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IGF-1 and cancer

Adam J Camblin, Emily A Pace, Sharlene Adams, Michael D Curley, Victoria Rimkunas, Lin Nie, Gege Tan, Troy Bloom, Sergio Iadevaia, Jason Baum, Charlene Minx, Akos Czibere, Chrystal U Louis, Daryl C Drummond, Ulrik B Nielsen, Birgit Schoeberl, J Marc Pipas, Robert M Straubinger, Vasileios Askoxylakis, Alexey A Lugovskoy
PURPOSE: Insulin-like growth factor receptor 1 (IGF-1R) is critically involved in pancreatic cancer pathophysiology, promoting cancer cell survival and therapeutic resistance. Assessment of IGF-1R inhibitors in combination with standard-of-care chemotherapy, however, failed to demonstrate significant clinical benefit. The aim of this work is to unravel mechanisms of resistance to IGF-1R inhibition in pancreatic cancer and develop novel strategies to improve the activity of standard-of-care therapies...
March 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Hidejiro Torigoe, Hiromasa Yamamoto, Masakiyo Sakaguchi, Chen Youyi, Kei Namba, Hiroki Sato, Kazuhiko Shien, Junichi Soh, Ken Suzawa, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka
Epidermal growth factor receptor (EGFR) is a member of the ErbB (HER) family that is known to play important roles in the pathogenesis of various human cancers. Mutations of the EGFR gene are commonly found as oncogenic driver mutations, and have been targeted for treatment in non-small cell lung cancer (NSCLC). Leucine-rich repeat and immunoglobulin-like domain protein-1 (LRIG1) is a cell-surface protein that is known as a negative regulator of the ErbB (HER) family. In this study, we first confirmed that the expression levels of LRIG1 were much lower in NSCLC than in non-malignant cells or tissues...
March 13, 2018: Carcinogenesis
Joanna Stanicka, Leonie Rieger, Sandra O'Shea, Orla Cox, Michael Coleman, Ciara O'Flanagan, Barbara Addario, Nuala McCabe, Richard Kennedy, Rosemary O'Connor
IGF-1 receptor (IGF-1R) and integrin cooperative signaling promotes cancer cell survival, proliferation, and motility, but whether this influences cancer progression and therapy responses is largely unknown. Here we investigated the non-receptor tyrosine adhesion kinase FES-related (FER), following its identification as a potential mediator of sensitivity to IGF-1R kinase inhibition in a functional siRNA screen. We found that FER and the IGF-1R co-locate in cells and can be co-immunoprecipitated. Ectopic FER expression strongly enhanced IGF-1R expression and phosphorylation on tyrosines 950 and 1131...
March 15, 2018: Oncogene
Julien Daubriac, Shiwei Han, Jelena Grahovac, Eve Smith, Abdel Hosein, Marguerite Buchanan, Mark Basik, Yves Boucher
Carcinoma-associated fibroblasts (CAFs) can remodel the extracellular matrix to promote cancer cell invasion, but the paracrine signaling between CAFs and cancer cells that regulates tumor cell migration remains to be identified. To determine how the interaction between CAFs and cancer cells modulates the invasiveness of cancer cells, we developed a 3-dimensional co-culture model composed of breast cancer (BC) MDA-MB-231 cell spheroids embedded in a collagen gel with and without CAFs. We found that the crosstalk between CAFs and cancer cells promotes invasion by stimulating the scattering of MDA-MB-231 cells, which was dependent on RhoA/ROCK/phospho MLC signaling in cancer cells but independent of RhoA in CAFs...
February 13, 2018: Oncotarget
Emilie Clement, Hiroyuki Inuzuka, Naoe T Nihira, Wenyi Wei, Alex Toker
The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of PIK3CA occur with high frequency in patients. Numerous small-molecule inhibitors targeting both PI3K and AKT are under clinical evaluation, but dose-limiting toxicities and the emergence of resistance limit therapeutic efficacy. Various resistance mechanisms to PI3K inhibitors have been identified, including de novo mutations, feedback activation of AKT, or cross-talk pathways...
March 13, 2018: Science Signaling
Asokan Devarajan, Feng Su, Victor Grijalva, Meghna Yalamanchi, Ashna Yalamanchi, Feng Gao, Hannah Trost, Josephine Nwokedi, Gina Farias-Eisner, Robin Farias-Eisner, Alan M Fogelman, Srinivasa T Reddy
Ovarian cancer (OC) is most lethal malignancy among all gynecological cancer. Large bodies of evidences suggest that mitochondrial-derived ROS play a critical role in the development and progression of OC. Paraoxonase 2 (PON2) is a membrane-associated lactonase with anti-oxidant properties. PON2 deficiency aggravates mitochondrial ROS formation, systemic inflammation, and atherosclerosis. The role of PON2 in cancer development remains unknown. In this report, in human, we identified that PON2 expression is higher in early stages (but not in late stages) of OC when compared to normal tissue...
March 12, 2018: Cell Death & Disease
Florencia Clément, Ayelen Martin, Marcela Venara, Maria de Luján Calcagno, Cecilia Mathó, Silvana Maglio, Mercedes García Lombardi, Ignacio Bergadá, Patricia A Pennisi
Nuclear localization of insulin-like growth factor receptor type 1 (IGF-1R) has been described as adverse prognostic factor in some cancers. We studied the expression and localization of IGF-1R in paediatric patients with gliomas, as well as its association with World Health Organization (WHO) grading and survival. We conducted a single cohort, prospective study of paediatric patients with gliomas. Samples were taken at the time of the initial surgery; IGF-1R expression and localization were characterized by immunohistochemistry (IHC), subcellular fractionation and western blotting...
March 9, 2018: Hormones & Cancer
Anthony B El-Khoueiry, Robert O'Donnell, Thomas J Semrad, Philip Mack, Suzette Blanchard, Nathan Bahary, Yixing Jiang, Yun Yen, John Wright, Helen Chen, Heinz-Josef Lenz, David R Gandara
PURPOSE: The insulin-like growth factor (IGF) pathway is activated in hepatocarcinogenesis. Cixutumumab is a monoclonal antibody against human insulin-like growth factor-1 receptor (IGF-1R). Given the cross-talk between the IGF and VEGF pathways, we performed a phase I study of the combination of cixutumumab and sorafenib in hepatocellular cancer (HCC). METHODS: Eligible patients with no prior systemic therapy for advanced HCC and Child-Pugh A to B7 were treated with sorafenib 400 mg BID and escalating doses of cixutumumab (2, 4, or 6 mg/kg IV weekly) in a 3 + 3 design...
March 8, 2018: Cancer Chemotherapy and Pharmacology
Wei Yang, Gary N Schwartz, Jonathan D Marotti, Vivian Chen, Nicole A Traphagen, Jiang Gui, Todd W Miller
The mTORC1 inhibitor RAD001 (everolimus) is approved for treatment of recurrent/metastatic estrogen receptor (ER)-positive breast cancer in combination with the aromatase inhibitor (AI) exemestane. The benefits of A) continued anti-estrogen therapy for anti-estrogen-resistant disease in the context of mTORC1 inhibition, and B) adjuvant everolimus in combination with anti-estrogen therapy for early-stage disease are being tested clinically, but molecular rationale remains unclear. We hypothesized that mTORC1 inhibition activates the IGF-1R/InsR/IRS-1/2 axis in an ER-dependent manner to drive PI3K/AKT and promote cancer cell survival, implicating ER in survival signaling induced by mTORC1 inhibition...
February 6, 2018: Oncotarget
Jianxia Hu, Xiaoyi Liu, Jingwei Chi, Kui Che, Yan Feng, Shihua Zhao, Zhongchao Wang, Yangang Wang
BACKGROUND: Epidemiological data have revealed that colorectal cancer (CRC) risk is increased in patients with Metabolic syndrome. OBJECTIVE: To explore the expressions of IGF-1, ERK, GLUT4, IRS-1 in MS patients with CRC and their associations with the clinical characteristics of CRC. METHODS: We investigated the expressions of IGF-1, ERK, GLUT4 and IRS-1 in greater omental adipose tissues of 168 MS patients with/without CRC, 85 CRC patients without MS and 98 healthy controls by RT-PCR, and analyzed the relationships between their expressions and clinical characteristics of CRC...
February 9, 2018: Cancer Biomarkers: Section A of Disease Markers
Dongfang Tang, Ruyong Yao, Dandan Zhao, Lin Zhou, Yun Wu, Yang Yang, Yifeng Sun, Liming Lu, Wen Gao
Insulin-like growth factor (IGF) signaling plays an important role in tumorigenesis and metastasis. Here, we analyzed insulin-like growth factor (IGF) binding protein-2 (IGFBP2) expression in 81 lung cancer patients and 36 controls consisting of healthy and benign pulmonary lesion participants for comparison, then validated the IGFBP2 expression in additional 84 lung cancer patients, and evaluated the prognostic and chemoresistant significance of IGFBP2 in two cohorts respectively. Next we detected the reversal effect of trichostatin A (TSA) on chemoresistance in cell lines with high IGFBP2 expression...
March 2, 2018: Scientific Reports
Timothy B Legare, Oteni Hamilton, Sarah Dhannoon, Sayed Ali
Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic condition caused most commonly by metastatic mesenchymal tumors. A 74-year-old non-diabetic male with an eight-year history of metastatic sarcomatoid lung cancer presented with altered mental status. His previous treatment included a lobectomy and radiation. Laboratory investigations were significant for blood glucose of 28 mg/dL, confirming hypoglycemia. He was hypokalemic, a condition seen in approximately 50% of patients with NICTH, at 2...
December 20, 2017: Curēus
Antonino Belfiore, Roberta Malaguarnera, Maria Luisa Nicolosi, Rosamaria Lappano, Marco Ragusa, Andrea Morrione, Veronica Vella
In the last decades increasing importance has been attributed to the Insulin/Insulin-like Growth Factor signaling (IIGFs) in cancer development, progression and resistance to therapy. In fact, IIGFs is often deregulated in cancer. In particular, the mitogenic insulin receptor isoform A (IR-A) and the insulin-like growth factor receptor (IGF-1R) are frequently overexpressed in cancer together with their cognate ligands IGF-1 and IGF-2. Recently, we identified discoidin domain receptor 1 (DDR1) as a new IR-A interacting protein...
February 28, 2018: Cell Adhesion & Migration
Yibin Xu, Geoffrey K-W Kong, John G Menting, Mai B Margetts, Carlie A Delaine, Lauren M Jenkin, Vladislav V Kiselyov, Pierre De Meyts, Briony E Forbes, Michael C Lawrence
Human type 1 insulin-like growth factor receptor is a homodimeric receptor tyrosine kinase that signals into pathways directing normal cellular growth, differentiation and proliferation, with aberrant signalling implicated in cancer. Insulin-like growth factor binding is understood to relax conformational restraints within the homodimer, initiating transphosphorylation of the tyrosine kinase domains. However, no three-dimensional structures exist for the receptor ectodomain to inform atomic-level understanding of these events...
February 26, 2018: Nature Communications
Adam Lassak, Mathew Dean, Dorota Wyczechowska, Anna Wilk, Luis Marrero, Jimena Trillo-Tinoco, A Hamid Boulares, Jann N Sarkaria, Luis Del Valle, Francesca Peruzzi, Augusto Ochoa, Krzysztof Reiss
Insulin receptor substrate 1 (IRS-1) is a common cytosolic adaptor molecule involved in signal transduction from insulin and IGF-1 receptors. IRS-1 can also be found in the nucleus. We report here a new finding of unique IRS-1 nuclear structures, which we observed initially in glioblastoma biopsies and glioblastoma xenografts. These nuclear structures can be reproduced in vitro by ectopic expression of IRS-1 cDNA cloned in frame with nuclear localization signal (NLS-IRS-1). In these structures, IRS-1 localizes at the periphery while the center harbors a key autophagy protein, LC3...
February 26, 2018: Molecular and Cellular Biology
Pedro Barata, Matthew Cooney, Allison Tyler, John Wright, Robert Dreicer, Jorge A Garcia
Background The inhibition of insulin-like growth factor receptor-1 (IGF-1R) induces cell cycle arrest and enhancing the effect of castration by delay of progression of human prostate cancer models. Linsitinib is a small molecule and potent dual inhibitor of IGF-1R and insulin receptor tyrosine kinase activity. We report results of a single-arm, phase II study evaluating the safety and efficacy of linsitinib in men with chemotherapy-naïve asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC)...
February 23, 2018: Investigational New Drugs
Ayse Ceren Mutgan, H Erdinc Besikcioglu, Shenghan Wang, Helmut Friess, Güralp O Ceyhan, Ihsan Ekin Demir
Pancreatic ductal adenocarcinoma (PDAC) is unrivalled the deadliest gastrointestinal cancer in the western world. There is substantial evidence implying that insulin and insulin-like growth factor (IGF) signaling axis prompt PDAC into an advanced stage by enhancing tumor growth, metastasis and by driving therapy resistance. Numerous efforts have been made to block Insulin/IGF signaling pathway in cancer therapy. However, therapies that target the IGF1 receptor (IGF-1R) and IGF subtypes (IGF-1 and IGF-2) have been repeatedly unsuccessful...
February 23, 2018: Molecular Cancer
Alexandra M V Wennberg, Clinton E Hagen, Ronald C Petersen, Michelle M Mielke
Insulin-like growth factor 1 (IGF-1) has been associated with osteoporosis, cardiovascular disease, cancer, neurodegenerative diseases, and mortality in middle and older aged adults. Cross-sectionally, IGF-1 decreases with age and levels of IGF-1 are markedly different between individuals. However, little is known about intra-individual trajectories of IGF-1. We examined baseline and serial measures of plasma total IGF-1, IGF binding protein (IGFBP)-3, and their ratio, which is a proxy for bioavailable IGF-1, among 1618 adults, aged 50-95, enrolled in the Mayo Clinic Study of Aging...
February 20, 2018: Experimental Gerontology
Hannah Oh, Ruth M Pfeiffer, Roni T Falk, Hisani N Horne, Jackie Xiang, Michael Pollak, Louise A Brinton, Anna Maria V Storniolo, Mark E Sherman, Gretchen L Gierach, Jonine D Figueroa
Lesser degrees of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini/TDLU, are associated with elevated breast cancer risk. In rodent models, the insulin-like growth factor (IGF) system regulates involution of the mammary gland. We examined associations of circulating IGF measures with TDLU involution in normal breast tissues among women without precancerous lesions. Among 715 Caucasian and 283 African American (AA) women who donated normal breast tissue samples to the Komen Tissue Bank between 2009 to 2012 (75% premenopausal), serum concentrations of IGF-I and binding protein (IGFBP)-3 were quantified using enzyme-linked immunosorbent assay...
February 22, 2018: International Journal of Cancer. Journal International du Cancer
Roberta Buono, Valter D Longo
Cancer cells are characterized by dysregulation in signal transduction and metabolic pathways leading to increased glucose uptake, altered mitochondrial function, and the evasion of antigrowth signals. Fasting and fasting-mimicking diets (FMDs) provide a particularly promising intervention to promote differential effects in normal and malignant cells. These effects are caused in part by the reduction in IGF-1, insulin, and glucose and the increase in IGFBP1 and ketone bodies, which generate conditions that force cancer cells to rely more on metabolites and factors that are limited in the blood, thus resulting in cell death...
February 17, 2018: Trends in Endocrinology and Metabolism: TEM
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