NOMENCLATURE OF GENE (III ), PANCREATIC CANCER!

BETA 4 INTEGRIN: a gene that does more than being an adhesion molecules
it is the road to a poorly described and not well recognized pathway

The LysRS-Ap₄A-MITF signaling pathway

The LysRS-Ap₄A-MITF signaling pathway was first discovered in mast cells, in which , the MAPK pathway is activated upon allergen stimulation. Lysyl-tRNA synthetase (LysRS), which normally resides in the multisynthetase complex with other tRNA synthetases, is phosphorylated on Serine 207 in a MAPK-dependent manner.^[30] This phosphorylation causes LysRS to change its conformation, detach from the complex and translocate into the nucleus, where it associates with the MITF-HINT1 inhibitory complex. The conformational change switches LysRS activity from aminoacylation of Lysine tRNA to diadenosine tetraphosphate (Ap₄A) production. Ap₄A binds to HINT1, which releases MITF from the inhibitory complex, allowing it to transcribe its target genes.^[31] Activation of the LysRS-Ap₄A-MITF signaling pathway by isoproterenol has been confirmed in cardiomyocytes, where MITF is a major regulator of cardiac growth and hypertrophy.<sup>[32][33](wikipedia)

Not only it gives Hypertrophy but epidermolysis goes through this intergrin, it participates in the ERBB pathways.  Mark my word these are critical pathways in pancreatic cancers.

MTIF GIVES YOU MOTIVES TO AFTER IT!
MAKING THE ERBIN A PLAUSIBLE TARGET.
MAKING ALSO A STRONGER CASE THAT MEMBRANE CYTOSKELETON SHOULD BE A GOOD TARGET BECAUSE OF THE WAY IT DRIVES ITS PATHWAY NOT THROUGH THE CYTOSOL( ALTHOUGH THERE IS A SECONDARY RAS/MAPK STIMULATION,) BUT THE PATHWAY HERE IS THROUGH THE RETICULUM ENDOTHELIUM DIRECTLY TO THE NUCLEUS!  CONCEPTUALLY, AN ANTIBODY TO LAMININ ATTACHED TO A SUBUNIT OF A LIPOLYTIC COMPOUND SHOULD HAVE A THERAPEUTIC OR CHEMICAL EFFECT AT THIS LEVEL.  AN INTERESTING APPROACH.  CHANCES ARE IT MAY ALSO HAVE A STRONG IMPACT ON THE WNT-PATHWAY WHICH TRAVELS CLOSE BY AND IS IMPORTANT IN BREAST CANCER!</sup>

MTA-1: THIS IS A REAL OPPORTUNITY
Here the cell stopped fooling around trying to lie to you.  Here the cell says to you this is one of my ways to metastasize.  yes this is my gene to metastasize and I will work like any CBF like molecule by attaching to DNA and make me protein that will have me spread like wild fire!   And by the way, I will use a growth hormone like Estrogen. No kidding around.
 "MTA1 has been shown to interact with HDAC1,^[4][5] Histone deacetylase 2,^[4][6][5] MTA2,^[4] Estrogen receptor alpha^[7][5] and MNAT1.^[8] MTA1 has also been shown to inhibit SMAD7 at the transcriptional level[9]<sup>"  

IT DOES NEED TGF TO WORK, TGF IS FOR LOCAL GROWTH ANYWAY, THAT IS WHY IT BLOCKS THE SMAD.</sup>

SPINT2
Mutation at SPINT2 leads to significant Malignant Ascites and peritoneal invasion, SPINT 2 is a suppressor of this phenomena. On the Intestinal membrane deficiency of SPINT2 leads to sodium induced/containing diarrhea.  This is also true in Ovarian cancer or peritoneal based tumors.  Targeting this is better than trying Avastin, a blind approach when it comes to effusion management.

MMP11

A metalloproteinase, aimed at breaking down extracellular matrix and be on the move.  Targeting MMP for cancer has proven futile.  The cell is not stupid, it does not put out things that are going to hunt it!  It builds first a strong inhibitor to metalloproteinases.  In fact, the lack of inhibitors has been recognized as the main pathogenesis of TTP.   With the ADAMs being the integrins involved!  and next is that Inhibitor which is, of course, expressed in pancreatic cancer.

TIMP1

TIMP1

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TIMP metallopeptidase inhibitor 1
PDB rendering based on 1d2b.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	TIMP1; CLGI; EPA; EPO; HCI; TIMP
External IDs	OMIM: 305370 MGI: 98752 HomoloGene: 36321 GeneCards: TIMP1 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7076	21857
Ensembl	ENSG00000102265	ENSMUSG00000001131
UniProt	P01033	P12032
RefSeq (mRNA)	NM_003254	NM_001044384
RefSeq (protein)	NP_003245	NP_001037849
Location (UCSC)	Chr X: 47.44 – 47.45 Mb	Chr X: 20.87 – 20.87 Mb
PubMed search	[1]	[2]

TIMP metallopeptidase inhibitor 1, also known as TIMP1, a tissue inhibitor of metalloproteinases, is a glycoprotein that is expressed from the several tissues of organisms.
This protein a member of the TIMP family. The glycoprotein is a natural inhibitor of the matrix metalloproteinases (MMPs), a group of peptidases involved in degradation of the extracellular matrix. In addition to its inhibitory role against most of the known MMPs, the encoded protein is able to promote cell proliferation in a wide range of cell types, and may also have an anti-apoptotic function.
==============
PRKCA  see PRKCG
Here Phorbol esters, diacylglycerol, and calcium become important for the cell performance of various functions.  Did I mention few targets, I truly believe I did!

CDH1  The Cadherin by excellence, not only important as adhesion molecule and role in metastasis.  Its role is amplified by what else anchors here such as Vinculin, and others molecules such as Plakoglobins, amplifying the role.  Remember even Cytochrome C is anchored at the mitochondrial membrane and its release leads to apoptosis!
The anchors are legitimate targets therefore, and brings to mind NACA1 in the anchoring to Histone deacetyl transferase (SEE OUR LEUKEMIA SECTION)  CDH13 THAT'S ANOTHER BALL GAME ALL TOGETHER.  THE CELL TWEACKS SOMETHING AND IT IS ANOTHER BALL GAME ALL TOGETHER!
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Building an Electronic Cancer Cell is a necessity

Natural death of cancer cells is the path to cure.
Experience of chemotherapy has shown that a blind and random attack of cancer cells is ineffective at assuring the death of cancer at a 100% curative rate. We believe that this is mostly due to the fact that chemotherapy most of the time does not inflict enough damage to the cell to lead to self destruction or Apoptosis. We believe that certain changes to the cell caused by chemotherapy could work counter the intended effect. This the basis of the trust in target therapy.
Now let us not approach Target therapy the same way we did for chemotherapy.  Target therapy has proven to work, no doubt about it. We need now to organize coordinated attacks on the cancer cells.  We know that Cancer cells' life processes seem to be organized in cascade, redundancy and escape mechanisms, but in a logical way. With one event following another.  This is why Target therapy works by cutting off or promoting upstream events in the cascade.The thing is that cells have downstream escape mechanisms, therefore that mechanism needs also to be struck down in a staged or coordinated attack.

We believe that the construction of an electronic model of a cell will help us identify gaps in the cascade of molecular events, and help identify critical new targets to go after, once these gaps are filled.
Some of the current targets
1. Adhesion Molecules
2. Cell membrane receptors
3. Signal transduction pathways
4. Transcription genes
5. Histones and promoter genes
6. Mitochondrial/ribosomes Metabolism disruption
7. Nuclear genetic material
8. Gene repair and mismatch repair mechanism
This list is not exhaustive, therefore the potential for investigation appears endless.

CLINICAL HYPOTHESIS IN CANCER RESEARCH AND COMMERCIALIZATION:

CLINICAL HYPOTHESIS IN CANCER RESEARCH AND COMMERCIALIZATION:

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 Apostolidou<sup>1*)

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.</sup>