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Insulin-like growth factor-binding protein-3 inhibition of prostate cancer growth involves suppression of angiogenesis

Oncogene volume 26, pages 1811–1819 (2007)Cite this article

Abstract

Insulin-like growth factor-binding protein-3 (IGFBP-3) is a multifunctional protein that induces apoptosis utilizing both insulin-like growth factor receptor (IGF)-dependent and -independent mechanisms. We investigated the effects of IGFBP-3 on tumor growth and angiogenesis utilizing a human CaP xenograft model in severe-combined immunodeficiency mice. A 16-day course of IGFBP-3 injections reduced tumor size and increased apoptosis and also led to a reduction in the number of vessels stained with CD31. In vitro, IGFBP-3 inhibited both vascular endothelial growth factor- and IGF-stimulated human umbilical vein endothelial cells vascular network formation in a matrigel assay. This action is primarily IGF independent as shown by studies utilizing the non-IGFBP-binding IGF-1 analog Long-R3. Additionally, we used a fibroblast growth factor-enriched matrigel-plug assay and chick allantoic membrane assays to show that IGFBP-3 has potent antiangiogenic actions in vivo. Finally, overexpression of IGFBP-3 or the non-IGF-binding GGG-IGFBP-3 mutant in Zebrafish embryos confirmed that both IGFBP-3 and the non-IGF-binding mutant inhibited vessel formation in vivo, indicating that the antiangiogenic effect of IGFBP-3 is an IGF-independent phenomenon. Together, these studies provide the first evidence that IGFBP-3 has direct, IGF-independent inhibitory effects on angiogenesis providing an additional mechanism by which it exerts its tumor suppressive effects and further supporting its development for clinical use in the therapy of patients with prostate cancer.

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Acknowledgements

This work was supported in part by a Prostate Cancer Foundation award and National Institutes of Health Grants RO1AG20954, P50CA92131 and RO1CA100938 (to PC), grants from the Stein-Oppenheimer Foundation, the Lawson Wilkins Pediatric Endocrinology Society, the UCLA Prostate Cancer SPORE and National Institutes of Health Grant 2K12HD34610 (to K-WL); and a National Institutes of Health Grant R01DK054508 (to SL).

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Authors and Affiliations

  1. Division of Pediatric Endocrinology, Department of Pediatrics, Mattel Children's Hospital, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

    B Liu, K-W Lee, M Anzo & P Cohen

  2. Center of Developmental Biology and Genetics, College of Life Sciences, Peking University, Beijing, PR China

    B Zhang

  3. Department of Urology and Chao Family Comprehensive Cancer Center, UCI, Irvine, CA, USA

    X Zi

  4. Division of Experimental Medicine, Department of Medicine and Department of Oncology, McGill University, Montreal, QC, Canada

    Y Tao & M Pollak

  5. INSMED Corp., Glen Allen, Charlottesville, VA, USA

    L Shiry

  6. Department of Molecular, Cell and Developmental Biology, UCLA, Los Angeles, CA, USA

    S Lin

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Correspondence to P Cohen.

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Liu, B., Lee, KW., Anzo, M. et al. Insulin-like growth factor-binding protein-3 inhibition of prostate cancer growth involves suppression of angiogenesis. Oncogene 26, 1811–1819 (2007). https://doi.org/10.1038/sj.onc.1209977

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