In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. LB-106-LB-106
Abstract:
We recently reported on a re-analysis of previously published gene expression data from a large set of primary solid and metastatic tumors originating from different tissues using the latest available tools for normalization, identification of differentially expressed genes and pathway analysis (Ptitsyn A., et al, BMC Bioinformatics 2008;9 Suppl: S8). Analysis of multiple independent datasets indicated significantly reduced oxidative phosphorylation in metastases compared to primary solid tumors, implying a potential enhancement of the Warburg phenotype in metastatic progression. We thus sought to determine if inhibition of anaerobic glycolysis with the competitive inhibitor 2-deoxy-D-glucose (2-DG) would reverse this metastatic bioenergetic phenotype in highly metastatic cancer cells. We evaluated the effects of 2-DG on DLM8 osteosarcoma cell migration and Matrigel invasion via Boyden chamber assays, and modulation of in vitro production of matrix metalloproteases, VEGF, and cathepsin L were evaluated by gelatin zymography, ELISA and western analysis respectively. The effects of 2-DG administration in vivo was evaluated in an orthotopic, spontaneously metastatic, luciferase-transfected postsurgical model of murine osteosarcoma utilizing DLM8, which is syngeneic to C3H mice. DLM8 cells were implanted into the distal tibias of C3H mice, followed by amputation of the affected limb 16 days later. 2-DG or saline were administered postoperatively (500 mg/kg IP 3x/week, n=5 per group) until sacrifice. Presence of metastasis was evaluated using biweekly bioluminescence imaging and metastasis-free interval calculated using the Kaplan-Meier method. Concentrations of 2-DG associated with minimal antiproliferative activity dramatically inhibited DLM8 cell migration and invasion. There was a dose-dependent decrease in cathepsin L expression upon 2-DG exposure, and VEGF production was inhibited at high 2-DG concentrations, but there were no repeatable changes in MMP activity within the concentration range associated with inhibition of migration and invasion. Postoperative administration of 2-DG significantly delayed DLM8 metastasis (median metastasis-free interval 8 vs 34 days, p = 0.049). In conclusion, glycolysis inhibition with 2-DG is associated with an inhibition of osteosarcoma migration, invasion and in vivo metastasis, at concentrations associated with minimal antiproliferative activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-106.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-LB-106
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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