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Published on: November 5, 2019
pS6 Expression in normal renal parenchyma, primary renal cell carcinomas and their metastases
Martina Hager1, Heike Haufe, Beate Alinger
1Department of Pathology, Paracelsus Medical University (PMU), Muellner Hauptstrasse 48, 5020, Salzburg, Austria. hager.martina@gmx.at
Abstract:
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.
Insights
Phosphorylated S6 protein (pS6) is overexpressed in renal cell carcinoma metastases compared to primary tumors. This finding is significant for targeted therapy, as high pS6 expression may indicate sensitivity to mammalian target of rapamycin (mTOR) inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Novel cancer therapies increasingly target the phosphoinositide-3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) pathway.
- Overexpression of phosphorylated S6 protein (pS6), a component of the 40S ribosomal subunit, has been linked to sensitivity to mTOR inhibitors.
Purpose of the Study:
- To investigate the expression levels of pS6 and phosphorylated mTOR (pmTOR) in normal renal parenchyma (NRP), primary renal cell carcinomas (PRCCs), and their corresponding metastases.
- To determine if pS6 expression differs between localized and metastasized PRCCs and normal tissue.
- To explore the clinical significance of pS6 overexpression in renal cell carcinoma progression and patient survival.
Main Methods:
- Immunohistochemical analysis of pS6 and pmTOR expression using a tissue microarray (TMA).
- Analysis included samples from localized PRCC (lPRCC, n=35), metastasized PRCC (mPRCC, n=45), their metastases (n=45), and NRP (n=45).
- Statistical analysis was performed to compare expression levels and correlate them with tumor characteristics and patient outcomes.
Main Results:
- pS6 expression was significantly higher in mPRCCs and metastases compared to NRP and lPRCCs (p<0.05).
- Higher pS6 levels were observed in high-grade and high-stage mPRCCs.
- pS6 overexpression was more frequent in metastases (88.9%) than in mPRCCs (53.3%) (p<0.05).
- Approximately 35.56% of cases showed pS6 overexpression exclusively in metastases.
- A trend towards shorter overall survival was noted in patients with pS6 overexpression in both mPRCCs and metastases.
- pS6 and pmTOR scores showed a positive correlation in both NRP and tumor tissues.
Conclusions:
- Metastases exhibit stronger pS6 expression and more frequent overexpression compared to their primary tumors.
- The exclusive overexpression of pS6 in metastases in a significant subset of patients is noteworthy for mTOR inhibitor therapy.
- These findings highlight the potential of pS6 as a biomarker for predicting response to mTOR-targeted therapies in advanced renal cell carcinoma.
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