Journal
KIDNEY INTERNATIONAL
Volume 65, Issue 4, Pages 1272-1279Publisher
ELSEVIER SCIENCE INC
DOI: 10.1111/j.1523-1755.2004.00535.x
Keywords
renal cell carcinoma; insulin-like growth factor I; insulin-like growth factor binding protein 3; DNA synthesis; immunohistochemistry; Western blotting
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Background. Insulin-like growth factor I (IGF-I), a potent proximal tubule cell (PTC) mitogen, has been implicated in the progression of many human cancers. Our previous work on human renal tissues has suggested that IGF-I and several of its binding proteins (IGFBP-3 and -6) are up-regulated in clear cell renal cell carcinoma (RCC). Methods. To further elucidate the role of IGF-I and IGFBPs in RCC growth, immunohistochemistry, thymidine incorporation, and Western analysis were performed in primary cultures of normal PTC (priPTC) and clear-cell RCC (priRCC), as well as in SN12K1 cells (a cell line derived from metastatic RCC). Results. By immunohistochemistry, IGFBP-3 and IGF-I were prominently expressed in SN12K1 cells, and weakly expressed in priPTC and priRCC. Incubation with 100 ng/mL IGF-I significantly augmented DNA synthesis by priPTC (mean+/-SD 120.7%+/-19.7% of controls, P<0.05), priRCC (238.7%+/- 279.9% of controls, P<0.01), and SN12K1( 120.0%+/-22.9% of controls, P<0.05). Neutralizing antibodies to IGF-I and IGF-I receptor significantly suppressed SN12K1 growth (81.9%+/- 13.5% of control, P<0.01 and 87.4%+/-16.2% of control, P<0.05, respectively). Removal of endogenous IGFBP-3 by an anti-IGFBP-3 increased SN12K1 DNA synthesis (243.9%+/- 35.3% of control, P<0.001), which was partially abrogated by coincubation with exogenous IGFBP-3 (135.97%+/-5.9% of controls, P<0.001). Using Western analysis, IGFBP-3 expression was enhanced in IGF-I-stimulated SN12K1 cells exposed to exogenous IGF-I. Coincubation with anti-IGFBP-3 further enhanced IGF-I-induced DNA synthesis. Conclusion. RCC cells express IGF-I and IGFBP-3, and are responsive to exogenous IGF-I stimulation. Moreover, in SN12K1 cells (derived from metastatic RCC), autocrine IGF-I and IGFBP-3 actions, respectively, stimulated and inhibited growth. These results suggest that IGF-I and IGFBP-3 may be potential candidates for therapeutic manipulation in patients with advanced RCC.
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