KSHV Induction of Angiogenic and Lymphangiogenic Phenotypes

Abstract

Kaposi's sarcoma (KS) is a highly vascularized tumor supporting large amounts of neo-angiogenesis. The major cell type in KS tumors is the spindle cell, a cell that expresses markers of lymphatic endothelium. KSHV, the etiologic agent of KS, is found in the spindle cells of all KS tumors. Considering the extreme extent of angiogenesis in KS tumors at all stages it has been proposed that KSHV directly induces angiogenesis in a paracrine fashion. In accordance with this theory, KSHV infection of endothelial cells in culture induces a number of host pathways involved in activation of angiogenesis and a number of KSHV genes themselves can induce pathways involved in angiogenesis. Spindle cells are phenotypically endothelial in nature, and therefore, activation through the induction of angiogenic and/or lymphangiogenic phenotypes by the virus may also be directly involved in spindle cell growth and tumor induction. Accordingly, KSHV infection of endothelial cells induces cell autonomous angiogenic phenotypes to activate host cells. KSHV infection can also reprogram blood endothelial cells to lymphatic endothelium. However, KSHV induces some blood endothelial specific genes upon infection of lymphatic endothelial cells creating a phenotypic intermediate between blood and lymphatic endothelium. Induction of pathways involved in angiogenesis and lymphangiogenesis are likely to be critical for tumor cell growth and spread. Thus, induction of both cell autonomous and non-autonomous changes in angiogenic and lymphangiogenic pathways by KSHV likely plays a key role in the formation of KS tumors.

Keywords: HHV-8; Kaposi’s Sarcoma; Kaposi’s Sarcoma-associated herpesvirus; angiogenesis; lymphangiogenesis; viral oncogenesis.

Figure 1

Overview of KSHV induction of angiogenic and lymphangiogenic pathways. Pro-angiogenic factors that are induced by KSHV are indicated in red ovals, pro-lymphangiogenic factors induced by KSHV are indicated in blue ovals. White ovals indicate the activated pathway necessary for KSHV induction of blood to lymphatic endothelial cell differentiation. KSHV genes known to induce angiogenic or lymphangiogenic pathways are indicated in green ovals. The upper left corner indicates phenotypes of angiogenesis that are activated in normal endothelium by KSHV-infected cells and the gradient of cytokines secreted by KSHV-infected cells is indicated by the red gradient. The blue gradient in the upper right hand corner indicates the gradient of lymphangiogenic cytokines induced by KSHV-infected cells that could induce lymphangiogenesis. The central box indicates angiogenic phenotypes induced by KSHV in a cell autonomous fashion.