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- Hedberg, Ylva, 1975-
(författare)
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Cell Cycle Regulation in Human Renal Cell Carcinoma
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ABSTRACTCell cycle regulation in human renal cell carcinomaYlva Hedberg, Departments of Medical Biosciences, Pathology, and Surgical andPerioperative Sciences, Urology Andrology, Umeå University, SwedenDeregulated growth control is a hallmark of neoplasia potentially caused by aberrant expression of cell cycle regulatory proteins. The importance of such aberrations in human renal cell carcinoma (RCC) has not been fully clarified. Therefore, the protein expressions of several G1/S regulatory proteins in human RCC were evaluated and their relation to clinico-pathological data was examined.Western blotting and immunohistochemistry were used to detect the proteinexpression of cyclin D1, D3, and E in 80 RCCs. Most tumors expressed higher levels of cyclin D1 (75%) and cyclin E (65%) compared to corresponding normal kidney cortex. In contrast, only 16 % of the tumors had high levels of cyclin D3. In conventional RCCs, low levels of cyclin D1 were associated with large tumor size, aneuploidy and a poor outcome for the patients. High expression of cyclin D3 and Ewere associated with aneuploidy, high proliferation, high TNM-stage, and high nuclear grade. Cyclin E was positively correlated to cyclin D3 but inversely associated with cyclin D1. Cyclin D3 and E were not associated with survival. The majority of RCCs had normal p27 levels, determined by immunohistochemistry, whereas the few tumors with low p27 levels were associated with large tumor size and poor survival.In order to confirm and extend our initial studies, a tissue microarray consisting of 218 RCCs was constructed and cyclin D1, D3, E, p27 were detected by immunohistochemistry. The tissue microarray results were validated by comparing the array data with western analyzes. Due to the large number of tumors analyzed we could evaluate potential differences in expression patterns of cell cycle regulators between conventional, papillary, and chromophobe RCCs. Interestingly, the protein expression differed between RCC types, showing that the conventional tumors generally had high cyclin D1 expression. In contrast, papillary and chromophobe RCCs had high cyclin E expression. Downregulation of p27 was found mostly in chromophobe RCCs. The retinoblastoma protein (pRb) was detected in all RCCs. Phosphorylation of pRb, detected by western blotting or immunohistochemistry and phospho-specific antibodies, was observed in approximately 50% of the tumors. The cdk-inhibitor p16 was not overexpressed suggesting that pRb was functional in the majority of RCCs.In summary, abnormal expression of G1-cyclins and the CDK-inhibitor p27 was common in RCC whereas the main G1/S-substrate, pRb, seemed to be functional. The aberrations further differed between the separate RCC subtypes and were linked to clinical behavior.
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- Jacobsen, Jan, et al.
(författare)
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Prognostic importance of serum vascular endothelial growth factor in relation to platelet and leukocyte counts in human renal cell carcinoma
- 2002
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Ingår i: European Journal of Cancer Prevention. - 0959-8278 .- 1473-5709. ; 11:3, s. 245-252
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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