Expression of c-kit, Flk-1, and Flk-2 receptors in benign and malignant tumors of follicular epithelial origin.
BACKGROUND
Vascular endothelial growth factor (VEGF) is a key regulator of physiologic as well as pathologic angiogenesis. The response of VEGF to endothelial cell mitogenesis and survival, as well as angiogenesis and microvascular permeability, is mainly mediated through its receptor-2, VEGFR2 (kinase domain receptor or fetal liver kinase-1, KDR or Flk-1). This study aimed to detect the expression of VEGFR2 in various forms of thyroid tumors. In addition, the expression of Flk-2 (receptor for Flt-3) and c-Kit (receptor for steel locus factor), which shows strong similarity to Flk-1, was also examined in thyroid tumors.


METHODS
RT-PCR analyses of c-Kit and immunohistochemical staining of c-Kit, Flk-1, and Flk-2 were performed in archived samples of 18 papillary thyroid carcinoma (PTC), 9 follicular thyroid carcinoma (FTC), 12 follicular adenoma (FA), and 7 nodular goiter (NG) samples. The data were correlated to clinicopathologic features.


RESULTS
By RT-PCR analyses, c-Kit expression was detected in 22% (4/18) of PTC, 22% (2/9) of FTC, 25% (3/12) of FA, and 57% (4/7) of NG samples. However, positive immunostaining signals of c-Kit were only observed in 17% (3/18) of PTC samples, and not in the others. Similarly, Flk-1 expression was only detected by immunohistochemistry in 67% (12/18) of PTC and 43% (3/7) of NG samples, and not in the others. Interestingly, the expression of Flk-2 was found in 89% (16/18) of PTC, 89% (8/9) of FTC, 75% (9/12) of FA, and 29% (2/7) of NG samples. An inverse relationship of thyroid cancer size with Flk-2 expression was found.


CONCLUSIONS
Flk-2 expression was detected in various forms of thyroid tumors and increased Flk-2 expression was correlated with thyroid tumors with increased transforming activity, suggesting that Flk-2 is involved in pathogenic development of thyroid malignancy. Similarly, Flk-1 expression was also found in some thyroid tumors, while the expression of c-Kit-mediated pathways may not play a major role in thyroid tumorigenesis.
Kung
Sung-Pao
SP
Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan, ROC.
Lee
Chen-Hsen
CH
Yang
An-Hang
AH
Chi
Chin-Wen
CW
Tseng
Ling-Ming
LM
Wu
Chew-Wen
CW
D018263:Adenocarcinoma, Follicular / Q000737:chemistry*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002291:Carcinoma, Papillary / Q000737:chemistry; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000737:chemistry* / Q000209:etiology / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis* / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000032:analysis* / Q000235:genetics
C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D040301:Vascular Endothelial Growth Factor Receptor-2; D051941:fms-Like Tyrosine Kinase 3