Immunoexpression status and prognostic value of mtor and hypoxia-induced pathway members in primary and metastatic clear cell renal cell carcinomas

Luciana Schultz, Alcides Chaux, Roula Albadine, Jessica Hicks, Jenny J. Kim, Angelo M. De Marzo, Mohamad E. Allaf, Michael A. Carducci, Ronald Rodriguez, Hans Joerg Hammers, Pedram Argani, Victor E. Reuter, George J. Netto

Research output: Contribution to journalArticle

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Abstract

The need for effective targeted therapies for renal cell carcinomas (RCCs) 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 ccRCCs. Immunoexpression levels were compared and correlated with clinicopathologic parameters and outcome. PTEN levels were significantly lower in primary and metastatic ccRCCs compared with benign tissues (P<0.001). Levels of phos-AKT, phos-S6, and 4E-binding protein-1 (4EBP1) were higher in metastatic ccRCC (P≤0.001). For phos-S6 and 4EBP1, levels were higher in primary ccRCC compared with 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 ccRCCs compared with 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 (DSS) (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.

Original languageEnglish (US)
Pages (from-to)1549-1556
Number of pages8
JournalAmerican Journal of Surgical Pathology
Volume35
Issue number10
DOIs
StatePublished - Oct 1 2011

Fingerprint

S 6
Neoplasms
Carrier Proteins
Renal Cell Carcinoma
Carcinogenesis
Clear-cell metastatic renal cell carcinoma
Hypoxia
Kidney
Survival
Therapeutics

Keywords

  • 4EBP1
  • AKT
  • c-MYC
  • clear cell renal cell carcinoma
  • HIF-1α
  • hypoxia-induced pathway
  • mammalian target of rapamycin pathway
  • p27
  • PTEN
  • S6

ASJC Scopus subject areas

  • Anatomy
  • Pathology and Forensic Medicine
  • Surgery

Cite this

Immunoexpression status and prognostic value of mtor and hypoxia-induced pathway members in primary and metastatic clear cell renal cell carcinomas. / Schultz, Luciana; Chaux, Alcides; Albadine, Roula; Hicks, Jessica; Kim, Jenny J.; De Marzo, Angelo M.; Allaf, Mohamad E.; Carducci, Michael A.; Rodriguez, Ronald; Hammers, Hans Joerg; Argani, Pedram; Reuter, Victor E.; Netto, George J.

In: American Journal of Surgical Pathology, Vol. 35, No. 10, 01.10.2011, p. 1549-1556.

Research output: Contribution to journalArticle

Schultz, L, Chaux, A, Albadine, R, Hicks, J, Kim, JJ, De Marzo, AM, Allaf, ME, Carducci, MA, Rodriguez, R, Hammers, HJ, Argani, P, Reuter, VE & Netto, GJ 2011, 'Immunoexpression status and prognostic value of mtor and hypoxia-induced pathway members in primary and metastatic clear cell renal cell carcinomas', American Journal of Surgical Pathology, vol. 35, no. 10, pp. 1549-1556. https://doi.org/10.1097/PAS.0b013e31822895e5
Schultz, Luciana ; Chaux, Alcides ; Albadine, Roula ; Hicks, Jessica ; Kim, Jenny J. ; De Marzo, Angelo M. ; Allaf, Mohamad E. ; Carducci, Michael A. ; Rodriguez, Ronald ; Hammers, Hans Joerg ; Argani, Pedram ; Reuter, Victor E. ; Netto, George J. / Immunoexpression status and prognostic value of mtor and hypoxia-induced pathway members in primary and metastatic clear cell renal cell carcinomas. In: American Journal of Surgical Pathology. 2011 ; Vol. 35, No. 10. pp. 1549-1556.
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