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The Role of the IGF Axis in Disease 3.0
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The Role of the IGF Axis in Disease 3.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: 31 July 2024 | Viewed by 6731

Special Issue Editors

Dr. Claire M. Perks

E-Mail Website
Guest Editor
Cancer Endocrinology Group, Bristol Medical School, Southmead Hospital, Bristol BS10 5NB, UK
Interests: metabolic disturbances; IGFs and epithelial cancers
Special Issues, Collections and Topics in MDPI journals
Dr. Rachel Barker

E-Mail Website
Guest Editor
Cancer Endocrinology Group, Bristol Medical School, Southmead Hospital, Bristol BS10 5NB, UK
Interests: prostate cancer; crosstalk between cancer and Alzheimer's disease; amyloid precursor protein and its processing in prostate cancer; IGFs in cancer

Special Issue Information

Dear Colleagues,

This Special Issue continues on from our previous Special Issues, "The Role of the IGF Axis in Disease" and “The Role of the IGF Axis in Disease 2.0”.

This research topic aims to highlight the key roles that members of the insulin-like growth factor (IGF) axis (including ligands, IGF-I and -II, IGF binding proteins (IGFBPs1-6) and IGF receptors) play in the risk and development of diseases. The IGF family can affect many physiological systems in the body by modulating cell processes, including proliferation, differentiation, survival, and metabolism. Consequently, they are often dysregulated in many pathological conditions, leading to the development of different strategies to target them.

Dr. Claire M. Perks
Dr. Rachel Barker
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • IGF axis
  • cancer
  • obesity
  • hallmarks of cancer

Published Papers (5 papers)

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Research

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16 pages, 1099 KiB  
Article
The IGF–PAPP-A–Stanniocalcin Axis in Serum and Ascites Associates with Prognosis in Patients with Ovarian Cancer
by Rikke Hjortebjerg, Claus Høgdall, Kristian Horsman Hansen, Estrid Høgdall and Jan Frystyk
Int. J. Mol. Sci. 2024, 25(4), 2014; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25042014 - 7 Feb 2024
Viewed by 695
Abstract
Pregnancy-associated plasma protein-A (PAPP-A) and PAPP-A2 modulate insulin-like growth factor (IGF) action and are inhibited by the stanniocalcins (STC1 and STC2). We previously demonstrated increased PAPP-A and IGF activity in ascites from women with ovarian carcinomas. In this prospective, longitudinal study of 107 [...] Read more.
Pregnancy-associated plasma protein-A (PAPP-A) and PAPP-A2 modulate insulin-like growth factor (IGF) action and are inhibited by the stanniocalcins (STC1 and STC2). We previously demonstrated increased PAPP-A and IGF activity in ascites from women with ovarian carcinomas. In this prospective, longitudinal study of 107 women with ovarian cancer and ascites accumulation, we determined corresponding serum and ascites levels of IGF-1, IGF-2, PAPP-A, PAPP-A2, STC1, and STC2 and assessed their relationship with mortality. As compared to serum, we found highly increased ascites levels of PAPP-A (51-fold) and PAPP-A2 (4-fold). Elevated levels were also observed for IGF-1 (12%), STC1 (90%) and STC2 (68%). In contrast, IGF-2 was reduced by 29% in ascites. Patients were followed for a median of 38.4 months (range: 45 days to 8.9 years), during which 73 patients (68.2%) died. Overall survival was longer for patients with high serum IGF-1 (hazard ratio (HR) per doubling in protein concentration: 0.60, 95% CI: 0.40–0.90). However, patients with high ascites levels of IGF-1 showed a poorer prognosis (HR: 2.00 (1.26–3.27)). High serum and ascites IGF-2 levels were associated with increased risk of mortality (HR: 2.01 (1.22–3.30) and HR: 1.78 (1.24–2.54), respectively). Similarly, serum PAPP-A2 was associated with mortality (HR: 1.26 (1.08–1.48)). Our findings demonstrate the presence and activity of the IGF system in the local tumor ecosystem, which is likely a characteristic feature of malignant disease and plays a role in its peritoneal dissemination. The potential clinical implications are supported by our finding that serum levels of the proteins are associated with patient prognosis. Full article
(This article belongs to the Special Issue The Role of the IGF Axis in Disease 3.0)
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18 pages, 845 KiB  
Article
Protein Plasma Levels of the IGF Signalling System Are Altered in Major Depressive Disorder
by Carlos Fernández-Pereira, Maria Aránzazu Penedo, Tania Rivera-Baltanás, Tania Pérez-Márquez, Marta Alves-Villar, Rafael Fernández-Martínez, César Veiga, Ángel Salgado-Barreira, José María Prieto-González, Saida Ortolano, José Manuel Olivares and Roberto Carlos Agís-Balboa
Int. J. Mol. Sci. 2023, 24(20), 15254; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242015254 - 17 Oct 2023
Cited by 2 | Viewed by 1737
Abstract
The Insulin-like growth factor 2 (IGF-2) has been recently proven to alleviate depressive-like behaviors in both rats and mice models. However, its potential role as a peripheral biomarker has not been evaluated in depression. To do this, we measured plasma IGF-2 and other [...] Read more.
The Insulin-like growth factor 2 (IGF-2) has been recently proven to alleviate depressive-like behaviors in both rats and mice models. However, its potential role as a peripheral biomarker has not been evaluated in depression. To do this, we measured plasma IGF-2 and other members of the IGF family such as Binding Proteins (IGFBP-1, IGFBP-3, IGFBP-5 and IGFBP-7) in a depressed group of patients (n = 51) and in a healthy control group (n = 48). In some of these patients (n = 15), we measured these proteins after a period (19 ± 6 days) of treatment with antidepressants. The Hamilton Depressive Rating Scale (HDRS) and the Self-Assessment Anhedonia Scale (SAAS) were used to measure depression severity and anhedonia, respectively. The general cognition state was assessed by the Mini-Mental State Examination (MMSE) test and memory with the Free and Cued Selective Reminding Test (FCSRT). The levels of both IGF-2 and IGFBP-7 were found to be significantly increased in the depressed group; however, only IGF-2 remained significantly elevated after correction by age and sex. On the other hand, the levels of IGF-2, IGFBP-3 and IGFBP-5 were significantly decreased after treatment, whereas only IGFBP-7 was significantly increased. Therefore, peripheral changes in the IGF family and their response to antidepressants might represent alterations at the brain level in depression. Full article
(This article belongs to the Special Issue The Role of the IGF Axis in Disease 3.0)
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16 pages, 3018 KiB  
Article
The IGF-Independent Role of IRS-2 in the Secretion of MMP-9 Enhances the Growth of Prostate Carcinoma Cell Line PC3
by Haruka Furuta, Yina Sheng, Ayaka Takahashi, Raku Nagano, Naoyuki Kataoka, Claire Marie Perks, Rachel Barker, Fumihiko Hakuno and Shin-Ichiro Takahashi
Int. J. Mol. Sci. 2023, 24(20), 15065; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242015065 - 11 Oct 2023
Viewed by 1073
Abstract
Insulin receptor substrate-2 (IRS-2), a substrate of the insulin-like growth factor (IGF)-I receptor, is highly expressed in the prostate cancer cell line, PC3. We recently demonstrated that extracellular signal-regulated kinase (Erk1/2), a kinase downstream of IGF signaling, is activated in PC3 cells under [...] Read more.
Insulin receptor substrate-2 (IRS-2), a substrate of the insulin-like growth factor (IGF)-I receptor, is highly expressed in the prostate cancer cell line, PC3. We recently demonstrated that extracellular signal-regulated kinase (Erk1/2), a kinase downstream of IGF signaling, is activated in PC3 cells under serum starvation, and this activation can be inhibited by IRS-2 knockdown. Here, we observed that adding an IGF-I-neutralizing antibody to the culture medium inhibited the activation of Erk1/2. Suppression of Erk1/2 in IRS-2 knockdown cells was restored by the addition of a PC3 serum-free conditioned medium. In contrast, the IRS-2-silenced PC3 conditioned medium could not restore Erk1/2 activation, suggesting that IRS-2 promotes the secretion of proteins that activate the IGF signaling pathway. Furthermore, gelatin zymography analysis of the conditioned medium showed that matrix metalloproteinase-9 (MMP-9) was secreted extracellularly in an IRS-2 dependent manner when PC3 was cultured under serum starvation conditions. Moreover, MMP-9 knockdown suppressed Erk1/2 activation, DNA synthesis, and migratory activity. The IRS-2 levels were positively correlated with Gleason grade in human prostate cancer tissues. These data suggest that highly expressed IRS-2 activates IGF signaling by enabling the secretion of MMP-9, which is associated with hyperproliferation and malignancy of prostate cancer cell line, PC3. Full article
(This article belongs to the Special Issue The Role of the IGF Axis in Disease 3.0)
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Review

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14 pages, 1241 KiB  
Review
Role of the Insulin-like Growth Factor System in Neurodegenerative Disease
by Moira S. Lewitt and Gary W. Boyd
Int. J. Mol. Sci. 2024, 25(8), 4512; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25084512 - 20 Apr 2024
Viewed by 655
Abstract
The insulin-like growth factor (IGF) system has paracrine and endocrine roles in the central nervous system. There is evidence that IGF signalling pathways have roles in the pathophysiology of neurodegenerative disease. This review focusses on Alzheimer’s disease and Parkinson’s disease, the two most [...] Read more.
The insulin-like growth factor (IGF) system has paracrine and endocrine roles in the central nervous system. There is evidence that IGF signalling pathways have roles in the pathophysiology of neurodegenerative disease. This review focusses on Alzheimer’s disease and Parkinson’s disease, the two most common neurodegenerative disorders that are increasing in prevalence globally in relation to the aging population and the increasing prevalence of obesity and type 2 diabetes. Rodent models used in the study of the molecular pathways involved in neurodegeneration are described. However, currently, no animal model fully replicates these diseases. Mice with triple mutations in APP, PSEN and MAPT show promise as models for the testing of novel Alzheimer’s therapies. While a causal relationship is not proven, the fact that age, obesity and T2D are risk factors in both strengthens the case for the involvement of the IGF system in these disorders. The IGF system is an attractive target for new approaches to management; however, there are gaps in our understanding that first need to be addressed. These include a focus beyond IGF-I on other members of the IGF system, including IGF-II, IGF-binding proteins and the type 2 IGF receptor. Full article
(This article belongs to the Special Issue The Role of the IGF Axis in Disease 3.0)
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34 pages, 3227 KiB  
Review
Insulin Receptor Isoforms and Insulin Growth Factor-like Receptors: Implications in Cell Signaling, Carcinogenesis, and Chemoresistance
by Mariam Ahmed Galal, Samhar Samer Alouch, Buthainah Saad Alsultan, Huda Dahman, Nouf Abdullah Alyabis, Sarah Ammar Alammar and Ahmad Aljada
Int. J. Mol. Sci. 2023, 24(19), 15006; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241915006 - 9 Oct 2023
Cited by 5 | Viewed by 2018
Abstract
This comprehensive review thoroughly explores the intricate involvement of insulin receptor (IR) isoforms and insulin-like growth factor receptors (IGFRs) in the context of the insulin and insulin-like growth factor (IGF) signaling (IIS) pathway. This elaborate system encompasses ligands, receptors, and binding proteins, giving [...] Read more.
This comprehensive review thoroughly explores the intricate involvement of insulin receptor (IR) isoforms and insulin-like growth factor receptors (IGFRs) in the context of the insulin and insulin-like growth factor (IGF) signaling (IIS) pathway. This elaborate system encompasses ligands, receptors, and binding proteins, giving rise to a wide array of functions, including aspects such as carcinogenesis and chemoresistance. Detailed genetic analysis of IR and IGFR structures highlights their distinct isoforms, which arise from alternative splicing and exhibit diverse affinities for ligands. Notably, the overexpression of the IR-A isoform is linked to cancer stemness, tumor development, and resistance to targeted therapies. Similarly, elevated IGFR expression accelerates tumor progression and fosters chemoresistance. The review underscores the intricate interplay between IRs and IGFRs, contributing to resistance against anti-IGFR drugs. Consequently, the dual targeting of both receptors could present a more effective strategy for surmounting chemoresistance. To conclude, this review brings to light the pivotal roles played by IRs and IGFRs in cellular signaling, carcinogenesis, and therapy resistance. By precisely modulating these receptors and their complex signaling pathways, the potential emerges for developing enhanced anti-cancer interventions, ultimately leading to improved patient outcomes. Full article
(This article belongs to the Special Issue The Role of the IGF Axis in Disease 3.0)
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