About MCED


Abstract


We have discovered a novel and specific mechanism of endothelial cell death that has major implications for cardiovascular disease and potential implications for anti-angiogenic therapy of cancer.  We refer to this novel death mechanism as "Massively Calcified Endosomal Death," or MCED.  


We have documented that MCED occurs only in endothelial cells and not in any other form of nucleated normal or cancer cells we have studied.


Exposure of endothelial cells to non-specific toxins or other physical stresses induces death by traditional apoptotic and non-apoptotic mechanisms in a manner common to most other types of cells.  


In contrast, exposure of endothelial cells (but not other types of nucleated cells) to specific insults, such as oxidized pathogenic lipids (e.g. 7-Ketocholesterol) or agents with known anti-angiogenic activity (e.g. bevacizumab, certain tyrosine kinase inhibitors, etc.) triggers cell death via a novel pathway.  This pathway involves the formation of massively calcified endosomes.  The calcified endosomes then escape from dying endothelial cells as massively calcified exosomes.  


These endosomes/exosomes provoke an inflammatory response which is characterized by physical association of calcified microparticles with inflammatory cells (monocytes, lymphocytes, neutrophils).  This results in an increased release of an inflammatory mediator (TNF) into the culture medium. 


Traditional media for the culture of endothelial cells are profoundly inhibitory to MCED, as are some mammalian sera and many human sera, explaining why MCED had not been previously discovered and reported. 


Our discovery of MCED was unanticipated.  It resulted from our work with primary cultures of fresh human tumor cell clusters.  As we discovered, these clusters invariably contain microcapillary cells.  Our cell culture media are optimized for tumor cells and not for endothelial cells.  Thus the media permitted MCED to occur.  


Importantly, our experiments showed that sera obtained from different patients vary widely in the ability to support or inhibit MCED.  This may account for the wide variance of risk for atherosclerotic vascular disease which is known to exist among patients whose clinical risk factors are otherwise ostensibly identical.  


Isolating the inhibitory factor(s) from sera and/or from endothelial culture media may point the way to the development of pharmaceuticals which prevent and/ or treat atherosclerotic vascular disease.  This may also give rise to pharmaceuticals which enhance the effectiveness of anti-angiogenic cancer therapy.




New Discoveries in Cancer and Heart Disease

“Block MCED and you block inflammation - block inflammation and you block atherosclerotic vascular disease.”


For an MCED slide presentation please click here.