Abstract
Focal Adhesion Kinase (FAK) and Src have been reported to regulate tumor growth, invasion, metastasis and angiogenesis. The present study aimed to evaluate by immunohistochemistry the clinical significance of FAK and Src expression in 108 patients with benign and malignant thyroid lesions. Total FAK expression provided a distinct discrimination between malignant and benign (p = 0.00001), as well as between papillary carcinoma and hyperplastic nodules thyroid lesions (p = 0.00005), being also associated with follicular cells’ proliferative capacity (p = 0.0003). In malignant thyroid lesions, total FAK expression was associated with tumor size (p = 0.0455), and presence of capsular (p = 0.0102) and lymphatic (p = 0.0173) invasion. Total Src expression was borderline increased in cases of papillary carcinoma compared to hyperplastic nodules (p = 0.0993), being also correlated with tumor size (p = 0.0169). FAK and Src expression was ascribed to a significant extent to the phosphorylated forms of the enzymes, which provided a better discrimination between malignant and benign thyroid lesions. The current data revealed that FAK and to a lesser extent Src expression could be considered of clinical utility in thyroid neoplasia with potential use as therapeutic targets.
Similar content being viewed by others
References
Lipfert L, Haimovich B, Schaller MD et al (1992) Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp 125FAK in platelets. J Cell Biol 119:905–912
Zachary I, Sinnett-Smith J, Rozengurt E (1992) Bombesin, vasopressin, and endothelin stimulation of tyrosine phosphorylation in Swiss 3T3 cells. Identification of a novel tyrosine kinase as a major substrate. J Biol Chem 267:19031–19034
Ilic D, Furuta Y, Kanazawa S et al (1995) Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377:539–544
Cary LA, Chang JF, Guan JL (1991) Stimulation of cell migration by overexpression of focal adhesion kinase and its association with Src and Fyn. J Cell Sci 109:1787–17894
Li S, Kim M, Hu YL et al (1997) Fluid shear stress activation of focal adhesion kinase. Linking to mitogen-activated protein kinases. J Biol Chem 272:30455–30462
Xing Z, Chen HC, Nowlen JK et al (1994) Direct interaction of v-Src with the focal adhesion kinase mediated by the Src SH2 domain. Mol Biol Cell 5:413–421
Rahimi N, Hung W, Tremblay E et al (1998) c-Src kinase activity is required for hepatocyte growth factor-induced motility and anchorage-independent growth of mammary carcinoma cells. J Biol Chem 273:33714–33721
Zachary I (1997) Focal adhesion kinase. Int J Biochem Cell Biol 29:929–934
Cary LA, Guan JL (1999) Focal adhesion kinase in integrin-mediated signaling. Front Biosci 4:D102–D113
Schlaepfer DD, Hauck CR, Stieg DJ (1999) Signaling through focal adhesion kinase. Prog Biophys Mol Biol 71:435–478
Cox BD, Natarajan M, Stettner MR et al (2006) New concepts regarding focal adhesion kinase promotion of cell migration and proliferation. J Cell Biochem 99:35–52
Laird AD, Cherrington JM (2003) Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents. Expert Opin Investig Drugs 12:51–64
Chatzizacharias NA, Kouraklis GP, Theocharis SE (2007) Focal adhesion kinase: a promising target for anticancer therapy. Expert Opin Ther Targets 11:1315–1328
Talamonti MS, Roh MS, Curley SA et al (1993) Increase in activity and level of pp 60c-src in progressive stages of human colorectal cancer. J Clin Invest 91:53–60
Lutz MP, Esser IB, Flossmann-Kast BB et al (1998) Overexpression and activation of the tyrosine kinase Src in human pancreatic carcinoma. Biochem Biophys Res Commun 243:503–508
Verbeek BS, Vroom TM, Adriaansen-Slot SS et al (1996) c-Src protein expression is increased in human breast cancer. An immunohistochemical and biochemical analysis. J Pathol 180:383–388
Ito H, Gardner-Thorpe J, Zinner MJ et al (2003) Inhibition of tyrosine kinase Src suppresses pancreatic cancer invasiveness. Surgery 134:221–226
Myoui A, Nishimura R, Williams PJ et al (2003) C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Cancer Res 63:5028–5033
Duxbury MS, Ito H, Zinner MJ et al (2004) Inhibition of SRC tyrosine kinase impairs inherent and acquired gemcitabine resistance in human pancreatic adenocarcinoma cells. Clin Cancer Res 10:2307–2318
Chatzizacharias NA, Kouraklis GP, Theocharis SE (2008) Clinical significance of FAK expression in human neoplasia. Histol Histopathol 23:629–650
Gharib H, Papini E (2007) Thyroid nodules: clinical importance, assessment, and treatment. Endocrinol Metab Clin N Am 36:707–735
Gharib H, Papini E, Paschke R (2008) Thyroid nodules: a review of current guidelines, practices, and prospects. Eur J Endocrinol 159:493–505
Roberts SS, Mendonça-Torres MC, Jensen K, Francis GL, Vasko V (2009) GABA receptor expression in benign and malignant thyroid tumors. Pathol Oncol Res. doi:10.1007/s12253-009-9165-x
Ersoz S, Sert H, Yandi M, Erem C, Mungan S, Ersoz HO, Cobanoglu U, Hacihasanoglu A (2009) The significance of galectin-3 expression in the immunocytochemical evaluation of thyroid fine needle aspiration cytology. Pathol Oncol Res. doi:10.1007/s12253-008-9041-0
Fisher DA (2007) Thyroid function and dysfunction in premature infants. Pediatr Endocrinol Rev 4:317–328
Owens LV, Xu L, Dent GA et al (1996) Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer. Ann Surg Oncol 3:100–105
Kim SJ, Park JW, Yoon JS et al (2004) Increased expression of focal adhesion kinase in thyroid cancer: immunohistochemical study. J Korean Med Sci 19:710–715
Rothhut B, Ghoneim C, Antonicelli F et al (2007) Epidermal growth factor stimulates matrix metalloproteinase-9 expression and invasion in human follicular thyroid carcinoma cells through Focal adhesion kinase. Biochimie 89:613–624
Rosai J (2004) Appendix C. Staging of cancer. In: Houston M (ed) Rosai and Ackerman’s surgical pathology, 9th edn. London, Mosby, pp 2809–2810
Giaginis CT, Vgenopoulou S, Tsourouflis GS et al (2009) Expression and clinical significance of focal adhesion kinase in the two distinct histological types, intestinal and diffuse, of human gastric adenocarcinoma. Pathol Oncol Res. doi:10.1007/s12253-008-9120-2
Giaginis CT, Zarros AC, Papaefthymiou MA et al (2008) Clinical significance of tumor-associated antigen RCAS1 expression in human pancreatic ductal adenocarcinoma. Dig Dis Sci 53:1728–1734
Giaginis C, Zarros A, Alexandrou P et al (2009) Evaluation of Coxsackievirus and Adenovirus Receptor (CAR) expression in human benign and malignant thyroid lesions. AMPIS Accepted
Finn RS (2008) Targeting Src in breast. Ann Oncol 19:1379–1386
Han EK, McGonigal T (2007) Role of focal adhesion kinase in human cancer: a potential target for drug discovery. Anticancer Agents Med Chem 7:681–684
Chatzizacharias NA, Kouraklis G, Theocharis S (2008) Disruption of FAK signaling: a side mechanism in cytotoxicity. Toxicology 245:1–10
Cao X, You QD, Li ZY et al (2008) Recent progress of SRC family kinase inhibitors as anticancer agents. Mini Rev Med Chem 8:1053–1063
Miyaki T, Kato H, Nakajima M et al (2003) FAK overexpression is correlated with tumor invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma. Br J Cancer 89:140–145
Lark AL, Livasy CA, Dressler L et al (2005) High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype. Mod Pathol 18:1289–1294
Aguirre Ghiso JA (2002) Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo. Oncogene 21:2513–2524
Furuyama K, Ryuchiro D, Tomohiko M et al (2006) Clinical significance of focal adhesion kinase in resectable pancreatic cancer. World J Surg 30:219–226
Fuji T, Koshikawa K, Nomoto S et al (2004) Focal adhesion kinase is overexpressed in hepatocellular carcinoma and can be served as an independent prognostic factor. J Hepatol 41:104–111
Ohta R, Yamashita Y, Taketomi A et al (2006) Reduced expression of focal adhesion kinase in intrahepatic cholangiocarcinoma is associated with poor tumor differentiation. Oncology 71:417–422
Carelli S, Zadra G, Vaira V et al (2006) Up-regulation of focal adhesion kinase in non-small cell lung cancer. Lung Cancer 53:263–271
Wang D, Grammer JR, Cobbs CS et al (2000) p125 Focal adhesion kinase promotes malignant astrocytoma cell proliferation in vitro. J Cell Sci 113:4221–4230
Gabarra-Niecko V, Schaller MD, Dunty JM (2003) FAK regulates biological processes important for the pathogenesis of cancer. Cancer Metastasis Rev 22:359–374
Sood AK, Coffin JE, Schneider GB et al (2004) Biological significance of focal adhesion kinase in ovarian cancer: role in migration and invasion. Am J Pathol 165:1087–1095
Yu HG, Tong SL, Ding YM et al (2006) Enhanced expression of cholecystokinin-2 receptor promotes the progression of colon cancer through activation of focal adhesion kinase. Int J Cancer 119:2724–2732
Ito Y, Kawakatsu H, Takeda T et al (2002) Activation of c-Src is inversely correlated with biological aggressiveness of breast carcinoma. Breast Cancer Res Treat 76:261–267
Ito Y, Kawakatsu H, Takeda T et al (2001) Activation of c-Src gene product in hepatocellular carcinoma is highly correlated with the indices of early stage phenotype. J Hepatol 35:68–73
Conflict of interest statement
We declare that we have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
Christina Michailidi and Costas Giaginis contributed equally.
Rights and permissions
About this article
Cite this article
Michailidi, C., Giaginis, C., Stolakis, V. et al. Evaluation of FAK and Src Expression in Human Benign and Malignant Thyroid Lesions. Pathol. Oncol. Res. 16, 497–507 (2010). https://doi.org/10.1007/s12253-010-9269-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12253-010-9269-3