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Insulin-Like Growth Factors and Their Receptors on the Road to Personalized Medicine in Cancer: Fact or Fiction?

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 13843

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Special Issue Editor

Dr. Leonard Girnita

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Guest Editor

1. Department of Oncology-Pathology, Cellular and Molecular Tumor Pathology, Karolinska Institute, 17164 Stockholm, Sweden
2. Karolinska University Hospital, Solna, Sweden
Interests: signaling; RTK; GPCR; ubiquitination; cancer; arrestin; GRK; IGF-1R; targeted therapy insulin; Insulin/IGF axis; metabolic syndrome; molecular pathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Currently it is well established that IGF-1R is crucial in many physiological processes like growth, differentiation and aging, as well as it being an important player in disease development. IGF-1R is commonly expressed in human cancers and many cell lines are mitogenically responsive to physiological concentrations of IGFs. IGFs and IGFBPs also frequently show altered expression levels in human tumours and individuals with high levels of circulating IGFs have an increased risk of developing various forms of cancer.

Yet, therapeutics targeting the IGF-1R have had mostly disappointing results in clinical settings. IGF-1R is classified as a RTK and accordingly tyrosine phosphorylation was considered to be the central process governing IGF-1R signalling As such, most anti-IGF-1r strategies are designed to prevent kinase activation. The clinical success of nearly all tyrosine-kinase inhibitors is predicted by the presence of activating mutations or substantial receptor overexpression, but neither is the case with IGF-1R. IGF-1R does not show intrinsic receptor abnormalities, therefore other pathways and quantitative changes are being assessed.

A rigorous control of the IGF-1R signalling network activation entails feedback and feedforward loops, which are eventually responsible for the biological effects as well for efficient therapeutic control. Such regulatory mechanisms involve receptor-internalization machinery, scaffolding of signalling complexes, post-translational modifications as well as transcriptional control of signalling molecules. This Special Issue of Cells will follow the development of our understanding of the IGF-1R biology, the contradictions to the classical IGF-1R paradigms as well as the design of anti-IGF-1R therapeutics with a particular focus on those relating to cancer.

Dr. Leonard Girnita
Guest Editor

Manuscript Submission Information

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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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

RTK
GPCR
ubiquitination
signaling
cancer
arrestin
GRK
IGF-1R
targeted therapy
insulin

Published Papers (3 papers)

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Research

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22 pages, 3874 KiB

Open AccessFeature PaperArticle

Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells

by Veronica Vella, Marika Giuliano, Alessandro La Ferlita, Michele Pellegrino, Germano Gaudenzi, Salvatore Alaimo, Michele Massimino, Alfredo Pulvirenti, Alessandra Dicitore, Paolo Vigneri, Giovanni Vitale, Roberta Malaguarnera, Andrea Morrione, Andrew H. Sims, Alfredo Ferro, Marcello Maggiolini, Rosamaria Lappano, Ernestina Marianna De Francesco and Antonino Belfiore

Cells 2021, 10(11), 3145; https://doi.org/10.3390/cells10113145 - 12 Nov 2021

Cited by 15 | Viewed by 3217

Abstract

The insulin receptor isoform A (IR-A) plays an increasingly recognized role in fetal growth and tumor biology in response to circulating insulin and/or locally produced IGF2. This role seems not to be shared by the IR isoform B (IR-B). We aimed to dissect the specific impact of IR isoforms in modulating insulin signaling in triple negative breast cancer (TNBC) cells. We generated murine 4T1 TNBC cells deleted from the endogenous insulin receptor (INSR) gene and expressing comparable levels of either human IR-A or IR-B. We then measured IR isoform-specific in vitro and in vivo biological effects and transcriptome in response to insulin. Overall, the IR-A was more potent than the IR-B in mediating cell migration, invasion, and in vivo tumor growth. Transcriptome analysis showed that approximately 89% of insulin-stimulated transcripts depended solely on the expression of the specific isoform. Notably, in cells overexpressing IR-A, insulin strongly induced genes involved in tumor progression and immune evasion including chemokines and genes related to innate immunity. Conversely, in IR-B overexpressing cells, insulin predominantly induced the expression of genes primarily involved in the regulation of metabolic pathways and, to a lesser extent, tumor growth and angiogenesis. Full article

(This article belongs to the Special Issue Insulin-Like Growth Factors and Their Receptors on the Road to Personalized Medicine in Cancer: Fact or Fiction?)

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Review

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33 pages, 2408 KiB

Open AccessReview

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

by Caterina Mancarella, Andrea Morrione and Katia Scotlandi

Cells 2021, 10(8), 2075; https://doi.org/10.3390/cells10082075 - 13 Aug 2021

Cited by 6 | Viewed by 4837

Abstract

Aberrant bioactivity of the insulin-like growth factor (IGF) system results in the development and progression of several pathologic conditions including cancer. Preclinical studies have shown promising anti-cancer therapeutic potentials for anti-IGF targeted therapies. However, a clear but limited clinical benefit was observed only in a minority of patients with sarcomas. The molecular complexity of the IGF system, which comprises multiple regulators and interactions with other cancer-related pathways, poses a major limitation in the use of anti-IGF agents and supports the need of combinatorial therapeutic strategies to better tackle this axis. In this review, we will initially highlight multiple mechanisms underlying IGF dysregulation in cancer and then focus on the impact of the IGF system and its complexity in sarcoma development and progression as well as response to anti-IGF therapies. We will also discuss the role of Ephrin receptors, Hippo pathway, BET proteins and CXCR4 signaling, as mediators of sarcoma malignancy and relevant interactors with the IGF system in tumor cells. A deeper understanding of these molecular interactions might provide the rationale for novel and more effective therapeutic combinations to treat sarcomas. Full article

(This article belongs to the Special Issue Insulin-Like Growth Factors and Their Receptors on the Road to Personalized Medicine in Cancer: Fact or Fiction?)

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18 pages, 7335 KiB

Open AccessReview

Lessons Learned from Targeting IGF-I Receptor in Thyroid-Associated Ophthalmopathy

by Joseph A.M.J.L. Janssen and Terry J. Smith

Cells 2021, 10(2), 383; https://doi.org/10.3390/cells10020383 - 12 Feb 2021

Cited by 11 | Viewed by 4758

Abstract

Complex immunological mechanisms underlie the pathogenesis of thyroid-associated ophthalmopathy (TAO). Historical models of Graves’ disease and TAO have focused almost entirely on autoimmune reactivity directed against the thyrotropin receptor (TSHR). The insulin-like growth factor-I receptor (IGF-IR) has been proposed as a second participating antigen in TAO by virtue of its interactions with IGFs and anti-IGF-IR antibodies generated in Graves’ disease. Furthermore, the IGF-IR forms with TSHR a physical and functional complex which is involved in signaling downstream from both receptors. Inhibition of IGF-IR activity results in attenuation of signaling initiated at either receptor. Based on the aggregate of findings implicating IGF-IR in TAO, the receptor has become an attractive therapeutic target. Recently, teprotumumab, a human monoclonal antibody IGF-IR inhibitor was evaluated in two clinical trials of patients with moderate to severe, active TAO. Those studies revealed that teprotumumab was safe and highly effective in reducing disease activity and severity. Targeting IGF-IR with specific biologic agents may result in a paradigm shift in the therapy of TAO. Full article

(This article belongs to the Special Issue Insulin-Like Growth Factors and Their Receptors on the Road to Personalized Medicine in Cancer: Fact or Fiction?)

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