mTOR, VEGF, PDGFR, and c-kit signaling pathway activation in Kaposi Sarcoma

Publication date: Available online 12 May 2017
Source:Human Pathology
Author(s): Darcy A. Kerr, Satya Vara Prasad Busarla, Devon C. Gimbel, Aliyah R. Sohani, Rosalynn M. Nazarian
Kaposi sarcoma (KS) is a locally progressive, intermediate-grade vascular neoplasm with no known cure, high recurrence rates and potential for wide dissemination. Low efficacy and high toxicity limit current therapeutic options for advanced disease. Activation of mammalian target of rapamycin (mTOR), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and c-kit signaling pathways has been implicated in KS pathogenesis and may suggest a role for targeted inhibitors. KS cases were retrospectively retrieved (n=274), most (90%) associated with human immunodeficiency virus (HIV). Tissue microarray slides were stained with human herpes virus-8 (HHV-8), friend leukemia integration 1 transcription factor (FLI-1), CD117 (c-kit), phospho-S6 (pS6), PDGF receptor-beta (PDGFRΒ), VEGF, and phospho-mTOR (p-mTOR). Both intensity and extent of staining were scored. Multiplying these scores for each core yielded total staining H-scores. HHV-8 was positive in 87% and FLI-1 in 95.7% of cases. Most were also VEGF+ (97.6%), pS6+ (95.7%), CD117+ (92.5%), and PDGFRB+ (87.4%). Approximately half (55.6%) were p-mTOR+. There was no significant difference in staining among patients with low (<500 cells/mm³) or preserved CD4 T-cell counts. Immunohistochemistry confirms upregulation of the mTOR, PDGF, VEGF and c-kit pathways in a large cohort of KS samples. Of proteins tested, pS6, downstream of mTOR, demonstrated the highest proportion of strong positivity (67.1%). These results support the possibility of using targeted inhibitors in KS. Over-expression was independent of CD4 count, suggesting that even patients with low counts may be targeted therapy candidates.



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