Systemic IGF-I administration stimulates the in vivo growth of early, but not advanced, renal cell carcinoma.
Insulin-like growth factor I (IGF-I) is a potent mitogen and antiapoptotic factor. Although elevated serum IGF-I levels have been associated with increased cancer risk, it is not yet clear whether IGF-I sensitivity is sustained throughout tumor progression. To evaluate the biological effects of IGF-I during renal cell carcinoma (RCC) establishment and progression, we administered recombinant human IGF-I to severe combined immuno-deficient mice bearing early or more established Caki-2 human RCC tumors. IGF-I significantly enhanced the tumor growth 2.4-fold when administered early after tumor inoculation. This IGF-I-induced growth was accompanied with enhanced tumor cell proliferation, tumor vascularization, as well as increased intratumoral insulin-like growth factor binding protein 3 (IGFBP-3) and pSmad2 levels. In contrast, IGF-I administrated to more established RCC tumors showed no effect on tumor growth, with subsequently much lower Ki-67, IGFBP-3 and pSmad2 levels. Taken together, these data suggest that systemic IGF-I has potent actions during early RCC tumor development with a sustained long-term effect on proliferation and neovascularization although with progression, later tumors appear to become desensitized to systemic IGF-I effects.
Rosendahl
Ann H
AH
Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden. ann.rosendahl@med.lu.se
Holly
Jeff M P
JM
Celander
Mona
M
Forsberg
Göran
G
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000187:drug effects / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D051899:Smad2 Protein / Q000187:drug effects / Q000378:metabolism; D013995:Time
D000970:Antineoplastic Agents; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D051899:Smad2 Protein; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1