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Vascular endothelial growth factor in renal cell carcinoma
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background. Angiogenesis is essential for tumour growth. Vascular endothelial growth factor (VEGF) and its isoforms were investigated in relation to the clinical course in a large number of patients with renal cell carcinoma (RCC).

Methods. RCC subtypes and behaviour were established by clinicopathological criteria and surveillance. VEGF expression was analysed in serum by enzyme-linked immuno-sorbent assay (ELISA) and in tumour tissue by reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and Western blot (WB).

Results. Serum VEGF (S-VEGF) was increased in RCC compared to control group. S-VEGF correlated with tumour stage and grade and was associated with survival in men but not in women. S-VEGF correlated with blood platelet counts, which were inversely correlated to increasing age in women, and they were decreased in chronically medicated patients, particularly in men. In contrast to S-VEGF, platelet counts associated with survival only in patients free of medication and chronic diseases. RT-PCR showed a correlation between VEGF121/VEGF165 mRNA and between VEGF165/VEGF-R1 mRNA. There was no association between different VEGF mRNA isoforms and S-VEGF. Conventional renal cell carcinoma (CRCC) had higher VEGF165, VEGF121, and VEGF-R1 mRNA levels compared with papillary renal cell carcinoma (PRCC). IHC VEGF staining was strong in kidney cortex. Kidney tumour showed a considerable variation in cytoplasmatic VEGF expression, which correlated with tumour size. Although, there was no difference in VEGF expression between the RCC types, VEGF expression was associated with survival only in CRCC. WB showed a strong protein expression of both VEGF189 and VEGF165 in kidney cortex. In kidney tumour, expression of VEGF189 varied the most, VEGF165 less so, and VEGF121 was rarely detected. Both CRCC and PRCC expressed low levels of VEGF189 and VEGF165 compared with kidney cortex. Chromophobe renal cell carcinoma (ChRCC) expressed VEGF189 levels comparable to those from kidney cortex, while VEGF165 was lower. In PRCC and ChRCC, VEGF189 levels correlated inversely with advancing tumour stage, and in PRCC, VEGF165 levels correlated inversely with increasing tumour size. VEGF189 was an independent prognostic factor for survival in patients with PRCC.

Conclusions. S-VEGF has a stronger association to progression in RCC than platelet count. CRCC showed high levels of VEGF mRNA isoforms and VEGF-R1 mRNA compared to PRCC. VEGF mRNA isoforms expression decreased with advancing stage. IHC demonstrated VEGF expression in cell cytoplasm related to tumour growth, particular in CRCC. Different VEGF isoform patterns were found in different RCC types. Protein VEGF189 expression was associated with tumour stage and was an independent prognostic factor in PRCC. Protein VEGF165 expression was generally low and had no prognostic value. The trend for decreasing levels of VEGF isoforms in advanced tumour stages may indicate that angiogenic activity is an early event in tumour growth induced by VEGF, but that during later tumour progression the role of VEGF is less clear.

Place, publisher, year, edition, pages
Umeå: Kirurgisk och perioperativ vetenskap , 2006. , 100 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1006
Keyword [en]
VEGF, isoforms, quantitative RT-PCR, immunohistochemistry, tissue microarray, Western blot, stage, survival, renal cell carcinoma
National Category
Urology and Nephrology
Identifiers
URN: urn:nbn:se:umu:diva-713ISBN: 91-7264-029-4 (print)OAI: oai:DiVA.org:umu-713DiVA: diva2:144292
Public defence
2006-03-24, Sal 1, By 10, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2006-02-28 Created: 2006-02-28 Last updated: 2012-06-07Bibliographically approved
List of papers
1. Vascular endothelial growth factor as prognostic factor in renal cell carcinoma
Open this publication in new window or tab >>Vascular endothelial growth factor as prognostic factor in renal cell carcinoma
2000 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Journal of Urology, Vol. 163, no 1, 343-347 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-4966 (URN)10604387 (PubMedID)
Available from: 2006-02-28 Created: 2006-02-28 Last updated: 2017-12-14Bibliographically approved
2. Prognostic importance of serum vascular endothelial growth factor in relation to platelet and leukocyte counts in human renal cell carcinoma
Open this publication in new window or tab >>Prognostic importance of serum vascular endothelial growth factor in relation to platelet and leukocyte counts in human renal cell carcinoma
2002 (English)In: European Journal of Cancer Prevention, ISSN 0959-8278, E-ISSN 1473-5709, Vol. 11, no 3, 245-252 p.Article in journal (Refereed) Published
Abstract [en]

It has been shown that both serum vascular endothelial growth factor (VEGF) and also platelet counts are associated with survival in renal cell carcinoma (RCC). It is not known, however, whether VEGF in serum relates to the angiogenic activity of the tumour or is derived from circulating blood components. Therefore, the interrelation between serum VEGF, platelet and leukocyte counts compared with health history, clinicopathological findings and outcome was evaluated in patients with RCC. Blood samples were collected before nephrectomy in 161 patients. Serum VEGF165 was assessed by a quantitative ELISA method. Platelet and leukocyte counts were analysed routinely and obtained from medical records. The variables were compared using univariate and multivariate analysis. There were significant correlations between VEGF levels, and platelet (P < 0.001) and leukocyte counts (P < 0.001). Serum VEGF levels, platelet counts, as well as leukocyte counts correlated significantly to stage and grade. Platelet counts were significantly lower in men with medication (P = 0.042), and decreased with age particularly in women (P = 0.001). Age or medication did not affect VEGF levels or leukocyte counts. Both VEGF and platelets gave significant prognostic information in univariate analysis. Using Cox multivariate analysis, VEGF was the last variable to be excluded. Only stage and grade remained as independent prognostic factors. Both VEGF levels and platelet counts gave prognostic information but VEGF was more reliable as predictor of survival in patients with RCC.

Keyword
Prognosis, stage, survival, VEGF
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-4967 (URN)12131658 (PubMedID)
Available from: 2006-02-28 Created: 2006-02-28 Last updated: 2017-12-14Bibliographically approved
3. Tumour vascular endothelial growth factor (VEGF) mRNA in relation to serum VEGF protein levels and tumour progression in human renal cell carcinoma
Open this publication in new window or tab >>Tumour vascular endothelial growth factor (VEGF) mRNA in relation to serum VEGF protein levels and tumour progression in human renal cell carcinoma
Show others...
2003 (English)In: Urological research, ISSN 0300-5623, E-ISSN 1434-0879, Vol. 31, no 5, 335-40 p.Article in journal (Refereed) Published
Abstract [en]

Angiogenesis is gaining interest because of its importance in tumour growth and metastasis. Renal cell carcinoma (RCC) is known to be a well-vascularized tumour. The aim of this study was to evaluate the expression of VEGF mRNA and receptor flt-1 mRNA (VEGF R1) in a clinical material of RCCs compared with clinicopathological variables and serum VEGF levels. Total RNA was extracted from snap-frozen tumour tissue obtained from 61 patients. Expression of mRNA for VEGF121, VEGF165 and flt-1 were analysed using quantitative RT-PCR. Relative VEGF mRNA levels, corrected for corresponding cyclophilin value, were related to stage, grade, RCC type and survival time. Serum VEGF165 protein was analysed using a quantitative ELISA. Papillary RCC had significantly lower VEGF121 and flt-1 mRNA levels compared with conventional RCC (p=0.001). VEGF121 mRNA levels were significantly lower in locally advanced tumours in relation to tumours limited to the kidney and those with metastatic disease (p=0.047 and p=0.036). This statistical difference disappeared when only conventional RCCs were evaluated. No association was found between VEGF mRNA levels and nuclear grade. Patients with lower VEGF121 mRNA levels had significantly longer survival time compared with those with higher levels (when adjusted to stage, p=0.0097, log rank test). There was an inverse relation between VEGF165 mRNA and serum VEGF165 levels. The trend to lower VEGF121 mRNA levels in locally advanced RCC indicate that angiogenic activity and degradation might be up-regulated in tumours with a high ability to invade. The association with tumour progression shows that VEGF is a promising angiogenic factor especially important in conventional RCCs. VEGF expression might possibly be of help to identify RCCs susceptible for anti-angiogenic therapies.

Place, publisher, year, edition, pages
Springer-Verlag New York, 2003
Keyword
Renal cell carcinoma, mRNA, VEGF, flt-1, RT-PCR, Prognosis
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-27702 (URN)10.1007/s00240-003-0346-x (DOI)14574539 (PubMedID)
Available from: 2009-11-17 Created: 2009-11-17 Last updated: 2017-12-12Bibliographically approved
4. Expression of vascular endothelial growth factor protein in human renal cell carcinoma
Open this publication in new window or tab >>Expression of vascular endothelial growth factor protein in human renal cell carcinoma
Show others...
2004 (English)In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 93, no 3, 297-302 p.Article in journal (Refereed) Published
Keyword
VEGF, stage survival, prognosis, renal cell cancer
Identifiers
urn:nbn:se:umu:diva-15357 (URN)10.1111/j.1464-410X.2004.04605.x (DOI)14764126 (PubMedID)
Available from: 2007-09-13 Created: 2007-09-13 Last updated: 2017-12-14Bibliographically approved
5. Different isoform patterns for vascular endothelial growth factor between clear cell and papillary renal cell carcinoma
Open this publication in new window or tab >>Different isoform patterns for vascular endothelial growth factor between clear cell and papillary renal cell carcinoma
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4970 (URN)
Available from: 2006-02-28 Created: 2006-02-28 Last updated: 2010-01-13Bibliographically approved

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