Search tips
Search criteria 


Logo of ijcepLink to Publisher's site
Int J Clin Exp Pathol. 2011; 4(8): 755–764.
Published online 2011 October 30.
PMCID: PMC3225787

Immunohistochemical expressions of fatty acid synthase and phosphorylated c-Met in thyroid carcinomas of follicular origin


Thyroid carcinoma is the most common endocrine malignancy and the first cause of death among endocrine cancers. Fatty acid synthase (FASN) and c-Met are overexpressed in many types of human cancers. Recent studies have suggested a functional interaction between FASN and c-Met. However, their roles in thyroid carcinomas have not been fully investigated. In this study, we evaluated the expressions of FASN and phosphorylated (p)-c-Met by using immunohistochemistry in thyroid carcinomas of follicular origin, from 32 patients. The adjacent non-neoplastic thyroid tissue was also evaluated for comparison. Immunoreactive intensity and extensiveness were semi-quantified. The overexpression of FASN was observed in a subset of papillary thyroid carcinomas (PTC) including the classical type and tall cell, follicular, trabecular/insular and diffuse sclerosing variants, a subset of follicular thyroid carcinomas (FTC), and the PTC and FTC components in anaplastic thyroid carcinomas (ATC). No overexpression was observed in the ATCs per se and the columnar cell, solid, and cribriform variants of PTCs. All Hürthle cell variant FTCs and non-neoplastic Hürthle cells demonstrated positive staining for FASN while the non-neoplastic follicular cells without Hürthle cell change were negative. An association in overexpression between FASN and p-c-Met was observed in the majority of carcinomas as well as in the non-neoplastic Hürthle cells. In conclusion, overexpressions of FASN and p-c-Met were observed in a subset of thyroid carcinomas of follicular origin, which may be of values for targeted therapy and predicting prognosis while the positive immunostaining for these immunomarkers may be nonspecific for Hürthle cell thyroid carcinomas.

Keywords: C-Met, fatty acid synthase, immunohistochemistry, thyroid carcinoma


Fatty acid synthase (FASN) and c-Met have been increasingly studied as potential therapeutic targets in human cancers; however, their roles in thyroid carcinomas have not been fully elucidated.

Human FASN is an enzyme catalyzing syntheses of fatty acids. Recently it has been further divided into two types: type I and type II. The type I FASN is a 270-kDa cytosolic enzyme, a key enzyme catalyzing the synthesis of long-chain saturated fatty acids [1-3]. The type II FASN produces the fatty acids that play important roles in the mitochondrial function [4].

Normally, free fatty acids come from diet and de novo synthesis catalyzed by Type I FASN in lipogenic tissues. The level of FASN expression in the non-neoplastic cells is low because the cells preferentially use circulating free fatty acids from diet. Recently, FASN has been rediscovered as a marker for cancers because the type I FASN has been shown to have oncogenic activity [5]. The expression of FASN in neoplas-tic cells is up-regulated by de novo synthesis via multiple steps including gene amplification, transcription, translation and post-translational modifications and confers growth and survival advantages in many types of cancers [6]. It has been demonstrated that the overexpression of FASN causes resistance to both chemotherapy and radiation therapy in human cancers [7, 8]. While the FASN overexpression has been studied in various human cancers, the role of FASN in thyroid cancers has not been fully investigated [9]. There are only two previous studies published in the literature including one study of papillary thyroid carcinoma and the other one using cultured anaplastic thyroid carcinoma cell lines [10, 11].

Recent studies have suggested a functional interaction between FASN and some receptor tyrosine kinases for the promotion of tumori-genesis in tumors [12, 13]. c-Met is one of the receptor tyrosine kinases that has been implicated in playing a major role in tumorigenesis. c -Met is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor (HGFR) [14, 15]. The c-Met protein (HGFR) possesses tyrosine-kinase activity and its activation triggers tumor growth, angiogenesis and tumor metastasis [16]. c-Met expression has been demonstrated in thyroid cancers [17-21, 22, 23]. Some of the studies also indicate that the c-Met activation implicates aggressive behaviors including tumor invasiveness, metastasis and chemoradioresistance in cultured human thyroid cancer stem cells and PTCs [19-21, 22]. However, to our knowledge, the association of c -Met with FASN in thyroid cancers has not been reported.

Several FASN inhibitors including some commonly used drugs for diabetics and weight loss have shown to induce significant anti-tumor activity in human breast, endometrial, prostate, ovary, colon and mesothelial malignant neoplasm cell lines and xenografts [24, 25]. The inhibition of FASN appears to selectively kill neoplastic cells with minimal side effects to non -neoplastic cells, which makes FASN a potential good therapeutic target [7, 26-31]. A variety of c -Met pathway antagonists with potential clinical applications have also been investigated, which include both monoclonal antibodies and small-molecule tyrosine kinase inhibitors [32]. Therefore, it becomes more desirable than ever to define the roles of FASN and c-Met in thyroid cancers.

In the present study, we used immunohistochemistry to investigate expressions of FASN and the activated c-Met in a spectrum of thyroid carcinomas of follicular origin.

Materials and methods

Archival thyroidectomy specimens were obtained from 32 patients with thyroid carcinomas of follicular origin including 22 papillary thyroid carcinomas (PTC: 6 classical type and 6 follicular, 4 tall cell, 2 columnar cell, 1 diffuse sclerosing, 1 trabecular/insular, 1 solid and 1 cribriform variants), 8 follicular thyroid carcinomas (FTC: 3 conventional type and 5 Hürthle cell variant) and 2 anaplastic thyroid carcinomas (ATC: 1 with contiguous PTC and 1 with FTC), The protocol of this study was approved by the Institutional Review Board of the University of Texas Health Science Center at Houston.

Immunohistochemical staining

Immunohistochemical stains were performed on formalin-fixed and paraffin-embedded unstained sections of 4 μm thickness. Fatty acid synthase rabbit monoclonal antibodies (dilution 1:50, Cell Signaling Technology, Beverly, MA) and phospho-Met (Tyr1234/1235) (p-c-Met) rabbit monoclonal antibodies (dilution 1:100, Cell Signaling Technology) were utilized for immunohistochemical staining. The unstained sections were deparaffinized in xylene and rehydrated in a graded series of ethanols. Heat-induced epitope retrieval was performed. Endogenous pigments were quenched with 3% H2O2 in methanol for 10 minutes and rinsed with Tris Buffered Saline with Tween 20 (TBST). The remaining procedure took place on a DAKO Autostainer programmed to treat each slide with primary antibodies and with incubation at room temperature for one hour. VECTASTAIN Elite ABC Kit (Rabbit IgG) PK-6101 (Vector Laboratories, Inc. Burlingame, CA) was used. The slides were rinsed and incubated with DAB (3,3'-diaminobenzidine chromogen solution) for 10 minutes. The slides were rinsed again and counterstained with Mayer's hematoxylin, treated with xylene, and cover-slipped. Appropriate positive and negative controls for each case were obtained.

Assessment of immunohistochemical staining

Chromogenic signal was assessed by bright-field microscopy. Both staining intensity and extensiveness were evaluated. Staining intensity was graded as negative (0), weak (1+), moderate (2+), and strong (3+). Staining extensiveness was the percentage of tumor cells positively stained with a range from 0% to 100%. The overexpression was defined as a tumor with positive staining (1+ to 3+) in 10% or more tumor cells.


The expression of FASN was present in the cytoplasm. The overexpression was identified in 17 out of 32 cases including 9 of 22 PTCs (3/6 classical type and 1/6 follicular, 1/1 trabecular/insular, 1/1 diffuse sclerosing and 3/4 tall cell variants), 6 out of 8 FTCs (1/3 conventional type and 5/5 Hürthle cell variant) and 2/2 contiguous well differentiated thyroid carcinoma components of the ATCs (PTC component in one case and FTC component in the other case). There was no overexpression of FASN in the anaplastic component in both ATCs and 2/2 columnar cell, 1/1 cribriform and 1/1 solid variants of PTCs. The non-neoplastic thyroid follicular cells were negative for FASN except the follicular cells with Hürthle cell change.

The expression of p-c-Met was cytoplasmic and focally plasmalemmal. The overexpression was associated with that of FASN in both carcinoma tissue and the non-neoplastic Hürthle cells except one FASN negative columnar cell variant PTC that was weakly positive for p-c-Met. The expressions of FASN and p-c-Met are summarized in Table 1. Examples of overexpressions of FASN and p-c-Met in the thyroid carcinomas are demonstrated in Figures 1, ,22 and and33.

Figure 1
Immunohistochemical staining of fatty acid synthase (FASN) and phosphorylated (p)-c-Met showing cyto-plasmic positivity in papillary thyroid carcinomas of classical type (A: H&E; B: FASN; C: p-c-Met) and tall cell variant (D: H&E; E: FASN; ...
Figure 2
Anaplastic thyroid carcinoma: the anaplastic component (A: H&E) with no overexpressions of FASN (B) and p -c-Met (C); the contiguous component of papillary thyroid carcinoma (D: H&E) with overexpressions of FASN (E) and p-c-Met(F)(x400). ...
Figure 3
Overexpressions of FASN and p-c-Met in Hürthle cell variant of follicular thyroid carcinoma (A: H&E; B: FASN; C: p-c-Met; x 400) and non-neoplastic Hürthle cells in lymphocytic thyroiditis (D: H&E, x 400; E: FASN, x 100; ...
Table 1
Immunohistochemical overexpressions of FASN and p-c-Met in thyroid carcinomas of fol-licular origin


Our study demonstrates: (1) overexpressions of fatty acid synthase (FASN) and phosphorylated (p)-c-Met in a subset of PTCs and FTCs and all well differentiated thyroid carcinoma (PTC and FTC) components in ATCs, (2) no overexpressions of both FASN and p-c-Met in ATCs per se, (3) overexpressions of FASN and p-c-Met in all Hürthle cell variant FTCs as well as in non-neoplastic Hürthle cells, and (4) an association in overexpression between FASN and p-c-Met.

The oncogenic mechanisms of FASN have been under investigation since it was found that fatty acids synthesized by FASN in cancer cells were not only used for cellular membrane construction but also involved in the activation of oncogentic signaling pathways. The most attention has been drawn to the PI3K/Akt signaling pathway, one of the oncogenic signaling pathways, known to play an important role in cancer cell survival and resistance to chemoradiation therapy. Studies have demonstrated that the expression of FASN is linked with the PI3K/Akt signaling pathway in cancers of ovary, liver, prostate, colorectum and breast [33-37]. Recently, Uddin et al demonstrated that FASN was overexpressed in a subset of papillary thyroid carcinomas including classical type, follicular variant and tall cell variant and that the FASN expression was not associated with patients’ age, gender, histology type, extrathyroidal extension, and cancer stage, but correlated with overexpression of p-Akt by immunostaining patients’ tissue on tissue microarray [11]. They also observed that the inhibition of FASN caused not only down-regulation of FASN but also inactivation of Akt activity. In accordance, one of our previous studies showed Akt activation in PTCs as well [38]. Our current study concurs with Uddin et al of the overexpression of FASN in a subset of PTCs. Collectively, these findings support the hypothesis of the link between FASN and Akt signaling pathways.

Moreover, emerging evidence has suggested that FASN is upstream of c-Met and that the inhibition of FASN resulting downregulation of c-Met expression has been observed, which suggests that the FASN inhibitors play an important role in the cancers with the activation of FASN -c-Met pathway [39, 40]. Furthermore, several studies suggested a strong pathogenic role of c-Met via the Akt signaling pathway in a variety of tumors [40-43]. Therefore, the oncogenic signaling pathway of FASN-c-Met-PI3K/Akt has been postulated [39].

Phosphorylated status of c-Met protein represents the activated state because the interaction of the c-Met protein (HGFR) with hepatocyte growth factor (HGF) results in autophosphorylation at multiple tyrosines, which recruit several downstream signaling components including PI3K phosphorylation that subsequently activates Akt [44]. Phosphorylation of Tyr1234/1235 in the c-Met kinase domain is critical to its kinase activation [45]. The antibody for c-Met that we used in the current study is against phosphorylated c-Met protein and, thus, the immunoreactivity indicates the activated state of c-Met.

Our present study shows that the well differentiated thyroid carcinoma (PTC and FTC) components contiguous to ATCs overexpress both FASN and p-c-Met. The finding suggests that the well differentiated thyroid carcinomas with overexpressions of FASN and p-c-Met may be of aggressive nature. This postulation is supported by the observations reported in the literature that the high level of FASN expression is associated with poor prognosis, higher risk of recurrence, and shorter survival of human cancers of breast, prostate, lung, colon, ovary, endo-metrium, kidney, head and neck, sarcoma, melanoma and nephroblastoma [8, 46]. In addition to the interaction with c-Met, FASN has been found to be associated HER2 expression in breast carcinoma and higher Gleason grade in prostate cancer, respectively [35, 47]. The findings suggest that the activation of FASN may reflect a higher level of intrinsic aggressiveness in the cancers. The c-Met activation has also reported to implicate aggressive behaviors in many types of tumors including PTC [19, 21, 22]. Therefore, FASN and c-Met positive well differentiated thyroid carcinomas may have a more aggressive clinical behavior than FASN and c-Met negative well differentiated thyroid carcinomas.

In the current study, we also discover that ATC component per se does not overexpress FASN and p-c-Met. The finding coincides with the observation of Ruco LP et al [22]. They found that the immunoreactivity for Met protein was absent in two out of two ATCs. The consistent results of the absence of expressions of FASN and p-c-Met suggest that the tumorigenesis of this highly aggressive thyroid carcinoma is not due to the activation of FASN-c-Met pathway and may be signaled through other pathways, e.g. mTOR, especially mTORC2 pathway, for which the upstream regulators have not been defined, as demonstrated in our previous studies [38, 48].

In the present study, overexpressions of FASN and p-c-Met are identified in all the follicular carcinomas of Hürthle cell variant as well as non-neoplastic Hürthle cells while the non-neoplastic follicular cells without Hürthle cell change do not show overexpressions of both markers. These findings challenge the notation of FASN and p-c-Met overexpressions associating with an aggressive behavior in thyroid Hürthle cell carcinomas. To date, the clinical significance of the Hürthle cell carcinomas is still controversial. Some observations suggest that the Hürthle cell carcinomas have a more aggressive behavior and a poorer outcome compared with the conventional type follicular carcinoma [49-51] while growing evidence demonstrates that Hürthle cell carcinomas are not more aggressive than their conventional counterparts [52]. In the literature, there are only few studies that demonstrate the expression of c-Met protein in thyroid Hürthle cell carcinomas [22, 23] and no studies of FASN in thyroid Hürthle cell carcinomas found. Whether expressions of FASN and c-Met in Hürthle cell carcinomas are associated with an aggressive clinical course has not been reported. Our present study demonstrates the first observation of FASN overexpression associated with Hürthle cell morphology regardless of neoplastic or non-neoplastic process and the activated c-Met expression in neoplastic and non-neoplastic Hürthle cells that is consistent with the recent report of c-Met expression in Hashimoto's thyroiditis by Ruggeri RM et al [32]. Taken together, the findings suggest that overexpressions of FASN and c-Met in Hürthle cell lesions are not always associated with an aggressive behavior. The mechanisms of expressions of these markers in Hürthle cells are not clear. In 2003, Zhang et al first demonstrated that human mitochondria contained type II FASN distinct from the type I FASN [4]. The type II FASN may play an important role in mitochondrial function. According to these discovery and as we know that both neoplastic and non-neoplastic Hürthle cells have cytoplasm packed with mitochondria [53], the overexpression of FASN in the neoplastic and non-neoplastic Hürthle cells demonstrated in our current study may be due to the activation of type II FASN in mitochondria or even other unknown mechanisms causing the non-specific staining as well. Therefore, the overexpression of FASN in the Hürthle cells may not be specific for the cytosolic type I FASN. Because c-Met is downstream of FASN, it may show associated expression. Thus, the interpretation of overexpressions of these markers in Hürthle cell lesions should be with caution. In addition, our results suggest that a precaution should be taken to prevent potential adverse effect on the mitochondrial type II FASN while targeting type I FASN for cancer therapy.

In conclusion, this study demonstrates overexpressions of FASN and p-c-Met in a subset of papillary and follicular thyroid carcinomas but not in anaplatic thyroid carcinoma. The positive immunostaining for FASN or p-c-Met may or may not represent specific oncogenic markers and therapeutic targets in thyroid Hürthle cell carcinomas. The overexpressions of FASN and p-c-Met in the precursor neoplasms (PTC and FTC) concomitant to ATCs may imply the aggressive nature of differentiated thyroid carcinomas with overexpressions of these markers. These findings may be of values for targeted therapy and predicting prognosis for thyroid carcinomas.


The authors would like to thank Ms. Pamela K. Johnston, HT (ASCP) for her technical assistance and Ms. Bheravi Patel for secretarial and graphic design expertise.


1. Smith S, Witkowski A, Joshi AK. Structural and functional organization of the animal fatty acid synthase. Prog Lipid Res. 2003;42:289–317. [PubMed]
2. Wakil SJ. Fatty acid synthase, a proficient multi-functional enzyme. Biochemistry. 1989;28:4523–4530. [PubMed]
3. Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007;7:763–777. [PubMed]
4. Zhang L, Joshi AK, Smith S. Cloning, expression, characterization, and interaction of two components of a human mitochondrial fatty acid synthase. J Biol Chem. 2003;278:40067–40074. [PubMed]
5. Kuhajda FP. Fatty acid synthase and cancer: new application of an old pathway. Cancer Res. 2006;66:5977–5980. [PubMed]
6. Liu H, Liu JY, Wu X, Zhang JT. Biochemistry, molecular biology, and pharmacology of fatty acid synthase, and emerging therapeutic target and diagnosis/prognosis marker. Int J Biochem Mol Biol. 2010;1:69–89. [PMC free article] [PubMed]
7. Liu H, Liu Y, Zhang JT. A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction. Mol Cancer Ther. 2008;7:263–270. [PubMed]
8. Yang Y, Liu H, Li Z, Zhao Z, Yip Schneider M, Fan Q, Schmidt CM, Chiorean EG, Xie J, Cheng L, Chen JH, Zhang JT. Role of fatty acid synthase in gemcitabine and radiation resistance of pancreatic cancers. Int J Biochem Mol Biol. 2011;2:89–98. [PMC free article] [PubMed]
9. Kuhajda FP. Fatty acid synthase and cancer: new application of an old pathway. Cancer Res. 2006;66:5977–5980. [PubMed]
10. Sekiguchi M, Shiroko Y, Arai T, Kishino T, Sugawara I, Kusakabe T, Suzuki T, Yamashita T, Obara T, Ito K, Hasumi K. Biological characteristics and chemosensitivity profile of four human anaplastic thyroid carcinoma cell lines. Biomed Pharmacother. 2001;55:466–474. [PubMed]
11. Uddin S, Siraj AK, Al Rasheed M, Ahmed M, Bu R, Myers JN, Al Nuaim A, Al Sobhi S, Al Dayel F, Bavi P, Hussain AR, Al Kuraya KS. Fatty acid synthase and AKT pathway signaling in a subset of papillary thyroid cancers. J Clin Endocrinol Metab. 2008;93:4088–4097. [PubMed]
12. Coleman DT, Bigelow R, Cardelli JA. Inhibition of fatty acid synthase by luteolin post-transcriptionally down-regulates c-Met expression independent of proteosomal/lysosomal degradation. Mol Cancer Ther. 2009;8:214–224. [PMC free article] [PubMed]
13. Menendez JA, Vellon L, Mehmi I, Oza BP, Ropero S, Colomer R, Lupu R. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc Natl Acad Sci USA. 2004;101:10715–10720. [PubMed]
14. Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA. Identification of the hepatocyte growth factor receptor as the met proto-oncogene product. Science. 1991;251:802–904. [PubMed]
15. Galland F, Stefanova M, Lafage M, Birnbaum D. Localization of the 5’ end of the MCF2 oncogene to human chromosome 15q15-q23. Cytogenet Cell Genet. 1992;60:114–116. [PubMed]
16. Cooper CS. The met oncogene: from detection by transfection to transmembrane receptor for hepatocyte growth factor. Oncogene. 1992;7:3–7. [PubMed]
17. Chatopadhyay C, El Naggar AK, Williams MD, Clayman GL. Small molecule c-MET inhibitor PHA665752: effect on cell growth and motility in papillary thyroid carcinoma. Head Neck. 2008;30:991–1000. [PubMed]
18. Looyenga BD, Furge KA, Dykema KJ, Koeman J, Swiatek PJ Giordano TJ, West AB, Resau JH, The BT, Mackeigan JP. Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas. Pro Natl Acad Sci USA. 2011;108:1439–1444. [PubMed]
19. Scarpino S, Duranti E, Stoppacciaro A, Pilozzi E, Natoli G, Sciacchitano S, Luciani E, Ruco L. COX-2 is induced by HGF stimulation in Met-positive thyroid papillary carcinoma cells and is involved in tumour invasiveness. J Pathol. 2009;218:487–494. [PubMed]
20. Todaro M, Iovino F, Eterno V, Cammareri P, Gambara G, Espina V, Gulotta G, Dieli F, Giordano S, De Maria R, Stassi G. Tumorigenic and metastatic activity of human thyroid cancer stem cells. Cancer Res. 2010;70:8874–8885. [PubMed]
21. Lin CI, Whang EE, Donner DB, Du J, Lorch J, He F, Jiang X, Price BD, Moore FD, Jr, Ruan DT. Autophagy induction with RAD001 enhances chemosensitivity and radiosensitivity through Met inhibition in papillary thyroid cancer. Mol Cancer Res. 2010;8:1217–1226. [PubMed]
22. Ruco LP, Ranalli T, Marzullo A, Bianco P, Prat M, Comoglio PM, Baroni CD. Expression of Met protein in thyroid tumours. J Pathol. 1996;180:266–270. [PubMed]
23. Bartolone L, Vermiglio F, Finocchiaro MD, Violi MA, French D, Pontecorvi A, Trimarchi F, Benvenga S. Thyroid follicular oncogenesis in iodine-deficient and iodine-sufficient areas: search for alterations of the ras, met and bFGF oncogenes and of the Rb anti-oncogene. J Endocrinol Invest. 1998;21:680–687. [PubMed]
24. Lupu R, Menendez JA. Pharmacological inhibitors of fatty acid synthase (FASN)-catalyzed endogenous fatty acid biogenesis: a new family of anti-cancer agents? Curr Pharm Biotechnol. 2006;7:483–493. [PubMed]
25. Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer. 2010;17:351–360. [PubMed]
26. Pizer ES, Wood FD, Heine HS, Romantsey FE, Pasternack GR, Kuhaida FP. Inhibition of fatty acid synthesis delays disease progression in a xenograft model of ovarian cancer. Cancer Res. 1996;56:1189–1193. [PubMed]
27. Pizer ES, Thupari J, Han WF, Pinn ML, Chrest FJ, Frehywot L, Townsend CA, Kuhajda FP. Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts. Cancer Res. 2000;60:213–218. [PubMed]
28. Pizer ES, Pflug BR, Bova GS, Han WF, Udan MS, Nelson JB. Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression. Prostate. 2001;47:102–110. [PubMed]
29. Alli PM, Pinn ML, Jaffee EM, McFadden JM, Kuhajda FP. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene. 2005;24:39–46. [PubMed]
30. Orita H, Coulter J, Tully E, Kuhajda FP, Gabrielson E. Inhibiting fatty acid synthase for chemoprevention of chemically induced lung tumors. Clin Cancer Res. 2008;14:2458–2464. [PubMed]
31. Kridel SJ, Axelrod F, Rozenkrantz N, Smith JW. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 2004;64:2070–2075. [PubMed]
32. Ruggeri RM, Vitarelli E, Barresi G, Trimarchi F, Benvenga S, Trovato M. The tyrosine kinase receptor c-met, its cognate ligand HGF and the tyrosine kinase receptor trasducers STATs, PI3K and RHO in thyroid nodules associated with Hashimoto's thyroiditis: an immunohistochemical characterization. Eur J Histochem. 2010;54:e24. Jun 3. [PMC free article] [PubMed]
33. Uddin S, Jehan Z, Ahmed M, Alyan A, Al Dayel F, Hussain A, Bavi P, Al Kuraya KS. Over expression of fatty acid synthase in Middle Eastern epithelial ovarian carcinoma activates AKT and its inhibition potentiates cisplatin induced apoptosis. Mol Med. 2011;17:635–645. [PMC free article] [PubMed]
34. Calvisi DF, Wang C, Ho C, Ladu S, Lee SA, Mattu S, Destefanis G, Delogu S, Zimmermann A, Ericsson J, Brozzetti S, Staniscia T, Chen X, Dombrowski F, Evert M. Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology. 2011;140:1071–1083. [PMC free article] [PubMed]
35. Van de Sande T, Roskams T, Lerut E, Joniau S, Van Poppel H, Verhoeven G, Swinnen JV. High-level expression of fatty acid synthase in human prostate cancer tissues is linked to activation and nuclear localization of Akt/PKB. J Pathol. 2005;206:214–219. [PubMed]
36. Uddin S, Hussain AR, Ahmed M, Abubaker J, Al Sanea N, Abduljabbar A, Ashari LH, Alhomoud S, Al Dayel F, Bavi P, Al Kuraya KS. High prevalence of fatty acid synthase expression in colorectal cancers in Middle Eastern patients and its potential role as a therapeutic target. Am J Gastroenterol. 2009;104:1790–1801. [PubMed]
37. Menendez JA, Ropero S, Mehmi I, Atlas E, Colomer R, Lupu R. Overexpression and hyper-activity of breast cancer-associated fatty acid synthase (oncogenic antigen-519) is insensitive to normal arachidonic fatty acid-induced suppression in lipogenic tissues but it is selectively inhibited by tumoricidal alpha-linolenic and gamma-linolenic fatty acids: a novel mechanism by which dietary fat can alter mammary tumorigenesis. Int J Oncol. 2004;24:1369–1383. [PubMed]
38. Liu J, Brown RE. Morphoproteomics demonstrates activation of mammalian target of rapamycin (MTOR) pathway in papillary thyroid carcinomas with nuclear translocation of MTOR in aggressive histologic variants. Mod Pathol. 2011 Aug 5. Doi: 10.1038/modpathol.2011.121 [Epub ahead of print] [PubMed]
39. Uddin S, Hussain AR, Ahmed M, Bu R, Ahmed SO, Ajarim D, Al Dayel F, Bavi P, Al Kuraya KS. Inhibition of fatty acid synthase suppresses c-Met receptor kinase and induces apoptosis in diffuse large B-cell lymphoma. Mol Cancer Ther. 2010;9:1244–1255. [PubMed]
40. Hung CM, Kuo DH, Chou CH, Su YC, Ho CT, Way TD. Osthole suppresses hepatocyte growth factor (HGF)-induced epithelial-mesenchymal transition via repression of the c-Met/Akt/mTOR pathway in human breast cancer cells. J Agric Food Chem. 2011;59:9683–9690. [PubMed]
41. Yoshizawa Y, Yamada Y, Kanayama S, Shigetomi H, Kawaguchi R, Yoshida S, Nagai A, Furukawa N, Oi H, Kobayashi H. Signaling pathway involved in cyslooxygenase-2 up-regulation by hepatocyte growth factor in endometrial cancer cells. Oncol Rep. 2011;26:957–964. [PubMed]
42. Carr BI, Wang Z, Wang M, Cavallini A, D'Alessandro R, Refolo MG. c-Met-Akt pathway-mediated enhancement of inhibitory c-Raf phosphorylation is involved in vitamin K1 and sorafenib synergy on HCC growth inhibition. Cancer Biol Ther. 2011 Sep 15; 12. [Epub ahead of print] [PubMed]
43. Pavone LM, Cattaneo F, Rea S, De Pasquale V, Spina A, Sauchelli E, Mastellone V, Ammendola R. Intracellular signaling cascades triggered by the NK1 fragment of hepatocyte growth factor in human prostate epithelial cell line PNT1A. Cell Signal. 2011 Jul 12. [Epub ahead of print] [PubMed]
44. Fresno Vara JA, Cassado E, de Castro J, Cejas P, Belda Iniesta C, Gonzalez Baron M. PI3K/ Akt signaling pathway and cancer. Cancer Treat Rev. 2004;30:193–204. [PubMed]
45. Schaeper U, Behring NH, Fuchs KP, Sachs M, Kempkes B, Birchmeier W. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. J Cell Biol. 2000;149:1419–1432. [PMC free article] [PubMed]
46. Kuhajda FP. Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition. 2000;16:202–208. [PubMed]
47. Zhang D, Tai LK, Wong LL, Chiu LL, Sethi SK, Koay ES. Proteomic study reveals that proteins involved in metabolic and detoxification pathways are highly expressed in HER-2/neu-positive breast cancer. Mol Cell Proteomics. 2005;4:1686–1696. [PubMed]
48. Liu J, Brown RE. Morphoproteomics demonstrates activation of the mTOR pathway in anaplastic thyroid carcinoma: a preliminary observation. Ann Clin Lab Sci. 2010;40:211–217. [PubMed]
49. Shaha AR, Loree TR, Shah JP. Prognostic factors and risk group analysis in follicular carcinoma of the thyroid. Surgery. 1995;118:1131–1136. [PubMed]
50. Haq M, Harmer C. Differentiated thyroid carcinoma with distant metastases at presentation: prognostic factors and outcome. Clin Endocrinol (Oxf) 2005;63:87–93. [PubMed]
51. Mills SC, Haq M, Smellie WJ, Harmer C. Hürthle cell carcinoma of the thyroid: retrospective review of 62 patients treated at Royal Marsden Hospital between 1946 and 2003. Eur J Surg Oncol. 2009;35:230–234. [PubMed]
52. Barnabei A, Ferretti E, Baldelli R, Procaccini A, Spriano G, Appetecchia M. Hürthle cell tumours of the thyroid. Personal experience and review of the literature. Act Otorhinolaryngol Ital. 2009;29:305–311. [PMC free article] [PubMed]
53. Feldman PS, Horvath E, Kovacs K. Ultrastructure of three Hürthle cell tumors of the thyroid. Cancer. 1972;30:1279–1285. [PubMed]

Articles from International Journal of Clinical and Experimental Pathology are provided here courtesy of e-Century Publishing Corporation