Glucose transporter-1 expression and the antiproliferative effects of 2-deoxy-d-glucose in osteosarcoma models
Date
2010
Authors
Lori, Janet Carolyn, author
Lana, Susan E., advisor
Thamm, Douglas, advisor
Biller, Barbara J., committee member
Ehrhart, Eugene J., committee member
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Abstract
Osteosarcoma (OSA) is the most common bone tumor in the dog, more common in large to giant breed dogs. 90% of dogs diagnosed with OSA will die of metastatic disease within one year of diagnosis. There have been no great advances in therapy for canine OSA over the last 20 years. Hypoxia in tumors has been associated with an increased resistance to radiation and chemotherapy, and increased metastatic potential. Hypoxia-inducible factor 1-a (HIF-la) is a transcription factor stabilized by hypoxia. Glucose transporter 1 (GLUT-1), a downstream product of HIF-la pathway activation, is over-expressed in a variety of human tumors. We sought to determine if GLUT-1 is expressed in canine OSA and if expression is related to tumor necrosis and outcome. Immunohistochemistry was performed on 44 histologically confirmed OSA tissue samples to assess expression of GLUT-1. Of 44 cases, 27 (61%) expressed GLUT-1. There was no statistical correlation between GLUT-1 and disease-free interval, survival time, or percent necrosis. As hypothesized, GLUT-1 is present in most canine appendicular OSA. A more objective evaluation of GLUT-1 and other proteins in the HIF-la pathway may be warranted. Some cells within a tumor may be poorly perfused, and therefore less susceptible to traditional chemotherapy. Cancer cells, especially those hypoxic cells that are distant from the stromal blood vessels, require more glucose than normal cells as they utilize anaerobic glycolysis, rather than oxidative phosphorylation, to survive. 2-deoxy-Dglucose (2-DG) is a glucose analog that is preferentially captured by cancer cells, _ blocking the first step of glycolysis. We evaluated the sensitivity of various OSA (canine and murine) cell lines to 2-DG, and attempted correlation to the protein GLUT-1 with western analysis. There was no statistical correlation between 2-DG and GLUT-1 or Akt expression, although it did correlate with total ERK expression. In a murine OSA model, 2-DG was shown to inhibit metastasis, possibly through the inhibition of invasion and migration, as assessed by Boyden chamber assays in vitro using the same OSA murine cell line.
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Subject
Dogs -- Diseases
Osteosarcoma
Cancer in animals