Profiling through at the CRBCM!

At the CRBCM something is coming through:

1. Deterioration at membrane receptor by lack of stimulation or "false or abnormal stimulation" could not only alter the nature of the "glycan" covering the protein portion of the receptor, but also induce stress like molecules.(HSP)
2. As a result of receptor failure new cytokines and TGFs are secreted which unfortunately fail at the initial receptor, but induce other receptors, amplifying standard pathways like RAS or PIK
3. Certains TGFs have an intrinsic power to maintain life of cells no matter what and induce metastasis.
4. Certain genes have an auto-phosphorylation or self-limiting mechanism that can easily go wrong  (RAS, FAK) driving to neoplastic process
5. FAK plays a larger role in aggressive prostate cancer than it has been recognized!
6. FAK has a closer relation to Androgen than recognized
7. NOTCH has closer relation with MEK and "stem cell potential" than recognized.
8. FAK disturbance prominence in cancer explains its sensitivity to Taxanes!  That is on top of Microtubule disturbances induced by the drug!
9. Metalloproteases are the ultimate Biomarkers of membrane events !
10.  Epigenetic methylation and its patterns are one of the largest mystery still to be elucidated!

THE "CHELOID FACTOR" AT THE CELLULAR MEMBRANE!

We tend to be excited about intracellular pathways as they travel through the Cytosol and affect epigenetic and nuclear phenomena. And our excitement has been justified since we have been able to affect cellular life by targeting various pathway molecules.  But one should stress a particular event occurring at the membrane that mimics "wound phenomena".  Aside for providing a physical boundary of the cell, the membrane is one of the most important "organs" of the cell.  It is in itself a very chemically vibrant living "cellular tissue ".  When you start reading about the cell they tell you about the layers of proteins and lipids that make up the cellular membranes.  But this picture is far from the truth, the membrane is like the wall of a brick house.  With each brick different from the next.  Some of these bricks are called Integrins (I guess because they are an integral part of the membrane).  Some of these bricks have a Cyclin, some have a growth factor!  In fact, the membrane here serves as a reserve of these molecules. Some bricks can be divided in 2 portions.  One portion that can "FLIP" inside when needed (This portion contains the cyclin, for example) and one portion that can "FLOP" outside (this portion contains a Metalloprotease).  (see my post on FLIPPASE and FLOPPASE) The point is that once the brick is used there remains a hole with sharp edges.  These edges are called "FOCAL ADHESION Molecules" (KINASES) in a cell and are governed by the PTK2 gene!  (and of course PYK2)

PTK2:

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Protein tyrosine kinase 2
PDB rendering of the C-terminal FAT domain based on 1k04[1].
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	PTK2; FADK; FAK; FAK1; FRNK; PPP1R71; p125FAK; pp125FAK
External IDs	OMIM: 600758 MGI: 95481 HomoloGene: 7314 ChEMBL: 2695 GeneCards: PTK2 Gene
EC number	2.7.10.2
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5747	14083
Ensembl	ENSG00000169398	ENSMUSG00000022607
UniProt	Q05397	P34152
RefSeq (mRNA)	NM_001199649	NM_001130409
RefSeq (protein)	NP_001186578	NP_001123881
Location (UCSC)	Chr 8: 141.67 – 142.01 Mb	Chr 15: 73.21 – 73.42 Mb
PubMed search	[1]	[2]

PTK2 protein tyrosine kinase 2 (PTK2), also known as Focal Adhesion Kinase (FAK), is a protein that, in humans, is encoded by the PTK2 gene.^[2] PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick to each other and their surroundings) and spreading processes (how cells move around).^[3] It has been shown that when FAK was blocked, breast cancer cells became less metastastic due to decreased mobility.<sup>[4](Wikepedia
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AND THEY ARE PLENTY TALKED ABOUT! 
===============================================================  I.E....</sup>

"Integrin-dependent translocation of phosphoinositide 3-kinase to the cytoskeleton of thrombin-activated platelets involves specific interactions of p85 alpha with actin filaments and focal adhesion kinase(JCB)"

 

The point is that at the membrane healing should occur after the "integrin" has been plucked off, but failure to heal may trigger the "cheloid effect".  In the cell, this is where the Src gene is, the Wnt (catenins) and the Notch are here, Caspase 3 is present, and death Receptors,etc... (things can get complicated really fast with these guys around! unless of course phosphorylation or other taming mechanisms come to play!)

Focal Adhesion kinases (FAK)

". FAK is typically located at structures known as focal adhesions, these are multi-protein structures that link the extracellular matrix (ECM) to the cytoplasmic cytoskeleton. Additional components of focal adhesions include actin, filamin, vinculin, talin, paxillin, tensin^[7] and RSU-1."  This is what Taxol and Taxotere find their might!  (components of microtubules)

remember tensin is same as PTEN

NIH

" PTEN1

Also known as

BZS; DEC; CWS1; GLM2; MHAM; TEP1; MMAC1; PTEN1; 10q23del

Summary

This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. [provided by RefSeq, Jul 2008]"

CANCER CELLS AND THE CURE

A living cell is in constant motion. At any given time, there are periods of chemical reactions unfolding in a living cell. These processes are occurring 24/7. Despite their large number, they are not random, but are coordinated and purposeful. They have one overall objective which is the survival of the cell against all odds. However, when they cannot preserve life, they initiate the programmed cellular death. 
These cellular reactions respect basic chemical laws of ion and atom interactions. However, the general direction from reactions is imposed by the cellular mission which is clearly determined by the location of the cell in a tissue or organ and the expected function to be performed by the organ. At any given point in time, the cell is either in differentiation or proliferation, or changing to adapt to current circumstances of the cell. These functions and adaptations are caused by environmental stimuli reaching the cell.
 These stimuli could be chemical, hormonal, traumatic or electric and they reach receptors which cross the cellular boundaries or membrane, and affect the molecules belonging to a signal transduction pathway. The signal goes on to affect genes in the nucleus of the cell where DNA will be replicated to achieve or respond to the stimuli accordingly. All reactions follow a certain flow to achieve a purpose for the cell. To control the general direction of reaction the cell uses several methods: the first is to silence un-needed genes and to amplify the expression of needed genes that carry the code for the mission to be performed. 
The cell will enter division and proliferation of those genes to impose the general direction or flow of the reaction. The second method used to impose the general direction is the formation of genes that can catalyze or force the reaction to go a certain way: these are called "enzymes" for that particular reaction. If an enzyme is not formed, the reaction is not allowed to progress. Therefore, the control of what is happening is occurring this way. A third way to control the flow of direction is to promote proteins called "regulators". The more the regulators in a reaction, the more likely that regulated reaction can occur in a controlled fashion. The fourth way of controlling reaction is mole fraction which puts together certain regulators and enzymes or proteins in general which are aligned in a chain and forces molecules to go from one protein to another in the mole in a certain direction so that the output is what is needed for the mission. 
These mole-like complexes of proteins are called "core binding factors". Any protein function not needed will not be incorporated in the complex. Genes are silenced by methylation, or simply by being attached to patches of molecules that belong to the histones, the histones that cover genetic material. At any given point, when a gene is needed, the cover can be re-opened or pulled back, which is called "gene remodeling". A cancer cell will tend to move away from the location where it is located not because of its intention to kill the host, but because in that location the nutrients and local conditions will be inadequate eventually to allow further growth. It will seek another location to survive. Before it moves away, it has to take steps to protect its survival. It will break adhesion to surrounding cells; this is mostly achieved by decreasing its surface adhesion molecules. It will secrete proteins that can break fibers on its way in order to get through and detection of these proteins called “metalloproteases” can signal doctors that the disease, the cancer, is on the move. In certain circumstances, it produces a mucus to protect itself against detection by the immune system. 
When it arrives in the new location, the cell will produce a hormone or growth factor which gives itself advantage over the already present cells in that location. This is generally called a “tumor growth factor”. The potential for proliferation, division and growth advantage is driven through the signal transduction pathway inside the cell. This is generally achieved by the expression of a driver gene which is amplified or over-expressed forcing reaction for downstream pathways. This is called a “driver mutation”. 
Experience with chemotherapy which was like a bomb with an indiscriminate effect affecting both good and bad cells of the host has only been able to achieve 20 to 30% of cure. Today, scientists are targeting the driver mutations to stop pathways of growth of cancer cells. We are now getting higher response rates and starting to see response in cancers that were resistant to chemotherapy, e.g. melanoma. People used to talk about cure without believing in their own statement, but with the advance of target therapy, cure is a real possibility. We are just at the beginning of our understanding of the various targets. Cure will be achieved.

S100A4, AN IMPORTANT TARGET FOR SURE! LOCATED AT 1q21

The importance of a molecule in the body is determined  by its chemical properties, the pathogenesis of the disease in which it is  participating or how critical a function it is performing in the cascade of a pathway. The importance of a gene is determined by its product's shape and function which is sometimes defined by atoms hanging at its periphery, ready for business of attracting other electrons or ions.  It is also determined by genes in a linkage relationship at the chromosome level. This last point is important to be clarified by researchers who have the tools to explore the coexistence of genes on an arm of a specific chromosome.  And a lot of research forgets to look at that aspect of the problem gene. (don't forget "q" most of the time portends for worse prognosis than "p" , that is it may induce a malignant phenotype.  In fact, co-expression of homologue "p" will mitigate the phenotype. And the homologue gene is on a p arm and on a different numbered chromosome)

By now you also know that cell life is directed in one direction at a time frequently.  Cells are under function performance, differentiation, proliferation or neoplastic transformation.  Neoplastic cells are in concert with surrounding cells from which it avoids to be in conflict with to escape detection.  Neoplastic Cells will be soon stressed because of their increased needs and through the c-JUN -FOS will increase a Tumor Growth factor liberated from the cellular membrane with concomittent release of Metalloproteases in the extracellular membrane through flippase-floppase activity.  The Metalloprotease goes out, the Growth factor goes in.
IT WOULD BE GOOD TO KNOW WHICH METALLOPROTEASE IS SPECIFICALLY LINKED TO WHICH PROTEIN IN ORDER TO KNOW WHAT IS GOING ON INSIDE THE CELL JUNK BY DETERMINING WHICH OF THE METALLOPROTEASE   FAMILY MEMBER IS IN THE EXTRACELLULAR SPACE OR BLOOD!   NICE LITTLE PROJECT RIGHT THERE.  "WHICH TYPE OF METALLOPROTEASE FOR WHICH CANCER"  I BET, BRAIN TUMOR WILL RELEASE A DIFFERENT METALLOPROTEASE THAN OVARIAN CANCER.  BECAUSE THE GROWTH HORMONE RELEASED IN THE CELL WILL BE DIFFERENT.

By now you also know that in certain proliferative processes, there is an increased aspect of only 1 or 2 functions.  In Leukemias, for example, it is amplification of a certain Core binding complex which attaches certain molecules with specific functions.  And the cell follows the cascade of functions to go in a certain cell life trend.  Some of these proteins are gene regulators.  In fact, Leukemia would be better controlled if we just determined the proteins on CBF and the regulators that are promoted in the cell.  ANOTHER EASY PROJECT : THE PATTERNS OF GENE REGULATORS IN A SPECIFIC LEUKEMIA (BY WETERN OR SOUTHERN BLOT).

One of those regulators is the S100A4, a potent regulator which not only is at the differentiation, meaning when mutated or amplified it will create phenotypic havoc for sure.  It is handling Calcium, therefore will affect some Microtubules (good or bad for Taxanes?):  Time to find out more! Read these articles!

1. High expression of S100A4 in cytoplasm at the advancing front of stage C colonic tumours indicates a poor prognosis.
2. The S100A4 protein, mostly studied in cancer, is overexpressed in the damaged human and rodent brain and released from stressed astrocytes.
3. we show for the first time the intratumoral knock down of S100A4 via systemic application of S100A4shRNA plasmid DNA, restricts metastasis formation in a xenografted mouse model of colorectal cancer.
4. SRX forms a complex with S100A4 (and has stronger affinity for S-glutathionylated S100A4), regulates its activity, and mediates redox regulation of the interaction of S100A4 with nonmuscle myosin heavy chain II-A.
5. S100A4 and its downstream factors play important roles in pancreatic cancer invasion, and silencing A100A4 can significantly contain the invasiveness of pancreatic cancer.
6. HBXIP up-regulates S100A4 through activating S100A4 promoter involving STAT4 and inducing PTEN/PI3K/AKT signaling to promote growth and migration of breast cancer cells.
7. S100A4 and VEGF mRNA levels were up-regulated in clear cell renal cell carcinoma (CCRCC), tissue compared with control; upregulated tumour S100A4 and VEGF mRNA levels were independent risk factors for the presence of invasion and/or metastasis
8. High S100A4 is associated with ovarian cancer invasiveness.
9. FSP1 localized to podocytes in focal segmental glomerulosclerosis & minimal change disease. The number of FSP1(+) podocytes per glomerular profile was higher in patients with FSGS than in MCD. There was a corresponding difference in FSP1 mRNA levels.
10. Asymmetric mode of Ca-S100A4 interaction with nonmuscle myosin IIA generates nanomolar affinity required for filament remodeling in epithelial carcinoma cells.

NOTE HBXIP S100A4:  AN IMPORTANT TARGET FOR CERTAIN!

CLINICAL RESEARCH AND COMMERCIALIZATION FOR OUR CPRIT SUBMISSION.

Our suggestion of a CPRIT submission formulated on Oct 14th (see our posts) has excited our readers
we felt compelled to dig deeper in this story.  We basically suggested that in Prostate Cancer, the incidence was much higher as opposed to a relative low mortality.  We went on to say that this paradox begs scientists to find ways of discriminating which Prostate Cancer should be considered dangerous for our patient to compel us to aggressively treat the patient.  We suggested that a cancer that is spreading needs to be treated because only metastasis ( spread of the cancer) can kill the patient.  How to tell which cancer will spread?  We submitted that cancer cells before they spread, needed to lose their attachments to other cells by decreasing their Membrane Adhesion Molecules.  One of the Adhesion Molecule of interest was E-Cadherin.  We therefore suggested that in all cancers of the prostate, dosing the amount of Adhesion molecule was a way to predict its potential for spreading.  If we make it simple to quantify E-Cadherin, a kit can be commercialized to determine quickly the spread of disease.  We also suggested that cancer cells to penetrate tissues and leading to organ failure and killing the host, must create its road through cellular tissues.  It needs to secrete enzymes called Metalloproteases (2,9) to break through.  We suggested that a high level of these Metalloproteases in the biopsy tissue could predict a moving cancer.  A Kit to detect Metalloproteases could be commercialized to help Doctors take medical decisions for the benefit of patients.  All this, if proven in our intended research could advance medical practice.

There is further discussion to have about this:

1. Could Blocking Metalloprotease gene stop the spread of disease?
2. Could restoring E-Cadherin level or function stop the spread of disease?
Scientist from California believe that  activating P120 could restore E-Cadherin function efficiently enough to restore or correct deficiency of E-cadherin function.  Should we use this approach to slow down cancer.

The story of E-Cadherin is just beginning.  We know that cancer in fact spread very early.  In small cell lung cancers, Doctors perform a bone marrow biopsy to see that even in early stage, the cancer has already invaded away from the lung.  This is true also in Breast cancer where even in stage I (the first stage of Breast cancer) the Bone marrow could already be invaded.  The meaning of this distant invasion has been interpreted with controversy.  But even in these cases, it portend a bad prognosis.  Worse prognosis then that of patient with negative Bone Marrow finding. DOES E-CADHERIN REDUCTION CORRELATES WITH POSITIVE INVASION OF THE BONE MARROW?  COULD WE SPARE PATIENTS A BONE MARROW PROCEDURE IF THE E-CADHERIN IS LOW. These are some of the question that have a bearing on clinical matter and would impact today practice as we move forward.

The level of E-Cadherin has broad implications.  In Colon cancers, particularly in the Familial Adenomatous Polyposis (FAP), The E-cadherin level could predict not only evolution to cancer state of the Polyposis but also and again predict metastasis.  He even beg to suggest that it could have prognosis implication.  The decrease of E-cadherin has profound consequence on the amount the Beta-catenin that E-cadherin can not longer "sequester".   Whether this will lead to increase the Cyclin D level down the line could be assumed and therefore sustain life of cancer cell.  It is also worth mentioning that in the sequence of gene Mutation leading to Colorectal cancer, the loss of 5q (ADENOMA PHASE)which seems to correspond to the phase where Beta- Catenin is important is the earliest stage in the sequence of transformation.  This fact correspond to the "good Prognosis" of these cancer....COULD E-CADHERIN REDUCTION BE  AN EARLY SIGN OF COLORECTAL CANCER METASTASIS?  OR SHOULD THIS MODEL BE CHALLENGED?

Assuming we find a Molecule A which, when it is incorporated by the cell, it opens up and adopt a conformational change increasing phosphorylation of Beta-Catenin leading it to proteasomic destruction, could that decrease Cyclin D formation and induce Apoptosis?  What would be the impact if that incorporation was selective to cancer cells?  These are the challenges we face!

Through genetic intervention, could we restore the wnt-signalling pathways to prevent FAP and prevent removal of the Colon in FAP? Remember this, 80-85% of sporadic colorectal cancers have disturbance in the wnt pathways, what we are talking about could impact the majority of Colorectal cncers (second leading cause of cancer death in the United States)

Does the wide spread use of Calcium based product for Osteoporosis prevention correspond to decrease of Colorectal cancer in the terminal colon.  Calcium is critical in the function of membrane receptors.

The cure is achievable, let get it!