Differential Sensitivity of Human Hepatocellular Carcinoma Xenografts to an IGF-II Neutralizing Antibody May Involve Activated STAT3.

Autor:	Greenall SA; CSIRO Manufacturing, Parkville, VIC 3052, Australia; Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; Monash University, Clayton, VIC 3168, Australia. Electronic address: sameer.greenall@hudson.org.au., Donoghue J; Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; Monash University, Clayton, VIC 3168, Australia. Electronic address: jacqueline.donoghue@hudson.org.au., Johns TG; Oncogenic Signalling Laboratory and Brain Cancer Discovery Collaborative Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; Monash University, Clayton, VIC 3168, Australia; Telethon Kids Institute, Subiaco, WA 6008, Australia. Electronic address: terrance.johns@telethonkids.org.au., Adams TE; CSIRO Manufacturing, Parkville, VIC 3052, Australia. Electronic address: Tim.Adams@csiro.au.
Jazyk:	angličtina
Zdroj:	Translational oncology [Transl Oncol] 2018 Aug; Vol. 11 (4), pp. 971-978. Date of Electronic Publication: 2018 Jun 22.
DOI:	10.1016/j.tranon.2018.05.011
Abstrakt:	Hepatocellular carcinoma (HCC) is highly refractory to current therapeutics used in the clinic. DX-2647, a recombinant human antibody, potently neutralizes the action of insulin-like growth factor-II (IGF-II), a ligand for three cell-surface receptors (IGF-IR, insulin receptor A and B isoforms, and the cation-independent mannose-6-phosphate receptor) which is overexpressed in primary human HCC. DX-2647 impaired the growth of tumor xenografts of the HCC cell line, Hep3B; however, xenografts of the HCC cell line, HepG2, were largely unresponsive to DX-2647 treatment. Analysis of a number of aspects of the IGF signaling axis in both cell lines did not reveal any significant differences between the two. However, while DX-2647 abolished phospho (p)-IGF-IR, p-IR and p-AKT signaling in both cell lines, HepG2 showed high levels of p-STAT3, which was unaffected by DX-2647 treatment and was absent from the Hep3B cell line. The driver of p-STAT3 was found to be a secreted cytokine, and treatment of HepG2 cells with a pan- JAK kinase inhibitor resulted in a loss of p-STAT3. These findings implicate the activation of STAT3 as one pathway that may mediate resistance to IGF-II-targeted therapy in HCC. (Copyright © 2018 BAYLOR COLLEGE OF MEDICINE. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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