The Expression Of Thrombospondin-1 And P53 In CCRCC: Its Relationship To Angiogenesis, Cell Proliferation, And Cancer Specific Survival

Main Category: Cancer / Oncology
Also Included In: Urology / Nephrology
Article Date: 30 Jan 2010 - 0:00 PDT

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UroToday.com - Clear cell renal cell carcinoma (CCRCC) is the most prevalent of the subtypes of renal cell carcinoma (RCC). Its prognosis is unpredictable because even small tumors may progress and end in metastatic disease and death. There is an urgent need for new molecular prognostic markers and new treatment targets. CCRCC is frequently associated with mutations in the von Hippel-Lindau tumor suppressor gene bringing about an increased VEGF expression and neovascularization. The putative role of trombospondin-1 (TSP-1) which is one of the most potent endogenous inhibitors of angiogenesis in the tumor-associated stroma is largely ignored in CCRCC.

We evaluated possible associations among TSP-1, p53, micro vessel density (MVD), cell proliferation index (KI-67) Fuhrman grade (NG), tumor stage, tumor size and cancer specific survival (CSS) in CCRCC patients. Our study demonstrated TSP-1 expression was significantly associated with prognostic tumor features. We found a significant correlation between p53 status and TSP-1 expression that to our knowledge previously not has been reported. Interestingly, a relative high percent (53 %) of the tumors was p53 positive, and that might imply upregulation of wild type protein in some cases. This is supported by the report of Chemeris et al.1 which demonstrated an adverse impact on prognosis in CCRCC of upregulation of the wild type p53 protein. Posttranslational changes of the wild type p53 protein might account for the non-functionality of the protein.

In multivariate analyses TSP-1 was an independent prognosticator of CSS. No or low expression of TPS-1 conveyed a 5.85 hazard rate of dying from CCRCC compared with moderate or high TSP-1. In accordance with our results Arai et al.2 reported frequent hypermethylation of the CpG island of the TSP-1 gene in CCRCC associated with adverse prognosis. In our study TSP-1 and MVD were inversely associated, and high expression was detected in areas with stroma fibrosis and in the tumor pseudo capsule. The hot spots of MVD and TSP-1 were selected independently. It would be of interest to see whether high TSP-1 activity corresponded with low MVD in the same areas. We postulate such association which opens up for further investigations on the relationship between TSP-1, angiogenesis and fibrosis.

The inhibitory impact of TSP-1 on angiogenesis observed in CCRCC will most likely be utilized therapeutically. In fact, a peptide analogue of an angiogenic sequence of TSP-1 has shown some effect on survival in phase 1 and 2 trials of untreated metastatic RCC. The development of new agents that mimic the antiangiogenetic properties of TSP-1 warrants further clinical investigations.

Reference:
1. Chemeris G, Loktinov A, Rempel A, Schwarz M, Bannasch P. Elevated content of p53 protein in the absence and p53 gene mutation as a possible prognostic marker for human renal cell tumours. Virchows Arch, 1995, 426:563

2. Arai E, Ushijima S, Tsuda H, Fujimoto H, Hosoda F, Shibata T et al. Genetic clustering of clear cell renal cell carcinoma based on array-comparative genomic hybridization: its association with DNA methylation alteration and patient outcome. Clin Cancer Res 14(17), 2008

Written by Dragomir P. Zubac, MD, and Svein A. Haukaas, MD, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations, etc., of their research by referencing the published abstract.

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