Insulin receptor isoform a and insulin-Like growth factor II as additional treatment targets in human osteosarcoma

Sofia Avnet, Laura Sciacca, Manuela Salerno, Giovanni Gancitano, Maria Francesca Cassarino, Alessandra Longhi, Mahvash Zakikhani, Joan M. Carboni, Marco Gottardis, Armando Giunti, Michael Pollak, Riccardo Vigneri, Nicola Baldini

Research output: Contribution to journalArticlepeer-review

Abstract

Despite the frequent presence of an insulin-like growth factor I receptor (IGFIR)-mediated autocrine loop in osteosarcoma (OS), interfering with this target was only moderately effective in preclinical studies. Here, we considered other members of the IGF system that might be involved in the molecular pathology of OS. We found that, among 45 patients with OS, IGF-I and IGFBP-3 serum levels were significantly lower, and IGF-H serum levels significantly higher, than healthy controls. Increased IGF-II values were associated with a decreased disease-free survival. After tumor removal, both 1GF-1 and IGF-II levels returned to normal values. In 23 of 45 patients, we obtained tissue specimens and found that all expressed high mRNA level of IGF-II and >IGF-I. Also, isoform A of the insulin receptor (IR-A) was expressed at high level in addition to IGFIR and IR-A/IGFIR hybrids receptors (HR A). These receptors were also expressed in OS cell lines, and simultaneous impairment of IGFIR, IR, and Hybrid-Rs by monoclonal antibodies, siRNA, or the tyrosine kinase inhibitor BMS-536924, which blocks both IGFIR and IR, was more effective than selective anti-IGFIR strategies. Also, anti-IGF-II-siRNA treatment in low-serum conditions significantly inhibited MG-63 OS cells that have an autocrine circuit for IGF-II. In summary, IGF-II rather than IGF-I is the predominant growth factor produced by OS cells, and three different receptors (IR-A, HR A, and IGFIR) act complementarily for an IGF II- mediated constitutive autocrine loop, in addition to the previously shown IGFIR/IGF-I circuit. Cotargeting IGFIR and IR-A is more effective than targeting IGF-IR alone in inhibiting OS growth.

Original languageEnglish
Pages (from-to)2443-2452
Number of pages10
JournalCancer Research
Volume69
Issue number6
DOIs
Publication statusPublished - Mar 15 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Fingerprint Dive into the research topics of 'Insulin receptor isoform a and insulin-Like growth factor II as additional treatment targets in human osteosarcoma'. Together they form a unique fingerprint.

Cite this