Assistant Lecturer/ PhD student, Nelson Mandela African Institution of Science and Technology
Search for new cytokine based HIV related malignancy therapy
My research area is on trying to understand how the HIV associated cancer known as Kaposi's sarcoma behaves in order to be able to come up with better treatment modalities for this cancer.
Abstract: The major transmission route for Kaposi's sarcoma-associated herpesvirus (KSHV) infection is the oral cavity through saliva. Kaposi's sarcoma (KS) frequently occurs in the oral cavity in HIV-positive individuals and is often the first presenting sign of AIDS. However, the oral target cells for KSHV infection and the cellular origin of KS remain unknown. Here we present clinical and experimental evidences that KS spindle cells may originate from virally modified oral mesenchymal stem cells (MSC). AIDS-KS spindle cells expressed neuroectodermal stem cell marker (Nestin) and oral MSC marker CD29, suggesting an oral/craniofacial MSC lineage of AIDS-associated KS. Furthermore, oral MSC were highly susceptible to KSHV infection, and infection promoted multi-lineage differentiation and mesenchymal-to-endothelial transition (MEndT). KSHV infection of oral MSCs resulted in expression of a large number of cytokines, a characteristic of KS, and upregulation of KS signature and MEndT-associated genes. These results suggest that KS may originate from pluripotent MSC and KSHV infection transforms MSC to KS-like cells through MEndT.
Pub.: 27 Oct '17, Pinned: 17 Nov '17
Abstract: The intracellular pro-inflammatory mediator interleukin (IL)-32 is associated with tumor progression; however, the mechanisms remain unknown. We studied the IL-32 mRNA expression as well as other pro-inflammatory cytokines and mediators including IL-1α, IL-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, the pro-angiogenic and anti-apoptotic enzyme COX-2, the IL-8 receptor CXCR1, and the intracellular kinase FAK-1. The interaction of IL-32 expression with expression of IL-6, TNFα, IL-8, and COX-2 was also investigated. Biopsies of 11 human immunodeficiency (HIV)-related, seven non HIV-related Kaposi sarcoma (KS), and seven normal skin tissues of Dutch origin were analyzed. RNA was isolated from the paraffin material and gene expression levels of IL-32α, β, and γ isoforms, IL1a, IL1b, IL6, IL8, TNFA, PTGS2, CXCR1, and PTK2 were determined using quantitative real-time PCR. Significantly higher expression of IL-32β and IL-32γ isoforms was observed in HIV-related KS biopsies compared to non HIV-related KS and normal skin tissue. The splicing ratio of the IL-32 isoforms showed IL-32γ as the highest expressed isoform, followed by IL-32β in HIV-related KS cases compared to non HIV-related KS and normal skin tissue. Our data suggest a possible survival mechanism by the splicing of IL-32γ to IL-32β and also IL-6, IL-8, and CXCR1 signalling pathways to reverse the pro-apoptotic effect of IL-32γ isoform leading to tumor cell survival and thus favoring tumor progression.
Pub.: 19 Oct '17, Pinned: 17 Nov '17