KSHV proteins viral G protein-coupled receptor (vGPCR), K1, K15, and vIL-6 in B-cells and endothelial cells contribute to KSHV-mediated cellular transformation and angiogenesis through autocrine and paracrine mechanisms. KSHV GPCR and K1 promote cellular signaling through phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinases (MAPK) phosphoinositide-dependent kinase (PDK), AKT/protein kinase B (AKT/PKB), and mTOR signaling pathways. Activation of these signaling pathways stimulates the activity of various cellular transcription factors, such as activating protein-1 (AP-1), nuclear factor (NF)-B, hypoxia-inducible factor-1 (HIF1) and Nuclear factor of activated T-cells (NFAT). These transcription factors, in turn, upregulate the secretion of pro-angiogenic growth factors. Signaling through KSHV GPCR is shown as solid black lines and signaling through K1 is shown as black dotted lines. The cellular signaling mediated through K15 and IL-6 receptors are shown as solid red and blue lines, respectively.
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