Paracrine Factors of Human Fetal MSCs Inhibit Liver Cancer Growth Through Reduced Activation of IGF-1R/PI3K/Akt Signaling

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death in the world. The multikinase inhibitor sorafenib only demonstrated marginal improvement in overall survival for advanced disease prompted the search for alternative treatment options. Human mesenchymal stem cells (MSC...

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Bibliographic Details
Published in:	Molecular therapy Vol. 23; no. 4; pp. 746 - 756
Main Authors:	Yulyana, Yulyana, Ho, Ivy A W, Sia, Kian Chuan, Newman, Jennifer P, Toh, Xin Yi, Endaya, Berwini B, Chan, Jerry K Y, Gnecchi, Massimiliano, Huynh, Hung, Chung, Alexander Y F, Lim, Kiat Hon, Leong, Hui Sun, Iyer, Narayanan Gopalakrishna, Hui, Kam Man, Lam, Paula Y P
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01.04.2015 Elsevier Limited Nature Publishing Group
Subjects:	Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - pathology Cell Proliferation Culture Media, Conditioned Fetus - cytology Gene Knockdown Techniques Humans Indoles - therapeutic use Liver cancer Liver Neoplasms - drug therapy Liver Neoplasms - pathology Mesenchymal Stromal Cells - metabolism Niacinamide - analogs & derivatives Niacinamide - therapeutic use Original Phenylurea Compounds - therapeutic use Phosphatidylinositol 3-Kinases - metabolism Proto-Oncogene Proteins c-akt - metabolism Pyrroles - therapeutic use Receptor, IGF Type 1 - genetics Receptor, IGF Type 1 - metabolism Signal Transduction
ISSN:	1525-0016, 1525-0024, 1525-0024
Online Access:	Get full text
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Summary:	Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death in the world. The multikinase inhibitor sorafenib only demonstrated marginal improvement in overall survival for advanced disease prompted the search for alternative treatment options. Human mesenchymal stem cells (MSCs) have the ability to home to tumor cells. However, its functional roles on the tumor microenvironment remain controversial. Herein, we showed that conditioned media derived from human fetal MSC (CM-hfMSCs) expressed high level of the insulin growth factor binding proteins IGFBPs and can sequester free insulin-like growth factors (IGFs) to inhibit HCC cell proliferation. The inhibitory effect of IGFBPs on IGF signaling was further evident from the reduction of activated IGF-1R and PI3K/Akt, leading eventually to the induction of cell cycle arrest. We also demonstrated that CM-hfMSCs could enhance the therapeutic efficacy of sorafenib and sunitinib. To the best of our knowledge, this is the first report to show that CM-hfMSCs has a tumor-specific, antiproliferative effect that is not observed with normal human hepatocyte cells and patient-derived matched normal tissues. Our results thus suggest that CM-hfMSCs can provide a useful tool to design alternative/adjuvant treatment strategies for HCC, especially in related function to potentiate the effects of chemotherapeutic drugs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 The first two authors shared cofirst authorship.
ISSN:	1525-0016 1525-0024 1525-0024
DOI:	10.1038/mt.2015.13