PMID- 30193324 OWN - NLM STAT- MEDLINE DCOM- 20190419 LR - 20240312 IS - 1552-5783 (Electronic) IS - 0146-0404 (Print) IS - 0146-0404 (Linking) VI - 59 IP - 11 DP - 2018 Sep 4 TI - Targeting the Platelet-Derived Growth Factor-beta Stimulatory Circuitry to Control Retinoblastoma Seeds. PG - 4486-4495 LID - 10.1167/iovs.18-24359 [doi] AB - PURPOSE: Vitreous seeding remains the primary reason for treatment failure in eyes with retinoblastoma (Rb). Systemic and intra-arterial chemotherapy, each with its own inherent set of complications, have improved salvage rates for eyes with advanced disease, but the location and biology of vitreous seeds present a fundamental challenge in developing treatments with minimal toxicity and risk. The aim of this study was to target the platelet-derived growth factor (PDGF)- PDGF-receptor beta (PDGFRbeta) signaling pathway and investigate its role in the growth of Rb seeds, apoptotic activity, and invasive potential. METHODS: We performed ex vivo analyses on vitreous samples from Rb patients that underwent enucleation and from patient-derived xenografts. These samples were evaluated by quantitative PCR, immunohistochemistry, and ELISA. The effects of disruption of the PDGF-PDGFRbeta signaling pathway, both by pharmacologic and genomic knockdown approaches, were evaluated in vitro by cell proliferation and apoptotic assays, quantitative PCR analyses, Western blotting, flow cytometry, and imaging flow cytometry. A three-dimensional cell culture system was generated for in-depth study of Rb seeds. RESULTS: Our results demonstrated that PDGFRbeta signaling is active in the vitreous of Rb patients and patient-derived xenografts, sustaining growth and survival in an AKT-, MDM2-, and NF-kappaB-dependent manner. The novel three-dimensional cell culture system mimics Rb seeds, as the in vitro generated spheroids have similar morphologic features to Rb seeds and mimicked their natural physiology. CONCLUSIONS: Targeting the PDGFRbeta pathway in vitro reduces Rb cell growth, survival, and invasiveness and could augment current therapies. This represents a novel signaling pathway for potential targeted therapy to further improve ocular survival in advanced Rb. FAU - Goldsmith, Zachary K AU - Goldsmith ZK AD - Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States. FAU - Coppess, William AU - Coppess W AD - Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States. FAU - Irvine, Andrew S AU - Irvine AS AD - Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States. FAU - Yuan, Kelley AU - Yuan K AD - Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States. FAU - Barsh, Samuel R AU - Barsh SR AD - Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States. FAU - Ritter, Madison K AU - Ritter MK AD - Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States. AD - Department of Biology, Furman University, Greenville, South Carolina, United States. FAU - McEwen, Matthew W AU - McEwen MW AD - Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States. FAU - Flores-Otero, Jacqueline AU - Flores-Otero J AD - Department of Anatomy and Neurobiology, University of Puerto Rico School of Medicine, San Juan, Puerto Rico, United States. AD - University of Puerto Rico Comprehensive Cancer Center, San Juan, Puerto Rico, United States. FAU - Garcia-Vargas, Aileen AU - Garcia-Vargas A AD - University of Puerto Rico Comprehensive Cancer Center, San Juan, Puerto Rico, United States. AD - Department of Pharmacology and Toxicology, University of Puerto Rico School of Medicine, San Juan, Puerto Rico, United States. FAU - Martinez-Ferrer, Magaly AU - Martinez-Ferrer M AD - University of Puerto Rico Comprehensive Cancer Center, San Juan, Puerto Rico, United States. AD - Department of Pharmaceutical Sciences, University of Puerto Rico School of Pharmacy, San Juan, Puerto Rico, United States. FAU - Brennan, Rachel C AU - Brennan RC AD - Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States. AD - Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States. FAU - Morales-Tirado, Vanessa M AU - Morales-Tirado VM AD - Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States. AD - Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, United States. FAU - Wilson, Matthew W AU - Wilson MW AD - Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, United States. AD - Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee, United States. LA - eng GR - R25 GM061838/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Invest Ophthalmol Vis Sci JT - Investigative ophthalmology & visual science JID - 7703701 RN - 0 (Antineoplastic Agents) RN - 0 (NF-kappa B) RN - 0 (Protein Kinase Inhibitors) RN - 8A1O1M485B (Imatinib Mesylate) RN - EC 2.3.2.27 (MDM2 protein, human) RN - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2) RN - EC 2.7.10.1 (PDGFRB protein, human) RN - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Antineoplastic Agents/*therapeutic use MH - Blotting, Western MH - Cell Culture Techniques MH - Drug Delivery Systems MH - Enzyme-Linked Immunosorbent Assay MH - Eye Enucleation MH - Flow Cytometry MH - Humans MH - Imatinib Mesylate/*therapeutic use MH - Immunohistochemistry MH - NF-kappa B/metabolism MH - *Neoplasm Seeding MH - Polymerase Chain Reaction MH - Protein Kinase Inhibitors/therapeutic use MH - Proto-Oncogene Proteins c-akt/metabolism MH - Proto-Oncogene Proteins c-mdm2/metabolism MH - Receptor, Platelet-Derived Growth Factor beta/*antagonists & inhibitors/metabolism MH - Retinal Neoplasms/*drug therapy/metabolism/pathology MH - Retinoblastoma/*drug therapy/metabolism/pathology MH - Retrospective Studies MH - Signal Transduction/physiology MH - Tumor Cells, Cultured MH - Vitreous Body/*metabolism PMC - PMC6133233 EDAT- 2018/09/08 06:00 MHDA- 2019/04/20 06:00 PMCR- 2018/09/01 CRDT- 2018/09/08 06:00 PHST- 2018/09/08 06:00 [entrez] PHST- 2018/09/08 06:00 [pubmed] PHST- 2019/04/20 06:00 [medline] PHST- 2018/09/01 00:00 [pmc-release] AID - 2702069 [pii] AID - IOVS-18-24359R1 [pii] AID - 10.1167/iovs.18-24359 [doi] PST - ppublish SO - Invest Ophthalmol Vis Sci. 2018 Sep 4;59(11):4486-4495. doi: 10.1167/iovs.18-24359.