Prostate specific membrane antigen (PSMA) expression in vena cava tumour thrombi of clear cell renal cell carcinoma suggests a role for PSMA-driven tumour neoangiogenesis.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a malignant renal neoplasm with a peculiar propensity to propagate as a contiguous tumor extension via the renal vein and inferior vena cava, occasionally reaching the right atrium. This intravascular tumor extension, often referred to as a tumor thrombus, represents the active growing front of the cancer. Prostate specific membrane antigen (PSMA), a glycoprotein that is extensively used in prostate cancer diagnostics, is a useful vascular marker for a variety of solid tumors. It is expressed in renal carcinomas. The aim of the current investigation was to analyse and compare the expression of PSMA at the growing front of the vena cava tumor extension with that found in the primary renal lesion. METHODS: Immunohistochemical (IHC) analysis of PSMA and CD34 was performed on archived paraffin embedded vena cava tumour thrombus tissue and matching renal tumours. These specimens were collected from radical nephrectomies of 10 patients with vena cava invasive (pT3b) ccRCC in a large tertiary hospital in Australia. Quantitative and qualitative morphometric analysis of PSMA IHC expression was performed with Aperio ImageScope morphometry using intensity and positive pixel counts of CD34 and PSMA from the IVC tumour slides and the corresponding renal tumour mass. RESULTS: PSMA and CD34 immunostaining were noted in the neovasculature of IVC tumour and renal tumour tissue. There was a higher PSMA/CD34 positive pixel count ratio noted in IVC tumour tissue when compared to renal tumour tissue. PSMA showed consistently increased expression in vena cava tumour, in comparison with the renal tumour mass. CONCLUSIONS: Intravascular venous tumour extension expresses PSMA more intensely compared to intrarenal tumour tissue neovasculature. Our data suggest a possible mechanism for PSMA in neoangiogenesis and local progression of ccRCC and therefore its usefulness as a biomarker of neoangiogenesis for future diagnostic and therapeutic advancements.

Carvedilol protects the kidneys of tumor-bearing mice without impairing the biodistribution or the genotoxicity of cisplatin.

Cisplatin (Cisp) is an effective antitumor drug; however, it causes severe nephrotoxicity. Minimization of renal toxicity is essential, but the interference of nephroprotective agents, particularly antioxidants, with the antitumor activity of cisplatin is a general concern. We have recently demonstrated that the anti-hypertensive and antioxidant drug carvedilol (CV) protects against the renal damage and increases the survival of tumor-bearing mice without impairing the tumor reduction by cisplatin. So far, reports on the antioxidant mechanism of CV are controversial and there are no data on the impact of CV on the antitumor mechanisms of cisplatin. Therefore, this study addresses the effect of CV on mechanisms underlying the tumor control by cisplatin. CV did not interfere with the biodistribution or the genotoxicity of cisplatin. We also addressed the antioxidant mechanisms of CV and demonstrated that it does not neutralize free radicals, but is an efficient chelator of ferrous ions that are relevant catalyzers in cisplatin nephrotoxicity. The present data suggest that oxidative damage and genotoxicity play different roles in the toxicity of cisplatin on kidneys and tumors and therefore, some antioxidants might be safe as chemoprotectors. Altogether, our studies provide consistent evidence of the beneficial effect of CV on animals treated with cisplatin and might encourage clinical trials.

Carvedilol efficiently protects kidneys without affecting the antitumor efficacy of cisplatin in mice.

Cisplatin is an effective anticancer drug which has been used to treat a wide range of tumors for the last 30 years. However, its use is associated with nephrotoxicity. Protective strategies have been reported, but their impact on the antitumor activity of cisplatin has not been clarified. We have previously reported the protective potential of carvedilol against cisplatin nephrotoxicity in tumor-free rats. Therefore, in the present study we used a tumor-bearing model to investigate the impact of carvedilol on the antitumor activity of cisplatin. The renal damage induced by cisplatin and the protective effect of carvedilol were demonstrated by the levels of blood urea nitrogen and plasma creatinine as well as by renal histopathology and immunohistochemistry. The mechanism of protection was associated with significantly decreased (i) oxidative stress markers, (ii) Bax expression, (iii) caspase-3 activity and (iv) TUNEL labeling for apoptosis. More importantly, evaluation of tumor mass, tumor remission rate and the survival curve showed that carvedilol did not impair the antitumor action of cisplatin. These findings suggest that the mechanisms underlying the nephrotoxic and the antitumor activity of cisplatin might be different. This is the first study to report such findings. Compared to other reported potential cytoprotectors against cisplatin-induced nephrotoxicity, carvedilol stands out due to the fact that it is already clinically-employed and well tolerated by the patients. Based on these features and on the present findings, carvedilol is a very promising candidate for future clinical trials as nephroprotector in patients treated with cisplatin.