Anti-Platelet-Derived Growth Factor Receptor-Beta Therapy Does Not Trigger Retinal Endothelial Cell Toxicity
DOI:
https://doi.org/10.17140/OOJ-4-121Keywords:
Retinoblastoma; Retinal endothelial cells; Ocular oncology; Imatinib mesylate.Abstract
Background
Retinoblastoma (Rb) is a highly angiogenic tumor, for which anti-vascular endothelial growth factor (VEGF) therapies have
shown limited success in clinical setting. Recent investigations demonstrated upregulation of ancillary axis including the plateletderived growth factor (PDGF) when VEGF is inhibited. This illustrates the need for novel therapeutics. Previous work from our
lab showed inhibition of the platelet-derived growth factor receptor-beta (PDGFR-β) by imatinibmesylate (IM), inhibited Rb
cells proliferation in vitro. Novel therapies ideally are tumor-specific, leaving normal non-cancerous cells a stroma to perform their
homeostatic functions. Rb treatments induce apoptosis of the retinal endothelial cells, causing the release of pro-inflammatory
cytokines and chemokines to the microenvironment.
Aims
We investigated the role of the PDGFR-β in the tumor microenvironment and how inhibition of this signaling pathway, as a
potential targeted therapy, impacts angiogenesis in human retinal microvascular endothelial cells (hRECs), specialized neurons
arborizing the retinal microvasculature.
Results
Our results demonstrated that inhibition of the PDGFR-β signaling pathway by IM affects the proliferation of the Rb cells, but
not hRECs. PDGFR-β signaling is not required for hRECs angiogenic activity, although it reduces the percentage of VEGF-Aproducing cells.
Conclusion
These results illustrate a lack of functional activity PDGFR-β signaling in hRECs and points to a more tumor-specific therapeutic
option. This is of critical importance as success of treatment also depends on the ability of the normal tissues to remain healthy
after sensitization and/or killing of the Rb tumor.
References
Rodriguez-Galindo C, Orbach DB, VanderVeen D. Retinoblas-toma. Pediatr Clin North Am. 2015; 62(1): 201-223. doi: 10.1016/j. pcl.2014.09.014
Goddard AG, Kingston JE, Hungerford JL. Delay in diagnosis of retinoblastoma: risk factors and treatment outcome. Br J Oph-thalmol. 1999; 83(12): 1320-1323. doi: 10.1136/bjo.83.12.1320
Rodriguez-Galindo C, Chantada GL, Haik BG, Wilson MW. Treatment of retinoblastoma: Current status and future perspec-tives. Curr Treat Options Neurol. 2007; 9(4): 294-307. doi: 10.1007/ s11940-007-0015-4
Balmer A, Zografos L, Munier F. Diagnosis and current man-agement of retinoblastoma. Oncogene. 2006; 25(38): 5341-5349. doi: 10.1038/sj.onc.1209622
Goldsmith ZK, Coppess W, Irvine AS, Yuan K, Barsh SR, Ritter MK, et al. Targeting the platelet-derived growth factor-beta stimu-latory circuitry to control retinoblastoma seeds. Invest Ophthalmol Vis Sci. 2018; 59(11): 4486-4495. doi: 10.1167/iovs.18-24359
Apte RS, Harbour JW. Inhibiting angiogenesis in retinoblastoma. Ophthalmic Res 2007; 39(4): 188-190. doi: 10.1159/000103578
Lee SY, Kim DK, Cho JH, Koh JY, Yoon YH. Inhibitory ef-fect of bevacizumab on the angiogenesis and growth of retino-blastoma. Arch Ophthalmol. 2008; 126(7): 953-958. doi: 10.1001/ archopht.126.7.953
Ravandi F. Managing Philadelphia chromosome-positive acute lymphoblastic leukemia: Role of tyrosine kinase inhibitors. Clin Lymphoma Myeloma Leuk. 2011; 11(2): 198-203. doi: 10.1016/j. clml.2011.03.002
Steinle JJ, Zhang Q, Thompson KE, Toutounchian J, Yates CR, Soderland C, et al. Intra-ophthalmic artery chemotherapy trig-gers vascular toxicity through endothelial cell inflammation and leukostasis. Invest Ophthalmol Vis Sci. 2012; 53(4): 2439-2445. doi:
1167/iovs.12-9466 10. Zhang Q, Jiang Y, Toutounchian J, Wilson MW, Morales-Tira-do V, Miller DD, et al. Novel quinic acid derivative KZ-41 prevents retinal endothelial cell apoptosis without inhibiting retinoblastoma cell death through p38 signaling. Invest Ophthalmol Vis Sci. 2013; 54(9): 5937-5943. doi: 10.1167/iovs.13-12326
Reid TW, Albert DM, Rabson AS, Russell P, Craft J, Chu EW, et al. Characteristics of an established cell line of retinoblastoma. JNCI Journal of the National Cancer Institute. 1974; 53(2): 347-360. doi: 10.1093/jnci/53.2.347
Webb AH, Gao BT, Goldsmith ZK, Irvine AS, Saleh N, Lee RP, et al. Inhibition of MMP-2 and MMP-9 decreases cellular mi-gration, and angiogenesis in in vitro models of retinoblastoma. BMC Cancer. 2017; 17(1): 434. doi: 10.1186/s12885-017-3418-y
Chintalapudi SR, Djenderedjian L, Stiemke AB, Steinle JJ, Jablonski MM, Morales-Tirado VM. Isolation and molecular pro-filing of primary mouse retinal ganglion cells: Comparison of phe-notypes from healthy and glaucomatous retinas. Front Aging Neuro-sci. 2016; 8: 93. doi: 10.3389/fnagi.2016.00093
Abramson DH, Dunkel IJ, Brodie SE, Marr B, Gobin YP. Su-perselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology. 2010; 117(8): 1623-1629. doi: 10.1016/j.ophtha.2009.12.030
Ghassemi F, Shields CL. Intravitreal melphalan for refrac-tory or recurrent vitreous seeding from retinoblastoma. Arch Ophthalmol. 2012; 130(10): 1268-1271. doi: 10.1001/archophthal-mol.2012.1983
Schmack I, Hubbard GB, Kang SJ, Aaberg TM, Jr., Gross-niklaus HE. Ischemic necrosis and atrophy of the optic nerve after periocular carboplatin injection for intraocular retinoblastoma. Am J Ophthalmol. 2006; 142(2): 310-315. doi: 10.1016/j.ajo.2006.02.044
Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH. In-tra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol. 2011; 129(6): 732-737. doi: 10.1001/archophthalmol.2011.5
Wong JR, Morton LM, Tucker MA, Abramson DH, Seddon JM, Sampson JN, Kleinerman RA. Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy. J Clin Oncol. 2014; 32(29): 3284- Submit your article to this journal | https://openventio.org/submit-manuscript/ 3290. doi: 10.1200/JCO.2013.54.7844
Daniels AB, Froehler MT, Pierce JM, Nunnally AH, Bozic I, Tao Y, et al. Efficacy, Toxicity and Biodistribution of Intra-arterial vs. Intravenous Chemotherapy in a Rabbit Retinoblastoma Model. In: Association for Research in Vision and Ophthalmology. Hono-lulu, HI; 2018.
Crane IJ, Liversidge J. Mechanisms of leukocyte migration across the blood–retina barrier. Semin Immunopathol. 2008; 30(2): 165-177. doi: 10.1007/s00281-008-0106-7
Xu H, Manivannan A, Goatman KA, Jiang HR, Liversidge J, Sharp PF, et al. Reduction in shear stress, activation of the en-dothelium, and leukocyte priming are all required for leukocyte passage across the blood--retina barrier. J Leukoc Biol. 2004; 75(2): 224-232. doi: 10.1189/jlb.1002479
Pennock S, Kim LA, Kazlauskas A. Vascular endothelial cell growth factor a acts via platelet-derived growth factor receptor al-pha to promote viability of cells enduring hypoxia. Mol Cell Biol. 2016; 36(18): 2314-2327. doi: 10.1128/MCB.01019-15
Steinle JJ. Retinal endothelial cell apoptosis. Apoptosis. 2012; 17(12): 1258-1260. doi: 10.1007/s10495-012-0777-3
Kang SJ, Grossniklaus HE. Rabbit model of retinoblastoma. Journal of Biomedicine and Biotechnology. 2011; 2011: 394730. doi: 10.1155/2011/394730
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