pS6 Expression in Normal Renal Parenchyma, Primary Renal Cell Carcinomas and their Metastases

In cancer therapy novel concepts focus on phosphoinositide-3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) inhibitors. In this context, phosphorylated S6 protein of the 40S ribosomal subunit (pS6) overexpression was previously shown to be associated with sensitivity to inhibitors of mTOR. The present study therefore evaluated pS6 expression in normal renal parenchyma (NRP), primary renal cell carcinomas (PRCC) and their metastases. pS6 and pmTOR expression was immunohistochemically analyzed in a tissue microarray (TMA) from localized primary renal cell carcinoma (lPRCC) (n=35), metastasized primary renal cell carcinoma (mPRCC) (n=45), their metastases (n=45), and NRP (n=45). pS6 expression was stronger in mPRCCs and metastases than in NRP and lPRCCs (p<0.05). In mPRCCs high-grade and high-stage tumors showed higher pS6 levels. pS6 overexpression was more frequently found in metastases (40/45; 88.9%) than in mPRCC (24/45; 53.3%) (p<0.05). Overexpression of pS6 in metastases without concomitant overexpression in their primary tumors was found in 16/45 (35.56%) cases. Patients with pS6 overexpression in mPRCCs but also in metastases showed a tendency to shorter overall survival. pS6 score and pmTOR score correlated positively in NRP and in tumorous tissue (mPRCC and metastases). In conclusion, the present study showed stronger pS6 expression and more frequent overexpression in metastases than in corresponding PRCCs. In approximately one-third of the cases pS6 overexpression was found exclusively in metastases, which is interesting with regard to the association between high pS6 expression and sensitivity to mTOR inhibitor therapy.