Copper lowering may modulate tumor blood vessels to normalize them, i.e.
ISSUES WITH BACKGATING FLOWJO 10 TRIAL
Importantly, decreasing bioavailable copper has shown promising results in animal models and in clinical trials in different cancers, including a single post surgical trial in patients with malignant mesothelioma. Therefore, therapeutic copper reduction achieved by lowering the levels of bioavailable copper using copper chelators, represents an anti-cancer approach that targets multiple pro-angiogenic factors and is reported to be relatively non-toxic. Copper (Cu), a trace metal involved in many essential processes, such as energy metabolism and hemoglobin production, also plays an integral role in tumor angiogenesis by functioning as a critical co-factor for several pro-angiogenic molecules including VEGF, basic fibroblast growth factor (bFGF), and angiogenin. Strategies that target vascular endothelial growth factor (VEGF) can be transiently successful until sabotaged by tumor up-regulation of other pro-angiogenic factors. A number have been tested, however, toxicity issues thwarted potentially promising outcomes. The realization that angiogenesis is essential for tumor growth, invasion and metastasis led to the development of anti-angiogenic therapies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This work was supported by the Cancer Council of WA and the Dust Diseases Board of NSW. Received: Accepted: JPublished: August 27, 2013Ĭopyright: © 2013 Crowe et al. PLoS ONE 8(8):Įditor: Xianglin Shi, University of Kentucky, United States of America In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes.Ĭitation: Crowe A, Jackaman C, Beddoes KM, Ricciardo B, Nelson DJ (2013) Rapid Copper Acquisition by Developing Murine Mesothelioma: Decreasing Bioavailable Copper Slows Tumor Growth, Normalizes Vessels and Promotes T Cell Infiltration. Copper lowering was also associated with a CD4 + T cell infiltrate. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. These data imply that copper uptake may play an important role in early tumor development.
Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry.
Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper.
However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF).
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