Productively Infected Murine Kaposi's Sarcoma-Like Tumors Define New Animal Models for Studying and Targeting KSHV Oncogenesis and Replication

Abstract

Kaposi's sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). KS tumors are composed of KSHV-infected spindle cells of vascular origin with aberrant neovascularization and erythrocyte extravasation. KSHV genes expressed during both latent and lytic replicative cycles play important roles in viral oncogenesis. Animal models able to recapitulate both viral and host biological characteristics of KS are needed to elucidate oncogenic mechanisms, for developing targeted therapies, and to trace cellular components of KS ontogeny. Herein, we describe two new murine models of Kaposi's sarcoma. We found that murine bone marrow-derived cells, whether established in culture or isolated from fresh murine bone marrow, were infectable with rKSHV.219, formed KS-like tumors in immunocompromised mice and produced mature herpesvirus-like virions in vivo. Further, we show in vivo that the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA/Vorinostat) enhanced viral lytic reactivation. We propose that these novel models are ideal for studying both viral and host contributions to KSHV-induced oncogenesis as well as for testing virally-targeted antitumor strategies for the treatment of Kaposi's sarcoma. Furthermore, our isolation of bone marrow-derived cell populations containing a cell type that, when infected with KSHV, renders a tumorigenic KS-like spindle cell, should facilitate systematic identification of KS progenitor cells.

PDGFRA defines the mesenchymal stem cell Kaposi’s sarcoma progenitors by enabling KSHV oncogenesis in an angiogenic environment

“…Although KSHV infection results in important morphological and transcriptional changes that convey traits of malignant transformation, few KSHV-infected cellular types had become fully tumorigenic [2,5]. They are the basis for models of KSHV-tumorigenesis in murine, rat and human cells [24][25][26][27][28]. In a KSHV tumorigenesis model in nude mice generated by transfecting KSHVBac36 to mouse endothelial lineage cells [26], we found that malignancy was only manifested in vivo and occurred with concomitant upregulation of oncogenic KSHV lytic genes, angiogenesis growth factors and their tyrosine kinase receptors that are characteristic of human KS lesions [2,26].…”

Binding of the Kaposi's Sarcoma-Associated Herpesvirus to the Ephrin Binding Surface of the EphA2 Receptor and Its Inhibition by a Small Molecule

“…Thus, pursuit of these chemical compounds, or derivatives of them, may be a useful direction to follow for the potential treatment of KSHV-associated diseases. Animal model studies, such as those described by Ashlock and coworkers (39), certainly seem warranted.…”

PDGFRA Defines the Mesenchymal Stem Cell Kaposi’s Sarcoma Progenitors by Enabling KSHV Oncogenesis in an Angiogenic Environment

“…Prior studies have suggested the role of mesenchymal stem cells (MSCs) as KSHV target and KS progenitors [28, 34–38]. In fact several KS models made from primary bone marrow-derived mouse endothelial lineage/adherent cells [26, 27] and one from rat MSCs [28] formed tumors in a KSHV-dependent manner, suggesting that these populations contain cell types in which KSHV infection is oncogenic. Sarcomas are cancers of mesenchymal origin [31], with Platelet-derived growth factor receptor (PDGFR) signaling playing a significant part in mesenchymal biology, including mesenchymal stem cell differentiation, growth, and angiogenesis [30].…”