IGF binding proteins in cancer: mechanistic and clinical insights

Baxter, Robert C.

doi:10.1038/nrc3720

Cited by 443 publications

(512 citation statements)

References 194 publications

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“…Of note, we localized the IGFBP-3:VN complexes to the invasive front of tumor cell clusters, as well as near blood vessels within the tumor. This is in concordance with evidence that VN and IGFBP-3 are abundant in the circulation and become deposited in tumor tissues (16,33). Interestingly, the VN receptor, avb3, is expressed at high levels in endothelial cells during angiogenesis (34) and in addition to providing a provisional ECM for invading tumor cells, VN localizes functional MMPs to the tumor-ECM boundary (35) allowing tumor cells to penetrate constraining interstitial tissue ECM.…”

Section: Discussionsupporting

confidence: 67%

“…1). Given that IGF-I is predominantly bound to IGFBPs (especially IGFBP-3) in vivo (33), and that IGF-I:IGFBP binding is unaffected by complexation to VN (2), it is reasonable to presume that IGF-I is bound to the IGFBP-3:VN complexes. Of note, we localized the IGFBP-3:VN complexes to the invasive front of tumor cell clusters, as well as near blood vessels within the tumor.…”

Section: Discussionmentioning

confidence: 99%

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

Kashyap

Shooter

Shokoohmand

et al. 2016

Molecular Cancer Therapeutics

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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 L 27 -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. Mol Cancer Ther; 15(7); 1602-13. Ó2016 AACR.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

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

Kashyap

Shooter

Shokoohmand

et al. 2016

Molecular Cancer Therapeutics

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“…However, the observations regarding the IGF1/IGFBP3 molar ratio should be interpreted cautiously in terms of its biological role. In fact, it has recently been questioned whether the IGF1/IGFBP3 molar ratio is a reliable marker of free bioactive IGF1, as this has not been validated and proven experimentally (40). The molar ratio changes in the same direction as bioavailable IGF1 in some, but not all situations (39).…”

Section: Discussionmentioning

confidence: 99%

Circulating IGF1 and IGFBP3 in relation to the development of β-cell autoimmunity in young children

Peet

Hämäläinen

Kool

et al. 2015

European Journal of Endocrinology

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Objective: This study aimed at investigating the role of IGF1 and IGF binding protein 3 (IGFBP3) in the development of b-cell autoimmunity. Methods: Five hundred and sixty-three subjects with HLA-conferred susceptibility to type 1 diabetes (T1D) were monitored for signs of seroconversion to positivity for insulin and/or GAD, IA2, and zinc transporter 8 autoantibodies by the age of 3 years. In 40 subjects who developed at least one autoantibody, IGF1 and IGFBP3 plasma concentrations were measured and compared with 80 control subjects who remained negative for autoantibodies, and were matched for age, sex, country of origin, and HLA genotype. The increments of IGF1, IGFBP3, and IGF1/IGFBP3 molar ratio before and after seroconverison were compared with corresponding time intervals in controls. Results: The IGF1 concentrations at the age of 12 months and the IGF1/IGFBP3 ratio at the age of 24 months were lower in the autoantibody-positive children (P!0.05). The increase in circulating IGFBP3 was significantly higher in the autoantibodypositive children before seroconversion than in the corresponding time intervals in controls (0.43 mg/l; 95% CI 0.29-0.56 vs 0.22 mg/l; 95% CI 0.10-0.34 mg/l; P!0.01). Children carrying the high-risk HLA genotype had lower plasma IGF1 and IGFBP3 concentrations at the age of 24 months than those with low-risk genotypes (P!0.05 and ! 0.01 respectively). Conclusions: Circulating IGF1 and IGFBP3 appear to have a role in early development of b-cell autoimmunity. The decreased IGF1 concentrations in children with the high-risk HLA genotype may contribute to the reduced growth previously described in such children.

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“…IGF actions are finely regulated by a family of six highaffinity IGFBPs (Firth & Baxter 2002, Bach et al 2005, Baxter 2014). These proteins have three domains, with a high degree of homology within their N-and C-terminal domains, which both contain IGF-binding determinants.…”

Section: Introductionmentioning

confidence: 99%

Endothelial cells and the IGF system

Bach¹

2014

Journal of Molecular Endocrinology

153

118

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Endothelial cells line blood vessels and modulate vascular tone, thrombosis, inflammatory responses and new vessel formation. They are implicated in many disease processes including atherosclerosis and cancer. IGFs play a significant role in the physiology of endothelial cells by promoting migration, tube formation and production of the vasodilator nitric oxide. These actions are mediated by the IGF1 and IGF2/mannose 6-phosphate receptors and are modulated by a family of high-affinity IGF binding proteins. IGFs also increase the number and function of endothelial progenitor cells, which may contribute to protection from atherosclerosis. IGFs promote angiogenesis, and dysregulation of the IGF system may contribute to this process in cancer and eye diseases including retinopathy of prematurity and diabetic retinopathy. In some situations, IGF deficiency appears to contribute to endothelial dysfunction, whereas IGF may be deleterious in others. These differences may be due to tissue-specific endothelial cell phenotypes or IGFs having distinct roles in different phases of vascular disease. Further studies are therefore required to delineate the therapeutic potential of IGF system modulation in pathogenic processes.

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IGF binding proteins in cancer: mechanistic and clinical insights

Cited by 443 publications

References 194 publications

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

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

Circulating IGF1 and IGFBP3 in relation to the development of β-cell autoimmunity in young children

Endothelial cells and the IGF system

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