title: mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis.
abstract: Kaposi sarcoma originates from endothelial cells and it is one of the most overt angiogenic tumors. In Sub-Saharan Africa, where HIV and the Kaposi sarcoma-associated herpesvirus (KSHV) are endemic, Kaposi sarcoma is the most common cancer overall, but model systems for disease study are insufficient. Here, we report the development of a novel mouse model of Kaposi sarcoma, where KSHV is retained stably and tumors are elicited rapidly. Tumor growth was sensitive to specific allosteric inhibitors (rapamycin, CCI-779, and RAD001) of the pivotal cell growth regulator mTOR. Inhibition of tumor growth was durable up to 130 days and reversible. mTOR blockade reduced VEGF secretion and formation of tumor vasculature. Together, the results show that mTOR inhibitors exert a direct anti-Kaposi sarcoma effect by inhibiting angiogenesis and paracrine effectors, suggesting their application as a new treatment modality for Kaposi sarcoma and other cancers of endothelial origin.
authors: Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Debasmita
authors: D
authors: Roy
authors: Sang-Hoon
authors: SH
authors: Sin
authors: Amy
authors: A
authors: Lucas
authors: Raman
authors: R
authors: Venkataramanan
authors: Ling
authors: L
authors: Wang
authors: Anthony
authors: A
authors: Eason
authors: Veenadhari
authors: V
authors: Chavakula
authors: Isaac B
authors: IB
authors: Hilton
authors: Kristen M
authors: KM
authors: Tamburro
authors: Blossom
authors: B
authors: Damania
authors: Dirk P
authors: DP
authors: Dittmer
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D055028:Comparative Genomic Hybridization; D004279:DNA, Viral / Q000235:genetics; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage; D005455:Fluorescent Antibody Technique; D019288:Herpesvirus 8, Human / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D012514:Sarcoma, Kaposi / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D004279:DNA, Viral; D042461:Vascular Endothelial Growth Factor A; D004317:Doxorubicin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
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