Advertisement

Clinical & Experimental Metastasis

, Volume 27, Issue 8, pp 611–617 | Cite as

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

  • Martina HagerEmail author
  • Heike Haufe
  • Lukas Lusuardi
  • Nikolaus Schmeller
  • Christian Kolbitsch
Research Paper

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.

Keywords

Metastases Overexpression p-AKT Renal cell carcinoma 

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

Notes

Acknowledgment

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

References

  1. 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 356:2271–2281CrossRefPubMedGoogle Scholar
  2. 2.
    Kapoor A, Figlin RA (2009) Targeted inhibition of mammalian target of rapamycin for the treatment of advanced renal cell carcinoma. Cancer 115:3618–3630CrossRefPubMedGoogle Scholar
  3. 3.
    Merseburger AS, Kuczyk MA (2008) Value of targeted therapies for renal cell cancer. Urologe A 47:1303–1310CrossRefPubMedGoogle Scholar
  4. 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 5:379–385CrossRefPubMedGoogle Scholar
  5. 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 182:2569–2577CrossRefGoogle Scholar
  6. 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 16:928–933CrossRefPubMedGoogle Scholar
  7. 7.
    Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927CrossRefPubMedGoogle Scholar
  8. 8.
    Downward J (2004) PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol 15:177–182CrossRefPubMedGoogle Scholar
  9. 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 96:4240–4245CrossRefPubMedGoogle Scholar
  10. 10.
    Liang J, Slingerland JM (2003) Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2:339–345PubMedGoogle Scholar
  11. 11.
    Manning BD, Cantley LC (2003) Rheb fills a GAP between TSC and TOR. Trends Biochem Sci 28:573–576CrossRefPubMedGoogle Scholar
  12. 12.
    Morgensztern D, McLeod HL (2005) PI3K/Akt/mTOR pathway as a target for cancer therapy. Anticancer Drugs 16:797–803CrossRefPubMedGoogle Scholar
  13. 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 10:6865–6871CrossRefPubMedGoogle Scholar
  14. 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 13:2181–2188CrossRefPubMedGoogle Scholar
  15. 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 169:710–713CrossRefPubMedGoogle Scholar
  16. 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 98:2853–2855CrossRefPubMedGoogle Scholar
  17. 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 64:5232–5236CrossRefPubMedGoogle Scholar
  18. 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 104:2430–2436CrossRefPubMedGoogle Scholar
  19. 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 61:6105–6111PubMedGoogle Scholar
  20. 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–R44CrossRefPubMedGoogle Scholar
  21. 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 12:3070–3077CrossRefPubMedGoogle Scholar
  22. 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 14:389–392PubMedGoogle Scholar
  23. 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 10:2846–2850CrossRefPubMedGoogle Scholar
  24. 24.
    Fuhrman SA, Lasky LC, Limas C (1982) Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 6:655–663CrossRefPubMedGoogle Scholar
  25. 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, LyonGoogle Scholar
  26. 26.
    Park JY, Lin PY, Weiss RH (2007) Targeting the PI3K-Akt pathway in kidney cancer. Expert Rev Anticancer Ther 7:863–870CrossRefPubMedGoogle Scholar
  27. 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 1772:1134–1142PubMedGoogle Scholar
  28. 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 372:449–456CrossRefPubMedGoogle Scholar
  29. 29.
    Patel PH, Chadalavada RS, Chaganti RS, Motzer RJ (2006) Targeting von Hippel-Lindau pathway in renal cell carcinoma. Clin Cancer Res 12:7215–7220CrossRefPubMedGoogle Scholar
  30. 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 112:2352–2358CrossRefPubMedGoogle Scholar
  31. 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 26:2255–2262CrossRefPubMedGoogle Scholar
  32. 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 10:1013–1023CrossRefPubMedGoogle Scholar
  33. 33.
    Huang WC, Hung MC (2009) Induction of Akt activity by chemotherapy confers acquired resistance. J Formos Med Assoc 108:180–194CrossRefPubMedGoogle Scholar
  34. 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 12:2035–2039PubMedGoogle Scholar
  35. 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 26:1603–1610CrossRefPubMedGoogle Scholar
  36. 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 32:1822–1834CrossRefPubMedGoogle Scholar
  37. 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 11:71–77CrossRefPubMedGoogle Scholar
  38. 38.
    Breau RH, Blute ML (2010) Surgery for renal cell carcinoma metastases. Curr Opin Urol 20:375–381CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Martina Hager
    • 1
    Email author
  • Heike Haufe
    • 1
  • Lukas Lusuardi
    • 2
  • Nikolaus Schmeller
    • 3
  • Christian Kolbitsch
    • 4
  1. 1.Department of PathologyParacelsus Medical University (PMU)SalzburgAustria
  2. 2.Department of UrologyParacelsus Medical University (PMU)SalzburgAustria
  3. 3.Department of UrologyHospital of Barmherzige BrüderSalzburgAustria
  4. 4.Department of Anaesthesiology and Intensive Care MedicineInnsbruck Medical University (MUI)InnsbruckAustria

Personalised recommendations