Decoding molecular interplay between RUNX1 and FOXO3a underlying the pulsatile IGF1R expression during acquirement of chemoresistance

Introduction Insulin-like growth factor type 1 receptor (IGF1R) is overexpressed in various malignant tumors, which relates to their transformation and recurrence. Craniopharyngioma is a benign tumor with malignant results, often accompanied by a severe inflammatory reaction. However, the relationship between IGF1R expression and the inflammatory response of craniopharyngioma is unclear. Methods We enrolled 85 patients with adamantinomatous craniopharyngioma (ACP) in a study to explore the relationship between IGF1R expression and clinical features of this disease. Results Patients in the IGF1R high expression group had a significantly higher incidence of hypopituitarism, higher recurrence rate and lower progression-free survival. Beta-catenin can further regulate expression of the stem cell marker, CD44, by regulating IGF1R. Using immunofluorescence, we found that tumor stem cell–like cells did not express phosphorylated (p)-ERK, although p-ERK activation was evident in the surrounding cells. Picropodophyllin, a specific inhibitor of IGF1R, increased the expression of p-ERK protein, and decreased the transcription level of interleukin-6. Conclusions High expression of IGF1R might promote inflammation of ACP, which might be an unfavorable factor for pituitary function and prognosis. The high expression of IGF1R in tumor cell stem-like cells might inhibit the expression of p-ERK and promote the generation of inflammatory factors. Insulin-like growth factor type 1 receptor plays a stemness maintenance role in ACP and regulates the production of inflammatory factors through a p-ERK pathway, which suggests that targeting IGF1R and p-ERK might provide a new direction for alleviating tumor inflammation.

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Intra-Pancreatic Insulin Nourishes Cancer Cells: Do Insulin-Receptor Antagonists such as PGG and EGCG Play a Role?

The American Journal of Chinese Medicine ◽

10.1142/s0192415x20500482 ◽

2020 ◽

Vol 48 (04) ◽

pp. 1005-1019

Author(s):

Lijuan Hu ◽

Xijuan Chen ◽

Shuai Qiu ◽

Jing Yang ◽

Hongyi Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Insulin Receptor ◽

Cancer Cells ◽

Human Pancreatic Cancer ◽

Pancreatic Tumors ◽

Pancreatic Cancer Cells ◽

Pancreatic Insulin ◽

Igf1r Expression ◽

Expression And Activity

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-[Formula: see text]-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.

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A Novel Mutation in Insulin-Like Growth Factor 1 Receptor (c.641-2A>G) Is Associated with Impaired Growth, Hypoglycemia, and Modified Immune Phenotypes

Hormone Research in Paediatrics ◽

10.1159/000510764 ◽

2020 ◽

Vol 93 (5) ◽

pp. 322-334

Author(s):

Melanie R. Shapiro ◽

Timothy P. Foster ◽

Daniel J. Perry ◽

Ron G. Rosenfeld ◽

Andrew Dauber ◽

...

Keyword(s):

Growth Factor ◽

Mononuclear Cells ◽

Phenotypic Expression ◽

The Body ◽

Mrna Splicing ◽

Insulin Like Growth Factor ◽

T Helper ◽

Adaptive Immune Cells ◽

Immune Phenotypes ◽

Igf1r Expression

Introduction: Insulin-like growth factor 1 receptor (IGF1R) mutations lead to systemic disturbances in growth and glucose homeostasis due to widespread IGF1R expression throughout the body. IGF1R is expressed by innate and adaptive immune cells, facilitating their development and exerting immunomodulatory roles in the periphery. Case Presentation: We report on a family presenting with a novel heterozygous IGF1R mutation with characterization of the mutation, IGF1R expression, and immune phenotyping. Twin probands presented clinically with short stature and hypoglycemia. Variable phenotypic expression was seen in 2 other family members carrying the IGF1R mutation. The probands were treated with exogenous growth hormone therapy and dietary cornstarch, improving linear growth and reducing hypoglycemic events. IGF1R c.641-2A>G caused abnormal mRNA splicing and premature protein termination. Flow cytometric immunophenotyping demonstrated lower IGF1R on peripheral blood mononuclear cells from IGF1R c.641-2A>G subjects. This alteration was associated with reduced levels of T-helper 17 cells and a higher percentage of T-helper 1 cells compared to controls, suggesting decreased IGF1R expression may affect CD4+ Th-cell lineage commitment. Discussion: Collectively, these data suggest a novel loss-of-function mutation (c.641-2A>G) leads to aberrant mRNA splicing and IGF1R expression resulting in hypoglycemia, growth restriction, and altered immune phenotypes.

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Abstract 5283: MicroSPECT imaging of IGF1R expression with radiolabeled R1507 in osteosarcoma models

10.1158/1538-7445.am2011-5283 ◽

2011 ◽

Author(s):

Emmy DG Fleuren ◽

Yvonne MH Versleijen-Jonkers ◽

Addy CM van de Luijtgaarden ◽

Janneke DM Molkenboer-Kuenen ◽

Melissa HS Roeffen ◽

...

Keyword(s):

Igf1r Expression

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Abstract P1-01-12: Prevalence of insulin-like growth factor-1 receptor (IGF1R) expression in circulating tumor cells (CTCs) of patients with early breast cancer and its association with E-cadherin expression and patient survival

10.1158/1538-7445.sabcs16-p1-01-12 ◽

2017 ◽

Cited By ~ 1

Author(s):

S Agelaki ◽

M Spiliotaki ◽

M Kokotsaki ◽

A Matikas ◽

E-K Vetsika ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Early Breast Cancer ◽

Patient Survival ◽

Insulin Like Growth Factor ◽

Igf1r Expression ◽

E Cadherin

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Decoy Oligonucleotide Rescues IGF1R Expression from MicroRNA-223 Suppression

PLoS ONE ◽

10.1371/journal.pone.0082167 ◽

2013 ◽

Vol 8 (12) ◽

pp. e82167 ◽

Cited By ~ 7

Author(s):

Li Hui Wu ◽

Qian Qian Cai ◽

Yi Wei Dong ◽

Rong Wang ◽

Bao Mei He ◽

...

Keyword(s):

Decoy Oligonucleotide ◽

Igf1r Expression

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Association of insulin-like growth factor-1 receptor (IGF1R) expression in circulating tumor cells (CTCs) with E-cadherin (E-CAD) expression and improved survival in breast cancer (BC).

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.e23041 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. e23041-e23041

Author(s):

Sofia Agelaki

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Insulin Like Growth Factor ◽

Igf1r Expression ◽

E Cadherin

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Association between insulin-like growth factor-1 receptor (IGF1R) expression in circulating tumor cells (CTCs) and prognosis in patients with metastatic breast cancer (MBC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.1086 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 1086-1086

Author(s):

Alessandra Gennari ◽

Rita Zamarchi ◽

Dino Amadori ◽

Andrea De Censi ◽

Oriana Nanni ◽

...

Keyword(s):

Univariate Analysis ◽

Prognostic Significance ◽

Metastatic Breast ◽

Striking Difference ◽

Prognostic Role ◽

Prognostic Effect ◽

Increased Risk ◽

Risk Of Progression ◽

Igf1r Expression

1086 Background: CTCs are strongly associated with prognosis in MBC. In a recent metanalysis on 1944 patients, a CTC count > 5/7.5 ml was associated with a 2-fold increased risk of progression and death. Little evidence is available on the prognostic role of phenotypic CTC assessment, however. In this study, nested in a randomized clinical trial of Ist line chemotherapy ± metformin, we evaluated the prognostic role of IGF1R expression in CTCs, given its potential growth promoting effect. Methods: CTCs were isolated from blood samples of enrolled patients; an automated sample preparation and analysis system (CellSearch) was customized for detecting IGF1R positive CTCs. The prognostic role of total CTCs, IGF1R positive (+ve) and negative (-ve) CTCs was assessed by fitting different PFS and OS multivariate Cox’s models.Results: CTC evaluation at baseline was performed in 72 of 126 patients, of whom 30 (42%) had CTCs ≥5/7,5ml and 41 (57%) had at least one IGF1R+ve CTC. In univariate analysis the prognostic role of total CTCs was confirmed: PFS ( < 5 vs ≥5) HR = 1.69, 95%CI 1.01-2.69, p 0.042 and OS HR = 2.80, 95%CI 1.47-5.30, p 0.002).However, when total CTCs were split in IGF1R+ve and IGF1R–ve, a striking difference was seen in the prognostic effect of these cell types.While no association was detected between an increasing number of IGF1R+ve CTCs and PFS or OS (p = 0.56 and p = 0.99), the number of IGF1R-ve CTCs ( < 4 vs ≥4) was strongly associated with an increased risk of progression and death: HR 1.93 (95%CI 1.15-3.23, p 0.013) and 3.65 (95%CI 1.88-7.09, p 0.001). In multivariate analysis, adjusted for metformin, the prognostic role of the number of IGF1R-ve CTCs was confirmed, while no residual prognostic role of total CTCs or number of IGF1R+ve cells was found (p = 0.55 and p = 0.64 for PFS; p = 0.86 in both cases for OS). Conclusions: In our study, the loss of IGF1R expression in CTCs exhibited a significant adverse prognostic effect, whereas no significant effect of total CTCs and IGF1R+ve CTCs was observed. This finding supports the biological characterization of CTCs as a critical step for further definition of their prognostic significance.

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Insulin-like growth factor 1 receptor expression in advanced non-small-cell lung cancer and its impact on overall survival

Radiology and Oncology ◽

10.1515/raon-2017-0020 ◽

2017 ◽

Vol 51 (2) ◽

pp. 195-202 ◽

Cited By ~ 4

Author(s):

Mojca Humar ◽

Izidor Kern ◽

Gregor Vlacic ◽

Vedran Hadzic ◽

Tanja Cufer

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Growth Factor ◽

Small Cell Lung Cancer ◽

Squamous Cell ◽

Advanced Nsclc ◽

Small Cell ◽

Small Cell Lung ◽

Nsclc Patients ◽

Igf1r Expression

Abstract Background The insulin-like growth factor 1 receptor (IGF1R) expression has been addressed as a potential prognostic marker in non-small-cell lung cancer (NSCLC) in various studies; however, the associations between IGF1R expression and prognosis of advanced NSCLC patients is still controversial. The aim of our observational, cohort study was to evaluate the expression of IGF1R in advanced NSCLC and its prognostic role. A subgroup analysis was performed to address the influence of pre-existing type 2 diabetes mellitus (T2DM) status on IGF1R expression and overall survival (OS). Patients and methods IGF1R expression was evaluated in 167 consecutive advanced NSCLC patients (stage IIIB and IV), diagnosed and treated at one university institution, between 2005 and 2010. All patients received at least one line of standard cytotoxic therapy and 18 of them had pre-existing T2DM. IGF1R expression was determined by immunohistochemical (IHC) staining, with score ≥ 1+ considered as positive. Information on baseline characteristics, as well as patients’ follow-up data, were obtained from the hospital registry. Associations of IGF1R expression with clinical characteristics and overall survival were compared. Results IGF1R expression was positive in 79.6% of patients, significantly more often in squamous-cell carcinoma (SCC) compared to non-squamous-cell (NSCC) histology (88.7% vs. 74.3%; P = 0.03). IGF1R positivity did not correlate with T2DM status or with other clinical features (sex, smoking status, performance status). Median OS was similar between IGF1R positive and IGF1R negative group (10.2 vs. 8.5 months, P = 0.168) and between patients with or without T2DM (8.7 vs. 9.8 months, P = 0.575). Neither IGF1R expression nor T2DM were significant predictors of OS. Conclusions IGF1R or T2DM status were not significantly prognostic in described above collective of advanced NSCLC treated with at least one line of chemotherapy. In addition, no association between T2DM status and IGF1R expression was found. Further studies on IGF1R expression and its prognostic as well as therapeutic consequences in a larger collective of advanced NSCLC patients, with or without T2DM, are needed.

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