Insulin‐like growth factor axis targeting in cancer and tumour angiogenesis – the missing link

Beijnum, Judy R. van; Pieters, Wietske; Nowak-Śliwińska, Patrycja; Griffioen, Arjan W.

doi:10.1111/brv.12306

Cited by 31 publications

(35 citation statements)

References 164 publications

(238 reference statements)

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“…IGF2 and its family members have been linked to the process of angiogenesis in general [4,12]. For example, levels of IGF1 and IGF2 in vitreous in the eye increase upon hypoxia, and IGF2 expression is upregulated in the growth phase of capillary hemangiomas [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

IGF-binding proteins 3 and 4 are regulators of sprouting angiogenesis

et al. 2020

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Purpose We have previously identified insulin-like growth factor 2 (IGF2) and insulin-like growth factor 1 receptor (IGF1R) as essential proteins for tip cell maintenance and sprouting angiogenesis. In this study, we aim to identify other IGF family members involved in endothelial sprouting angiogenesis. Methods Effects on sprouting were analyzed in human umbilical vein endothelial cells (HUVECs) using the spheroid-based sprouting model, and were quantified as mean number of sprouts per spheroid and average sprout length. RNA silencing technology was used to knockdown gene expression. Recombinant forms of the ligands (IGF1 and IGF2, insulin) and the IGF-binding proteins (IGFBP) 3 and 4 were used to induce excess effects. Effects on the tip cell phenotype were analyzed by measuring the fraction of CD34 + tip cells using flow cytometry and immunohistochemistry in a 3D angiogenesis model. Experiments were performed in the presence and absence of serum. Results Knockdown of IGF2 inhibited sprouting in HUVECs, in particular when cultured in the absence of serum, suggesting that components in serum influence the signaling of IGF2 in angiogenesis in vitro. We then determined the effects of IGFBP3 and IGFBP4, which are both present in serum, on IGF2-IGF1R signaling in sprouting angiogenesis in the absence of serum: knockdown of IGFBP3 significantly reduced sprouting angiogenesis, whereas knockdown of IGFBP4 resulted in increased sprouting angiogenesis in both flow cytometry analysis and immunohistochemical analysis of the 3D angiogenesis model. Other IGF family members except INSR did not affect IGF2-IGF1R signaling. Conclusions Serum components and IGF binding proteins regulate IGF2 effects on sprouting angiogenesis. Whereas IGFBP3 acts as co-factor for IGF2-IGF1R binding, IGFBP4 inhibits IGF2 signaling.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Section: Introductionmentioning

confidence: 99%

IGF-binding proteins 3 and 4 are regulators of sprouting angiogenesis

et al. 2020

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“… 26 In addition, there is clear evidence that the IGF signaling pathway has a key role in the onset and progress of various malignant tumors and can be targeted for therapeutic intervention. 10 , 25 To the best of our knowledge, this is the first study that shows significant lower IGF-1 serum values in OPL patients compared to healthy controls. Regarding lower levels in OSCC patients compared to healthy controls, two further clinical studies supported our results.…”

Section: Discussionmentioning

confidence: 69%

“…Recently described pro- and anti-angiogenic factors were matrix metalloproteinases (MMPs) and insulin-like growth factors (IGFs). 10 Analysis of these molecules could be highly useful for the early detection as well as for the determination of the individual prognosis of (pre-)malignant lesions in the oral cavity. 11 …”

Section: Introductionmentioning

confidence: 99%

“…The IGF system comprises a multifaceted network of ligands (IGF-1 and -2), their related receptors (IGFR-1 and -2), IGF-binding proteins (IGFBP1–6), and IGFBP proteases. 10 , 24 Regarding carcinogenesis, the IGF family members regulate proliferation and inhibition of cell apoptosis, influence cell transformation through the synthesis of numerous regulatory proteins and control clonal expansion and metastases of cells. 25 IGF-binding proteins (IGFBPs) modulate the bioavailability of IGFs and regulate the interaction between IGFs and cell-surface receptors.…”

Section: Introductionmentioning

confidence: 99%

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The matrix metalloproteinase and insulin-like growth factor system in oral cancer – a prospective clinical study

Schiegnitz¹,

Kämmerer²,

Schön³

et al. 2017

OTT

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AimThe absence of reliable single serum biomarkers for oral premalignant lesion (OPL) and oral squamous cell carcinoma (OSCC) limits early diagnosis, monitoring of advanced disease, and prediction of prognosis.MethodsIn this prospective study, serum levels of matrix metalloproteinase (MMP)-2, MMP-3, MMP-13, insulin-like growth factor (IGF)-1, and IGF-binding protein (IGFBP)-3 were measured in 81 untreated OSCC patients, 49 healthy subjects, and 75 individuals with OPLs, and correlated with clinicopathological parameters.ResultsSerum levels of MMP-3 were significantly higher in OSCC patients compared to healthy subjects (p=0.004). Mean IGF-1 and IGFBP-3 levels in OSCC patients were significantly lower in healthy subjects (p=0.001 and p<0.001). OSCC patients with an IGF-1 serum value <130 ng/mL (median) showed a significantly lower survival rate compared to ≥130 ng/mL (p=0.049). Combined use of IGF-1 (<130 ng/mL) and IGFBP-3 (<3.1 μg/mL) resulted in a significantly lower 12-month cumulative survival compared to the complementary set (78.5% vs 93.8%; p=0.031). There was a significantly positive correlation between IGF-1 and IGFBP-3 serum values (rs =0.625, p<0.001).ConclusionThis study shows that IGF-1 and IGFBP-3 have a vital role in the pathogenesis of OSCC and indicates for the first time that IGF-1 and IGFBP-3 in combination may be applied as potential tools for prognosis of OSCC.

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“…Therefore, they can participate in the pathogenesis of various diseases that are associated with pathological angiogenesis. 9 Locally produced IGFs seem to be especially important in the development of ocular diseases such as AMD, diabetic retinopathy, or retinopathy of prematurity (ROP). 10 …”

Section: Introductionmentioning

confidence: 99%

Gene expression levels of the insulin-like growth factor family in patients with AMD before and after ranibizumab intravitreal injections

Strzałka‐Mrozik

Kimsa-Furdzik

Kabiesz

et al. 2017

CIA

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PurposeThe present study focused on the assessment of the mRNA levels of the insulin-like growth factor (IGF) family in patients with the exudative form of age-related macular degeneration (AMD) before and after ranibizumab intravitreal injections.Patients and methodsAn analysis of the expression profile of the IGF family of genes in patients with AMD was carried out using the oligonucleotide microarray and quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) methods.ResultsIn the peripheral blood mononuclear cells (PBMCs) obtained from AMD group receiving ranibizumab compared to the peripheral blood mononuclear cells from AMD group before ranibizumab treatment using oligonucleotide microarray technique, six statistically significant differentially expressed transcripts related to the IGF family were detected (unpaired t-test, p<0.05, fold change >1.5). Moreover, analysis using the real-time RT-qPCR technique revealed statistically significant differences in the IGF2 and IGF2R mRNA levels (Mann–Whitney U test, p<0.05) between the two groups that were studied. Statistical analyses of both oligonucleotide microarray and real-time RT-qPCR results demonstrated a significant decreased expression only for IGF2 mRNA.ConclusionOur results revealed a changed expression of IGF2 mRNA after ranibizumab treatment.

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Insulin‐like growth factor axis targeting in cancer and tumour angiogenesis – the missing link

Cited by 31 publications

References 164 publications

IGF-binding proteins 3 and 4 are regulators of sprouting angiogenesis

IGF-binding proteins 3 and 4 are regulators of sprouting angiogenesis

The matrix metalloproteinase and insulin-like growth factor system in oral cancer – a prospective clinical study

Gene expression levels of the insulin-like growth factor family in patients with AMD before and after ranibizumab intravitreal injections

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Insulin‐like growth factor axis targeting in cancer and tumour angiogenesis – the missing link

Cited by 31 publications

References 164 publications

IGF-binding proteins 3 and 4 are regulators of sprouting angiogenesis

IGF-binding proteins 3 and 4 are regulators of sprouting angiogenesis

The matrix metalloproteinase and insulin-like growth factor system in oral cancer &ndash; a prospective clinical study

Gene expression levels of the insulin-like growth factor family in patients with AMD before and after ranibizumab intravitreal injections

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The matrix metalloproteinase and insulin-like growth factor system in oral cancer – a prospective clinical study