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R Folberg, X Chen, D Wu, J Pe'er, A Maniotis; Control of Uveal Melanoma Morphogenesis and Endothelial Cell Survival by Extracellular Matrix . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1827.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:If high microvascular density is a marker of aggressive uveal melanoma behavior, then it is necessary to explain mechanisms by which aggressive uveal melanoma cells simultaneously permit the ingrowth of angiogenic vessels while themselves simultaneously expressing proteolytic pathways. This study compared the morphogenetic properties of uveal melanoma cells with endothelial cells under varying matrix distributions and quantities, and tested interactions between melanoma cells and endothelial cells. Methods:Endothelial cells from various lineages, non-aggressive and aggressive uveal melanoma cells were studied in monocultures and coculture under constant levels of growth factors. Gels containing melanoma cells were grafted onto chick chorioallantoic membranes (CAMs). Results:Highly aggressive uveal melanoma cells, like endothelial cells, formed networks of cords on thin matrix (which was not blocked with TNP-470), but did not form cobblestone monolayers as expected of endothelial cells (an in vitro characteristic simulating the endothelial lining of blood vessels) on serum proteins adsorbed to rigid surfaces. Highly aggressive melanoma cells also did not form branching cords as did endothelial cells when embedded in thick matrix, but instead, formed patterned amalgams of matrix and tumor cells. Aggressive melanoma cells did not permit only short-term survival of endothelial cells in co-culture. Both non-aggressive and aggressive melanoma cells stimulated angiogenesis on the CAM, but aggressive pattern-forming melanoma cells damaged CAM vessels, rendering them incompetent. In human uveal melanomas, fibrinogen, a marker of plasma, was detected within matrix-rich patterns adjacent to blood vessels. Conclusion:Matrix quantity and distribution regulate an epigenetic morphologic response by aggressive melanoma cells to generate matrix-rich patterns. Aggressive melanoma cells may stimulate angiogenesis but then damage blood vessels. Plasma and red cells from damaged vessels may be transported through patterned matrix-rich amalgams generated by these aggressive tumor cells.
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