KSHV Down-regulates Tropoelastin in Both an in-vitro and in-vivo Kaposi's Sarcoma Model.

Abstract

Kaposi's sarcoma (KS), a common cancer in individuals with HIV/AIDS, lacks a curative therapy. Few studies have examined changes in extracellular matrix (ECM) protein profiles in the development of KS. Here we used an in vitro (human dermal microvascular endothelial cells, DMVEC) and an in vivo mECK mouse model of Kaposi's to study the impact of infection on tropoelastin. Using DMVEC, Kaposi's sarcoma-associated herpesvirus (KSHV) reduced tropoelastin transcription when examined at 2, 5, 7, and 10 days post addition, a finding that was inversely correlated with a rise in viral latency associated nuclear antigen (LANA) transcription. Immunohistochemical/immunofluorescence data confirmed that DMVEC cells were KSHV-infected (evidenced by LANA production) and that there was a loss of tropoelastin protein compared to controls. Using the mECK36 mouse model of KS we observed a reduced expression of tropoelastin mRNA in 3 of 3 tumor biopsies compared to controls. Immunofluorescence staining showed high levels of viral LANA expression in the tumor core, while immunohistochemical staining showed high levels of LANA expression and spindle cells in tumors. Dual label immunohistochemistry on formalin-fixed paraffin-embedded tumor tissue revealed reduced expression of tropoelastin in LANA positive spindle cell regions quantified by Ariol SL-50 scanning analysis. Together, this suggests that alterations in tropoelastin may play an important role in the development of Kaposi's and could serve as an early marker of this disease. This information will also allow us to explore the potential role of tropoelastin anti angiogenic properties in an in vivo model for KS disease.