Expression of the von Hippel-Lindau Tumor Suppressor Gene in Nonneoplastic and Neoplastic Lesions of the Thyroid.
Alterations of the von Hippel-Lindau (VHL) gene, which is supposed to act as a tumor suppressor gene, can cause hereditary tumors associated with the VHL syndrome and are found in different sporadic cancers as well. While VHL protein is distinctly detectable in thyroid follicles, so far its expression in nonneoplastic and neoplastic lesions of the thyroid has not been investigated comprehensively. To illuminate the role of VHL for thyroid tumorigenesis, we investigated 12 follicular adenomas; 22 follicular carcinomas; 11 papillary carcinomas; 6 poorly differentiated carcinomas (PDTCs); 9 undifferentiated carcinomas (UTCs); 8 medullary carcinomas; 13 cases with nonneoplastic as well as normal thyroid tissue of 10 patients with antibodies against VHL, vascular endothelial growth factor (VEGF); and the proliferation marker MIB1 immunohistochemically; and selected cases by Western blot analysis. VHL was clearly expressed in nonneoplastic lesions and differentiated tumors derived from follicular epithelium, diminished in PDTCs and very weakly or not detectable in UTCs (p = 0.001), nonneoplastic, and neoplastic C-cells. Although slightly increased in certain differentiated tumors, VEGF was found to be reduced in UTCs as well. In summary, VHL is expressed differently in nonneoplastic and neoplastic lesions of the thyroid in proportion to the level of differentiation. VHL gene alterations appear to be a late event in tumorigenesis of the thyroid and a reduction in VHL protein expression is associated with a loss of differentiation and increased aggressiveness in thyroid tumors. There is no apparent inverse correlation between VHL and VEGF expression as described for other sporadic carcinomas. Therefore, the role of VHL for angiogenesis and the molecular basis of the inactivation of VHL in thyroid tumors remains to be elucidated.
Raoul
R
Hinze
Carsten
C
Boltze
Axel
A
Meye
Hans-Jürgen
HJ
Holzhausen
Henning
H
Dralle
Friedrich-Wilhelm
FW
Rath