Kaposi sarcoma herpesvirus–induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma

Abstract

The biology of Kaposi sarcoma is poorly understood because the dominant cell type in Kaposi sarcoma lesions is not known 1-4. We show by gene expression microarrays that neoplastic cells of Kaposi sarcoma are closely related to lymphatic endothelial cells (LECs) and that Kaposi sarcoma herpesvirus (KSHV) 5,6 infects both LECs and blood vascular endothelial cells (BECs) in vitro. The gene expression microarray profiles of infected LECs and BECs show that KSHV induces transcriptional reprogramming of both cell types. The lymphangiogenic molecules VEGF-D and angiopoietin-2 were elevated in the plasma of individuals with acquired immune deficiency syndrome and Kaposi sarcoma. These data show that the gene expression profile of Kaposi sarcoma resembles that of LECs, that KSHV induces a transcriptional drift in both LECs and BECs and that lymphangiogenic molecules are involved in the pathogenesis of Kaposi sarcoma. The cellular origin of the spindle cells of Kaposi sarcoma lesions is poorly defined 3,7. Kaposi sarcoma spindle cells express endothelial cell markers but also have features of other cell lineages, including fibroblasts, macrophages and smooth muscle cells 1-3. Kaposi sarcoma could be a tumor originating from LECs, as spindle cells ubiquitously express VEGFR-3 and podoplanin and stain with the antibody D2-40 recognizing LECs 4,8. But these markers can also be expressed on angiogenic blood vessels, or on other cell types 9. Furthermore, some BEC markers (e.g., CD34) are expressed in all Kaposi sarcoma spindle cells 1. KSHV is the infectious cause of Kaposi sarcoma 5,6. In vitro, KSHV can infect both micro-and macrovascular endothelial cells, and these cells are useful to study the role of KSHV in the pathogenesis of Kaposi sarcoma 10-12 .

The insulin receptor is essential for virus-induced tumorigenesis of Kaposi's sarcoma

“…IGF-IR was detected by immunohistochemistry in tumor spindle cells (Catrina et al, 2005). Overexpression of the IR in KS tissue compared to normal skin was reported by Wang et al (2004) in a comprehensive microarray study, and we have independently shown that IR gene expression is induced in KSHV-infected primary DMVEC, AIDS-KS tissue and TIME cells. Furthermore, we show that the upregulated IR is phosphorylated and we observed increased activation of the downstream Erk pathway, but not the PI3K pathway, in KSHV-infected cells.…”

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

“…Recent gene expression profiling analyses have shown that spindle cells, which form the major cellular component of the lesions, most closely resemble lymphatic endothelium [19]. The lesions also contain a variable inflammatory and mononuclear cell infiltrate.…”

“…The lesions also contain a variable inflammatory and mononuclear cell infiltrate. Studies published beginning in the late 1980s indicated that spindle cells derived from KS lesions could release, proliferate, and/or migrate in response to various growth factors that stimulate angiogenesis, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukins -1, -6 and -8, and platelet-derived growth factor (PDGF), and over-express receptors for multiple cytokines [19][20][21][22]. Activation of these receptors stimulates multiple pro-growth and anti-apoptotic pathways via PI3kinase/Akt/mTOR and extracellular receptor kinase (ERK) [23].…”

Development of the lymphatic vascular system: A mystery unravels

“…This KSHV-mediated upregulation of Prox1 leads to reprogramming of BEC to adopt LEC phenotypes by overexpressing more than 70% of lymphatic-associated genes and by downregulating many BEC-specific genes ). In contrast, expression of Prox1 is downregulated in KSHV-infected cultured LEC, which is associated with a transcriptional drift toward to BEC (Wang et al, 2004). This Prox1-mediated cell fate reprogramming in KSHV-infected cells provides an additional support to the notion that Prox1 is a master control gene specifying lymphatic endothelial cell fates Wang et al, 2004).…”