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Previous issue date: 2016-03-18 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Tumor microenvironment and inflammatory diseases promote alterations in our
immune system along with their development. Several molecules are implicated in this
modulation and are therefore considered therapeutic targets. Gastrin-releasing peptide
(GRP) is produced in tumors where it promotes cellular proliferation. It is also correlated with
chronic diseases, as in rheumatoid arthritis and asthma, and in the acute condition of sepsis.
Recently, our group found a direct GRP action over neutrophils, promoting migration. This
work aimed to study the interface between GRP-producing tumors and the recruitment of
immune cells, as well as extend the cellular studies about neutrophil activation and migration
processes promoted by the peptide. In tumors, we observed that a lung adenocarcinoma cell
line does not proliferate in response to GRP. Yet, it is induced to migrate when exposed to
the peptide, indicating a potential role for GRP in metastasis of this type of cancer. In our
tumor immunology studies, we established a novel in vivo model by overexpressing GRP in a
melanoma cell line (B16F10). We observed the augment of infiltrating inflammatory
monocytes in the tumor microenvironment of these tumors. In parallel, we verified that
reactive oxygen species production and migration in response to GRP is dependent of the
NADPH oxidase complex. GRP stimulation promotes an intense activation, which
culminates in neutrophil extracellular traps (NETs) release. In addition, the GRP receptor
(GRPR) antagonist RC-3095 presented anti-inflammatory potential, inhibiting neutrophil
migration towards IL-8 and reducing the extent of acetaminophen-induced liver damage. This
effect was due to motility alterations in infiltrating neutrophils within the tissue and reduction
of cell adhesion molecules. The results presented herein demonstrate the wide panorama of
GRP?s interactions in tumor and immune biology. / O microambiente tumoral e as doen?as inflamat?rias promovem altera??es nas
c?lulas do nosso sistema imune ? medida que progridem. Diversas mol?culas est?o
envolvidas nessa modula??o, e por isso s?o alvos terap?uticos. O pept?deo liberador de
gastrina (GRP) ? produzido por tumores, onde promove prolifera??o celular. Este tamb?m
est? correlacionado com doen?as cr?nicas como a artrite reumatoide e asma, e em doen?as
agudas, como a sepse. Recentemente, nosso grupo descobriu a??o direta do GRP em
neutr?filos, promovendo indu??o de migra??o. O presente trabalho se prop?s a estudar a
interface entre tumores produtores de GRP e o recrutamento celular, assim como
aprofundar os estudos celulares sobre os processos de ativa??o e migra??o de neutr?filos
promovidos pelo pept?deo. Em tumores, observamos que uma linhagem de adenocarcinoma
pulmonar n?o prolifera quando exposto ao GRP, por?m ? induzida a migrar quando exposta
ao pept?deo, estabelecendo um potencial papel deste na promo??o de met?stases para
esse tipo tumoral. Na interface da imunologia tumoral, atrav?s do desenvolvimento de um
modelo in vivo de superexpress?o de GRP em melanoma murino (B16F10), observamos
que esse aumento do GRP induz a infiltra??o de mon?citos inflamat?rios no microambiente
tumoral. Em paralelo, verificamos que a produ??o de esp?cies reativas de oxig?nio e a
migra??o em dire??o ao GRP s?o dependentes do complexo NADPH oxidase. Esse
est?mulo promove ativa??o intensa, culminando na produ??o de redes extracelulares de
neutr?filos (NETs). J? o antagonista do seu receptor, GRPR, apresentou potencial antiinflamat?rio,
sendo capaz de inibir a migra??o neutrof?lica via modula??o de IL-8 e reduzindo
a extens?o da les?o hep?tica induzida por paracetamol (acetaminofeno), alterando a
motilidade dos neutr?filos no tecido e a express?o de mol?culas de ades?o. Assim, os
resultados aqui apresentados demonstram um panorama amplo da fun??o do GRP na
biologia tumoral e no sistema imune.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/7588 |
| Date | 18 March 2016 |
| Creators | Czepielewski, Rafael Sanguinetti |
| Contributors | Bonorino, Cristina, Porto, B?rbara Nery |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Biologia Celular e Molecular, PUCRS, Brasil, Faculdade de Bioci?ncias |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 8198246930096637360, 500, 500, 500, 600, 36528317262667714, -1634559385931244697, 2075167498588264571 |
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