Article

Mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) in carcinogenesis.

Division of Molecular Medicine, Rudjer Bosković Institute, Zagreb, Croatia.
Cancer letters (Impact Factor: 5.02). 08/2009; 289(1):11-22. DOI: 10.1016/j.canlet.2009.06.036
Source: PubMed

ABSTRACT The cation-independent mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) is a multifunctional receptor. It is involved in a variety of cellular processes which become dysregulated in cancer. Its tumor suppressor role was recognized a long time ago. However, due to its multifunctionality, it is not easy to understand the extent of its relevance to normal cellular physiology. Accordingly, it is even more difficult understanding its role in carcinogenesis. This review presents critical and focused highlights of data relating to M6P/IGF2R, obtained during more than 25 years of cancer research.

0 Bookmarks
 · 
95 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background & Aims Pathogenesis of intrahepatic cholangiocarcinoma (ICC), the second-most common hepatic cancer, is a poorly understood and its incidence is increasing worldwide. We searched for mutations in human ICC tumor samples and investigated how they affect ICC cell function. Methods We performed whole-exome sequencing of 7 paired ICCs and their surrounding, non-tumor tissues to detect somatic alterations. We then screened 124 pairs of ICC and non-tumor samples for these mutations, including 7 exomes. We compared mutations in PTPN3 with tumor recurrence in 124 patients, and PTPN3 expression levels with recurrence in 322 patients (the combination of both in 86 patients). The functional effects of PTPN3 variations were determined by RNA interference and transgenic expression in cholangiocarcinoma cell lines (RBE, HCCC-9810, and Huh28). Results Based on exome sequencing, pathways that regulate protein phosphorylation were among the most frequently altered in ICC samples, and genes encoding protein tyrosine phosphatases (PTPs) were among the most frequently mutated. We identified mutations in 9 genes encoding PTPs in 4/7 ICC exomes. In the prevalence screen of 124 paired samples, 51.6% of ICCs contained somatic mutations in at least 1/9 PTP genes; 41.1% had mutations in PTPN3.Transgenic expression of PTPN3 in cell lines increased cell proliferation, colony formation, and migration. PTPN3L232R and PTPN3L384H, which were frequently detected in ICC samples, were found to be gain-of-function mutations; their expression in cell lines further increased cell proliferation, colony formation, and migration. ICC-associated variants of PTPN3 had altered phosphatase activity. Patients whose tumors contained activating mutations or higher levels of PTPN3 protein than non-tumor tissues had higher rates of disease recurrence than patients without. Conclusions Using whole-exome sequencing of ICC samples from patients, we found that more than 40% contain somatic mutations in PTPN3. Activating mutations in and high expression levels of PTPN3 were associated with tumor recurrence in patients.
    Gastroenterology 01/2014; · 12.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: For safe and effective therapy, drugs should be delivered selectively to their target tissues or cells at an optimal rate. Drug delivery system technology maximizes the therapeutic efficacy and minimizes unfavorable drug actions by controlling their distribution profiles. Ligand-receptor binding is a typical example of specific recognition mechanisms in the body; therefore, ligand-modified drug carriers have been developed for active targeting based on receptor-mediated endocytosis. Among the various ligands reported thus far, sugar recognition is a promising approach for active targeting because of their high affinity and expression. Glycosylation has been applied for both macromolecular and liposomal carriers for cell-selective drug targeting. Recently, the combination of ultrasound exposure and glycosylated bubble liposomes has been developed. In this review, recent advances of glycosylation-mediated targeted drug delivery systems are discussed.
    Journal of Controlled Release 06/2014; · 7.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor (IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed such as monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor II rather than insulin growth factor I. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-I signaling pathway for hepatocellular carcinoma treatment.
    World journal of hepatology. 10/2014; 6(10):716-37.

Similar Publications