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Jacomassi MD. Involvement of PAFR activation during chemotherapy in the melanoma repopulation phenomenon [dissertation]. São Paulo: “Faculdade de Medicina, Universidade de São Paulo”; 2018. One of the recurrent challenges in the clinical practice of Oncology is the process of repopulation, in which therapy-resistant tumor cells can proliferate and reconstitute the tumor. However, the mechanisms involved in this phenomenon were still little explored. The understanding of these events is, therefore, needed to avoid therapeutic failure. Melanomas are good models for studying repopulation due to the low rates of progression-free survival and the high rates of resistance to therapies associated to this type of solid tumor. It is known that the exposure of tumor cells to microenvironmental stress conditions, such as hypoxia and hypoxia/reoxygenation, as well as the exposure to antitumor treatment itself, are selective pressures frequently found in solid tumors that favor therapy resistance and tumor repopulation. Previous studies have indicated that the signaling mediated by the Platelet Activation Factor (PAF), a bioactive lipid related to various physiological functions, and its receptor, PAFR, is associated with resistance of melanoma cells to cytotoxic treatments and with tumor growth. Therefore, the aim of this study was to investigate the involvement of PAFR signaling upon the adverse conditions described above in the phenomenon of melanoma repopulation. Mass spectrometry results indicated that hypoxia increased the generation of PAF in human melanoma cell lines SKmel05 and A375, but not in A375M, although this increase was not observed after reoxygenation. In addition, they showed that SKmel37 exhibited the highest PAF basal levels, whose generation increased substantially after different times of hypoxia and hypoxia/reoxygenation exposure. We also investigated the generation of other PAFR ligands, but none were found in the samples. The results of PAFR detection by Western Blot and/or flow cytometry revealed that protein levels were not modulated by these conditions in any of the cell lines and that, at baseline, SKmel37 and SKmel05 showed the highest levels. These lines were therefore submitted to proliferation assays, which showed that the treatment with the PAFR antagonist, WEB2086, under conditions of hypoxia and hypoxia/reoxygenation, led to proliferation reduction and death-associated morphology in SKmel37 cells only. Propidium iodide incorporation studies indicated that the treatment of these cells exposed to hypoxia/reoxygenation with WEB2086 led to accumulation in SG2M, cell death and cisplatin sensitization. In addition, immunofluorescence of frozen sections of SKmel37induced tumors revealed that PAFR was found accumulated in hypoxic areas and its surroundings. Regarding the model of exposure to antitumor treatments, concentration and time curves with Vemurafenib showed that SKmel37 and A375 were resistant to the drug, whereas SKmel05 and UACC62 were sensitive. In addition, WEB2086 potentiated the effect of Vemurafenib-induced death on sensitive cell lines but did not affect the resistant ones. Considering the clinical aspects of initial response with subsequent repopulation triggering, we continued using the sensitive cell lines and we verified by cytometry that this drug increased ROS in both cell lines but only increased extracellular PAFR in SKmel05. The combined treatment potentiated the generation of ROS and led to the activation of caspase3/7 in SKmel05 only. This cell line was then submitted to clonogenic assays whose results showed that treatment with Vemurafenib reduced the number of clones and that WEB2086 did not potentiate this effect. Thus, the set of results presented highlights that PAFR signaling participates in the survival outcomes upon hypoxia/reoxygenation and/or antitumor treatments, and may, in some way, contribute to the repopulation of melanomas. Descriptors: melanoma; platelet activating factor; hypoxia, chemotherapy; drug resistance; recurrence. LISTA DE ABREVIATURAS E SIGLAS AA ANOVA ATM Ácido araquidônico Análise de variância Ataxia Telangiectasia mutada BSA Albumina do soro bovino BCL cAMP CD Linfoma de células B Monofosfato de adenosina cíclico Grupo de diferenciação CIS Cisplatina COX-2 Ciclooxigenase-2 CO2 Dióxido de carbono DC DMEM DMSO Célula dendrítica Do inglês Dulbecco’s Modified Eagle’s Medium Dimetilsulfóxido DNA Ácido desoxirribonucleico EDTA Ácido etilenodiamino tetra-acético FDA Do inglês Food and Drug Administration FMUSP Faculdade de Medicina da Universidade de São Paulo GFP Do inglês Green fluorescent protein HIF-1 HIP HIP/REOX H2O Fator induzido por hipóxia-1 Hipóxia Hipóxia seguida de reoxigenação Água H2O2 Peróxido de hidrogênio ICESP Instituto do Câncer do Estado de São Paulo IFN Interferon Ig Imunoglobulina IL Interleucina NFκB NOR NP40 O2 Fator nuclear kappa B Normóxia “Nonidet P40” Oxigênio PAF PAF-AH PAFR PBS Fator de Ativação de Plaquetas PAF-Acetilhidrolase Receptor do Fator de Ativação de Plaquetas Tampão fosfato salina PCR Reação em cadeia da polimerase PGE2 pH Prostaglandina E2 Potencial hidrogeniônico PI PKC Iodeto de propídio Proteína quinase C PLA2 PLX PMSF PVDF PC Fosfolipase A2 PLX4032 ou Vemurafenib Fluoreto de fenilmetilsulfonil Do inglês Hydrophobic polyvinylidene difluoride Fosfatidilcolina RNA Ácido ribonucleico RGP ROS SFB Fase de crescimento radial Espécies reativas de oxigênio Soro fetal bovino SUS Sistema Único de Saúde TBS Tampão Salina Tris TNF-α Fator de necrose tumoralα UV Ultravioleta VEGF VGP WEB Fator de crescimento endotelial vascular Fase de crescimento vertical WEB2086 ou Apafant

Envolvimento da ativação de PAFR frente à quimioterapia no fenômeno de repopulação de melanomas