Elsevier

Biochimie

Volume 81, Issue 4, April 1999, Pages 403-407
Biochimie

Original article
Insulin/IGF-I hybrid receptors play a major role in IGF-I signaling in thyroid cancer

https://doi.org/10.1016/S0300-9084(99)80088-1Get rights and content

Abstract

The insulin-like growth factor-I (IGF-I) plays an important role in determining the biological behavior of a variety of malignancies. We measured IGF-I, its receptor and related receptors in thyroid cancer. IGF-I was present both in normal thyroid tissue and in thyroid cancer tissue and it was produced by stromal cells but not by thyrocytes. Values were significantly higher in malignant than in normal tissue. IGF-I receptors (IGF-I-Rs) and the homologous insulin receptors (IRs) were found overexpressed in both thyroid cancer cell lines (n = 4) and specimens (n = 17) as compared to normal values. In addition, high levels of hybrid IGF-I/insulin receptors (IR/IGF-I-Rs) were present in both thyroid cancer specimens and cell lines. IR/IGF-I-R hybrids were the most represented type of receptor in 14/17 specimens and exceeded the IGF-I-R content in all cases. Hybrid content correlated with the IR and IGF-I-R content, suggesting that in thyroid tissue hybrid formation occurs by random assembly of IR and IGF-I-R half receptors. Hybrid receptor autophosphorylation was stimulated by IGF-I with high affinity. In cells with a high IR/IGF-I-Rs content, blocking antibodies specific to these receptors substantially inhibited IGF-I induced cell growth. These data indicate that the IGF-I system is overactivated in thyroid cancer and that IR/IGF-I-R hybrid receptors play an important role in IGF-I mitogenic signaling in these tumors.

Introduction

Differentiated tumors with papillary or follicular histotype represent approximately 90% of thyroid carcinomas originating from the follicular epithelium. The remaining 10% is represented by undifferentiated tumors. Cancer mortality, due to hematogenous metastases or local invasion, ranges from approximately 10% in differentiated tumors up to 100% in undifferentiated tumors [1]. The factors and the mechanisms determining thyroid cancer aggressiveness and/or de-differentiation are incompletely understood [2]. In differentiated thyroid cancer pituitary TSH is a major growth factor [1]. TSH suppression, however, in many cases is not sufficient to prevent or inhibit metastatic spread, indicating that other factors may play an important role in the metastatic process of these tumors [1]. In fact, a variety of tyrosine kinase growth factor receptors (including EGF, Erb-B2 and HGF/SF receptors) may be abnormally expressed and influence the biological behavior of thyroid cancer [2], [3], [4], [5].

Insulin-like growth factor-I (IGF-I) is a major proliferation and survival factor which plays an important role in many cancers [6]. Previous studies, carried out by immunohistochemistry and in situ hybridization, suggest that IGF-I and its receptor are present in thyroid cancer [7]. IGF-I is believed, therefore, to signal in an autocrine/paracrine manner via its specific receptor (IGF-I-R). However, when strategies have been tested to inhibit cancer growth by blocking IGF-I-R binding and function, blockade of IGF-I receptor was enable to fully prevent IGF-I-stimulated growth [8], raising the possibility that the signaling system for IGF-I is complex and that other receptors are involved. In other tissues and cancer cells atypical receptors have been described that bind both insulin and IGF-I with high affinity [9], [10]. In cells and tissues co-expressing both insulin receptors (IRs) and IGF-I-Rs, IGF-I binding may also occur to hybrid IR/IGF-I-R (heterodimers formed by one IR α and β subunit complex and one IGF-I-R α and β subunit complex). These receptors behave like IGF-I-Rs rather than IRs since they bind IGF-I, but not insulin, with a high affinity [11], [12].

In order to evaluate the function and role of the IGF-I and its receptors in thyroid cancer, we measured IRs, IGF-I-Rs and IR/IGF-I-R hybrids by specific ELISAs in thyroid cancers with a different degree of differentiation, and explored their functional significance in the context of the IGF-I system.

Section snippets

Materials and methods

The following materials were purchased: fetal calf serum (FCS), glutamine and gentamicin obtained from Gibco Laboratories (Paisley, UK); modified Eagle's medium (MEM), bovine serum albumin (BSA, radioimmunoassay grade), bacitracin, phenylmethylsulphonyl fluoride (PMSF), and porcine insulin from Sigma Chemical Co. (St. Louis, MO, USA). The following monoclonal antibodies to the IR were used: MA-20 and MA-51, that react with the α-subunit at an epitope close to the insulin binding site and do not

IR, IGF-I-R and IR/IGF-I-R hybrid content in human thyroid cancer

IRs were always higher in cancer than in normal tissue (P = 0.018) and there was a trend towards a higher IR content in less differentiated and anaplastic as compared to well differentiated papillary cancers (table I). Mean IGF-I-R content was also increased, although not significantly, in cancer as compared to normal tissue. IR/IGF-I-R content was significantly increased in all cancers as compared to normal tissue (P = 0.028). Hybrid receptors represented approximately 60–70% of total IGF-I

Discussion

IGF-I-R has been shown to be a potent mitogenic and anti-apoptotic factor and to have a permissive role in the development of the transformed phenotype [6]. Since IGF-I is locally produced in tumors and activates the IGF-I-R in an autocrine/paracrine manner, the IGF-I/IGF-I-R loop is the target of a variety of strategies aimed to inhibit IGF-I signaling [8], [20]. Like the IGF-I-R, the highly homologous IR, is also overexpressed in certain cancers and appears to have a similar biological role 

Acknowledgements

This work was supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC). We thank Dr. I.D. Goldfine, San Francisco, USA, and Dr. K. Siddle, Cambridge, UK, for kindly providing us with anti-IR and anti-IGF-I-R antibodies. We also thank Dr. Y. Fujta-Yamaguchi for providing the IR/IGF-I-R purified standard.

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