Immunoexpression Status and Prognostic Value of mTOR and Hypoxia-Induced Pathway Members in Primary and Metastatic Clear Cell Renal Cell Carcinomas

Abstract

The need for effective targeted therapies for renal cell carcinomas (RCC) has fueled the interest for understanding molecular pathways involved in the oncogenesis of kidney tumors. Aiming to analyze the expression status and prognostic significance of mTOR and hypoxia-induced pathway members in patients with clear cell RCC (ccRCC) tissue microarrays were constructed from 135 primary and 41 metastatic ccRCC. Immunoexpression levels were compared and correlated with clinicopathologic parameters and outcome. PTEN levels were significantly lower in primary and metastatic ccRCC compared to benign tissues (P<0.001). Levels of phos-AKT, phos-S6, and 4EBP1 were higher in metastatic ccRCC (P≤0.001). For phos-S6 and 4EBP1, levels were higher in primary ccRCC compared to benign tissues (P<0.001). c-MYC levels were higher in metastatic ccRCC (P<0.0001) and incremental p27 levels were observed in benign, primary ccRCC, and metastatic ccRCC (P<0.0001). HIF-1α levels were significantly higher in primary and metastatic ccRCC compared to benign tissues (P<0.0001). In primary ccRCC, levels of all mTOR and hypoxia-induced pathway members were significantly associated with pT stage (P≤0.036), p27 levels with Fuhrman grade (P=0.031), and 4EBP1, p27, and HIF-1α levels with tumor size (P≤0.025). Tumor size, HIF-1α and phos-S6 levels were associated with disease-specific survival (P≤0.032) and tumor progression (P≤0.043). In conclusion, both mTOR and hypoxia-induced pathways were activated in primary and metastatic ccRCC. PTEN loss seems to be an early event during tumorigenesis. Tumor size, HIF-1α and phos-S6 expression were found to be independent predictors of both DSS and tumor progression in primary ccRCC.

Sperm-Associated Antigen 4, a Novel Hypoxia-Inducible Factor 1 Target, Regulates Cytokinesis, and Its Expression Correlates with the Prognosis of Renal Cell Carcinoma

“…In ccRCC, carbonic anhydrase 9 (CA9) is one of the most studied and most promising biomarkers. 51 Patients with low CA9 expression were reported to have worse prognosis; in metastatic disease, high CA9 expression was associated with better survival. 51 SPAG4 could be a clinically useful biomarker in combination with other biomarkers, such as CA9.…”

Glycoprotein non-metastatic melanoma protein B as a predictive prognostic factor in clear-cell renal cell carcinoma following radical nephrectomy

“…Mutant p53 expression was also significantly higher in metastatic tumors compared with primary tumors (51.8% vs. 22.8%) in a study by Zigeuner et al (21), and p53 overexpression (risk ratio, 2.9; 95% confidence interval, 1.3-6.7; P=0.01) was revealed to be an independent prognostic factor for metastasis-free survival, although the specimens were not matched. In a study of mammalian target of rapamycin-and hypoxia-induced pathway members, which included 135 primary RCCs and 41 unrelated metastases, differential global patterns of expression were measured (22). The levels of p-AKT, p-S6, 4EBP1 and c-myc were higher in metastatic lesions compared with primary tissues.…”

Constitutive Expression of HIF-α Plays a Major Role in Generation of Clear-cell Phenotype in Human Primary and Metastatic Renal Carcinoma

“…Furthermore, HIF-1α proved to be a prognostic marker for ccRCC . 16 Based on these current findings, it appears that HIF-1α is more important than HIF-2α in ccRCC, although HIF-2α is co-expressed frequently with HIF-1α and suggests its potential influence in ccRCC. In a recent xenograft study with human RCC cell lines, loss of HIF-2α expression impaired tumor growth , whereas loss of HIF-1α expression increased tumor growth.…”

“…The greater expression of HIF-1α in metastatic foci than in primary ccRCC is in agreement with a previous study in which levels of HIF-1α were higher in metastatic than in primary ccRCC. 16 The roles of HIF-1α and HIF-2α are not clearly distinct in ccRCC. In a previous transgenic study, stable expression of HIF-1α, but not HIF-2α, induced ccRCC in mice.…”