The IGF system in thyroid cancer: new concepts

Abstract

In recent years, the activation of the insulin-like growth factor (IGF) system in cancer has emerged as a key factor for tumour progression and resistance to apoptosis. Therefore, a variety of strategies have been developed to block the type I IGF receptor (IGF-I-R), which is thought to mediate the biological effects of both IGF-I and IGF-II. However, recent data suggest that the IGF signalling system is complex and that other receptors are involved. To unravel the complexity of the IGF system in thyroid cancer, IGF-I and IGF-II production, and the expression and function of their cognate receptors were studied. Both IGFs were found to be locally produced in thyroid cancer: IGF-I by stromal cells and IGF-II by malignant thyrocytes. Values were significantly higher in malignant tissue than in normal tissue. IGF-I-Rs were overexpressed in differentiated papillary carcinomas but not in poorly differentiated or undifferentiated tumours, whereas insulin receptors (IRs) were greatly overexpressed in all tumour hystotypes, with a trend for higher values in dedifferentiated tumours. As a consequence of IR overexpression, high amounts of IR/IGF-I-R hybrids (which bind IGF-I with high affinity) were present in all thyroid cancer histotypes. Because of recent evidence that isoform A of IR (IR-A) is a physiological receptor for IGF-II in fetal life, the relative abundance of IR-A in thyroid cancer was measured. Preliminary data indicate that overexpressed IRs mainly occur as IR-A in thyroid cancer. These data indicate that both IR/IGF-I-R hybrids and IR-A play an important role in the overactivation of the IGF system in thyroid cancer and in IGF-I mitogenic signalling in these tumours. J Clin PATHOL: Mol Pathol

Figures

Figure 1

(A) Insulin-like growth factor I receptor (IGF-I-R), (B) insulin receptor (IR), and (C) hybrid IR/IGF-I receptor (Hybrid-R) content (mean ±SEM) of normal thyroid (n = 7) and cancer thyroid specimens. PTC, papillary thyroid cancer (n = 8); FTC, follicular (poorly differentiated) thyroid cancer (n = 6); ATC, anaplastic thyroid cancer (n = 4).

Figure 2

Thyroid cancer BC-PAP cell growth stimulated by insulin-like growth factor I (IGF-I) in the absence or the presence of antibodies blocking either IGF-I receptors (αIR-3) or hybrid insulin/IGF-I receptors (Ab 47-9).

Figure 3

Structural diagrams of the insulin receptor (IR), the insulin-like growth factor I receptor (IGF-I-R), and the hybrid IR/IGF-I receptor (Hybrid-R). Insert: structural schematics of the two IR isoforms (arrow indicates the location of the 12 amino acid residues encoded by exon 11 at the C-terminus of the α subunit).