The Circulating IGF System in Hepatocellular Carcinoma: The Impact of Liver Status and Treatment

Espelund, Ulrick; Grønbæk, Henning; Villadsen, Gerda Elisabeth; Simonsen, Kira; Vestergaard, P; Jørgensen, Jens Otto Lunde; Flyvbjerg, Allan; Vilstrup, Hendrik; Frystyk, Jan

doi:10.1016/j.ghir.2015.05.002

Cited by 18 publications

(19 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results are consistent with previous findings of reduced IGF-1 levels in cirrhosis (36)(37)(38)(39)(40). Reduced levels of IGF-1 in patients with hepatic cirrhosis are attributed to liver damage, as hepatocytes are the primary source of IGF-1 in response to GH stimulation (35,41). The observation that IGF-1 synthesis reflects the severity of liver fibrosis in chronic hepatitis C supports this hypothesis (35).…”

Section: Discussion Discussionsupporting

confidence: 93%

“…Reduced levels of IGF-1 in patients with hepatic cirrhosis are attributed to liver damage, as hepatocytes are the primary source of IGF-1 in response to GH stimulation (35,41). The observation that IGF-1 synthesis reflects the severity of liver fibrosis in chronic hepatitis C supports this hypothesis (35). Further, in agreement with our findings, previous Table 3 -Correlation between background clinical variables and freedom of liver recurrence (FLR), disease-free survival (DFS) and overall survival (OS) in HCC patients undergoing surgical treatments.…”

Section: Discussion Discussionmentioning

confidence: 99%

“…For example, lower baseline serum IGF-1 levels were associated with shorter overall survival (OS) in patients with HCC after surgical resection and were proposed as a prognostic factor for early recurrence (34). Similarly, lower pretreatment serum IGF-1 was associated with higher risk of relapse following TACE in HCC patients (34,35). Given this dual biological and prognostic role of IGF-1 pathway in underlying chronic liver disease and in HCC progression, respectively, we evaluated plasma and serum IGF-1 in an observational study of HCC patients, with or without cirrhosis, who underwent surgical treatments at a single institution.…”

Section: Introduction Introductionmentioning

confidence: 99%

See 2 more Smart Citations

An Observational Study of Circulating Plasma and Serum Insulin-Like Growth Factor 1 as Prognostic Biomarkers in Surgical Hepatocellular Carcinoma Patients

Kaseb¹,

Dima²,

Pestana³

et al. 2019

SGO

View full text Add to dashboard Cite

Identification of biomarkers that correlate with prognosis is crucial in hepatocellular carcinoma (HCC) because of the high recurrence rates seen after surgical treatments. Serum levels of α-fetoprotein (AFP) are widely used clinically, but the prognostic value of AFP remains unclear. AFP levels are influenced not only by the presence of HCC but also by the severity of the underlying liver disease. Furthermore, AFP could be normal in up to 30% of HCC patients. Thus, additional biomarkers are needed. Insulin-like growth factors 1 (IGF-1) is a growth factor with dose-dependent proliferation and anabolic effects, and its interaction with IGF-1 receptor (IGF-1R) may promote tumor progression. On the other hand, hepatic synthesis of IGF-1 is significantly reduced due to underlying chronic liver disease in HCC patients, and previous studies demonstrated that circulating IGF-1 is a useful predictor of hepatic reserve in HCC patients. We evaluated circulating IGF-1 and AFP levels in a cohort of HCC patients undergoing liver resection or liver transplantation at a single institution (Fundeni Clinical Institute, Romania). We found that plasma IGF-1 was decreased in HCC patients as compared with healthy individuals, and that plasma IGF-1 was associated with the presence of cirrhosis in HCC patients. In addition, we found that plasma IGF-1 levels were significantly associated with disease-free survival (DFS) and overall survival (OS). This correlation was due to the significant association between higher IGF-1 and more favorable DFS and OS following liver transplantation. Independent validation of this biomarker is warranted in the setting of liver transplantation to confirm and further define the prognostic implications of plasma IGF-1 in HCC patients.

show abstract

Section: Discussion Discussionsupporting

confidence: 93%

Section: Discussion Discussionmentioning

confidence: 99%

Section: Introduction Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An Observational Study of Circulating Plasma and Serum Insulin-Like Growth Factor 1 as Prognostic Biomarkers in Surgical Hepatocellular Carcinoma Patients

Kaseb¹,

Dima²,

Pestana³

et al. 2019

SGO

View full text Add to dashboard Cite

show abstract

“…For VEGF, the concentration that we used in the serum-free experiments (25 ng/mL) was similar to the concentration in medium supplemented with 20% human serum (22-45 ng/mL) [50][51][52]. However, the concentrations of IGF2 and IGFBP3 were relatively low in our experimental setup as compared to medium supplemented with 20% serum and especially that of IGFBP3 [24,[53][54][55]. A comparison of these concentrations can only be performed with caution because of the interactions between these proteins and other IGF family members [11].…”

Section: Discussionmentioning

confidence: 69%

“…Both ligands are transported in the circulation after complex formation with IGFBP3 and acid-labile subunit (ALS). The latter protein is also produced in the liver and reduces bioavailability and degradation of IGFs in the blood [20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma

et al. 2022

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Serine-arginine rich splicing factor 3 (SRSF3) plays a critical role in hepatocyte function and its loss in mice promotes chronic liver damage and leads to HCC. Hepatocyte-specific SRSF3 knockout mice (SKO mice) also overexpress insulin-like growth factor 2 (IGF2). In the present study, double deletion of Igf2 and Srsf3 (DKO mice) prevents hepatic fibrosis and inflammation, and completely prevents tumor formation, and is associated with decreased proliferation, apoptosis and DNA damage, and restored DNA repair enzyme expression. This is confirmed in vitro, where IGF2 treatment of HepG2 hepatoma cells decreases DNA repair enzyme expression and causes DNA damage. Tumors from the SKO mice also show mutational signatures consistent with homologous recombination and mismatch repair defects. Analysis of frozen human samples shows that SRSF3 protein is decreased sixfold in HCC compared to normal liver tissue but SRSF3 mRNA is increased. Looking at public TCGA data, HCC patients having high SRSF3 mRNA expression show poor survival, as do patients with alterations in known SRSF3-dependent splicing events. The results indicate that IGF2 overexpression in conjunction with reduced SRSF3 splicing activity could be a major cause of DNA damage and driver of liver cancer.

show abstract

The Circulating IGF System in Hepatocellular Carcinoma: The Impact of Liver Status and Treatment

Cited by 18 publications

References 40 publications

An Observational Study of Circulating Plasma and Serum Insulin-Like Growth Factor 1 as Prognostic Biomarkers in Surgical Hepatocellular Carcinoma Patients

An Observational Study of Circulating Plasma and Serum Insulin-Like Growth Factor 1 as Prognostic Biomarkers in Surgical Hepatocellular Carcinoma Patients

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

Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma

Contact Info

Product

Resources

About