Abstract
Background
The up regulation of Phospho-Src family kinase oncogene has been correlated with reduced post-operative survival in various cancers but never in tongue cancer.
Methods
We analyzed phospho-Src family kinase in 39 tongue (mobile) cancer patients by immunohistochemistry, compared these results with similar analysis for TUNEL and c-erbB-2 and with both clinical tumor characteristics and patient survival probability rates.
Results
Phospho-Src family kinase overexpression was found in most tongue cancer biopsies (62%), significantly correlating with tumors larger in size (P = 0.05), progression—lymph node metastasis (0.004) and stage (P = 0.05), and correlating with TUNEL (P = 0.01) and c-erbB-2 (P = 0.05) expression rates. At 60 months, survival probability for negative phospho-Src family kinase level (=0) patients was 67%, but 30% for positive phospho-Src family kinase level (>0) patients (P = 0.05).
Conclusions
Inverse correlation between phospho-Src family kinase and patient survival demonstrates the prognostic role of phospho-Src family kinase in tongue cancer. These findings suggest a novel link between phospho-Src family kinase and TUNEL and c-erbB-2 pathways, tilting the balance toward cell proliferation.
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References
Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T (1986) The product of the human C-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. Science 232:1644–1646. doi:10.1126/science.3012781
Alho OP, Kantola S, Pirkola U, Laara E, Jokinen K, Pukkala E (1999) Cancer of the mobile tongue in Finland—increasing incidence, but improved survival. Acta Oncol 38:1021–1024. doi:10.1080/028418699432293
Alper O, Bowden ET (2005) Novel insights into c-Src. Curr Pharm Des 11:1119–1130. doi:10.2174/1381612053507576
Alvarez RH, Kantarjian HM, Cortes JE (2006) The role of Src in solid and hematologic malignancies: development of new-generation Src inhibitors. Cancer 107:1918–1929. doi:10.1002/cncr.22215
Bahar G, Feinmesser R, Shpitzer T, Popovtzer A, Nagler RM (2007) Salivary analysis in oral cancer patients: DNA and protein oxidation, reactive nitrogen species and antioxidant profile. Cancer 101:54–59. doi:10.1002/cncr.22386
Ben-Izhak O, Kablan F, Laster Z, Nagler RM (2005) Oropharyngeal cancer pathogenesis: ubiquitin proteolytic, apoptotic and epidermal growth factor related pathways act in concert—first report. Oral Oncol 41:851–860. doi:10.1016/j.oraloncology.2005.04.012
Ben-Izhak O, Kaplan-Cohen V, Ilan N, Gan S, Vlodavsky I, Nagler R (2006) Heparanase expression in malignant salivary gland tumors inversely correlates with long-term survival. Neoplasia 8:879–884. doi:10.1593/neo.06382
Ben-Izhak O, Laster Z, Araidy S, Nagler RM (2007) TUNEL—an efficient prognosis predictor of salivary malignancies. Br J Cancer 96:1101–1106. doi:10.1038/sj.bjc.6603655
Chong YP, Ia KK, Mulhern TD, Cheng HC (2005) Endogenous and synthetic inhibitors of the Src-family protein tyrosine kinases. Biochim Biophys Acta 1754:210–220
Conway WC, Van der Voort van Zyp J, Thamilselvan V, Walsh MF, Crowe DL, Basson MD (2006) Paxillin modulates squamous cancer cell adhesion and is important in pressure-augmented adhesion. J Cell Biochem 98:1507–1516. doi:10.1002/jcb.20819
Dehm SM, Bonham K (2004) SRC gene expression in human cancer: the role of transcriptional activation. Biochem Cell Biol 82:263–274. doi:10.1139/o03-077
Ducker CE, Upson JJ, French KJ, Smith CD (2005) Two N-myristoyltransferase isozymes play unique roles in protein myristoylation, proliferation and apoptosis. Mol Cancer Res 3:463–476. doi:10.1158/1541-7786.MCR-05-0037
Finlay CA, Hinds PW, Tan TH, Eliyahu D, Oren M, Levine AJ (1988) Activating mutations for transformation by p53 produce a gene product that forms an HSC70–p53 complex with an altered half-life. Mol Cell Biol 8:531–539
Fukuda S, Kaga S, Sasaki H, Zhan L, Zhu L, Otani H, Kalfin R, Das DK, Maulik N (2004) Angiogenic signal triggered by ischemic stress induces myocardial repair in rat during chronic infarction. J Mol Cell Cardiol 36:547–549. doi:10.1016/j.yjmcc.2004.02.002
Grasl-Kraupp B, Ruttkay-Nedecky B, Koudelka H, Bukowska K, Bursch W, Schulte-Hermann R (1995) In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology 21:1465–1469
Hakam A, Fang Q, Karl R, Coppola D (2003) Coexpression of IGF-1R and c-Src proteins in human pancreatic ductal adenocarcinoma. Dig Dis Sci 48:1972–1978. doi:10.1023/A:1026122421369
Hanna W, Kahn HJ, Trudeau M (1999) Evaluation of HER-2/neu (erbB-2) status in breast cancer: from bench to bedside. Mod Pathol 12:827–834
Ishizawar R, Parsons SJ (2004) C-Src and cooperating partners in human cancer. Cancer Cell 6:209–214. doi:10.1016/j.ccr.2004.09.001
Jackson MS, Wrench AA, Soutar DS, Robertson AG (1999) Carcinoma of the tongue: the speech therapist’s perspective. Br J Oral Maxillofac Surg 37:200–204. doi:10.1054/bjom.1999.0032
Kantola S, Parikka M, Jokinen K, Hyrynkangs K, Soini Y, Alho OP, Salo T (2000) Prognostic factors in tongue cancer—relative importance of demographic, clinical and histopathological factors. Br J Cancer 83:614–619. doi:10.1054/bjoc.2000.1323
Kim H, Chan R, Dankort DL, Zuo D, Najoukas M, Park M, Muller WJ (2005) The c-Src tyrosine kinase associates with the catalytic domain of ErbB-2: implications for ErbB-2 mediated signaling and transformation. Oncogene 24:7599–7607. doi:10.1038/sj.onc.1208898
Martin GS (2004) The road to Src. Oncogene 23:7910–7917. doi:10.1038/sj.onc.1208077
McCarty MF, Block KI (2005) Multifocal angiostatic therapy: an update. Integr Cancer Ther 4:301–314. doi:10.1177/1534735405282475
Muir C, Weiland L (1995) Upper aerodigestive tract cancers. Cancer 75:147–153. doi:10.1002/1097-0142(19950101)75:1+<147::AID-CNCR2820751304>3.0.CO;2-U
Myers JN, Elkins T, Roberts D, Byers RM (2000) Squamous cell carcinoma of the tongue in young adults: increasing incidence and factors that predict treatment outcomes. Otolaryngol Head Neck Surg 122:44–51. doi:10.1016/S0194-5998(00)70142-2
Nagler RM, Barak M, Ben-Aryeh H, Peled M, Filatov M, Laufer D (1999) Early diagnostic and treatment monitoring role of Cyfra 21–1 and TPS in oral squamous cell carcinoma. Cancer 35:1018–1025. doi:10.1002/(SICI)1097-0142(19990301)85:5<1018::AID-CNCR2>3.0.CO;2-R
Nagler RM, Kerner H, Ben-Eliezer S, Minkov I, Ben-Itzhak O (2003) Prognostic role of apoptotic, Bcl-2, c-erbB-2 and p53 tumor markers in salivary gland malignancies. Oncology 64:389–398. doi:10.1159/000070298
Nagler R, Bahar G, Shpitzer T, Feinmesser R (2006) Concomitant analysis of salivary tumor markers—a new diagnostic tool for oral cancer. Clin Cancer Res 12:3979–3984. doi:10.1158/1078-0432.CCR-05-2412
Nagler R, Ben-Izhak O, Cohen-Kaplan V, Shafat I, Vlodavsky I, Akrish S, Ilan N (2007) Heparanase up-regulation in tongue cancer: tissue and saliva analysis. Cancer 110:2732–2739. doi:10.1002/cncr.23095
Nestor M, Ekberg T, Dring J, van Dongen GA, Wester K, Tolmachev V, Anniko M (2007) Quantification of CD44v6 and EGFR expression in head and neck squamous cell carcinomas using a single-dose radioimmunoassay. Tumour Biol 28:253–263. doi:10.1159/000110898
Quenel N, Wafflart J, Bonichon F, de Mascarel I, Trojani M, Durand M, Avril A, Coindre JM (1995) The prognostic value of C-erbB-2 in primary breast carcinoma: a study of 942 cases. Breast Cancer Res Treat 35:283–291. doi:10.1007/BF00665980
Ribeiro KC, Kowalski LP, Latorre MR (2000) Impact of comorbidity, symptoms, and patients’ characteristics on the prognosis of oral carcinomas. Arch Otolaryngol Head Neck Surg 126:1079–1085
Shpitzer T, Bahar G, Feinmesser R, Nagler RM (2007) A comprehensive salivary analysis for oral cancer diagnosis. J Cancer Res Clin Oncol 133:613–617. doi:10.1007/s00432-007-0207-z
Tamura I, Sakaki T, Chaqour B, Howard PS, Ikeo T, Macarak EJ (2003) Correlation of P-cadherin and beta-catenin expression and phosphorylation with carcinogenesis in rat tongue cancer induced with 4-nitroquinoline 1-oxide. Oral Oncol 39:506–514. doi:10.1016/S1368-8375(03)00013-7
Vadlamudi RK, Sahin AA, Adam L, Wang RA, Kumar R (2003) Heregulin and HER2 signaling selectively activates c-Src phosphorylation at tyrosine 215. FEBS Lett 543(1–3):76–80. doi:10.1016/S0014-5793(03)00404-6
Warmuth M, Damoiseaux R, Liu Y, Fabbro D, Gray N (2003) SRC family kinases: potential targets for the treatment of human cancer and leukemia. Curr Pharm Des 9:2043–2059. doi:10.2174/1381612033454126
Wilson GR, Cramer A, Welman A, Knox F, Swindell R, Kawakatsu H, Clarke RB, Dive C, Bundred NJ (2006) Activated c-SRC in ductal carcinoma in situ correlates with high tumour grade, high proliferation and HER2 positivity. Br J Cancer 95:1410–1414. doi:10.1038/sj.bjc.6603444
Wood JM, Bold G, Buchdunger E, Cozens R, Ferrari S, Frei J, Hofmann F, Mestan J, Mett H, O’Reilly T, Persohn E, Rosel J, Schnell C, Stover D, Theuer A, Towbin H, Wenger F, Woods-Cook K, Menrad A, Siemeister G, Schirner M, Thierauch KH, Schneider MR, Drevs J, Martiny-Baron G, Totzke F (2000) PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 60:2178–2189
Wyllie AH, Bellamy CO, Bubb VJ, Clarke AR, Corbet S, Curtis L, Harrison DJ, Hooper ML, Toft N, Webb S, Bird CC (1999) Apoptosis and carcinogenesis. Br J Cancer 80(Suppl 1):34–37
Yeole BB, Sankaranarayanan R, Sunny M, Sc L, Swaminathan R, Parkin DM (2000) Survival from head and neck cancer in Mumbai (Bombay), India. Cancer 89:437–444. doi:10.1002/1097-0142(20000715)89:2<437::AID-CNCR32>3.0.CO;2-R
Zetser A, Bashenko Y, Edovitsky E, Levy-Adam F, Vlodavsky I, Ilan N (2006) Heparanase induces vascular endothelial growth factor expression: correlation with p38 phosphorylation levels and Src activation. Cancer Res 66:1455–1463. doi:10.1158/0008-5472.CAN-05-1811
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The authors thank Mrs S. Gan for her assistance in statistical analysis.
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Ben-Izhak, O., Cohen-Kaplan, V. & Nagler, R.M. The prognostic role of phospho-Src family kinase analysis in tongue cancer. J Cancer Res Clin Oncol 136, 27–34 (2010). https://doi.org/10.1007/s00432-009-0633-1
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DOI: https://doi.org/10.1007/s00432-009-0633-1