Is copper chelation an effective anti-angiogenic strategy for cancer treatment?

Angiogenesis and the acquisition of an angiogenic phenotype is important for cancer cell proliferation. Copper in an essential trace element that participates in many enzymatic complexes like the cytochrome c, superoxide dismutase and lysyl oxidase and it is involved in processes, like embryogenesis, growth, angiogenesis and carcinogenesis. In particular, its involvement in carcinogenesis was described for the first time in oral submucous fibrosis, where fibroblasts produce large amounts of collagen in the presence of copper. Copper's action in carcinogenesis is two-fold: (1) it participates in reactions with an increased redox potential that result in the production of oxidative products and oxidative stress. Through this mechanism, copper may cause DNA mutations in the nucleus and mitochondria or alterations to membrane phospholipids, (2) it participates in angiogenesis even in the absence of angiogenic molecules, as it was reported for the first time in rabbit cornea models with copolymer pellets charged with PGE1. Copper chelation regimens like penicillamine and tetrathiomolybdate are being described in the literature as having anti-angiogenic, anti-fibrotic and anti-inflammatory actions. Animal models of brain cancer that evaluated the anti-angiogenic properties of copper, have proven evidence of the reduction of tumor's microvascular supply, tumor volume and vascular permeability after plasma copper levels reduction. Interestingly, plasma copper levels reduction was shown to suppress micrometastases generation in mice models of breast cancer. We hypothesize that copper chelation therapy: increases oxidative stress in cancer cells to a level that does not allow survival because of the reduction of anti-oxidative enzymes production. It may also result in inhibition of angiogenesis and of the initiation of the angiogenic switch, because copper normally enhances endothelial cell migration and proliferation, improves binding of growth factors to endothelial cells and enhances the expression of angiogenic molecules. Copper chelation may also reduce extracellular matrix degradation and cancer spread, through reduction of MMP-9 production and probably of other collagenases and may inhibit propagation of micrometastases. However, copper chelation therapy may enhance angiogenesis through reduction of thrombospondin-1, that results into an increase in VEGF-VEGFR2 complexes and a high level of active MMP-9. These hypotheses help in understanding of the anti-angiogenic action of copper chelation therapies and of the complex network of interactions between copper and other molecules involved in angiogenesis. It may also stimulate further research regarding differences in copper metabolism, the effects of anti-copper regimens on organs, the development of resistance, and their possible angiogenic action through thrombospondin expression reduction.

Bone-vasculature interactions in the mandible: is bone an angiogenic tissue?

Starting from early stages of craniofacial development, the leading role of vasculature, in particular endothelial progenitor cells, becomes apparent. They are probably the cells that synthesize the appropriate bone morphogenetic protein (BMP), that precedes neural crest cell migration and determines their final destination and skeletal development. During postnatal osteosynthesis in the mandible, angiogenesis similarly goes before osteosynthesis, regulates this process with the production of BMP-2 and serves as a scaffold for osteoblasts. This growth factor is involved in bone metabolism and bone injury repair. The dependence of bone from vasculature, is better understood when looking to osseous changes that result from vasculopathies and arteritides, like in diabetes mellitus and polyarteritis nodosa respectively, that affect the mandible more frequently than previously suspected. These changes are not only the result of a dysregulation of osteoblasts and osteoclasts, but of a complex network of factors that affect the vasculature, like VEGF and hypoxia. Abnormal vasculature results in qualitatively degradated bone, with an atypical architecture or even in bone necrosis. The dynamic interplay between vasculature and bone of the mandible, with the vasculature endothelium playing an initiating and regulatory role in osteosynthesis, supports the hypothesis of an angiogenic origin of bone. This hypothesis, helps in understanding of bone pathology, like avascular necrosis and of the impact of interventions and medications that affect vasculature, on bone metabolism.