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.

NEXT TO THE MTOR,

We are getting closer to the cure every day, we are clearly at the door of the cure acquiring process,
just learning the language spoken by the cell. Already it seems we are overwhelmed by what we find.
There are things we are learning though, and fast:
1. That forces within the cell can be followed through laws of nature, as grouped here:  THAT AMPLIFICATION, PROLIFERATION AND DIFFERENTIATION ARE GOVERNED BY SETS OF GENES AND HAVE VARIOUS LEVELS OF EXPRESSION.
2. That treatment strategies can be made following different steps in pathways
3. That Death traps are located at the membrane, cytoplasm, mitochondria and Nucleus
4. That downstream targets inhibition can overcome resistance to earlier target inhibition
5. That Inactivation and down-regulation of gene expression appears to be more important in Oncogenesis
6. That most of the time MAPK amplification results from the down regulation of PI3K/PTEN
7. That MTOR inhibition is deeper than EGFR/VEGF and PI3k inhibition
8. That VELCADE or antiproteasome will disturb all the pathways of which products need Ubiquitination for degradation
9. That Velcade may worsen VHL depedent syndromes
10. Then, even deeper, that MTOR, are Histone de-acyl- transferases

BUT WHAT WE HAVE NOT TALKED ABOUT ENOUGH IS THE POSSIBILITY OF CURE HIDDEN EVEN DEEPER IN THE DIFFERENTIATION.: HERE ARE HIDDEN THE SO- CALLED "PATHWAYS OF SECONDARY METABOLISM"  AND SURPRISE SURPRISE THAT THE ROLE OF ANTIBIOTICS RE-EMERGES!
HERE, WE LOOK FOR DIMBOA PATHWAYS AND DNA REPLICATION
ASSOCIATION WITH STRESS (FOS, C-JUN)
ASSOCIATION WITH P450
ASSOCIATION WITH UDPG GLUCOSYL TRANSFERASES AND SOME DIOXYGENASE

WE NEED TO EXPLORE ANTIBIOTICS COMING FROM FUNGI.

LET ME COME TO THE CHASE OF BX1, BX2, AS THEY ARE TIED TO U11, U12, AND CHROMOSOME 4.  THIS IS THE NEW BATTLEGROUND!

RESEARCHERS, PLEASE GO BACK TO WORK!

FOLLOWING UP ON THE 3RD LAW. (SWING OF THE PENDULUM)

WITH CELL DIFFERENTIATION AT ONE EXTREME, AND CELL PROLIFERATION AT THE OTHER SIDE.  During Malignant transformation, the pendulum swings from de-differentiation to proliferation.  Pushing the EXIT-door open.  At the molecular level, there is an increased expression of genes involved in promoter regulation (TTK, E2F1), but also a gene is involved with the resumption of mitotic phases BUB1, MCM2,CDC.  Microfilament formation and Histone related molecules also reappear ((NUSAP1,ZWINT,CENPA), but also CEP55, CKAP).  Activity at the promoter region is proven by overexpression of EZH.  Relevent cyclins involved are proven by activation of CDKN2 .   Over-expression of any combination of these genes marks the first sign of a Cancerous trend in a differentiated cell.

Of all these, E2F1 and NUSAP-1 seem to be the focus of target therapy as interactions with HMGA are suggested in the literature!

THIRD LAW OF NATURE, NO PROLIFERATION AND CONCURRENT DIFFERENTIATION. HOW THIS LAW CAN BE USED FOR CANCER CURE

While the first and second law refer to the well being of the nucleus for protection of the cell division and its integrity, the 3rd law pertain to cell differentiation.  Basically the first law say that if DNA is altered, cell need to be stopped to allow correction.  And the powerful P53 Activation has been put in place for that.   Significant alteration of DNA will send powerful signal to P53, cause itS activation, and lead to cell cycle arrest.  This is where the power of Cisplatin based combinations reside.  And sure enough, this the basis of the notion that strong repair system will weaken this type of drug.  The all notion of Microsatellite Instability and its role in cancer is based on this law.

The 2nd law, is significant destruction of the scaffold of Mitosis, the Microtuble and all actinic or actinic like molecules which makes mitosis impossible should lead to cell destruction no matter what.  The intergrity of this system of Microtubule and filament not only control the critical phases of Mitosis (Metaphase, Anaphase), it control the integrity of membrane but also the cytoskeleton and cell mobility.  It is the nervous system of the cell and the control of various anchors.  Organelles of the cell are not just free flowing in general, they are anchored  to the Reticulum membrane most of the time (unless destined to Autophagia for cell preservation) and important Molecules involved in Apoptosis such as Cytochrome are attached to Mitochondrial membranes.   Suffice is to say that major alteration to these line of proteins will bypass major Cytosol based protection including the Bcl-2.  This is the strenghth  base of Taxol and Ixabepilone.  It is the explanation for neuropathy and cardiac toxicity of Adriamycin. It is partially the explanation of Q-T prolongation etc.

The 3rd law is more complex, cell differentiation should not go with full proliferation.  Cell that are fully differentiated should not be multiplying like crazy. and for sure, we do not want hundred  of livers, 3 brain or 99 lungs.  Have wonder why Atypia goes along with cancer transformation.  Well you have to lose differentiation to restart multiplying again!  And the poorly differentiated, the worse the magnitude of cancer.
The story of differentiation goes like this:

All cells have the same genome.  But based on their position, internal and external stimuli, they will  go one way or the other to specialize in a certain function for tissue and organ specialty.  The external stimuli could be a change of Oxygen content, Ph, or messages from your neighbor cells sending growth messages etc.  Internal stimuli are cytokines, morphogens, growth factors and signaling molecules or intracellular particulates.  These will stimulate Receptors or pathways (such as the NF-kB) and cause genetic and epigenetic consequences in the Nucleus.  Expression of genes which the cell want and need to be specialized will be achieved through heavy duty transcription of genes.  On the other hand, to control the uniqueness of the tissue, epigenetic closure of  multiplying capability genes is first completed to seal the deal on the fate of the cell.  Differentiation is like an EXIT door.   you can enter, but don't try coming back.  And once you enter, immediately you are taking care by the transcription machinery directing you to where you should be going and you lose multiplication ability.   The door however is not fully irreversibly closed.  In cancer the flow of force reverse and instead of moving forward, the door is reopen and the differentiation machinery is reversed or disabled (poor differentiation), the door is reopen, and the cell start to multiply again as part of the cancerous process.   Studies of Estrogen effect Vs Progesterone has shed some light in this case.  When one look at estrogen, it has more effect on the Exit door, constantly pushing that door toward Multiplication than Progesterone that has little effect of the door but with similar effect on the terminal differentiation.  Making Estrogen more cancer inducing than progesterone.  Yes taking Estrogen gives you the relief of symptoms but it is the push toward reversing the Exit door flow (toward proliferation transcription) that is the problem!
Is expression of H3K or FG2 the markers of Exit door tinkering, we are working hard to determine this.

AS ONE LOOK AT THIS FLOW TOWARD DIFFERENTIATION, A SLEW OF THERAPEUTIC TARGETS  EMERGE, THE ARRAY GOES FROM :

1. NEIGHBOR MESSAGES
2. ENVIRONMENT CHANGES
3. BLOCKING RECEPTOR UPSTREAM THE NF-kB AND COMPARABLE PATHWAYS
4. BLOCKING  THE PATHWAYS
5. SEALING THE DOOR
6. METHYLATION OF GENES, AND PARALYZING OR MODULATING ENZYMES INVOLVED IN EPIGENETIC CHANGES (PCAF, p300 MAY BE)
7. BLOCKING TRANSCRIPTION MACHINERY, EXPRESSION OR GENES DIRECTLY.

CERTAINLY, SIGNS OF RESUMPTION IN ACTIVITY OF GENES MEANT FOR PROLIFERATION IS AN EARLY SIGN OF CANCEROUS TRANSFORMATION, AND The BEST WAY TO DETERMINE THAT A DRUG IS CANCER PRODUCING.

AS A MATTER OF FACT, THIS IS HOW PAMIDRONATE AND OTHER BIPHOSPHONATE ACT TO CONTROL CANCER, BY INCREASING DIFFERENTIATION AND RELIEVING PRESSURE ON THE EXIT DOOR.

WELL DIFFERENTIATED TUMORS WILL HAVE A BETTER PROGNOSIS BECAUSE THEIR GENERAL FLOW OF FORCE IS STILL TOWARD DIFFERENTIATION AND NOT THROUGH THE PROLIFERATION DOOR .

WE ARE WORKING HARD AT CRBCM!