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Formylpeptide receptor 1 expression in human glioblastoma

Sleen, Y. van (2013) Formylpeptide receptor 1 expression in human glioblastoma. Master's Thesis / Essay, Biology.

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Introduction: Glioblastoma (GBM) is the most malignant type of brain tumors in adults. Activation of the formylpeptide receptor 1 (FPR1) in phagocytic leukocytes leads to chemotaxis towards a bacterial infection and phagocytosis. FPR1 expression is also found in many human GBMs, where its activation promotes angiogenesis, proliferation and tumor cell migration. The main goal of this study was to investigate why the majority of the recently cultured GBM cell lines (the GG cell lines) are lacking FPR1 expression. Another goal of this study was to investigate the effect of the FPR1 antagonist Chemotaxis inhibitory protein of S. aureus (CHIPS) on the only FPR1 positive cell line GG5 in vivo. We also investigated whether variation in FPR1 expression correlates with the molecular GBM subtypes (proneural, mesenchymal, classic and neural). Material and methods: A staining for FPR1 was performed on snap-frozen human GBMs (n=36) and formalin fixed, paraffin embedded (FFPE) human GBMs (n=128) on a tissue micro-array (TMA). FPR1 expression was quantified on snap frozen tissues by evaluating the percentage of positive cells and the antigenic load and for the FFPE with an intensity scale from 0-3. The FPR1 expression on frozen tissues was matched with survival data and the FPR1 expression on FFPE tissues with their molecular GBM subtype. A fluorescent doublestaining of FPR1 CD68, CD163 and GFAP was performed on human FFPE GBM tissues. Five GG cell lines were implanted in mouse brains and the FPR1 expression of the resulting tumor was evaluated. CHIPS(n=6) and PBS (n=3) treated GG5 xenografts were stained for: Angiopoeitin-1, Angiopoeitin-2, Tie-2, Ki67, cleaved caspase-3 and FPR1 on snap frozen or FFPE tissue. A GLUT-1 staining helped distinguishing normoxic from hypoxic regions, as the expression of each marker was separately evaluated for the normoxic and hypoxic zone. Results: FPR1 expression is found in all human GBM tissues. The average percentage of FPR1 positive cells in snap frozen GBMs was 35%, while the majority of the FFPE GBMs showed FPR1 expression in every cell. A negative trend was found between the percentage of FPR1 positive cells in snap frozen GBMs and patient survival. No significant differences were found in the FPR1 intensity score for the four molecular GBM subtypes. FPR1 is found to co-express with CD68, CD163 and GFAP in all patients specimens. All five tumors resulting from implanted GG cell lines in mouse brains are FPR1 positive. No differences were found in angiogenesis, proliferation and apoptosis markers between tumors of CHIPS treated and untreated animals. Conclusion: This study shows widespread FPR1 expression in all human GBMs, but its expression does not correlate with any molecular subtype or with patient survival. Microenvironmental factors may be necessary to maintain FPR1 expression in GBM cells. CHIPS treatment of GG5 xenografts did not show any effects on proliferation and apoptosis

Item Type: Thesis (Master's Thesis / Essay)
Degree programme: Biology
Thesis type: Master's Thesis / Essay
Language: English
Date Deposited: 15 Feb 2018 07:55
Last Modified: 15 Feb 2018 07:55

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