title: Insulin receptor isoform A and insulin-like growth factor II as additional treatment targets in human osteosarcoma.
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-II serum levels significantly higher, than healthy controls. Increased IGF-II values were associated with a decreased disease-free survival. After tumor removal, both IGF-I 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.
authors.affiliation: Laboratory for Pathophysiology, Rizzoli Orthopaedic Institute, Bologna, Italy. sofia.avnet@ior.it
authors.forename: Sofia
authors.initials: S
authors.lastname: Avnet
authors.forename: Laura
authors.initials: L
authors.lastname: Sciacca
authors.forename: Manuela
authors.initials: M
authors.lastname: Salerno
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gancitano
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Cassarino
authors.forename: Alessandra
authors.initials: A
authors.lastname: Longhi
authors.forename: Mahvash
authors.initials: M
authors.lastname: Zakikhani
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Marco
authors.initials: M
authors.lastname: Gottardis
authors.forename: Armando
authors.initials: A
authors.lastname: Giunti
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: Riccardo
authors.initials: R
authors.lastname: Vigneri
authors.forename: Nicola
authors.initials: N
authors.lastname: Baldini
mesh_terms: D000293:Adolescent; D001859:Bone Neoplasms / Q000097:blood* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002648:Child; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008297:Male; D012516:Osteosarcoma / Q000097:blood* / Q000473:pathology; D020033:Protein Isoforms; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017526:Receptor, IGF Type 1 / Q000097:blood; D011972:Receptor, Insulin / Q000097:blood*
chemical_list: C515497:IGFBP3 protein, human; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D020033:Protein Isoforms; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin