Haverdings, H.L. (Hester Laura) (2013) Delineating activated signal transducer and activator of transcription 3 as a potential biomarker in renal cell carcinoma. thesis, Medicine.
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Abstract
Introduction and objectives: Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor activated by phosphorylation at tyrosine Y705 (pSTAT3), hereby initiating dimerization and translocation into the nucleus to regulate the expression of genes that mediate cell survival, proliferation and angiogenesis. STAT3 is aberrantly activated in various types of human malignancies, though the expression of pSTAT3 and STAT3 in renal cell carcinomas (RCCs) has not been fully characterized yet. This study will evaluate whether pSTAT3 and STAT3 are associated with pathological features, represent potential prognostic markers in RCC and have therapeutic indications. Materials and Methods: Three tissue microarrays were constructed from 246 primary and metastatic RCC specimens. Through immunohistochemical staining with anti-phospho-STAT3 and anti-STAT3 monoclonal antibodies, expression levels were scored and quantified by intensity, percentage of tumor cells staining per core and the H-score, what incorporates both parameters. Using a retrospective chart review, pSTAT3 and STAT3 expression levels were correlated with multiple clinicopathological features, including Fuhrman nuclear grade, pathologic stage, histological subtypes, metastatic status and clinical outcome. Results: The RCCs showed in the tumor cells positive pSTAT3 and STAT3 staining in 54% and 90% of the cores, respectively. Metastases showed significantly higher pSTAT3 H-scores than primary tumors (p=0.003), the different sites of metastases did not influence outcome. Low graded and staged tumors showed significantly higher pSTAT3 H-scores than high graded (p=0.03) and staged (p=0.004) tumors. STAT3 correlations showed similar results. No significant difference was seen between different histologic subtypes of RCC such as clear cell, papillary and chromophobe carcinomas. Unexpectedly, pSTAT3 expression showed a better prognosis as regarding for overall survival (p=0.008) and progression-free survival (p=0.006), independently of stage, grade and histological subtype. In conformity, STAT3 expression showed better prognosis in progression-free survival (p=0.013). In patients with metastases, pSTAT3 expression level showed no prognostic value. In contrary, the overall-survival curve for STAT3 staining showed a tendency (p=0.07) towards poor prognosis. Conclusion: In our study we found high pSTAT3 and STAT3 expression correlating with low graded and staged primary RCCs or its metastases. At the same time we found significantly higher pSTAT3 and STAT3 in metastases than in the primary RCCs. Taken into account the contradicting evidence published so far, we conclude STAT3 activation has double-sided effects on tumor progression and thus, may not be useful to predict the prognosis of patients with RCC. Likewise, the development of targeted therapy inhibiting the STAT3-pathway for therapeutic indications requires caution. Future studies are needed to improve the understanding of the basic biology of RCC initiation and progression and the significance of STAT3 activation in this emerging field.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Kappelle, Dr. J. W. |
| Supervisor name: | Chevalier, Dr. S. and McGill University Health Center and and Research Institute |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 11:02 |
| Last Modified: | 25 Jun 2020 11:02 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/2202 |
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