Carcinogenesis Advance Access originally published online on January 7, 2006
Carcinogenesis 2006 27(5):962-971; doi:10.1093/carcin/bgi336
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Insulin-like growth factor 1 is a potent stimulator of cervical cancer cell invasiveness and proliferation that is modulated by 
vß3 integrin signaling
1 Department of Pharmacology, 2 Department of Obstetrics and Gynecology, 3 Institute of Basic Medical Sciences, 4 Department of Physiology, College of Medicine and 5 Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 704, Taiwan
* To whom correspondence should be addressed at: Dr Cheng-Yang Chou, Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, 138 Sheng-Li Road, Tainan 704, Taiwan Tel: +886 6 2353535 ext. 5608; Fax: +886 6 2766185; Email: chougyn{at}mail.ncku.edu.tw
Insulin-like growth factor 1 (IGF-1) has been implicated in promoting mitogenic, metastatic and antiapoptotic phenotypes in several types of cancer. But little is known about the signal interaction of IGF-1 and integrin in the regulation of cervical cancer development and progression. This study is to investigate the regulatory mechanism of IGF-1 receptor (IGF-1R) signaling and its importance in cervical cancer formation. The growth and invasiveness of cervical cancer cells (SiHa and CaSki) were dose-dependently stimulated by IGF-1, whereas those of normal cervical epithelial cells were not. The immunoblot showed that IGF-1R proteins were abundant in cervical cancer cell lines. In contrast, IGF-1R protein was nearly undetectable in normal cervical epithelial cells. IGF-1-stimulated invasion and proliferation were abolished by functional-blocking monoclonal antibody against IGF-1R, whereas these cellular functions were unaffected by either IgG or monoclonal antibody to insulin receptor. Functional-blocking monoclonal antibody against integrins 
vß3, but not 2, 3, 4, 6, ß1, ß4 or 2ß1, inhibited the IGF-1-stimulated invasion and proliferation in cervical cancer cells. vß3 integrin modulated IGF-1R phosphorylation by altering the rate of Src homology 2-containing phosphotyrosine phosphatase (SHP-2) recruitment to the activated IGF-1R. The modulation of vß3 occupancy also affected the activation of IGF-1R downstream-signaling elements, including activation of Akt and extracellular signal-regulated protein kinases 1/2 (Erk1/2). The treatment of blocking antibody of vß3 integrin or IGF-1R significantly inhibited tumor growth and caused tumor regression in SCID mice model. Immunoblots of tumor tissues confirmed that the phosphorylation of IGF-1R and downstream targets of Akt and Erk1/2 were remarkably decreased in SCID mice treated with blocking antibodies of vß3 or IGF-1R. Thus, these data suggest that the signal interaction between IGF-1R and vß3 integrin plays an important role in promoting the development and progression of cervical cancer.
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