Rapid copper acquisition by developing murine mesothelioma: Decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration
MetadataShow full item record
Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an antiangiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. 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. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. 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. Copper lowering was also associated with a CD4+ T cell infiltrate. 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.
© 2013 Crowe et al. 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.
Showing items related by title, author, creator and subject.
Murine mesothelioma induces locally-proliferating IL-10<sup>+</sup>TNF-a<sup>+</sup>CD206<sup>-</sup>CX3CR1<sup>+</sup> M3 macrophages that can be selectively depleted by chemotherapy or immunotherapyJackaman, Connie; Yeoh, T.; Acuil, M.; Gardner, Joanne; Nelson, Delia (2016)© 2016 Taylor & Francis Group, LLC.We used a murine model to monitor changes to myeloid cell subsets, i.e., myeloid-derived suppressor cells (MDSCs), M1 macrophages that secrete pro-inflammatory cytokines and express CD40 ...
Schaefer, Rainer (2008)At present, most cancers are treated with surgery, radiotherapy and chemotherapy, used alone or in combination. Surgery and radiotherapy are the primary treatment modalities after early detection of cancers and they ...
Gardner, J.; Mamotte, Cyril; Patel, P.; Yeoh, T.; Jackaman, Connie; Nelson, Delia (2015)Dendritic cells (DCs) play an important role in the generation of anti-cancer immune responses, however there is evidence that DCs in cancer patients are dysfunctional. Lipid accumulation driven by tumor-derived factors ...