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Life
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Insulin-Like Growth Factor from Physiology to Cancer
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Insulin-Like Growth Factor from Physiology to Cancer

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Physiology and Pathology".

Deadline for manuscript submissions: closed (28 June 2023) | Viewed by 11429

Special Issue Editor

Dr. Caterina Mancarella

E-Mail Website
Guest Editor
IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
Interests: cancer biology; sarcoma; IGF system; RNA-binding proteins; drug resistance; cell cultures
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The IGF system is a dynamic network of ligands, receptors, extracellular binding proteins, and downstream signaling pathway effectors. A fine-tuned regulation of this axis is necessary for health since IGFs drive crucial physiological processes such as growth, metabolism, and differentiation. Aberrant expression or function of the IGF signaling characterizes many pathologic conditions, including cancer. The IGF network is implicated in the regulation of most hallmarks of cancer, such as cell proliferation, resistance to cell death, stemness, and cell dissemination. Accordingly, multiple anti-IGF targeted therapies have been developed and tested in different tumor types with disappointing results in clinical trials. However, previously underrated, biological responses elicited by the IGF system not only depend on its few canonical components but also rely on functional interactions which integrate signals from multiple factors, posing a major limitation in the use of anti-IGF agents. Epigenetic and post-transcriptional mechanisms can affect IGF component expression. In parallel, cross-talks with other cancer-related pathways lead to signaling redundancy or compensation mechanisms.

This research topic aims to collect the most recent advancements in the comprehension of the molecular mechanisms surrounding the IGF system and the implications of this complexity in cancer development, progression, and response to therapies.

Dr. Caterina Mancarella
Guest Editor

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. Life is an international peer-reviewed open access monthly 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 2600 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

  • IGF-1 receptor
  • insulin receptor
  • target therapies
  • cancer
  • anti-cancer therapy resistance
  • IGF axis
  • molecular mechanisms
  • epigenetic mechanisms
  • post-transcriptional regulation
  • network analysis
  • hallmark of cancer

Published Papers (4 papers)

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Research

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14 pages, 2543 KiB  
Article
IGFBP-6 Alters Mesenchymal Stromal Cell Phenotype Driving Dasatinib Resistance in Chronic Myeloid Leukemia
by Daniela Cambria, Lucia Longhitano, Enrico La Spina, Sebastiano Giallongo, Laura Orlando, Rosario Giuffrida, Daniele Tibullo, Paolo Fontana, Ignazio Barbagallo, Vincenzo Giuseppe Nicoletti, Giovanni Li Volti, Vittorio Del Fabro, Anna Rita Daniela Coda, Arcangelo Liso and Giuseppe Alberto Palumbo
Life 2023, 13(2), 259; https://doi.org/10.3390/life13020259 - 17 Jan 2023
Cited by 1 | Viewed by 1857
Abstract
Chronic myeloid leukemia (CML), BCR-ABL1-positive, is classified as a myeloproliferative characterized by Philadelphia chromosome/translocation t(9;22) and proliferating granulocytes. Despite the clinical success of tyrosine kinase inhibitors (TKi) agents in the treatment of CML, most patients have minimal residual disease contained in the bone [...] Read more.
Chronic myeloid leukemia (CML), BCR-ABL1-positive, is classified as a myeloproliferative characterized by Philadelphia chromosome/translocation t(9;22) and proliferating granulocytes. Despite the clinical success of tyrosine kinase inhibitors (TKi) agents in the treatment of CML, most patients have minimal residual disease contained in the bone marrow microenvironment, within which stromal cells assume a pro-inflammatory phenotype that determines their transformation in cancer-associated fibroblasts (CAF) which, in turn can play a fundamental role in resistance to therapy. Insulin-like Growth Factor Binding Protein-6 (IGFBP-6) is expressed during tumor development, and is involved in immune-escape and inflammation as well, providing a potential additional target for CML therapy. Here, we aimed at investigating the role of IGFBP-6/SHH/TLR4 axis in TKi response. We used a CML cell line, LAMA84-s, and healthy bone marrow stromal cells, HS-5, in mono- or co-culture. The two cell lines were treated with Dasatinib and/or IGFBP-6, and the expression of inflammatory markers was tested by qRT-PCR; furthermore, expression of IGFBP-6, TLR4 and Gli1 were evaluated by Western blot analysis and immumocytochemistry. The results showed that both co-culture and Dasatinib exposure induce inflammation in stromal and cancer cells so that they modulate the expression of TLR4, and these effects were more marked following IGFBP-6 pre-treatment suggesting that this molecule may confer resistance through the inflammatory processes. This phenomenon was coupled with sonic hedgehog (SHH) signaling. Indeed, our data also demonstrate that HS-5 treatment with PMO (an inducer of SHH) induces significant modulation of TLR4 and overexpression of IGFPB-6 suggesting that the two pathways are interconnected with each other and with the TLR-4 pathway. Finally, we demonstrated that pretreatment with IGFBP-6 and/or PMO restored LAMA-84 cell viability after treatment with Dasatinib, suggesting that both IGFBP-6 and SHH are involved in the resistance mechanisms induced by the modulation of TLR-4, thus indicating that the two pathways may be considered as potential therapeutic targets. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factor from Physiology to Cancer)
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9 pages, 734 KiB  
Article
Let-7 microRNAs Are Possibly Associated with Perineural Invasion in Colorectal Cancer by Targeting IGF Axis
by Andrei Marian Niculae, Maria Dobre, Vlad Herlea, Teodora Ecaterina Manuc, Bogdan Trandafir, Elena Milanesi and Mihail Eugen Hinescu
Life 2022, 12(10), 1638; https://doi.org/10.3390/life12101638 - 19 Oct 2022
Cited by 6 | Viewed by 1952
Abstract
Increased insulin-like growth factor (IGF) axis activity is associated with the development and progression of different types of malignancies, including colorectal cancer (CRC). MicroRNAs (miRNAs) belonging to the let-7 family have been reported to target genes involved in this axis and are known [...] Read more.
Increased insulin-like growth factor (IGF) axis activity is associated with the development and progression of different types of malignancies, including colorectal cancer (CRC). MicroRNAs (miRNAs) belonging to the let-7 family have been reported to target genes involved in this axis and are known as tumor suppressors. In this study, in silico bioinformatic analysis was performed to assess miRNA–mRNA interactions between eight miRNAs belonging to the let-7 family and genes involved in the IGF signaling pathway, coding for receptors and substrates. miRNAs’ expression analysis revealed that hsa-let-7a-5p, hsa-let-7b-5p, hsa-let-7c-5p, hsa-let- 97 7d-5p, hsa-let-7e-5p, hsa-let-7f-5p, and hsa-let-7g-5p were significantly down-regulated in 25 CRC tumoral tissues (T) compared to the corresponding adjacent peritumoral tissues (PT). Moreover, our results showed an upregulation of miR-let-7e-5p in CRC tissues with mutations in KRAS codon 12 or 13, and, for the first time, found a specific dysregulation of let-7a-5p, let-7b-5p, let-7c-5p, let-7d-5p, and let-7i-5p in CRC with perineural invasion. Our results sustain the relationship between the IGF axis, let-7 miRNAs, and CRC and suggest an association between the expression of these miRNAs and perineural invasion. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factor from Physiology to Cancer)
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Review

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21 pages, 1394 KiB  
Review
The Insulin-like Growth Factor Signaling Pathway in Breast Cancer: An Elusive Therapeutic Target
by Ji-Sun Lee, Claire E. Tocheny and Leslie M. Shaw
Life 2022, 12(12), 1992; https://doi.org/10.3390/life12121992 - 29 Nov 2022
Cited by 19 | Viewed by 4549
Abstract
In this review, we provide an overview of the role of the insulin-like growth factor (IGF) signaling pathway in breast cancer and discuss its potential as a therapeutic target. The IGF pathway ligands, IGF-1 and IGF-2, and their receptors, primarily IGF-1R, are important [...] Read more.
In this review, we provide an overview of the role of the insulin-like growth factor (IGF) signaling pathway in breast cancer and discuss its potential as a therapeutic target. The IGF pathway ligands, IGF-1 and IGF-2, and their receptors, primarily IGF-1R, are important for normal mammary gland biology, and dysregulation of their expression and function drives breast cancer risk and progression through activation of downstream signaling effectors, often in a subtype-dependent manner. The IGF signaling pathway has also been implicated in resistance to current therapeutic strategies, including ER and HER2 targeting drugs. Unfortunately, efforts to target IGF signaling for the treatment of breast cancer have been unsuccessful, due to a number of factors, most significantly the adverse effects of disrupting IGF signaling on normal glucose metabolism. We highlight here the recent discoveries that provide enthusiasm for continuing efforts to target IGF signaling for the treatment of breast cancer patients. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factor from Physiology to Cancer)
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23 pages, 1655 KiB  
Review
The Insulin-like Growth Factor System and Colorectal Cancer
by Nikola Gligorijević, Zorana Dobrijević, Miloš Šunderić, Dragana Robajac, Danilo Četić, Ana Penezić, Goran Miljuš and Olgica Nedić
Life 2022, 12(8), 1274; https://doi.org/10.3390/life12081274 - 20 Aug 2022
Cited by 5 | Viewed by 2450
Abstract
Insulin-like growth factors (IGFs) are peptides which exert mitogenic, endocrine and cytokine activities. Together with their receptors, binding proteins and associated molecules, they participate in numerous pathophysiological processes, including cancer development. Colorectal cancer (CRC) is a disease with high incidence and mortality rates [...] Read more.
Insulin-like growth factors (IGFs) are peptides which exert mitogenic, endocrine and cytokine activities. Together with their receptors, binding proteins and associated molecules, they participate in numerous pathophysiological processes, including cancer development. Colorectal cancer (CRC) is a disease with high incidence and mortality rates worldwide, whose etiology usually represents a combination of the environmental and genetic factors. IGFs are most often increased in CRC, enabling excessive autocrine/paracrine stimulation of the cell growth. Overexpression or increased activation/accessibility of IGF receptors is a coinciding step which transmits IGF-related signals. A number of molecules and biochemical mechanisms exert modulatory effects shaping the final outcome of the IGF-stimulated processes, frequently leading to neoplastic transformation in the case of irreparable disbalance. The IGF system and related molecules and pathways which participate in the development of CRC are the focus of this review. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factor from Physiology to Cancer)
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