Browsing School of Dentistry by Subject "Sarcoma, Kaposi"
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Molecular Basis of Kaposi's Sarcoma Herpesvirus vGPCR-induced Paracrine NeoplasiaKaposi's sarcoma (KS), one of the most common AIDS-associated neoplasms, is a multifocal vascular tumor invariably associated with infection with the KS-associated herpesvirus (KSHV or HHV8). KS has a complex histopathology with respect to its cellular composition, origin and pathogenesis. The driving force of the KS lesion is the KSHV-infected spindle-shaped tumor cell, thought to have a vascular endothelial or endothelial precursor origin. KS tumors are also characterized by infiltrating inflammatory cells, slit-like blood vessels, and extravasated erythrocytes. The recruitment of these cells and the promotion of the angiogenic phenotype in these lesions are thought to be mediated by elevated levels of pro-inflammatory and pro-angiogenic secretions (cytokines, chemokines and growth factors) from the KS tumor cells. We have previously found that expression of a single KSHV gene, the viral G protein-coupled receptor (vGPCR) is able to recapitulate KS-like lesions in mice. Indeed, our results suggest that vGPCR may be responsible for KS initiation, progression and tumor maintenance, underscoring the key role of this viral oncogene in Kaposi's sarcomagenesis. vGPCR has proven to be a powerful oncogene and a potent angiogenic activator by inducing intracellular signaling pathways that promote the survival and transformation of expressing cells and by releasing secreted factors (cytokines, chemokines and growth factors), that may promote the recruitment and subsequent paracrine transformation of neighboring endothelial cells. However, the role of these vGPCR angiogenic factors, and their relative contribution to KS development, remains unclear. Here we describe 1) the molecular mechanism by which vGPCR paracrine secretions upregulate vascular endothelial growth factor (VEGF) in KS lesions; 2) the upregulation by vGPCR of a novel angiopoietin-related factor, angiopoietin-like 4 (ANGPTL4), that plays a critical role in promoting vGPCR-induced angiogenesis and vascular permeability; and 3) the essential role of the transcription factor hypoxia inducible factor (HIF) in vGPCR sarcomagenesis, highlighting the therapeutic potential of HIF inhibitors as an alternative treatment for KS.
The Role of the Akt/TSC/mTOR Signaling Pathway in Kaposi's Sarcoma- Associated Virus G Protein-Coupled Receptor NeoplasiaKaposi's sarcoma (KS), a multifocal vascular neoplasm, is the most frequent cancer arising in HIV-infected individuals and in immunosuppressed patients. KS is caused by the KS-associated herpesvirus (KSHV). A single lytic gene of KSHV genes, G protein-coupled receptor (vGPCR), is sufficient to induce Kaposi-like sarcomas in mice. This vGPCR has been shown to promote the activation of PI3K/Akt, involved in transformation of endothelial cells. However, the Akt downstream effectors required for vGPCR to promote Kaposi's sarcomagenesis are still unknown. Here, we have found that vGPCR induces the phosphorylation and inactivation of tuberin (TSC2), promoting the activation of mTOR. Moreover, over-activation of TSC/mTOR is sufficient to render endothelial cells oncogenic. Treatment with rapamycin (mTOR inhibitor) efficiently prevented the growth of vGPCR tumors in vivo. Collectively, these results implicate the mTOR signaling route in Kaposi's sarcomagenesis and provide experimental evidence demonstrating that drugs targeting mTOR may represent an effective mechanism-based therapy for the treatment of KS. We have observed that, although rapamycin has been shown to be an efficient therapy for patients with iatrogenic or classic KS, the activity of Akt was transiently increased in vGPCR-expressing endothelial cells (EC-vGPCR). We therefore investigated the efficacy of PI-103, a novel dual PI3Kα/mTOR inhibitor, in preventing vGPCR transformation. PI-103 treatment effectively and independently blocked the activation of both PI3K and mTOR in EC-vGPCR. This resulted in the effective inhibition of endothelial cell proliferation and survival in vitro, and tumor growth in vivo, suggesting that PI-103 may be an effective therapeutic option for the treatment of KS. We also found that the angiogenic growth factors secreted by EC-vGPCR can induce the activity of mTOR in endothelial cells, suggesting that vGPCR regulates mTOR through both direct and indirect (paracrine) mechanisms. In addition, we found that the effect of rapamycin on vGPCR sarcomagenesis is not dependent on the direct activation of mTOR in vGPCR-expressing cells. Rather, the profound sensitivity of these tumors to rapamycin treatment may be due, in part, to the inhibition of the paracrine activation of mTOR in neighboring (bystander) cells by the angiogenic factors elaborated by EC-vGPCR. Collectively, these results support the key role of paracrine transforming mechanisms in vGPCR sarcomagenesis.