Antagonists of IGF: Vitronectin Interactions Inhibit IGF-I-Induced Breast Cancer Cell Functions

摘要

We provide proof-of-concept evidence for a new class of therapeutics that target growth factor: extracellular matrix (GF: ECM) interactions for the management of breast cancer. Insulinlike growth factor-I (IGF-I) forms multiprotein complexes with IGF-binding proteins (IGFBP) and the ECM protein vitronectin (VN), and stimulates the survival, migration and invasion of breast cancer cells. For the first time we provide physical evidence for IGFBP-3: VN interactions in breast cancer patient tissues; these interactions were predominantly localized to tumor cell clusters and in stroma surrounding tumor cells. We show that disruption of IGF-I: IGFBP: VN complexes with L27-IGF-II inhibits IGF-I: IGFBP: VN-stimulated breast cancer cell migration and proliferation in two-and three-dimensional assay systems. Peptide arrays screened to identify regions critical for the IGFBP-3/-5: VN and IGF-II: VN interactions demonstrated IGFBP-3/-5 and IGF-II binds VN through the hemopexin-2 domain, and VN binds IGFBP-3 at residues not involved in the binding of IGF-I to IGFBP-3. IGFBP-interacting VN peptides identified from these peptide arrays disrupted the IGF-I: IGFBP: VN complex, impeded the growth of primary tumor-like spheroids and, more importantly, inhibited the invasion of metastatic breast cancer cells in 3D assay systems. These studies provide first-in-field evidence for the utility of small peptides in antagonizing GF: ECM-mediated biologic functions and present data demonstrating the potential of these peptide antagonists as novel therapeutics. (C) 2016 AACR.