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p-AKT overexpression in primary renal cell carcinomas and their metastases

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Abstract

In cancer therapy novel concepts focus on phosphoinositide 3-kinase (PI3K)/activated protein kinase B (p-AKT)/mammalian target of rapamycin (mTOR) inhibitors. In this context, p-AKT overexpression was previously shown to be associated with sensitivity to inhibitors of mTOR. The present study evaluated p-AKT expression in a tissue microarray of primary renal cell carcinomas (PRCCs) (n = 45), their metastases (primary onset n = 45, secondary onset n = 5), and normal renal parenchyma (n = 45) by means of immunohistochemistry. Total p-AKT overexpression was found in 24/45 (53.3%) PRCCs, in 32/45 (71.1%) primary and in 3/5 (60%) secondary onset metastases. Membranous p-AKT overexpression was seen more frequently in PRCCs, namely 11/45 (24.4%), than in primary onset metastases 1/45 (2.2%). Overexpression of total p-AKT solely in metastases without overexpression in PRCC was exclusively demonstrated in primary onset metastases, namely in 28.9%. Patients with total p-AKT overexpression in primary carcinomas showed a trend to longer, and those with total p-AKT overexpression in metastases a tendency to shorter survival. In conclusion, the present study shows total p-AKT overexpression to be more frequent in metastases than in PRCCs. Total p-AKT overexpression in metastases without concomitant overexpression in their primary tumors was found in approximately one-third of primary onset metastases, which is interesting with regard to the association between high p-AKT expression and sensitivity to mTOR inhibitor therapy.

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Abbreviations

AKT:

Serine threonine kinase AKT, protein kinase B

p-AKT:

Activated serine/threonine kinase AKT, activated protein kinase B

PRCC:

Primary renal cell carcinoma

mTOR:

Mammalian target of rapamycin

TMA:

Tissue microarray

PI3K:

Phosphoinositide 3-kinase

IL2:

Interleukin-2

IFN:

Interferon alpha

References

  1. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt Wolf IG, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281

    Article  CAS  PubMed  Google Scholar 

  2. Kapoor A, Figlin RA (2009) Targeted inhibition of mammalian target of rapamycin for the treatment of advanced renal cell carcinoma. Cancer 115:3618–3630

    Article  CAS  PubMed  Google Scholar 

  3. Merseburger AS, Kuczyk MA (2008) Value of targeted therapies for renal cell cancer. Urologe A 47:1303–1310

    Article  CAS  PubMed  Google Scholar 

  4. Cho D, Signoretti S, Dabora S, Regan M, Seeley A, Mariotti M, Youmans A, Polivy A, Mandato L, McDermott D, Stanbridge E, Atkins M (2007) Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 5:379–385

    Article  CAS  PubMed  Google Scholar 

  5. Porta C, Figlin RA (2007) Phosphatidylinositol-3-kinase/Akt signaling pathway and kidney cancer, and the therapeutic potential of phosphatidylinositol-3-kinase/Akt inhibitors. J Urol 182:2569–2577

    Article  Google Scholar 

  6. Hara S, Oya M, Mizuno R, Horiguchi A, Marumo K, Murai M (2005) Akt activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor. Ann Oncol 16:928–933

    Article  CAS  PubMed  Google Scholar 

  7. Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927

    Article  CAS  PubMed  Google Scholar 

  8. Downward J (2004) PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol 15:177–182

    Article  CAS  PubMed  Google Scholar 

  9. Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96:4240–4245

    Article  CAS  PubMed  Google Scholar 

  10. Liang J, Slingerland JM (2003) Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2:339–345

    CAS  PubMed  Google Scholar 

  11. Manning BD, Cantley LC (2003) Rheb fills a GAP between TSC and TOR. Trends Biochem Sci 28:573–576

    Article  CAS  PubMed  Google Scholar 

  12. Morgensztern D, McLeod HL (2005) PI3K/Akt/mTOR pathway as a target for cancer therapy. Anticancer Drugs 16:797–803

    Article  CAS  PubMed  Google Scholar 

  13. David O, Jett J, LeBeau H, Dy G, Hughes J, Friedman M, Brody AR (2004) Phospho-Akt overexpression in non-small cell lung cancer confers significant stage-independent survival disadvantage. Clin Cancer Res 10:6865–6871

    Article  CAS  PubMed  Google Scholar 

  14. Hager M, Haufe H, Kemmerling R, Hitzl W, Mikuz G, Moser PL, Kolbitsch C (2009) Increased activated Akt expression in renal cell carcinomas and prognosis. J Cell Mol Med 13:2181–2188

    Article  PubMed  Google Scholar 

  15. Horiguchi A, Oya M, Uchida A, Marumo K, Murai M (2003) Elevated Akt activation and its impact on clinicopathological features of renal cell carcinoma. J Urol 169:710–713

    Article  CAS  PubMed  Google Scholar 

  16. Hsu J, Shi Y, Krajewski S, Renner S, Fisher M, Reed JC, Franke TF, Lichtenstein A (2001) The AKT kinase is activated in multiple myeloma tumor cells. Blood 98:2853–2855

    Article  CAS  PubMed  Google Scholar 

  17. Kreisberg JI, Malik SN, Prihoda TJ, Bedolla RG, Troyer DA, Kreisberg S, Ghosh PM (2004) Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res 64:5232–5236

    Article  CAS  PubMed  Google Scholar 

  18. Massarelli E, Liu DD, Lee JJ, El Naggar AK, Lo ML, Staibano S, De Placido S, Myers JN (2005) Akt activation correlates with adverse outcome in tongue cancer. Cancer 104:2430–2436

    Article  CAS  PubMed  Google Scholar 

  19. Ringel MD, Hayre N, Saito J, Saunier B, Schuppert F, Burch H, Bernet V, Burman KD, Kohn LD, Saji M (2001) Overexpression and overactivation of Akt in thyroid carcinoma. Cancer Res 61:6105–6111

    CAS  PubMed  Google Scholar 

  20. Stal O, Perez-Tenorio G, Akerberg L, Olsson B, Nordenskjold B, Skoog L, Rutqvist LE (2003) Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Res 5:R37–R44

    Article  CAS  PubMed  Google Scholar 

  21. Tomita Y, Morooka T, Hoshida Y, Zhang B, Qiu Y, Nakamichi I, Hamada K, Ueda T, Naka N, Kudawara I, Aozasa K (2006) Prognostic significance of activated AKT expression in soft-tissue sarcoma. Clin Cancer Res 12:3070–3077

    Article  CAS  PubMed  Google Scholar 

  22. Uegaki K, Kanamori Y, Kigawa J, Kawaguchi W, Kaneko R, Naniwa J, Takahashi M, Shimada M, Oishi T, Itamochi H, Terakawa N (2005) PTEN-positive and phosphorylated-Akt-negative expression is a predictor of survival for patients with advanced endometrial carcinoma. Oncol Rep 14:389–392

    CAS  PubMed  Google Scholar 

  23. Yamamoto S, Tomita Y, Hoshida Y, Morooka T, Nagano H, Dono K, Umeshita K, Sakon M, Ishikawa O, Ohigashi H, Nakamori S, Monden M, Aozasa K (2004) Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma. Clin Cancer Res 10:2846–2850

    Article  CAS  PubMed  Google Scholar 

  24. Fuhrman SA, Lasky LC, Limas C (1982) Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 6:655–663

    Article  CAS  PubMed  Google Scholar 

  25. Eble JN, Sauter G, Epstein JI, Sesterhenn A (2004) WHO classification of tumours. Tumors of the urinary system and male genital organs, IARC Press, Lyon

    Google Scholar 

  26. Park JY, Lin PY, Weiss RH (2007) Targeting the PI3K-Akt pathway in kidney cancer. Expert Rev Anticancer Ther 7:863–870

    Article  CAS  PubMed  Google Scholar 

  27. He L, Fan C, Gillis A, Feng X, Sanatani M, Hotte S, Kapoor A, Tang D (2007) Co-existence of high levels of the PTEN protein with enhanced Akt activation in renal cell carcinoma. Biochim Biophys Acta 1772:1134–1142

    CAS  PubMed  Google Scholar 

  28. Motzer RJ, Escudier B, Oudard S, Hutson T, Porta C, Bracarda S, Grünwald V, Thompson J, Figlin R, Hollaender N, Urbanowitz G, Berg W, Kay A, Lebwohl D, Ravaud A (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449–456

    Article  CAS  PubMed  Google Scholar 

  29. Patel PH, Chadalavada RS, Chaganti RS, Motzer RJ (2006) Targeting von Hippel-Lindau pathway in renal cell carcinoma. Clin Cancer Res 12:7215–7220

    Article  CAS  PubMed  Google Scholar 

  30. Akcakanat A, Sahin A, Shaye AN, Velasco MA, Meric-Bernstam F (2008) Comparison of Akt/mTOR signaling in primary breast tumors and matched distant metastases. Cancer 112:2352–2358

    Article  CAS  PubMed  Google Scholar 

  31. Frost P, Shi Y, Hoang B, Lichtenstein A (2007) AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells. Oncogene 26:2255–2262

    Article  CAS  PubMed  Google Scholar 

  32. Noh WC, Mondesire WH, Peng J, Jian W, Zhang H, Dong J, Mills GB, Hung MC, Meric Bernstam F (2004) Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res 10:1013–1023

    Article  CAS  PubMed  Google Scholar 

  33. Huang WC, Hung MC (2009) Induction of Akt activity by chemotherapy confers acquired resistance. J Formos Med Assoc 108:180–194

    Article  CAS  PubMed  Google Scholar 

  34. Pollock RE, Lang A, Luo J, El Naggar AK, Yu D (1996) Soft tissue sarcoma metastasis from clonal expansion of p53 mutated tumor cells. Oncogene 12:2035–2039

    CAS  PubMed  Google Scholar 

  35. Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, Martinelli E, Ramon y Cajal S, Jones S, Vidal L, Shand N, Macarulla T, Ramos F, Dimitrijevic S, Zoellner U, Tang P, Stumm M, Lane H, Lebwohl D, Baselga J (2008) Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 26:1603–1610

    Article  CAS  PubMed  Google Scholar 

  36. Amin MB, Paner GP, Alvarado-Cabrero I, Young A, Stricker HJ, Lyles RH, Moch H (2008) Chromophobe renal cell carcinoma: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 145 cases. Am J Surg Pathol 32:1822–1834

    Article  PubMed  Google Scholar 

  37. Beck SD, Manish I, Patel MI, Snyder ME, Kattan MW, Motzer RJ, Reuter VE, Russo P (2004) Effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma. Ann Surg Oncol 11:71–77

    Article  PubMed  Google Scholar 

  38. Breau RH, Blute ML (2010) Surgery for renal cell carcinoma metastases. Curr Opin Urol 20:375–381

    Article  PubMed  Google Scholar 

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Acknowledgment

The authors are indebted to Ms. Ines Brosch, Department of Pathology, Innsbruck Medical University (MUI), Austria.

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Authors and Affiliations

  1. Department of Pathology, Paracelsus Medical University (PMU), Salzburg, Austria

    Martina Hager & Heike Haufe

  2. Department of Urology, Paracelsus Medical University (PMU), Salzburg, Austria

    Lukas Lusuardi

  3. Department of Urology, Hospital of Barmherzige Brüder, Salzburg, Austria

    Nikolaus Schmeller

  4. Department of Anaesthesiology and Intensive Care Medicine, Innsbruck Medical University (MUI), Innsbruck, Austria

    Christian Kolbitsch

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  1. Martina Hager
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  2. Heike Haufe
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  5. Christian Kolbitsch
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Correspondence to Martina Hager.

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Hager, M., Haufe, H., Lusuardi, L. et al. p-AKT overexpression in primary renal cell carcinomas and their metastases. Clin Exp Metastasis 27, 611–617 (2010). https://doi.org/10.1007/s10585-010-9351-y

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  • DOI: https://doi.org/10.1007/s10585-010-9351-y

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