Review Article Disease evidence for IGFBP-2 as a key player in prostate cancer progression and development of osteosclerotic lesions
David J. DeGraff, Adam A. Aguiar, Robert A. Sikes
Laboratory for Cancer Ontogeny and Therapeutics, Center for Translational Cancer Research, Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
Received January 9, 2009; accepted January, 2009; available online January, 2009
Abstract: Accumulating evidence indicates that alterations in the IGF axis contribute to the development of chemo- and radio-resistant, advanced-stage cancers. Additionally, they contribute to hormonal insensitivity in adenocarcinomas such as those derived from prostate and breast. The ligands, IGF-I and IGF-II, along with their receptors, IGF-IR and IGF-IIR, have been implicated in a wide range of disease. Activation and subsequent signal transduction through the receptors is attenuated, and/or potentiated, by the interactions of IGF axis ligands, IGF-I/II, with the high affinity IGF-binding proteins 1 to 6 (IGFBP1-6). New evidence indicates that the IGFBPs, irrespective of ligand interactions, correlate with the development and metastatic behavior of several cancers. Increased expression of insulin-like growth factor binding protein 2 (IGFBP-2) is found in advanced cancers of the ovary, breast, stomach, adrenal gland, bladder, CNS, and prostate. Further, IGFBP-2 seemingly has ligand-independent effects that participate in the development and dissemination of advanced cancer cells. As such, IGFBP-2 can assist in the development of the lethal phenotype for some cancers. While several reports have shown an important role for IGFBP-2 in the development of androgen insensitivity and the proliferation of AI PCa cells in vivo, these studies have not tested a role for IGFBP-2 in the metastatic spread of AI PCa cells. Additionally, the mechanism of IGFBP-2 action in these events has not been elucidated. The redundancy and abundance of the IGFBPs have precluded a clear understanding of the means by which IGFBP-2 signals. Components of these signaling pathways, particularly IGFBP-2, are being evaluated currently in clinical trials. (AJTR901001).
Address all correspondence to: Robert A. Sikes, PhD Laboratory for Cancer Ontogeny and Therapeutics Center for Translational Cancer Research Department of Biological Sciences University of Delaware Newark, DE 19716 USA E-mail: rasikes@UDel.Edu