Evaluation of Wilm's tumour suppressor gene and insulin-like growth factor receptors in parathyroid glands

Abstract

Abstract Background The precise cause of hyperparathyroidism (HPT) is uncertain. Alteration of growth factors (epidermal growth factor, fibroblast growth factor) and genetic mutations (parathyroid hormone (PTH) gene (11p15), PRAD1 oncogene (11q13) and multiple endocrine neoplasia type 1 (MEN1) gene (11q13)) are implicated in the pathogenesis. The escape of secretory function from physiological control and excess growth is still incompletely understood. The insulin-like growth factor (IGF) axis is a ubiquitous growth and regulatory system (IGF-1 and -II, IGF receptors (IGFRs) and binding proteins (IGFBPs)). Hormonal/endocrine signals (e.g. androgens, thyroid-stimulating hormone) and tumour supressor genes (e.g. Wilms' tumour suppressor gene (WT-1) (11p13) and p53) modulate the IGF axis. Expression of the WT-1 gene is tissue specific (kidney, mesothelium, prostate). Wild-type WT-1 governs normal kidney development and mutation results in Wilm's tumour. Loss of transcriptional repression of WT-1 and IGF control can lead to mitogenesis. A mutation (chromosome 11) appears to be the key event in the evolution of primary HPT. This mutation may increase IGFR expression, IGF production giving rise to unregulated autocrine growth. In polyclonal hyperplasia (secondary HPT and MEN1) a serum factor initiates polyclonal growth, thereby increasing the susceptibility to mutation and resulting in nodular hyperplasia. Methods Immunohistochemical examination of paraffin-embedded parathyroid glands was done using polyclonal anti-WT-1 (C19, Santa Cruz) and anti-IGFR-I (C20, Santa Cruz) antibodies and a horseradish peroxidase-labelled secondary antibody for detection. The strength of immunoreactivity was graded using a standardized colour chart and assessed independently by three observers. Results Two hundred and fifty-four parathyroid glands from 112 patients were examined. There were 81 women and 31 men (2·6: 1). Of these, 94 had primary HPT (70 women) and 18 secondary HPT (11 women). Immunoreactivity to WT-1 was found in normal parathyroid glands. In contrast, reduced WT-1 immunostaining was observed in abnormal parathyroid glands. Positive immunostaining for IGFR-I was found in all parathyroid glands. Increased immunoreactivity was found in pathological compared with normal glands. Conclusion WT-1 and IGFR are expressed in parathyroid cells. Abnormal expression of WT-1 and the IGF axis may play a role in the pathogenesis of HPT.