Increased expression of insulin-like growth factor-1 receptor is correlated with tumor metastasis and prognosis in patients with osteosarcoma.
ABSTRACT The aim of this study was to investigate the association of insulin-like growth factor-1 receptor (IGF-1R) with metastasis and prognosis of osteosarcoma patients.
RT-PCR and Western blot assays were performed to detect IGF-1R mRNA and protein expression in 26 osteosarcoma and noncancerous bone tissues. Immunohistochemistry was performed to analyze the correlation of IGF-1R expression in 84 osteosarcoma tissues with clinicopathological factors or survival of patients. Lentivirus-mediated RNA interference system was employed to downregulate IGF-1R expression and analyze the effects of IGF-1R downregulation on invasion and metastasis of osteosarcoma cells.
The relative levels of IGF-1R mRNA and protein expression were significantly higher in osteosarcoma tissues than in corresponding noncancerous bone tissues. The expression of IGF-1R protein was closely associated with surgical stage and distant metastasis of osteosarcoma patients. Osteosarcoma patients with high IGF-1R expression had poorer survival, and multivariate Cox analyses showed that high IGF-1R expression was an independent prognostic maker. Lentivirus-mediated targeting IGF-1R could significantly inhibit adhesion, migration, invasion, and metastasis of osteosarcoma cells, which might be correlated with of inactivation of Akt signaling pathway.
IGF-1R is an independent prognostic marker for osteosarcoma patients and increased expression of this molecular is correlated with metastasis of osteosarcoma.
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ABSTRACT: Due to the emergence of adjuvant and neoadjuvant chemotherapy, the survival rate has been greatly improved in osteosarcoma (OS) patients with localized disease. However, this survival rate has remained unchanged over the past 30 years, and the long-term survival rate for OS patients with metastatic or recurrent disease remains poor. To a certain extent, the reason behind this may be ascribed to the chemoresistance to anti-OS therapy. Chemoresistance in OS appears to be mediated by numerous mechanisms, which include decreased intracellular drug accumulation, drug inactivation, enhanced DNA repair, perturbations in signal transduction pathways, apoptosis- and autophagy-related chemoresistance, microRNA (miRNA) dysregulation and cancer stem cell (CSC)-mediated drug resistance. In addition, methods employed to circumvent these resistance mechanism have been shown to be effective in the treatment of OS. However, almost all the current studies on the mechanisms of chemoresistance in OS are in their infancy. Further studies are required to focus on the following aspects: i) Improving the delivery of efficacy through novel delivery patterns; ii) improving the understanding of the signal transduction pathways that regulate the proliferation and growth of OS cells; iii) elucidating the signaling pathways of autophagy and its association with apoptosis in OS cells; iv) utilizing high-throughput miRNA expression analysis to identify miRNAs associated with chemoresistance in OS; and v) identifying the role that CSCs play in tumor metastasis and in-depth study of the mechanism of chemoresistance in the CSCs of OS.Oncology letters 05/2014; 7(5):1352-1362. · 0.24 Impact Factor
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ABSTRACT: Osteosarcoma (OS) and Ewing sarcoma (ES) are the two most common types of primary bone cancer, which mainly affect children and young adults. Despite intensive multi-modal treatment, the survival of both OS and ES has not improved much during the last decades and new therapeutic options are awaited. One promising approach is the specific targeting of transmembrane receptor tyrosine kinases (RTKs) implicated in these types of bone cancer. However, despite encouraging in vitro and in vivo results, apart from intriguing results of Insulin-like Growth Factor-1 Receptor (IGF-1R) antibodies in ES, clinical studies are limited or disappointing. Primary resistance to RTK inhibitors is frequently observed in OS and ES patients, and even patients that initially respond well eventually develop acquired resistance. There are, however, a few remarks to make concerning the current set-up of clinical trials and about strategies to improve RTK-based treatments in OS and ES. This review provides an overview concerning current RTK-mediated therapies in OS and ES and discusses the problems observed in the clinic. More importantly, we describe several strategies to overcome resistance to RTK inhibitors which may significantly improve outcome of OS and ES patients.Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 04/2014; · 9.03 Impact Factor
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ABSTRACT: Osteosarcoma (OSA) is the most common form of malignant bone cancer in children and dogs, although the disease occurs in dogs approximately 10 times more frequently than in people. Multidrug chemotherapy and aggressive surgical techniques have improved survival; however, new therapies for OSA are critical, as little improvement in survival times has been achieved in either dogs or people over the past 15 years, even with significant efforts directed at the incorporation of novel therapeutic approaches. Both clinical and molecular evidence suggests that human and canine OSA share many key features, including tumor location, presence of microscopic metastatic disease at diagnosis, development of chemotherapy-resistant metastases, and altered expression/activation of several proteins (e.g. Met, ezrin, phosphatase and tensin homolog, signal transducer and activator of transcription 3), and p53 mutations, among others. Additionally, canine and pediatric OSA exhibit overlapping transcriptional profiles and shared DNA copy number aberrations, supporting the notion that these diseases are similar at the molecular level. This review will discuss the similarities between pediatric and canine OSA with regard to histology, biologic behavior, and molecular genetic alterations that indicate canine OSA is a relevant, spontaneous, large animal model of the pediatric disease and outline how the study of naturally occurring OSA in dogs will offer additional insights into the biology and future treatment of this disease in both children and dogs.ILAR journal / National Research Council, Institute of Laboratory Animal Resources 01/2014; 55(1):69-85. · 1.58 Impact Factor