Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer
| Autor: | Niamh C. O’Sullivan, Anthony J. Ryan, Paul A. Fitzpatrick, Silvia Napoletano, Judith H. Harmey, Caroline A Currid |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Vascular Endothelial Growth Factor A
Cancer Research Angiogenesis medicine.medical_treatment Apoptosis Insulin-like growth factor-binding protein Receptor IGF Type 1 Mice angiogenesis Insulin-like growth factor chemistry.chemical_compound 0302 clinical medicine Pregnancy-Associated Plasma Protein-A Insulin-Like Growth Factor I Mice Inbred BALB C 0303 health sciences Neovascularization Pathologic Recombinant Proteins 3. Good health Vascular endothelial growth factor Endothelial stem cell Vascular endothelial growth factor A Oncology 030220 oncology & carcinogenesis hormones hormone substitutes and hormone antagonists endocrine system medicine.medical_specialty insulin-like growth factor-binding protein-4 Cell Growth Processes Adenocarcinoma Biology pregnancy-associated plasma protein A insulin-like growth factor 03 medical and health sciences breast cancer Internal medicine medicine Animals Humans Molecular Diagnostics 030304 developmental biology Insulin-like growth factor 1 receptor Growth factor Mammary Neoplasms Experimental Disease Models Animal Endocrinology Insulin-Like Growth Factor Binding Protein 4 chemistry Mutation Cancer research biology.protein |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | Background: Insulin-like growth factor 1 (IGF1) promotes breast cancer and disease progression. Bioavailability of IGF1 is modulated by IGF-binding proteins (IGFBPs). IGFBP4 inhibits IGF1 activity but cleavage by pregnancy-associated plasma protein-A (PAPP-A) protease releases active IGF1. Methods: Expression of IGF pathway components and PAPP-A was assessed by western blot or RT–PCR. IGFBP4 (dBP4) resistant to PAPP-A cleavage, but retaining IGF-binding capacity, was used to block IGF activity in vivo. 4T1.2 mouse mammary adenocarcinoma cells transfected with empty vector, vector expressing wild-type IGFBP4 or vector expressing dBP4 were implanted in the mammary fat pad of BALB/c mice and tumour growth was assessed. Tumour angiogenesis and endothelial cell apoptosis were assessed by immunohistochemistry. Results: 4T1.2 cells expressed the IGF1R receptor and IGFBP4. PAPP-A was expressed within mammary tumours but not by 4T1.2 cells. Proliferation and vascular endothelial growth factor (VEGF) production by 4T1.2 cells was increased by IGF1(E3R) (recombinant IGF1 resistant to binding by IGFBPs) but not by wild-type IGF1. IGF1-stimulated microvascular endothelial cell proliferation was blocked by recombinant IGFBP4. 4T1.2 tumours expressing dBP4 grew significantly more slowly than controls or tumours expressing wild-type IGFBP4. Inhibition of tumour growth by dBP4 was accompanied by the increased endothelial cell apoptosis. Conclusion: Protease-resistant IGFBP4 blocks IGF activity, tumour growth and angiogenesis . |
| Databáze: | OpenAIRE |
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