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Oncology: Theory & Practice
Title
Oncology: Theory & Practice
Editor
iConcept Press
Price
USD$109.99
ISBN
978-1-922227-80-5
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26765

Chapter 1

Oncology: Theory & Practice

Insulin-like Growth Factor-1 (IGF-1): A Double-Edged Sword In Ewing Tumour Cell Death

by Frans Van Valen, Henning Harrer, Marc Hotfilder, Uta Dirksen, Borna Truckenbrod, Thomas Pap, George Gosheger, Hans-Ulrich Humpf and Herbert Jürgens

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Abstract

Insulin-like growth factor-1 (IGF-1) reputedly opposes chemotoxicity in Ewing sarcoma family of tumour (ESFT) cells. Here, we evaluated the role of IGF-1 in regulating ESFT cell death in response to apoptosis ligand 2 (Apo2L)/tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), thought to be a first-line effector molecule in tumour surveillance and novel chemotherapeutic agent. We find that depending on treatment duration IGF-1 is a life-to-death switch in the context of Apo2L/TRAIL lethality. Furthermore, the specific IGF-1 receptor (IGF-1R) antibody alpha-IR3 is functionally equivalent to IGF-1. Short term IGF-1 treatment activates AKT kinase and increases X chromosome-linked inhibitor of apoptosis (XIAP) protein that is associated with decreased Apo2L/TRAIL lethality, whereas long term IGF-1 treatment results in repression of XIAP protein through ceramide formation derived from de novo synthesis that is associated with increased Apo2L/TRAIL lethality. During the process, IGF-1 induces downregulation of IGF-1 receptor prior to the onset of its pro-apoptotic effects. Noteworthy, the resistance to conventional chemotherapy is maintained in cells following long term IGF-1 treatment. Overall, our findings indicate that beyond its role in chemoresistance, IGF-1 can circumvent this resistance and sensitize ESFT cells selectively to apoptosis triggered by Apo2L/TRAIL. These findings may have important implications for the biology as well as the clinical management of refractory ESFT. Recently, interest has focused on the use of IGF-1R antibody as potential therapy in ESFT patients. In view of our finding demonstrating the apoptosis-sensitizing effect of alpha-IR3 in ESFT cells in vitro, it is tempting to speculate that the clinical benefit of IGF-1R antibody therapy could extend to more patients when it is combined with Apo2L/TRAIL-based regimens.

Author Details

Frans Van Valen
Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Germany
Henning Harrer
Institute of Food Chemistry, University Münster, Germany
Marc Hotfilder
Department of Paediatric Haematology and Oncology, University Children’s Hospital Münster, Germany
Uta Dirksen
Department of Paediatric Haematology and Oncology, University Children’s Hospital Münster, Germany
Borna Truckenbrod
Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Germany
Thomas Pap
Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Germany
George Gosheger
Department of Orthopaedic Surgery, University Hospital Münster, Germany
Hans-Ulrich Humpf
Institute of Food Chemistry, University Münster, Germany
Herbert Jürgens
Department of Paediatric Haematology and Oncology, University Children’s Hospital Münster, Germany

Citation

Frans Van Valen, Henning Harrer, Marc Hotfilder, Uta Dirksen, Borna Truckenbrod, Thomas Pap, George Gosheger, Hans-Ulrich Humpf and Herbert Jürgens. Insulin-like Growth Factor-1 (IGF-1): A Double-Edged Sword In Ewing Tumour Cell Death. In Oncology: Theory & Practice. ISBN:978-1-922227-80-5. iConcept Press. 2014.

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