A crucial requirement for the stepwise, continued growth of a brain tumor is the acquisition of a blood supply from the host, i.e. angiogenesis. The mechanisms of copper activity linked to neovascular and neoplastic growth are largely unknown. Copper ion was shown to be a cofactor for angiogenesis. / We tested the effect of copper depletion achieved by a low copper diet and a copper chelator D-penicillamine, on the intracerebral growth of two experimental brain tumors. We developed in in vivo brain tumor model using the VX2 carcinoma. Implantation of 5 $ times$ 10$ sp5$ VX2 carcinoma cells into the parietal lobe of normocupremic rabbits consistently yielded large hemorrhagic, necrotic, vascularized tumors. The cortical surface revealed numerous, hypertrophied, tortuous new vessels with feeding arteries and draining veins similar to the angioarchitecture of malignant human brain tumors. We report here that copper depletion prevents tumor neovascularization and restricts tumor growth of the VX2 carcinoma in the rabbit brain. Low copper diet and penicillamine are both necessary to achieve angiogenic inhibition. We also tested the effect of copper depletion on the 9L gliosarcoma. We observed that invasive growth of the tumor was blocked in rats depleted of copper. Electron microscopy revealed the absence of cytoplasmic extensions, including pseudopodia, by contrast, in normocupremic controls, cytoplasmic extensions, typical of mobile cells, invaded the surrounding neuropil. Our findings link the activity of copper in vascular and neoplastic growth. / We found an increase in the peritumoral brain water content in the copper depleted animals and that copper depletion by itself in nontumor implanted animal has no effect on brain water content. / Because of the ability to pharmacologically suppress capillary growth induced by the VX2 carcinoma, we could test the relative contribution of breakdown of the blood-brain barrier compared with that of angiogenesis in the appearance of contrast enhancement in computed tomographic examinations. We conclude from our data that tumor neovascularization, in our brain tumor model, is the key determinant for the appearance of contrast enhancement. / The same protocol used in the brain failed to prevent tumor neovascularization and growth of the VX2 carcinoma in the muscle of the rabbit thigh indicating the crucial role played by the milieu (muscle versus brain) for the growth of malignant tumor. In the same manner, lung metastases were not prevented.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.70205 |
| Date | January 1988 |
| Creators | Zagzag, David. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Neurology and Neurosurgery.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001643439, proquestno: AAINN72035, Theses scanned by UMI/ProQuest. |
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