KSHV Paracrine Effects on Tumorigenesis

Abstract

In 1994, Chang and colleagues isolated two viral DNA fragments from Kaposi’s sarcoma (KS) patients which showed homologies to, but were distinct from, genes coding for capsid and tegument proteins of two herpesviruses namely, Epstein-Barr virus and Herpesvirus saimiri (Y. Chang et al., 1994). These new herpesvirus-like sequences led to the definition of a new human herpesvirus, namely, Kaposi’s sarcoma-associated herpesvirus (KSHV, or human herpesvirus type-8, HHV-8). Shortly afterwards it was shown that KSHV is closely associated with KS tumours (Dupin et al., 1995; Huang et al., 1995; Moore & Chang, 1995), indicating that KSHV is the etiologic agent of KS. KSHV infection can be detected in several different cell types, including B-cells (Monini et al., 1999), T-cells (Harrington et al., 1996; Sirianni et al., 1997b), monocytes (Blasig et al., 1997), macrophages (Sirianni et al., 1997a), endothelial cells (Boshoff et al., 1995), and dendritic cells (Rettig et al., 1997). Apart from KS, infection with KSHV leads to the development of two other tumour diseases: primary effusion lymphoma (PEL), and a subset of multicentric Castleman’s disease (MCD) (Cesarman et al., 1995; Soulier et al., 1995). While PEL and MCD are primary disorders of the B-cell lineage, KS originates from endotheliumderived cells. KS is classified into four different epidemiological forms: classic KS, iatrogenic KS, African endemic KS, and AIDS-associated epidemic KS. All forms have the same histological features, but reveal different progression rates and risk factors, and evolve in different populations (Friedman-Kien & Saltzman, 1990). The classic KS primarily affects elderly men of Eastern European or Mediterranean origin and usually proceeds very slowly. Patients receiving immunosuppressive therapy (e.g. after solid-organ transplantation) are at increased risk for iatrogenic KS. This rare form of KS is more aggressive than classic KS (Stickler & Friedman-Kien, 1991). The interruption or modulation of the immunosuppressive therapy is usually sufficient for the regression of iatrogenic KS (Stallone et al., 2005; Wijnveen et al., 1987). The African endemic KS is much more aggressive and affects adults as well as children, predominantly in SubSaharan Africa (Stickler & Friedman-Kien, 1991). In the endemic regions, KS accounts for up to 13% of all malignancies (Parkin et al., 2008). The most clinically aggressive form of KS is the AIDS-associated epidemic KS (AKS). This entity is the most common cancer in