Biochemical Characterization of Individual Human Glycosylated pro-Insulin-like Growth Factor (IGF)-II and big-IGF-II Isoforms Associated with Cancer

Greenall, Sameer A.; Bentley, John D.; Pearce, Lesley A.; Scoble, Judith A.; Sparrow, Lindsay G.; Bartone, Nicola; Xiao, Xiaowen; Baxter, Robert C.; Cosgrove, Leah; Adams, Timothy E.

doi:10.1074/jbc.m112.432013

Cited by 37 publications

(54 citation statements)

References 36 publications

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“…Our observation that the concentration of IGFBP-6 increased over the duration of culture may suggest a functional regulatory role for the concomitant rise of IGF-2 levels, because IGFBP-6 has a high affinity for IGF-2 [21]. Also, IGFBP-3 has high affinity for IGF-2 [22][23][24][25] which may explain increase of its levels in culture medium during the course of the study. In general, proteins of the IGF family have a profound impact on embryo and placenta development [5,19,26].…”

Section: Discussionmentioning

confidence: 88%

Growth factors and their receptors derived from human amniotic cells in vitro

Grzywocz

Pius-Sadowska

Kłos

et al. 2014

Folia Histochem Cytobiol.

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Abstract:In vitro studies have shown that amnion-produced growth factors participated in angiogenesis, re-epithelialization, and immunomodulation. The aim of our study was to investigate the growth factors and receptors produced by human amnion tissue and amniotic cells. Human amnions (hAM) were isolated, and amnion circles were dissected for in vitro analysis. Some amnion fragments were digested by the use of different methods to obtain two cell fractions, which were analysed for mesenchymal and epithelial cell markers. Amniotic circles and human amniotic cell fractions were cultured in a protein-free medium. Proteins secreted into the culture medium were analysed with a human growth factor antibody array. Conditioned culture media were added to human umbilical vein epithelial cells (HUVECs) to test for stimulation of migration (scratch test) and proliferation (Ki67 expression). Fraction 1 cells expressed both cytokeratin and mesenchymal cell markers which indicated that it was composed of a mixture of human amnion epithelial cells (hAECs) and mesenchymal stromal cells (hAMSCs). Fraction 2 cells mainly expressed cytokeratin and, therefore, were designed as hAECs. Secretion of proteins by the cultured cells increased with time. The hAM cultures secreted EGF-R, IGF, and IGFBP-2, -3 and -6; Cell Fraction 1 secreted NT-4, whereas Cell Fraction 2 secreted G-CSF, M-CSF, and PDGF. Conditioned media of hAM cultures stimulated HUVECs migration. We have showed for the first time that human amnions and amniotic cells secreted IGFBP-6, MCSF-R, PDGF-AB, FGF-6, IGFBP-4, NT-4, and VEGF-R3. We found that Cell Fraction 1, Cell Fraction 2, and the whole amnion secreted different proteins, possibly due to different proportions of amnion-derived cells and different cell-cell interactions. The hAM cell factors remained functional in vitro and induced intensified migration of HUVECs. The growth factors and receptors found in amnion or amniotic cell media might be used for regenerative medicine.

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Section: Discussionmentioning

confidence: 88%

Growth factors and their receptors derived from human amniotic cells in vitro

Grzywocz

Pius-Sadowska

Kłos

et al. 2014

Folia Histochem Cytobiol.

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“…The increased binary complex formation that occurs in the presence of excessive big IGF2 probably increases its bioavailability. Big IGF2 isoforms bind less readily to IGF2R, which may impair their clearance further increasing bioavailability (Greenall et al 2013). Interestingly, NICTH and glucose intolerance were recently reported in the same patient (Thabit et al 2011).…”

Section: Mechanism Of Hypoglycaemiamentioning

confidence: 99%

“…The glycosylation on big IGF2 may promote ternary complex formation in serum. Big IGF2 also forms binary complexes with IGFBP2, IGFBP3 and IGFBP5 (Qiu et al 2010, Greenall et al 2013.…”

Section: Igf2mentioning

confidence: 99%

IGF2 and cancer

Livingstone¹

2013

Endocrine-Related Cancer

254

227

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Insulin-like growth factor 2 (IGF2) is a 7.5 kDa mitogenic peptide hormone expressed by liver and many other tissues. It is three times more abundant in serum than IGF1, but our understanding of its physiological and pathological roles has lagged behind that of IGF1. Expression of the IGF2 gene is strictly regulated. Over-expression occurs in many cancers and is associated with a poor prognosis. Elevated serum IGF2 is also associated with increased risk of developing various cancers including colorectal, breast, prostate and lung. There is established clinical utility for IGF2 measurement in the diagnosis of non-islet cell tumour hypoglycaemia, a condition characterised by a molar IGF2:IGF1 ratio O10. Recent advances in understanding of the pathophysiology of IGF2 in cancer have suggested much novel clinical utility for its measurement. Measurement of IGF2 in blood and genetic and epigenetic tests of the IGF2 gene may help assess cancer risk and prognosis. Further studies will determine whether these tests enter clinical practice. New therapeutic approaches are being developed to target IGF2 action. This review provides a clinical perspective on IGF2 and an update on recent research findings.

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“…The IGF1R has two ligands, IGF-1 and IGF-2, and they are polypeptides of approximately 7.5 kDa that are structurally and functionally related to insulin. Some tumors also produce IGF-2 in larger precursor forms with variable receptor reactivity (Greenall et al 2013). In addition to their high-affinity interaction with IGF1R, the IGFs bind with much lower affinity (about 1%) to the structurally related insulin receptor (InsR) in its main metabolically active isoform (isoform B), whereas IGF-2 and insulin itself are potent activators of the more mitogenic InsR isoform A (Morcavallo et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

Ochnik

Baxter

2016

Endocrine-Related Cancer

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Insulin-like growth factor receptor (IGF1R) signaling as a therapeutic target has been widely studied and clinically tested. Despite the vast amount of literature supporting the biological role of IGF1R in breast cancer, effective clinical translation in targeting its activity as a cancer therapy has not been successful. The intrinsic complexity of cancer cell signaling mediated by many tyrosine kinase growth factor receptors that work together to modulate each other and intracellular downstream mediators in the cell highlights that studying IGF1R expression and activity as a prognostic factor and therapeutic target in isolation is certainly associated with problems. This review discusses the current literature and clinical trials associated with IGF-1 signaling and attempts to look at new ways of designing novel IGF1R-directed breast cancer therapy approaches to target its activity and/or intracellular downstream signaling pathways in IGF1R-expressing breast cancers. 23:11 Review A M Ochnik and R C BaxterDual IGF-directed breast cancer therapies

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Biochemical Characterization of Individual Human Glycosylated pro-Insulin-like Growth Factor (IGF)-II and big-IGF-II Isoforms Associated with Cancer

Cited by 37 publications

References 36 publications

Growth factors and their receptors derived from human amniotic cells in vitro

Growth factors and their receptors derived from human amniotic cells in vitro

IGF2 and cancer

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

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