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Hypoxia-inducible factor-2alpha mRNA expression in human renal cell carcinoma
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
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2009 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, no 6, 909-914 p.Article in journal (Refereed) Published
Abstract [en]

Background. Hypoxia-inducible factor (HIF)-2alpha is upregulated in hypoxia or by inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene. In a number of malignancies, increased HIF-2alpha expression may indicate worse prognosis. The aim of this study was to evaluate the prognostic information of HIF-2alpha mRNA expression in renal cell carcinoma (RCC). Material and methods. HIF-2alpha mRNA was quantified by real time polymerase chain reaction (rt-PCR) in tumour tissue samples from 202 patients. Samples from 50 corresponding kidney cortex tissue were analysed as controls. mRNA levels were evaluated in relation to tumour cell type, TNM stage, nuclear grade and disease specific survival. Results. The levels of HIF-2alpha mRNA were significantly higher in 168 clear cell (c)RCC than in 23 papillary (p)RCC (p<0.001) or 11 chromophobe (ch)RCC (p<0.006). Among cRCC there was an inverse correlation between HIF-2alpha mRNA levels and TNM stage I and II-IV tumours (p=0.01), and nuclear grade (p=0.006). After a median follow-up time of 99 months (range 34-247), 106 patients had died of RCC. No correlation of HIF-2alpha mRNA to survival was observed. A multivariate analysis of prognostic factors in cRCC showed that TNM stage alone was an independent predictor of prognosis; HIF-2alpha mRNA levels did not add further prognostic information. Discussion. The results demonstrated that HIF-2alpha mRNA levels were higher in cRCC compared to pRCC and chRCC. Furthermore, HIF-2alpha mRNA levels were inversely related to TNM stage and nuclear grade in cRCC.

Place, publisher, year, edition, pages
2009. Vol. 48, no 6, 909-914 p.
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-26034DOI: 10.1080/02841860902824891PubMedID: 19322701OAI: oai:DiVA.org:umu-26034DiVA: diva2:236144
Available from: 2009-09-21 Created: 2009-09-21 Last updated: 2012-08-15Bibliographically approved
In thesis
1. Angiogenesis in human renal cell carcinoma: hypoxia, vascularity and prognosis
Open this publication in new window or tab >>Angiogenesis in human renal cell carcinoma: hypoxia, vascularity and prognosis
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Angiogenesis is recognised as a critical step in tumour progression. The angiogenic switch is activated by various trigger signals, such as hypoxia, low pH, and genetic mutations. Renal cell carcinoma (RCC) is often an aggressive tumour, and advanced disease has limited treatment options and bad prognosis. This study was focused on markers of angiogenesis in RCC: endoglin (CD105) and CD31 assessing microvessel density (MVD), and carbonic anhydrase (CA) IX and hypoxia-inducible factor (HIF)-2α expressed at hypoxia. Upregulation of HIF is also associated with inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene, which is common in conventional/clear cell (c)RCC.

Method: A tumour bank containing 308 tumours from patients operated 1982-2003 was used. The tumours were well characterised regarding tumour type, TNM stage, nuclear grade, tumour size, and patient survival. The tumours were prepared in tissue microarrays and fresh frozen in whole sections. To analyse the expression of endoglin, CD31, CA IX, and HIF-2α mRNA, immunohistochemistry and real-time PCR were used.

Results: There was a higher endoglin expression in cRCC than in papillary (p)RCC and chromophobe (ch)RCC, and a higher CD31 expression in cRCC than in pRCC. MVD correlated inversely to TNM stage and nuclear grade in cRCC. There was also an inverse correlation between tumour diameter and CD31 expression in cRCCs. Patients with cRCC with high MVD had a more favourable prognosis than patients with lower MVD. Endoglin and CD31 were not independent prognostic factors.

The CA IX expression was higher in cRCC than in pRCC and chRCC. Patients with cRCC expressing low CA IX had a significantly less favourable prognosis compared with those with higher expression. CA IX is an independent prognostic factor.

There was a higher HIF-2α mRNA expression in cRCC than in pRCC and chRCC. In cRCC, there was a significant inverse correlation between HIF-2α mRNA expression, and TNM stage and nuclear grade. There was also an inverse correlation between HIF-2α mRNA expression and tumour size among patients with cRCC. HIF-2α was not an independent prognostic factor.

Conclusion: In these studies, the factors related to hypoxia and vascularity were all inversely correlated to tumour aggressiveness in cRCC. MVD, CA IX, and HIF-2α expression were also higher in cRCC than in pRCC and chRCC. The relationship between angiogenesis, vascularity, and hypoxia is ambiguous. A line of reasoning including mutations increasing angiogenesis in advanced disease may also be applied to RCC. Measurements of individual angiogenic factors seem to provide prognostic information, and can potentially be combined in patient monitoring and treatment.

Place, publisher, year, edition, pages
Umeå: Strålningsvetenskaper, 2007. 64 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1100
Keyword
Endoglin/CD105, CD31, prognosis, CA IX, HIF-2α, renal cell carcinoma, tissue microarray, immunohistochemistry, real-time PCR, stage, grade
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-1331 (URN)978-91-7264-315-4 (ISBN)
Public defence
2007-09-19, Sal 244, Lionssalen, 7, Norrlands universitetssjukhus, Umeå, 09:00 (English)
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Available from: 2007-09-03 Created: 2007-09-03 Last updated: 2010-01-18Bibliographically approved

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Sandlund, JohannaLjungberg, BörjeWikström, PernillaGrankvist, KjellLindh, GudrunRasmuson, Torgny

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