mTOR Signaling Pathway in Penile Squamous Cell Carcinoma: pmTOR and peIF4E Over Expression Correlate with Aggressive Tumor Behavior
2013; Lippincott Williams & Wilkins; Volume: 190; Issue: 6 Linguagem: Inglês
10.1016/j.juro.2013.06.015
ISSN1527-3792
AutoresCarla Ferrándiz‐Pulido, Emili Masferrer, Agustí Toll, Javier Hernández‐Losa, Sergi Mojal, Ramón M. Pujol, Santiago Ramón y Cajal, Inés de Torres, Vicente García‐Patos,
Tópico(s)Cancer Diagnosis and Treatment
ResumoNo AccessJournal of UrologyInvestigative Urology1 Dec 2013mTOR Signaling Pathway in Penile Squamous Cell Carcinoma: pmTOR and peIF4E Over Expression Correlate with Aggressive Tumor Behavior Carla Ferrandiz-Pulido, Emili Masferrer, Agustin Toll, Javier Hernandez-Losa, Sergio Mojal, Ramon M. Pujol, Santiago Ramon y Cajal, Ines de Torres, and Vicente Garcia-Patos Carla Ferrandiz-PulidoCarla Ferrandiz-Pulido Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain , Emili MasferrerEmili Masferrer Department of Dermatology, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain Department of Dermatology, Hospital del Mar-IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain , Agustin TollAgustin Toll Department of Dermatology, Hospital del Mar-IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain , Javier Hernandez-LosaJavier Hernandez-Losa Department of Pathology, Hospital Universitari Vall d'Hebron, Barcelona, Spain , Sergio MojalSergio Mojal Department of Statistics, Hospital del Mar-IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain , Ramon M. PujolRamon M. Pujol Department of Dermatology, Hospital del Mar-IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain , Santiago Ramon y CajalSantiago Ramon y Cajal Department of Pathology, Hospital Universitari Vall d'Hebron, Barcelona, Spain , Ines de TorresInes de Torres Department of Pathology, Hospital Universitari Vall d'Hebron, Barcelona, Spain , and Vicente Garcia-PatosVicente Garcia-Patos Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain View All Author Informationhttps://doi.org/10.1016/j.juro.2013.06.015AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Penile squamous cell carcinoma is a rare neoplasm associated with a high risk of metastasis and morbidity. There are limited data on the role of the mTOR signaling pathway in penile squamous cell carcinoma carcinogenesis and tumor maintenance. We assessed a possible role for mTOR signaling pathway activation as a potential predictive biomarker of outcome and a therapeutic target for penile cancer. Material and Methods: A cohort of 67 patients diagnosed with invasive penile squamous cell carcinoma from 1987 to 2010 who had known HPV status were selected for study. Tissue microarrays were constructed with 67 primary penile squamous cell carcinomas, matched normal tissues and 8 lymph node metastases. Immunohistochemical staining was performed for p53, pmTOR, pERK, p4E-BP1, eIF4E and peIF4E. Expression was evaluated using a semiquantitative H-score on a scale of 0 to 300. Results: Expression of pmTOR, p4E-BP1, eIF4E and peIF4E was increased in penile tumors compared with matched adjacent normal tissues, indicating activation of the mTOR signaling pathway in penile tumorigenesis. Over expression of pmTOR, peIF4E and p53 was significantly associated with lymph node disease. peIF4E and p53 also correlated with a poor outcome, including recurrence, metastasis or disease specific death. In contrast, pERK and p4E-BP1 were associated with lower pT stages. pmTOR and intense p53 expression was associated with HPV negative tumors. Conclusions: Activation of mTOR signaling may contribute to penile squamous cell carcinoma progression and aggressive behavior. Targeting mTOR or its downstream signaling targets, such as peIF4E, may be a valid therapeutic strategy. References 1 : Cancer of the penis. Crit Rev Oncol Hematol2005; 53: 165. Google Scholar 2 : Value of p16 (INK)4a in the pathology of invasive penile squamous cell carcinomas: a report of 202 cases. Am J Surg Pathol2011; 35: 253. Google Scholar 3 : Identification and genotyping of human papillomavirus in a Spanish cohort of penile squamous cell carcinomas: correlation with pathologic subtypes, p16(INK4a) expression, and prognosis. J Am Acad Dermatol2013; 68: 73. Google Scholar 4 : The role of pathologic prognostic factors in squamous cell carcinoma of the penis. World J Urol2009; 27: 169. Google Scholar 5 : The prognostic index: a useful pathologic guide for prediction of nodal metastases and survival in penile squamous cell carcinoma. Am J Surg Pathol2009; 33: 1049. Google Scholar 6 : p53 as a new prognostic factor for lymph node metastasis in penile carcinoma: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. J Urol2002; 168: 81. Link, Google Scholar 7 : Immunoexpression of p53 protein and proliferating cell nuclear antigen in penile carcinoma. J Urol2002; 167: 89. Link, Google Scholar 8 : The prognostic significance of p53, Ki-67, epithelial cadherin and matrix metalloproteinase-9 in penile squamous cell carcinoma treated with surgery. BJU Int2007; 100: 204. Google Scholar 9 : MYC copy number gains are associated with poor outcome in penile squamous cell carcinoma. J Urol2012; 188: 1965. Link, Google Scholar 10 : The mTOR signalling pathway in human cancer. Int J Mol Sci2012; 13: 1886. Google Scholar 11 : Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med2012; 367: 329. Google Scholar 12 : Decreased lymphangiogenesis and lymph node metastasis by mTOR inhibition in head and neck cancer. Cancer Res2011; 71: 7103. Google Scholar 13 : Morphoproteomic evidence of constitutively activated and overexpressed mTOR pathway in cervical squamous carcinoma and high grade squamous intraepithelial lesions. Int J Clin Exp Pathol2009; 2: 249. Google Scholar 14 : Alternative HER/PTEN/Akt pathway activation in HPV positive and negative penile carcinomas. PLoS One2011; 6: e175. Google Scholar 15 : EGFR overexpression in squamous cell carcinoma of the penis. Curr Oncol2010; 17: 4. Google Scholar 16 : PIK3CA, HRAS and KRAS gene mutations in human penile cancer. J Urol2008; 179: 2030. Link, Google Scholar 17 : Tissue microarrays for high-throughput molecular profiling of tumors specimens. Nat Med1998; 4: 844. Google Scholar 18 : Cell signaling in endometrial carcinoma: phosphorylated 4E-binding protein-1 expression in endometrial cancer correlates with aggressive tumors and prognosis. Hum Pathol2009; 40: 1418. Google Scholar 19 : Exploratory analysis of activation of PTEN-PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM). Lung Cancer2012; 77: 192. Google Scholar 20 : A "quickscore" method for immunohistochemical semiquantitation: validation for estrogen receptor in breast carcinomas. J Clin Pathol1995; 48: 876. Google Scholar 21 : Mutational spectra and immunohistochemical analyses of p53 in human cancers. Chest1992; 101: 19S. Google Scholar 22 : Therapeutic targets: MTOR and related pathways. Cancer Biol Ther2006; 5: 1065. Google Scholar 23 : Activation of ERK1/2 occurs independently of KRAS or BRAF status in endometrial cancer and is associated with favorable prognosis. Cancer Sci2007; 98: 652. Google Scholar 24 : Potential prognostic value of mitogen-activated protein kinase activity for disease-free survival of primary breast cancer patients. Int J Cancer2000; 89: 384. Google Scholar 25 : Mitogen-activated protein kinases (MAPK) as predictors of clinical outcome in serous ovarian carcinoma in effusions. Gynecol Oncol2003; 91: 160. Google Scholar 26 : eIF-4E expression and its role in malignancies and metastases. Oncogene2004; 23: 3189. Google Scholar 27 : Overexpression of phospho-eIF4E is associated with survival through AKT pathway in non-small cell lung cancer. Clin Cancer Res2010; 16: 240. Google Scholar 28 : eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression. Proc Natl Acad Sci U S A2010; 107: 14134. Google Scholar 29 : Protein phosphatase 2A negatively regulates eukaryotic initiation factor 4E phosphorylation and eIF4F assembly through direct dephosphorylation of Mnk and eIF4E. Neoplasia2010; 12: 848. Google Scholar 30 : Stabilization and functional impairment of the tumor suppressor p53 by the human papillomavirus type 16 E7 oncoprotein. Virology2002; 295: 74. Google Scholar © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byAndersson K (2018) This Month in Investigative UrologyJournal of Urology, VOL. 190, NO. 6, (1968-1969), Online publication date: 1-Dec-2013. Volume 190Issue 6December 2013Page: 2288-2295 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.Keywordspeniscarcinomasquamous cellbiological markersmTOR proteinhumanimmunohistochemistryAcknowledgmentsTania Lobato assisted with TMAs. Teresa Moliné assisted with immunohistochemistry. B. Lloveras, F. Xavier Bosch, Silvia de Sanjosé and Jo Ellen Klaustermeier from the RIS HPV TT and HPV VVAPO study groups from ICO assisted with HPV detection. Surgical treatment was provided by Jose Placer, Carlos Salvador and Juan Morote, Hospital Vall d'Hebron and Hospital del Mar. The Tumor Bank of Vall d'Hebron University Hospital Biobank provided half of the study samples.Metrics Author Information Carla Ferrandiz-Pulido Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain More articles by this author Emili Masferrer Department of Dermatology, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain Department of Dermatology, Hospital del Mar-IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain More articles by this author Agustin Toll Department of Dermatology, Hospital del Mar-IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain More articles by this author Javier Hernandez-Losa Department of Pathology, Hospital Universitari Vall d'Hebron, Barcelona, Spain More articles by this author Sergio Mojal Department of Statistics, Hospital del Mar-IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain More articles by this author Ramon M. Pujol Department of Dermatology, Hospital del Mar-IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain More articles by this author Santiago Ramon y Cajal Department of Pathology, Hospital Universitari Vall d'Hebron, Barcelona, Spain More articles by this author Ines de Torres Department of Pathology, Hospital Universitari Vall d'Hebron, Barcelona, Spain Equal study contribution. More articles by this author Vicente Garcia-Patos Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain Equal study contribution. More articles by this author Expand All Advertisement PDF downloadLoading ...
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