Thursday, December 27, 2012


E-cadherin related article

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Molecular Cell, Volume 48, Issue 6, 914-925, 15 November 2012
Copyright © 2012 Elsevier Inc. All rights reserved.
10.1016/j.molcel.2012.10.011

Authors

Yulia A. Komarovasend email, Fei Huang, Melissa Geyer, Nazila Daneshjou, Alexander Garcia,
 Luiza Idalino, Barry Kreutz, Dolly Mehta, Asrar B. MalikSee Affiliations



Molecular Cell, Volume 48, Issue 6, 914-925, 15 November 2012

Copyright © 2012 Elsevier Inc. All rights reserved.

10.1016/j.molcel.2012.10.011

Authors

Yulia A. Komarovasend email, Fei Huang, Melissa Geyer, Nazila Daneshjou, Alexander Garcia,
Luiza Idalino, Barry Kreutz, Dolly Mehta, Asrar B. MalikSee Affiliations

    Hint: Rollover Authors and Affiliations
    

Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612,
 USA The Center for Lung and Vascular Biology, University of Illinois College of Medicine,
Chicago, IL 60612, USA Corresponding author These authors contributed equally to this work

    Highlights
    VE-cadherin homophilic adhesion maintains Ca2+ homeostasis
    VE-cadherin-mediated adhesion suppresses MT growth
    VE-cadherin-mediated adhesion inhibits CaN-dependent dephosphorylation of EB3
    EB3 phosphorylation is required for suppression of MT growth and formation of AJs

Summary

Vascular endothelial (VE)-cadherin homophilic adhesion controls endothelial barrier permeability
through assembly of adherens junctions (AJs). We observed that loss of VE-cadherin-mediated
 adhesion
 induced the activation of Src and phospholipase C (PLC)γ2, which mediated Ca2+ release from
endoplasmic reticulum (ER) stores, resulting in activation of calcineurin (CaN), a Ca2+-dependent
phosphatase.
 Downregulation of CaN activity induced phosphorylation of serine 162 in end binding (EB) protein 3.
 This phospho-switch was required to destabilize the EB3 dimer, suppress microtubule (MT) growth,
and assemble AJs. The phospho-defective S162A EB3 mutant, in contrast, induced MT growth in
 confluent endothelial monolayers and disassembled AJs. Thus, VE-cadherin outside-in
 signaling regulates
 cytosolic Ca2+ homeostasis and EB3 phosphorylation, which are required for assembly of AJs.
 These results identify a pivotal function of VE-cadherin homophilic interaction in modulating endothelial
 barrier through the tuning of MT dynamics.
  =====================================================================


CLINICAL HYPOTHESIS IN CANCER RESEARCH AND COMMERCIALIZATION:
PUBLISHED 10/14/12

Of 186,000 Prostate cancers diagnosed each year, only 29,000 patients will die of this disease.
In fact 70% of men over 80 years of age may be found with Prostate Cancer.  Most will not die of this
cancer. This fact has made almost futile the testing for prostate cancer in elderly patients.  How does
 one chose who should be followed closely or treated? In other words how do you know what prostate
cancer to observe versus which one to actually treat? In more scientific terms, which are the predictive
factors that would prompt us to act versus observe the cancer? To make the matter more confusing,
the success of PSA (prostate Specific Antigen) testing has complicated the issue.  It has led to
 over-diagnosis,
 and experts are now recommending to use PSA findings with caution.
One thing is for sure: the difference between a benign and malignant tumor is that the malignant ones spread
and invade our body. This  is called "ability to metastasize".  It is by invading other organs that cancer
causes these organs to fail and finally causing death of the patient.  Researchers have now started to
 look at cancer cells to try to predict which ones will spread and therefore kill the individual.

The Hypothesis:

For a cancer to spread, it has to detach itself from its surroundings and  create a way to where it wants to go.
 Scientists have suggested that wherever a cell is located, it is maintained in place by ADHESION
 MOLECULES which tie them to the location.  To make its move, the cancer cell has to lose
these molecules.
This is why E-Cadherin has to be reduced by the cell, so that it can free itself from this environment.
The question now is:  Is a REDUCTION OF E-CADHERIN A PREDICTOR OF BAD CANCER?
 IN OTHER WORDS, SHOULD WE BE TESTING FOR THE REDUCTION OF E-CADHERIN
 IN PROSTATE CANCER TO PREDICT WHICH ONES NEEDS INTERVENTION?
This is thought provoking.
P120 and beta- catenins are 2 molecules which could potentially be surrogates of cancer metastasis..
.who knows for sure!

After it has freed itself,  the cancer cell has to move through tissues, it uses enzymes to break through
 the fibers. Some of these enzymes are called METALLOPROTEINASE. The current question is:
SHOULD WE BE MEASURING LEVELS OF METALLOPROTEINASES TO DETECT CANCER
 CELLS ON THE MOVE?

Matrix metalloproteinases 2 and 9 increase 

permeability of sheep pleura in vitro

Eleni Apostolidou1*)

These questions have been raised, it is time to work.
We could actually improve current means of screening for cancer by checking for reduction of E-Cadherin 
and increase of metalloproteinase in the tumor or blood if this is possible.  Potential for commercialization is high
 if we can conquer this detection technology.  "lets go to work! 
 
12/3/2012

METASTATASIS AND SEEDING INTO NEW OR INVADED TISSUE

When the cancer cell reaches the new location, it uses the TGF beta to help its growth and to create exceptional
 advantage for its growth versus surrounding tissue.   This Lead scientists to conclude that TGF beta presence is 
a sign of resistant disease.   When in facts,  it is first a late sign of metastasis already COMPLETED, TGF beta seems
 to be a sign of SEEDING INTO A NEW LOCATION.  TGF BETA NOT ONLY STIMULATE GROWTH BUT COULD
 BE AN INHIBITORY PROTEIN FOR THE HOST DEFENSE AND REJECTION.

QUESTION:

SHOULD TGF BETA INCREASE BE THE THE SIGN OF SEEDING VS LATE STEP OF METASTASIS. WE BELIEVE
 THAT BY THE TIME TGF BETA IS BEING ELEVATED, SEEDING HAS ALREADY OCCURRED.
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