Special Issue "Obesity, Diabetes, and Cancer: The Role of the Insulin/IGF Axis; Mechanisms and Clinical Implications"

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (28 January 2022) | Viewed by 14642

Special Issue Editors

Prof. Antonino Belfiore
E-Mail Website
Guest Editor
Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania, Catania, Italy
Interests: insulin receptor; insulin receptor isoforms; insulin and cancer; insulin-like growth factors I and II and cancer; obesity; diabetes and cancer; endocrine-related cancers
Special Issues, Collections and Topics in MDPI journals
Prof. Andrea Morrione
E-Mail Website
Guest Editor
Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Biolife Sciences Building Room 429b 1900 North 12th Street, Philadelphia, PA 19122, USA
Interests: insulin receptor; insulin receptor isoforms; insulin and cancer; insulin-like growth factors I and II and cancer; obesity; diabetes and cancer; endocrine-related cancers

Special Issue Information

Dear Colleagues,

Obesity and type 2 diabetes mellitus (T2DM) are strictly interconnected metabolic disorders, which are associated with Western diet and lifestyle and are progressively diffusing worldwide. Obesity has more than doubled its prevalence in the last 30 years, reaching a prevalence of 40% in the United States and 30% in Europe. Similarly, according to the WHO, the global prevalence of diabetes among adults over 18 years of age rose from 4.7% in 1980 to 8.5% in 2014. Approximately 14% of cancer-related deaths in men and 20% in women are somewhat attributed to obesity/T2DM. Cancers arising in obese/T2DM patients are often resistant to conventional as well as to targeted treatments, tend to metastasize faster, and have a worse prognosis. Considering the current trend of increasing average lifespan expectancy, it is most likely that costs related to care for these pathological conditions will grow unpredictably in the next future. Therefore, novel biomarkers and targets for personalized therapy of cancer in the context of obesity/T2DM represent an unmet need.

A dysregulated insulin/IGF axis including chronic insulin resistance is suspected to orchestrate several mechanisms involved in tumor progression and metastases in obese/T2DM patients, such as low-grade inflammation, altered adipocytokine production, estrogen-rich tumor microenvironment, stem-like cell phenotype, altered immune response, etc. Conversely, the tumor itself and several antitumor treatments may have a profound impact on the insulin/IGF axis, particularly in the contest of insulin resistance, which may sustain tumor resistance or relapse.

In this Biomolecules Special Issue on “Obesity, Diabetes and Cancer: The Role of the Insulin/IGF Axis; Mechanisms and Clinical Implications”, authors will dissect the impact of this fundamental axis in cancer progression, dissemination, and response to therapies, as well as critical clinical implications in cancer survivors.

Prof. Antonino Belfiore
Prof. Andrea Morrione
Guest Editors

Manuscript Submission Information

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Keywords

  • Insulin/IGF axis
  • Insulin
  • Insulin receptor
  • Insulin receptor isoforms
  • IGF-1 receptor
  • Obesity
  • Diabetes mellitus
  • Metabolic syndrome
  • Insulin resistance
  • Anticancer therapy resistance
  • Adipocytokines
  • Low-grade inflammation

Published Papers (8 papers)

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Editorial

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Editorial
Obesity, Diabetes, and Cancer: The Role of the Insulin/IGF Axis; Mechanisms and Clinical Implications
Biomolecules 2022, 12(5), 612; https://doi.org/10.3390/biom12050612 - 20 Apr 2022
Viewed by 1384
Abstract
This biomolecules Special Issue includes original research articles and reviews focusing on recent advances in the biology of the insulin-like growth factor (IGF) system [...] Full article

Research

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Article
DDR1 Affects Metabolic Reprogramming in Breast Cancer Cells by Cross-Talking to the Insulin/IGF System
Biomolecules 2021, 11(7), 926; https://doi.org/10.3390/biom11070926 - 22 Jun 2021
Cited by 3 | Viewed by 1944
Abstract
The insulin receptor isoform A (IR-A), a dual receptor for insulin and IGF2, plays a role in breast cancer (BC) progression and metabolic reprogramming. Notably, discoidin domain receptor 1 (DDR1), a collagen receptor often dysregulated in cancer, is involved in a functional crosstalk [...] Read more.
The insulin receptor isoform A (IR-A), a dual receptor for insulin and IGF2, plays a role in breast cancer (BC) progression and metabolic reprogramming. Notably, discoidin domain receptor 1 (DDR1), a collagen receptor often dysregulated in cancer, is involved in a functional crosstalk and feed forward loop with both the IR-A and the insulin like growth factor receptor 1 (IGF1R). Here, we aimed at investigating whether DDR1 might affect BC cell metabolism by modulating the IGF1R and/or the IR. To this aim, we generated MCF7 BC cells engineered to stably overexpress either IGF2 (MCF7/IGF2) or the IR-A (MCF7/IR-A). In both cell models, we observed that DDR1 silencing induced a significant decrease of total ATP production, particularly affecting the rate of mitochondrial ATP production. We also observed the downregulation of key molecules implicated in both glycolysis and oxidative phosphorylation. These metabolic changes were not modulated by DDR1 binding to collagen and occurred in part in the absence of IR/IGF1R phosphorylation. DDR1 silencing was ineffective in MCF7 knocked out for DDR1. Taken together, these results indicate that DDR1, acting in part independently of IR/IGF1R stimulation, might work as a novel regulator of BC metabolism and should be considered as putative target for therapy in BC. Full article
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Article
Identification of a Resistance Mechanism to IGF-IR Targeting in Human Triple Negative MDA-MB-231 Breast Cancer Cells
Biomolecules 2021, 11(4), 527; https://doi.org/10.3390/biom11040527 - 01 Apr 2021
Cited by 3 | Viewed by 1412
Abstract
Triple negative breast cancer (TNBC) is associated with unfavorable prognosis and high relapse rates following chemotherapy. There is an urgent need to develop effective targeted therapy for this BC subtype. The type I insulin-like growth factor receptor (IGF-IR) was identified as a potential [...] Read more.
Triple negative breast cancer (TNBC) is associated with unfavorable prognosis and high relapse rates following chemotherapy. There is an urgent need to develop effective targeted therapy for this BC subtype. The type I insulin-like growth factor receptor (IGF-IR) was identified as a potential target for BC management. We previously reported on the production of the IGF-Trap, a soluble IGF-1R fusion protein that reduces the bioavailability of circulating IGF-1 and IGF-2 to the cognate receptor, impeding signaling. In nude mice xenotransplanted with the human TNBC MDA-MB-231 cells, we found variable responses to this inhibitor. We used this model to investigate potential resistance mechanisms to IGF-targeted therapy. We show here that prolonged exposure of MDA-MB-231 cells to the IGF-Trap in vitro selected a resistant subpopulation that proliferated unhindered in the presence of the IGF-Trap. We identified in these cells increased fibroblast growth factor receptor 1 (FGFR1) activation levels that sensitized them to the FGFR1-specific tyrosine kinase inhibitor PD166866. Treatment with this inhibitor caused cell cycle arrest in both the parental and resistant cells, markedly increasing cell death in the latter. When combined with the IGF-Trap, an increase in cell cycle arrest was observed in the resistant cells. Moreover, FGFR1 silencing increased the sensitivity of these cells to IGF-Trap treatment in vivo. Our data identify increased FGFR1 signaling as a resistance mechanism to targeted inhibition of the IGF-IR and suggest that dual IGF-1R/FGFR1 blockade may be required to overcome TNBC cell resistance to IGF-axis inhibitors. Full article
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Review

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Review
Insulin-Responsive Transcription Factors
Biomolecules 2021, 11(12), 1886; https://doi.org/10.3390/biom11121886 - 15 Dec 2021
Cited by 2 | Viewed by 2201
Abstract
The hormone insulin executes its function via binding and activating of the insulin receptor, a receptor tyrosine kinase that is mainly expressed in skeletal muscle, adipocytes, liver, pancreatic β-cells, and in some areas of the central nervous system. Stimulation of the insulin receptor [...] Read more.
The hormone insulin executes its function via binding and activating of the insulin receptor, a receptor tyrosine kinase that is mainly expressed in skeletal muscle, adipocytes, liver, pancreatic β-cells, and in some areas of the central nervous system. Stimulation of the insulin receptor activates intracellular signaling cascades involving the enzymes extracellular signal-regulated protein kinase-1/2 (ERK1/2), phosphatidylinositol 3-kinase, protein kinase B/Akt, and phospholipase Cγ as signal transducers. Insulin receptor stimulation is correlated with multiple physiological and biochemical functions, including glucose transport, glucose homeostasis, food intake, proliferation, glycolysis, and lipogenesis. This review article focuses on the activation of gene transcription as a result of insulin receptor stimulation. Signal transducers such as protein kinases or the GLUT4-induced influx of glucose connect insulin receptor stimulation with transcription. We discuss insulin-responsive transcription factors that respond to insulin receptor activation and generate a transcriptional network executing the metabolic functions of insulin. Importantly, insulin receptor stimulation induces transcription of genes encoding essential enzymes of glycolysis and lipogenesis and inhibits genes encoding essential enzymes of gluconeogenesis. Overall, the activation or inhibition of insulin-responsive transcription factors is an essential aspect of orchestrating a wide range of insulin-induced changes in the biochemistry and physiology of insulin-responsive tissues. Full article
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Review
The Role of Nuclear Insulin and IGF1 Receptors in Metabolism and Cancer
Biomolecules 2021, 11(4), 531; https://doi.org/10.3390/biom11040531 - 02 Apr 2021
Cited by 9 | Viewed by 1714
Abstract
Insulin (InsR) and insulin-like growth factor-1 (IGF1R) receptors mediate the metabolic and growth-promoting actions of insulin and IGF1/IGF2, respectively. Evidence accumulated in recent years indicates that, in addition to their typical cell-surface localization pattern and ligand-activated mechanism of action, InsR and IGF1R are [...] Read more.
Insulin (InsR) and insulin-like growth factor-1 (IGF1R) receptors mediate the metabolic and growth-promoting actions of insulin and IGF1/IGF2, respectively. Evidence accumulated in recent years indicates that, in addition to their typical cell-surface localization pattern and ligand-activated mechanism of action, InsR and IGF1R are present in the cell nucleus of both normal and transformed cells. Nuclear translocation seems to involve interaction with a small, ubiquitin-like modifier protein (SUMO-1), although this modification is not always a prerequisite. Nuclear InsR and IGF1R exhibit a number of biological activities that classically fit within the definition of transcription factors. These nuclear activities include, among others, sequence-specific DNA binding and transcriptional control. Of particular interest, nuclear IGF1R was capable of binding and stimulating its cognate gene promoter. The physiological relevance of this autoregulatory mechanism needs to be further investigated. In addition to its nuclear localization, studies have identified IGF1R in the Golgi apparatus, and this particular distribution correlated with a migratory phenotype. In summary, the newly described roles of InsR and IGF1R as gene regulators, in concert with their atypical pattern of subcellular distribution, add a further layer of complexity to traditional models of cell signaling. Furthermore, and in view of the emerging role of IGF1R as a potential therapeutic target, a better understanding of the mechanisms responsible for nuclear IGF1R transport and identification of IGF1R interactors might help optimize target directed therapies in oncology. Full article
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Review
Novel Regulators of the IGF System in Cancer
Biomolecules 2021, 11(2), 273; https://doi.org/10.3390/biom11020273 - 12 Feb 2021
Cited by 11 | Viewed by 1876
Abstract
The insulin-like growth factor (IGF) system is a dynamic network of proteins, which includes cognate ligands, membrane receptors, ligand binding proteins and functional downstream effectors. It plays a critical role in regulating several important physiological processes including cell growth, metabolism and differentiation. Importantly, [...] Read more.
The insulin-like growth factor (IGF) system is a dynamic network of proteins, which includes cognate ligands, membrane receptors, ligand binding proteins and functional downstream effectors. It plays a critical role in regulating several important physiological processes including cell growth, metabolism and differentiation. Importantly, alterations in expression levels or activation of components of the IGF network are implicated in many pathological conditions including diabetes, obesity and cancer initiation and progression. In this review we will initially cover some general aspects of IGF action and regulation in cancer and then focus in particular on the role of transcriptional regulators and novel interacting proteins, which functionally contribute in fine tuning IGF1R signaling in several cancer models. A deeper understanding of the biological relevance of this network of IGF1R modulators might provide novel therapeutic opportunities to block this system in neoplasia. Full article
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Review
Insulin/IGF Axis in Breast Cancer: Clinical Evidence and Translational Insights
Biomolecules 2021, 11(1), 125; https://doi.org/10.3390/biom11010125 - 19 Jan 2021
Cited by 16 | Viewed by 1935
Abstract
Background: Breast cancer (BC) is the most common neoplasm in women. Many clinical and preclinical studies investigated the possible relationship between host metabolism and BC. Significant differences among BC subtypes have been reported for glucose metabolism. Insulin can promote tumorigenesis through a direct [...] Read more.
Background: Breast cancer (BC) is the most common neoplasm in women. Many clinical and preclinical studies investigated the possible relationship between host metabolism and BC. Significant differences among BC subtypes have been reported for glucose metabolism. Insulin can promote tumorigenesis through a direct effect on epithelial tissues or indirectly by affecting the levels of other modulators, such as the insulin-like growth factor (IGF) family of receptors, sex hormones, and adipokines. The potential anti-cancer activity of metformin is based on two principal effects: first, its capacity for lowering circulating insulin levels with indirect endocrine effects that may impact on tumor cell proliferation; second, its direct influence on many pro-cancer signaling pathways that are key drivers of BC aggressiveness. Methods: In the present review, the interaction between BC, host metabolism, and patients’ prognosis has been reviewed across available literature evidence. Conclusions: Obesity, metabolic syndrome, and insulin resistance are all involved in BC growth and could have a relevant impact on prognosis. All these factors act through a pro-inflammatory state, mediated by cytokines originated in fat tissue, and seem to be related to a higher risk of BC development and worse prognosis. Full article
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Review
Isoform- and Paralog-Switching in IR-Signaling: When Diabetes Opens the Gates to Cancer
Biomolecules 2020, 10(12), 1617; https://doi.org/10.3390/biom10121617 - 30 Nov 2020
Cited by 7 | Viewed by 1349
Abstract
Insulin receptor (IR) and IR-related signaling defects have been shown to trigger insulin-resistance in insulin-dependent cells and ultimately to give rise to type 2 diabetes in mammalian organisms. IR expression is ubiquitous in mammalian tissues, and its over-expression is also a common finding [...] Read more.
Insulin receptor (IR) and IR-related signaling defects have been shown to trigger insulin-resistance in insulin-dependent cells and ultimately to give rise to type 2 diabetes in mammalian organisms. IR expression is ubiquitous in mammalian tissues, and its over-expression is also a common finding in cancerous cells. This latter finding has been shown to associate with both a relative and absolute increase in IR isoform-A (IR-A) expression, missing 12 aa in its EC subunit corresponding to exon 11. Since IR-A is a high-affinity transducer of Insulin-like Growth Factor-II (IGF-II) signals, a growth factor is often secreted by cancer cells; such event offers a direct molecular link between IR-A/IR-B increased ratio in insulin resistance states (obesity and type 2 diabetes) and the malignant advantage provided by IGF-II to solid tumors. Nonetheless, recent findings on the biological role of isoforms for cellular signaling components suggest that the preferential expression of IR isoform-A may be part of a wider contextual isoform-expression switch in downstream regulatory factors, potentially enhancing IR-dependent oncogenic effects. The present review focuses on the role of isoform- and paralog-dependent variability in the IR and downstream cellular components playing a potential role in the modulation of the IR-A signaling related to the changes induced by insulin-resistance-linked conditions as well as to their relationship with the benign versus malignant transition in underlying solid tumors. Full article
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