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New Discoveries in Cancer and Heart Disease
By gdpawel at 2014-07-02 03:55
New Discoveries in Cancer and Heart Disease


Larry M. Weisenthal, M.D., Ph.D.


MCED: A newly-discovered mechanism of endothelial cell death


Using a patented laboratory test, we have discovered a new cell death pathway in endothelial cells which we refer to as Massively Calcified Endosomal Death (MCED).  Exploitation of this pathway may afford an effective approach to the treatment of cancer and to the prevention and treatment of atherosclerotic vascular disease, heart attack, and stroke.


MCED in Coronary and Vascular Disease


“Cholesterol levels might not matter.  The most important cause of heart attack, stroke, and arterial blockage might be the presence or absence of circulating MCED factors.”


The underlying mechanisms of atherosclerotic vascular disease are not well-understood by scientists.  It is not known, for example, precisely how pathogenic lipids trigger an inflammatory response in arterial walls.  Neither is it well-established how atherosclerotic arteries become calcified.  Likewise, the mechanisms underlying the cause of calcific cardiac valvular disease (e.g. mitral and aortic stenosis) remain largely unknown.  And why are cholesterol and other lipid levels only imperfect predictors of coronary artery disease? 


We have discovered a previously unknown biological mechanism that explains much of what is not understood about arterial blockage and heart disease.  Understanding the mechanism will allow for development of drugs that control it.


We postulate that massively calcified endosomal death death is the triggering event for both vascular inflammation and vascular calcium accumulation.  Interruption of the MCED pathway, using MCED-targeted drugs, may offer the most potent and specific approach to the prevention and treatment of coronary vascular disease.


MCED in Cancer


The highly-promising treatment paradigm of anti-angiogenic therapy has so far achieved only moderate success.  Anti-angiogenic research is severely hindered by the inadequacy of disease models and predictive biomarkers. Acquired resistance to anti-angiogenic agents is poorly understood, as is the mechanism through which treatment with bevacizumabtermterm increases the risk of cardiovascular disease


MCED induction - precisely the opposite of the goal in heart disease - may be effective in treating cancer.


“Activation of the MCED pathway may enhance effectiveness of anticancer drugs that work by destroying blood vessels necessary to feed the growth of the cancer.”

5 comments | 16719 reads

by gdpawel on Wed, 2014-07-02 03:59
Endothelial Massive Calcium Accumulation Death (MCAD): Mechanism, Target, and Predictive Biomarker for Anti-Angiogenic Therapy

Presented at the 13th international symposium on anti-angiogenic therapy: recent advances and future directions in basic and clinical cancer research. LaJolla, CA. Sponsor: MD Anderson Cancer Center; planning committee Robert S. Kerbel, Lee M Ellis, et al., 03 February 2011

Weisenthal Cancer Group


We cultured human umbilical vein endothelial cells with bevacizumab, with tyrosine kinase inhibitors known to be AA, and with traditional cytotoxic drugs. The images below show that, in the presence of physiological saline and non-favorable culture conditions, the vast majority of the endothelial cells undergo a “non-specific” type of cell death (NSCD), not associated with calcium accumulation, but with loss of cell membrane integrity, allowing uptake of the Fast Green dye, staining these dead dells a pale blue green. In the presence of known AA agents (e.g. bevacizumab, some TK inhibitors) a large percentage of the endothelial cells undergo death associated with massive calcium accumulation (MCAD), with these cells staining hyperchromatic, refractile, blue-black, precisely as reported in






MCAD is strikingly demonstrated by Fast Green/Alizarin staining as reported in


Traditional cytotoxic drugs (e.g. cisplatin) produce only NSCD and inhibit MCAD. We propose that MCAD is a cell death mechanism unique to endothelial cells and provides a practical biomarker to predict for AA activity in clinical oncology and drug development, as well as a potential drug target.


Nature Precedings doi:10.1038/npre.2011.6647.1

by gdpawel on Wed, 2014-07-02 09:40
The 16th International Symposium on Anti-Angiogenic Therapy: Recent Advances and Future Directions in Basic and Clinical Cancer Research.

Date:February 6-8, 2014

Location:San Diego, California 92122, United States

Description: The field of anti-angiogenic therapy is quite complicated with various results with individual agents in different disease types. In fact, the efficacy of such agents in the advanced setting is different from that of an early stage in the adjuvant setting. In addition to learning more about the efficacy and appropriate use of these agents, it is also important for health care providers to understand new toxicities that have been recognized in association with the use of anti-angiogenic agents. This symposium will provide a comprehensive overview of the appropriate use of anti-angiogenic therapy in patients with solid malignancies. In addition, this symposium will review the appropriate use of anti-angiogenic agents and allow the learner to recognize toxicity and potential biomarkers. The main area of feedback focused on biomarkers and the appropriate use of therapy. This is an inherent challenge as we do not have any biomarkers that are validated. However we will continue to scan the literature and seek speakers who can address the issue of biomarkers and patient selection. We will also seek speakers and discuss resistance pathways, which overlap with the above issues.

One Laboratory Oncologist has the answer; will they listen?

Poster Presentation:

Massive calcium accumulation death (MCAD) of endothelial cells as a putative mechanism for Avastin (bevacizumab) anti-angiogenesis and acquired resistance to bevacizumab.

Larry Weisenthal, Summer Williamson, Cindy Brunschweiler, and Constance Rueff-Weiesnthal

We have discovered that human endothelial cells undergo two forms of cell death.

1. A non-specific form of cell death, similar to that of other normal and neoplastic cells.

2. A unique form of cell death, seen only in endothelial cells, associated with massive accumulation of calcium. We call this massive calcium accumulation death or MCAD.

MCAD may be identified by cytochemical staining with:

a. Fast Green alone
b. Fast Green/Hematozylin
c. Fast Green/Wright-Giemsa
d. Alizarin red S (most advantageous)

Sera from different patients is variably inhibitory of MCAD; circulating pro-angiogenic factors may be the mechanism of bevacizumab failure and a test called AngioRx assay may identify sera with such factors.

Here is what's new this year: We have discovered that MCAD occurs when endothelial cells deprived of VEGF begin to form massively calcified endosomes, which result in a unique form of cell death, specific to endothelial cells, and triggered only by pharmaceuticals known to have anti-angiogenic effects. It is not triggered by traditional cytotoxic agents. When many calcified endosomes are formed, the cells die and release massively calcified exosomes into the cellular millieu.

We isolated calcified exosomes produced by incubating circulating endothelial cells from a normal blood donor for 3 days in the presence of bevacizumab. We then incubated freshly drawn buffy coat leukocytes from the same normal donor and found that (1) neutrophils, monocytes, and lymphocytes clustered around these calcified exosomes and appeared to interact with them and (2) this resulted in the release of TNF into the culture medium. Besides being an inflammatory mediator, TNF has been shown to promote retinal vasculogenesis in various occular models and TNF inhibition has been shown to inhibit retinal vasculogenesis, in a manner similar to VEGF depletion by bevacizumab. We think that this provides a mechanism for bevacizumab resistance, to wit:

VEGF depletion --> MCAD, with formation of massively calcified endosomes and exosomes --> provoke phagocytosis and other direct interactions with inflammatory cells which result in the release of TNF (and probably other pro-angiogenic mediators; studies in progress) --> rescue of microcapillaries from the vasculotoxic effect of VEGF depletion.

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