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Review
. 2023 Mar;29(3):188-200.
doi: 10.1016/j.molmed.2022.12.003. Epub 2023 Jan 10.

The Kaposi's sarcoma progenitor enigma: KSHV-induced MEndT-EndMT axis

Julian Naipauer  1 , Enrique A Mesri  2
Affiliations
Review

The Kaposi's sarcoma progenitor enigma: KSHV-induced MEndT-EndMT axis

Julian Naipauer et al. Trends Mol Med. 2023 Mar.

Abstract

Endothelial-to-mesenchymal transition has been described in tumors as a source of mesenchymal stroma, while the reverse process has been proposed in tumor vasculogenesis and angiogenesis. A human oncogenic virus, Kaposi's sarcoma herpes virus (KSHV), can regulate both processes in order to transit through this transition 'boulevard' when infecting KS oncogenic progenitor cells. Endothelial or mesenchymal circulating progenitor cells can serve as KS oncogenic progenitors recruited by inflammatory cytokines because KSHV can reprogram one into the other through endothelial-to-mesenchymal and mesenchymal-to-endothelial transitions. Through these novel insights, the identity of the potential oncogenic progenitor of KS is revealed while gaining knowledge of the biology of the mesenchymal-endothelial differentiation axis and pointing to this axis as a therapeutic target in KS.

Keywords: Kaposi´s sarcoma herpesvirus; angiogenesis; endothelial-to-mesenchymal differentiation axis; sarcomagenesis; virus oncogenesis.

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Conflict of interest statement

Declaration of interests None are declared by the authors.

Figures

Figure 1.
Figure 1.. Endothelial-Mesenchymal differentiation axis.
A) Scheme of an endothelial cell showing specific markers: CD31 (PECAM-1), VEGFR, and VE-cadherin. B) Scheme of a mesenchymal cell showing specific markers: PDGFR, FN (fibronectin), COL I (collagen type I), α-SMA (Alpha-smooth muscle actin), and Vimentin. C) Endothelial-Mesenchymal differentiation axis proposed mechanism for transitions: Endothelial-to-Mesenchymal Transition (EndMT) through tumor stroma formation and Mesenchymalto-Endothelial Transition (MEndT) through Vasculogenesis. The Mesenchymal/Endothelial intermediate states (M/E) are also depicted. Created with BioRender.com
Figure 2.
Figure 2.. Endothelial cell origin for KS spindle cells.
KSHV infection of primary blood vascular endothelial cells (BECs) or primary lymphatic endothelial cells (LECs) results in different viral expression programs with different outcomes, while the virus is latent in BECs with viral loss, it displays a spontaneously lytic replication program in LECs. Moreover, when growing in 3D spheroids KSHV reprograms LECs to invasive mesenchymal cells via EndMT, generating M/E intermediate state cells with KSHV abortive lytic infection . CD31 is an endothelial marker. VEGFR3, SOX18 and PROX1 are markers of lymphatic endothelium. PDGFR and Notch are MSC markers. Created with BioRender.com
Figure 3.
Figure 3.. Mesenchymal cell origin for KS spindle cells.
KSHV-infected human MSCs can acquire KS-like cell surface markers and angiogenic, invasive, and transforming phenotypes. (Top) While mesenchymal culture conditions induce MEndT with latent infection, this results in proliferation arrest or favors viral production with cell death of infected cells. (Bottom) By contrast KS-like pro-angiogenic environments are more permissive for KSHV abortive lytic infection enabling the proliferation of productively infected hMSC cultures and inducing MEndT, which renders Mesenchymal/endothelial (M/E) intermediate states and enhanced the transformation capacity of KSHV. Nestin, SCA-1 and PDFRA are MSC markers. PROX1 is a lymphatic endothelium marker. CD31 is an endothelial marker. Created with BioRender.com
See this image and copyright information in PMC

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