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 language | English |
|---|---|
| Pages (from-to) | 2443-2452 |
| Number of pages | 10 |
| Journal | Cancer Research |
| Volume | 69 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Mar 15 2009 |
Fingerprint
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Insulin receptor isoform a and insulin-Like growth factor II as additional treatment targets in human osteosarcoma. / Avnet, Sofia; Sciacca, Laura; Salerno, Manuela; Gancitano, Giovanni; Cassarino, Maria Francesca; Longhi, Alessandra; Zakikhani, Mahvash; Carboni, Joan M.; Gottardis, Marco; Giunti, Armando; Pollak, Michael; Vigneri, Riccardo; Baldini, Nicola.
In: Cancer Research, Vol. 69, No. 6, 15.03.2009, p. 2443-2452.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Insulin receptor isoform a and insulin-Like growth factor II as additional treatment targets in human osteosarcoma
AU - Avnet, Sofia
AU - Sciacca, Laura
AU - Salerno, Manuela
AU - Gancitano, Giovanni
AU - Cassarino, Maria Francesca
AU - Longhi, Alessandra
AU - Zakikhani, Mahvash
AU - Carboni, Joan M.
AU - Gottardis, Marco
AU - Giunti, Armando
AU - Pollak, Michael
AU - Vigneri, Riccardo
AU - Baldini, Nicola
PY - 2009/3/15
Y1 - 2009/3/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=65549161522&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=65549161522&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-08-2645
DO - 10.1158/0008-5472.CAN-08-2645
M3 - Article
C2 - 19258511
AN - SCOPUS:65549161522
VL - 69
SP - 2443
EP - 2452
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 6
ER -