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Biomedicines
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The IGF2-Regulated Cellular- and Genetic Network in Physiology and Disease:...
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The IGF2-Regulated Cellular- and Genetic Network in Physiology and Disease: A Call to Action

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: 15 May 2024 | Viewed by 8337

Special Issue Editor

Dr. Pierluigi Scalia

E-Mail Website
Guest Editor
1. Sbarro Institute for Cancer Research and Molecular Medicine, Biology Department, CST, Temple University, Philadelphia, PA 19122, USA
2. ISOPROG-Somatolink EPFP Network, Functional Research Unit, Philadelphia, PA 19104, USA and 93100 Caltanissetta, Italy
Interests: cancer biology; cell signaling; gene regulation

Special Issue Information

Dear Colleagues,

Dependency on Igf2 gene expression and its IGF-II product secretion associated with autocrine/paracrine signals is an established feature, common to physiological and pathological cellular processes observed in several eukaryotic and mammalian organisms, that regulates growth and proliferation. Both retrospective and recent studies have expanded the role of these IGF2-mediated circuits to a variety of physiological and pathological contexts where the net IGF2 gene and peptide effects exert key biological functions with intrinsic actionable value. This Special Issue focuses on original contributions that link the Igf2 gene and the IGF-II product with its paracrine and autocrine actions, the IGF-II-triggered intracellular signals and related target gene expression to specific cellular functions in the context of development, stem cell biology, tissue metabolism, angiogenesis, the tumor microenvironment and malignant switches in cancer. The Special Issue also provides space for articles that concern actionable strategies and/or solutions aiming to profile and/or modulate IGF2 signals either as part of the adopted experimental strategies or as study endpoints. Finally, original review/perspective contributions that summarize specific sub-areas of the above topics supported in part by work published by the submitting contributors is also encouraged.

Dr. Pierluigi Scalia
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. Biomedicines 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

  • IGF2
  • IGF1R
  • Insulin receptor
  • IGF2 LOI/LOH
  • IGF family isoform-paralog
  • IGF2-secreting cancer

Published Papers (3 papers)

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Review

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19 pages, 1391 KiB  
Review
Human IGF2 Gene Epigenetic and Transcriptional Regulation: At the Core of Developmental Growth and Tumorigenic Behavior
by Pierluigi Scalia, Stephen J. Williams and Yoko Fujita-Yamaguchi
Biomedicines 2023, 11(6), 1655; https://doi.org/10.3390/biomedicines11061655 - 07 Jun 2023
Cited by 3 | Viewed by 2749
Abstract
Regulation of the human IGF2 gene displays multiple layers of control, which secures a genetically and epigenetically predetermined gene expression pattern throughout embryonal growth and postnatal life. These predominantly nuclear regulatory mechanisms converge on the function of the IGF2-H19 gene cluster on Chromosome [...] Read more.
Regulation of the human IGF2 gene displays multiple layers of control, which secures a genetically and epigenetically predetermined gene expression pattern throughout embryonal growth and postnatal life. These predominantly nuclear regulatory mechanisms converge on the function of the IGF2-H19 gene cluster on Chromosome 11 and ultimately affect IGF2 gene expression. Deregulation of such control checkpoints leads to the enhancement of IGF2 gene transcription and/or transcript stabilization, ultimately leading to IGF-II peptide overproduction. This type of anomaly is responsible for the effects observed in terms of both abnormal fetal growth and increased cell proliferation, typically observed in pediatric overgrowth syndromes and cancer. We performed a review of relevant experimental work on the mechanisms affecting the human IGF2 gene at the epigenetic, transcriptional and transcript regulatory levels. The result of our work, indeed, provides a wider and diversified scenario for IGF2 gene activation than previously envisioned by shedding new light on its extended regulation. Overall, we focused on the functional integration between the epigenetic and genetic machinery driving its overexpression in overgrowth syndromes and malignancy, independently of the underlying presence of loss of imprinting (LOI). The molecular landscape provided at last strengthens the role of IGF2 in cancer initiation, progression and malignant phenotype maintenance. Finally, this review suggests potential actionable targets for IGF2 gene- and regulatory protein target-degradation therapies. Full article
(This article belongs to the Special Issue The IGF2-Regulated Cellular- and Genetic Network in Physiology and Disease: A Call to Action)
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19 pages, 1435 KiB  
Review
IGF2: A Role in Metastasis and Tumor Evasion from Immune Surveillance?
by Antonino Belfiore, Rosaria Valentina Rapicavoli, Rosario Le Moli, Rosamaria Lappano, Andrea Morrione, Ernestina Marianna De Francesco and Veronica Vella
Biomedicines 2023, 11(1), 229; https://doi.org/10.3390/biomedicines11010229 - 16 Jan 2023
Cited by 11 | Viewed by 3333
Abstract
Insulin-like growth factor 2 (IGF2) is upregulated in both childhood and adult malignancies. Its overexpression is associated with resistance to chemotherapy and worse prognosis. However, our understanding of its physiological and pathological role is lagging behind what we know about IGF1. Dysregulation of [...] Read more.
Insulin-like growth factor 2 (IGF2) is upregulated in both childhood and adult malignancies. Its overexpression is associated with resistance to chemotherapy and worse prognosis. However, our understanding of its physiological and pathological role is lagging behind what we know about IGF1. Dysregulation of the expression and function of IGF2 receptors, insulin receptor isoform A (IR-A), insulin growth factor receptor 1 (IGF1R), and their downstream signaling effectors drive cancer initiation and progression. The involvement of IGF2 in carcinogenesis depends on its ability to link high energy intake, increase cell proliferation, and suppress apoptosis to cancer risk, and this is likely the key mechanism bridging insulin resistance to cancer. New aspects are emerging regarding the role of IGF2 in promoting cancer metastasis by promoting evasion from immune destruction. This review provides a perspective on IGF2 and an update on recent research findings. Specifically, we focus on studies providing compelling evidence that IGF2 is not only a major factor in primary tumor development, but it also plays a crucial role in cancer spread, immune evasion, and resistance to therapies. Further studies are needed in order to find new therapeutic approaches to target IGF2 action. Full article
(This article belongs to the Special Issue The IGF2-Regulated Cellular- and Genetic Network in Physiology and Disease: A Call to Action)
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Other

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20 pages, 3346 KiB  
Perspective
Autocrine IGF-II-Associated Cancers: From a Rare Paraneoplastic Event to a Hallmark in Malignancy
by Pierluigi Scalia, Ignazio R. Marino, Salvatore Asero, Giuseppe Pandini, Adda Grimberg, Wafik S. El-Deiry and Stephen J. Williams
Biomedicines 2024, 12(1), 40; https://doi.org/10.3390/biomedicines12010040 - 22 Dec 2023
Viewed by 1345
Abstract
The paraneoplastic syndrome referred in the literature as non-islet-cell tumor hypoglycemia (NICTH) and extra-pancreatic tumor hypoglycemia (EPTH) was first reported almost a century ago, and the role of cancer-secreted IGF-II in causing this blood glucose-lowering condition has been widely established. The landscape emerging [...] Read more.
The paraneoplastic syndrome referred in the literature as non-islet-cell tumor hypoglycemia (NICTH) and extra-pancreatic tumor hypoglycemia (EPTH) was first reported almost a century ago, and the role of cancer-secreted IGF-II in causing this blood glucose-lowering condition has been widely established. The landscape emerging in the last few decades, based on molecular and cellular findings, supports a broader role for IGF-II in cancer biology beyond its involvement in the paraneoplastic syndrome. In particular, a few key findings are constantly observed during tumorigenesis, (a) a relative and absolute increase in fetal insulin receptor isoform (IRA) content, with (b) an increase in IGF-II high-molecular weight cancer-variants (big-IGF-II), and (c) a stage-progressive increase in the IGF-II autocrine signal in the cancer cell, mostly during the transition from benign to malignant growth. An increasing and still under-exploited combinatorial pattern of the IGF-II signal in cancer is shaping up in the literature with respect to its transducing receptorial system and effector intracellular network. Interestingly, while surgical and clinical reports have traditionally restricted IGF-II secretion to a small number of solid malignancies displaying paraneoplastic hypoglycemia, a retrospective literature analysis, along with publicly available expression data from patient-derived cancer cell lines conveyed in the present perspective, clearly suggests that IGF-II expression in cancer is a much more common event, especially in overt malignancy. These findings strengthen the view that (1) IGF-II expression/secretion in solid tumor-derived cancer cell lines and tissues is a broader and more common event compared to the reported IGF-II association to paraneoplastic hypoglycemia, and (2) IGF-II associates to the commonly observed autocrine loops in cancer cells while IGF-I cancer-promoting effects may be linked to its paracrine effects in the tumor microenvironment. Based on these evidence-centered considerations, making the autocrine IGF-II loop a hallmark for malignant cancer growth, we here propose the functional name of IGF-II secreting tumors (IGF-IIsT) to overcome the view that IGF-II secretion and pro-tumorigenic actions affect only a clinical sub-group of rare tumors with associated hypoglycemic symptoms. The proposed scenario provides an updated logical frame towards biologically sound therapeutic strategies and personalized therapeutic interventions for currently unaccounted IGF-II-producing cancers. Full article
(This article belongs to the Special Issue The IGF2-Regulated Cellular- and Genetic Network in Physiology and Disease: A Call to Action)
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