EVENTS GOVERNING CELLULAR LIFE

Overall, life at the cellular level enters a new phase as the sperm enters the Ovocyte, here the activity of life is driven by Nuclear events; cell division (and motility of cells) is the driving trend of forces to be amplified and the Embryo formation (Embryogenesis) is the ultimate objective.  As the embryo is being formed, there a transition of forces from proliferation to tissue differentiation. This transition from PROLIFERATION with an AMPLIFIED MITOSIS AND MOVEMENT OF CELL FOR POSITIONING IN THE BODY OF THE EMBRYO characterizes early life and is driven by promoter genes, amplified pathways, driven metabolism at Ribosome, histone, and genetic levels.  The processing of internal and external stimuli triggers the flow of forces.  A change of stimuli eventually occurs, followed by responses imposed by growth factors, variation in needs, and overall  cellular communications, and soon enough the trend of forces is toward differentiation.  In order to protect future life, SANCTUARY tissues are created to keep DIVISION POTENTIAL ACTIVE (Ovaries, testicles keep proliferative potential and controlled activity).   DIFFERENTIATION becomes the name of the game and is AMPLIFIED.  To commit resouces to this activity exclusively, proliferation is shut down at genes, enzymes, and chromatin levels to shield proliferation related  promoters.  Tissue differentiation is pushed to allow life, survival and adaptation leading to races and other phenotypic differentiation.  Each step is amplified to perfection (whatever the perfection is or implied).  REPRESSION OF A GENE THAT NORMALLY SHOULD BE AMPLIFIED OR STAT TRANSCRIPTION UNDER THESE CIRCUMSTANCES, MEANS ONCOGENIC SUPPRESSION AND A SIGN OF MALIGNANT PROLIFERATION AND POTENTIALLY ASSOCIATED RESUMPTION OF MITOSIS AND MIGRATION (METASTASIS).  IT IS ALSO ASSOCIATED WITH LOSS OF DIFFERENTIATION AND ATYPICAL PHENOTYPIC TRANSFORMATION.

This implies that whenever cancerous trending forces are triggered, they happen in a cell which will de-differentiate, but will switch to proliferation, mobility and perfect for survival and adaptation.  A cell trained to escape mechanism of local and distant defense, and full of survival and adaptation skills!  The ESCAPE include eluding local attacks by change in receptors, glycocalyx and level of pump and MDR gene expression,   but also distant (escape Anoikis) cell rejection.

Cancer is a formidable opponent with so many opportunities for target intervention if you know where to touch or block the flow of things for the cure.  The timing of change of the flow of forces/trends provides as much opportunity as a check point.  One may want to target these events.

CURE IS POSSIBLE WHEN YOU LOOK AT THIS WAY OF THINKING!

WITH EVERY LAW COMES A SET OF SPECIFIC GENES, ENZYMES, REGULATORS, PATHWAYS AND POTENTIAL DRIVERS, WE WILL HUNT THEM, STUDY THEM AND DEVELOP TARGET THERAPY OVER THE NEXT FEW YEARS, FEEL FREE TO DO THE SAME, THE RACE IS ON!!!!!

STRATEGIES FOR THE CURE

Since the work of Weinberg and Hanahan, we know that despite the varieties of cancer, 6 driving forces lead to cancer cell survival.  The "Hallmarks of cancer" result from:

1.Self sufficiency in growth signals: Cancer cells escape Anoikis,  They secrete their own growth factors to achieve an autocrine stimulation.

2.Insensitivity to anti-growth signals. This is achieved by changing membranes' receptors composition and number, boosting its own global growth, and secreting Tumor Necrosis factors to tamper with surrounding cell machinery.

3.Sustained Angiogenesis, to maintain "feeding" of the new tumor mass.  This is mostly critical for solid tumors.  It is critical in tumors that bleed easily such as renal cell cancers.

4.Limitless replicative potential.  By removing stops to mass formation, natural boundary sensors which contribute to shaping organs, Telomerase activation again.

5. Suppressing or escaping Apoptosis: By using cyclins and Bcl-2 and related molecules. Shielding Mitochondria and avoiding FAS/BAX, activating loopholes routes and impairing ubiquitination of growth molecules!

6.Tissue invasion and metastasis. Here the tumor cells alter composition, nature and amount of the cell receptors and adhsions molecules, cluster of differentiation (CD), and produce Tumor growth factors (TGF) which give it growth advantage vis-a-vis the surrounding tissue.

This list is by no mean exhaustive given the variety of possible oncogene mutations.  However, when one gene is causing one of the 6 pathways, it is dubbed a DRIVER mutation for that cancer, and may have significant therapeutic importance.

This 6 venues are made of important molecular structures that can be a Target for therapy. Researcher are combing them one by one and targeting them.  The successful experience with Multikinase therapy suggest that interrupting several points of the cascade appears beneficial.  Computer models are being developed to see if sequential attacks or coordinated combinations would be better models for future therapies.  The CRBCM is working to develop such a model. Our model will be complete after we enumerate all laws of nature (see our related series).

Model of cures should embrace these 6 venues in a mathematical equation...the challenge is launched!
 

AT A CHECK POINT IN CELL DIVISION 2 MAIN THINGS HAPPEN:

1. DNA is checked for mistakes and corrections are undertaken.2. Chromosome segregation to eventual daughter cells is checked to avoid uneven distribution of the chromosome. 
This last event seems to rely heavily on activity on unattached chinetochores where check point proteins (MAS 1 & 2, UB1 etc.) accumulate and block the APX (Anaphase promoting complex) until the checking is completed and Cyclin B and Securins are ubiquitinated and destroyed to release the check hold and allow mitosis to proceed.

The need for ubiquitination of Cyclin B elevate the role of Proteasome. That is why Antiproteasome appears very important in hematologic conditions where signal transduction and subsequent cyclin activity are the driving forces toward multiplictaion of cancer cells as we stated.

When all this is  going on, the cancer cell is at its weak point. That is why chemotherapy, particularly the Taxanes and the Vinca-alkaloids, is more effective. It not only disturbs the microtubule (inducing the 2nd law), but also breaks the actinic anchors to the cytoskeleton of membranes and cellular matrix causing the "Anoikis" like phenomenon within the cell. Lesion to actin like molecules (anchors) within the central nervous system could lead to neuropathy. As we know it has the side effect of these drugs (proof of concept to follow).

ANOIKIS, detachment induced cell death

Review: Nature Reviews Cancer 7, 429–440 (1 June 2007) |

The cofilin pathway in breast cancer invasion and metastasis

Weigang Wang , Robert Eddy & John Condeelis

Abstract

Recent evidence indicates that metastatic capacity is an inherent feature of breast tumors and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumor cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis.

To read this article in full you may need to log in, make a payment or gain access through a site license (see right).

======================================================================

Also read:

Thymosin B

Sling Shot Homolog

Chronofin

Filamin

staurosporin

Coronin-1

HMW Isoform TM-1

Anti Rho Kinase

ADF

=====================================================================

This strategy of fighting cancer  is an important one; one of the main differences between a benign tumor and a malignant one is its ability to spread.  It is by spreading that the cancer will invade sensitive tissues of the host and lead to killing them by causing failure of that tissue.

We can't obviously protect against abnormality to occur and cause cancer,  the approach emphasized here is to block the cancer from spreading.  It is an important approach.

One of the ways to achieve this is ANOIKIS (detachment induced cell death). Cells within a tissue are destined to live together.  And any cell that becomes undone, will trigger more likely the 2nd law of nature through its cytoskeleton alteration and enter Apoptosis or programmed cell death.  It appears that the cancer cell prepares its departure by changing its membrane receptor composition, altering its cytoskeleton and undergo numerous changes before embarking in the metastatic process.  The Cofilin system described above by scientists is linked to the activity of ACTIN, a major component of the Cytoskeleton.  It is suspected that the entire cell has a nerve system made of Actin based complex which makes the microfilament.  This is why our 2nd law is so powerful.  Destabilization of the microfilament apparatus in the cell will beak loose all things attached to cell membrane (including Cytochrome C, the activator of caspases but also cause detachment of organelles attached to sarcoplasmic or reticulum membranes).  Again, the second law is so powerful because it is caused basically by Actin change or break.  Attacking Actin for the cell  is like attacking the skeletal and nervous system of the human being.  At the Nuclear level, attacking Actin seems to activate Endonucleases which in turn will break the DNA and trigger the first law. We are still working at the CRBCM to ascertain some of the proofs of principle mentioned here!