IGF1R as a Potential Pharmacological Target in Allergic Asthma

Background: Asthma is a chronic lung disease characterized by reversible airflow obstruction, airway hyperresponsiveness (AHR), mucus overproduction and inflammation. Although Insulin-like growth factor 1 receptor (IGF1R) was found to be involved in asthma, its pharmacological inhibition has not previously been investigated in this pathology. We aimed to determine if therapeutic targeting of IGF1R ameliorates allergic airway inflammation in a murine model of asthma. Methods: C57BL/6J mice were challenged by house dust mite (HDM) extract or PBS for four weeks and therapeutically treated with the IGF1R tyrosine kinase inhibitor (TKI) NVP-ADW742 (NVP) once allergic phenotype was established. Results: Lungs of HDM-challenged mice exhibited a significant increase in phospho-IGF1R levels, incremented AHR, airway remodeling, eosinophilia and allergic inflammation, as well as altered pulmonary surfactant expression, all of being these parameters counteracted by NVP treatment. HDM-challenged lungs also displayed augmented expression of the IGF1R signaling mediator p-ERK1/2, which was greatly reduced upon treatment with NVP. Conclusions: Our results demonstrate that IGF1R could be considered a potential pharmacological target in murine HDM-induced asthma and a candidate biomarker in allergic asthma.

Circ-MFN2 Positively Regulates the Proliferation, Metastasis, and Radioresistance of Colorectal Cancer by Regulating the miR-574-3p/IGF1R Signaling Axis

Numerous studies have shown that the expression of circular RNA (circRNA) is closely related to the malignant progression of cancer. However, the role of circ-MFN2 in colorectal cancer (CRC) is unclear. Our study aims to explore the role and mechanism of circ-MFN2 in CRC progression. The relative expression levels of circ-MFN2, microRNA (miR)-574-3p and insulin-like growth factor 1 receptor (IGF1R) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability was determined using 3-(4, 5-dimethyl-2 thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The colony number and radioresistance of cells were assessed using colony formation assay. Moreover, the migration and invasion of cells were measured using transwell assay. Tumor xenograft model was constructed to evaluate the effect of circ-MFN2 knockdown on CRC tumor growth. Furthermore, dual-luciferase reporter assay was used to verify the interaction between miR-574-3p and circ-MFN2 or IGF1R. In addition, the protein level of IGF1R was evaluated by western blot (WB) analysis. Circ-MFN2 expression was elevated in CRC tissues and cells. Knockdown of circ-MFN2 restrained the proliferation, migration, invasion, and radioresistance of CRC cells in vitro. Furthermore, silenced circ-MFN2 also reduced the tumor volume and weight of CRC in vivo. MiR-574-3p could be sponged by circ-MFN2, and its inhibitor reversed the suppression effect of circ-MFN2 silencing on CRC progression. Moreover, IGF1R was a target of miR-574-3p, and its overexpression reversed the inhibition effect of miR-574-3p mimic on CRC progression. In addition, circ-MFN2 could positively regulate IGF1R expression by sponging miR-574-3p. Our results revealed that circ-MFN2 promoted the proliferation, metastasis and radioresistance of CRC through regulating the miR-574-3p/IGF1R axis, suggesting that circ-MFN2 might be a novel therapeutic biomarker for CRC.

Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients

Insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation. Upregulation of the IGF1R pathway constitutes a common paradigm shared with other receptor tyrosine kinases such as EGFR, HER2, and MET in different cancer types, including colon cancer. The main IGF1R signaling pathways are PI3K-AKT and MAPK-MEK. However, different processes, such as post-translational modification (SUMOylation), epithelial-to-mesenchymal transition (EMT), and microenvironment complexity, can also contribute to intrinsic and acquired resistance. Here, we discuss new strategies for adequate drug development in metastatic colorectal cancer patients.

Hypothalamic Rax+ tanycytes contribute to tissue repair and tumorigenesis upon oncogene activation in mice

Hypothalamic tanycytes in median eminence (ME) are emerging as a crucial cell population that regulates endocrine output, energy balance and the diffusion of blood-born molecules. Tanycytes have recently been considered as potential somatic stem cells in the adult mammalian brain, but their regenerative and tumorigenic capacities are largely unknown. Here we found that Rax+ tanycytes in ME of mice are largely quiescent but quickly enter the cell cycle upon neural injury for self-renewal and regeneration. Mechanistically, Igf1r signaling in tanycytes is required for tissue repair under injury conditions. Furthermore, Braf oncogenic activation is sufficient to transform Rax+ tanycytes into actively dividing tumor cells that eventually develop into a papillary craniopharyngioma-like tumor. Together, these findings uncover the regenerative and tumorigenic potential of tanycytes. Our study offers insights into the properties of tanycytes, which may help to manipulate tanycyte biology for regulating hypothalamic function and investigate the pathogenesis of clinically relevant tumors.

Igf signaling couples retina growth with body growth by modulating progenitor cell division

ABSTRACT How the body and organs balance their relative growth is of key importance for coordinating size and function. This is of particular relevance in organisms, which continue to grow over their entire life span. We addressed this issue in the neuroretina of medaka fish (Oryzias latipes), a well-studied system with which to address vertebrate organ growth. We reveal that a central growth regulator, Igf1 receptor (Igf1r), is necessary and sufficient for proliferation control in the postembryonic retinal stem cell niche: the ciliary marginal zone (CMZ). Targeted activation of Igf1r signaling in the CMZ uncouples neuroretina growth from body size control, and we demonstrate that Igf1r operates on progenitor cells, stimulating their proliferation. Activation of Igf1r signaling increases retinal size while preserving its structural integrity, revealing a modular organization in which progenitor differentiation and neurogenesis are self-organized and highly regulated. Our findings position Igf signaling as a key module for controlling retinal size and composition, with important evolutionary implications.

Novel Regulators of the IGF System in Cancer

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.