THE Wnt PATHWAY

THE Wnt PATHWAY
It is one of the most complex and versatile pathways.  It is a powerful pathway because Mutations here have direct impact on cell totipotentiality, metastasis and cell differentiation and survival. It involves the most genes .
1.The Wnt interacts with E-Cadherin and therefore intervenes in the Cell Adhesion and Metastatic spread of cancers.
2. The Wnt influences Calcium concentration in the cell.
Remenber Calcium have influence on Calmodulin function and in Alzheimer dementia, microtubule entanglement is worsened by influx of Calcium
3.  Interaction with the Frizzled assure membrane polarity
?control of the flippase or calcium channels?
4. It has nuclear effect through activation of beta-Catenin (through activation OCT4) which is normally degraded by Ubiquitination, therefore opening the door to Velcade
5. Totipotentiality of cells comes back through the Wnt (through Nanog derepression by removing TCF3 influence)
6. Activate the MTOR to ensure cell survival (through GSK)
8. It controls Mesodermal differentiation (through FLK1)
9. It attenuates the Sonic HedgeHog (through GSK)
10. It has full control of the Neurologic sytem of the cell, and through is wingless system, determines where the function will be displayed
11. It is a stimulator of the c-JUN through RAC-1
12. It confers the status of Neuroendocrine differentiation, control where nerves go or do not go!
It is why Cisplatin has a role in in Neuroendocrine differentiated tumor
13. It is the master of Embryonal Gastrulation
Watch out: attacking Wnt can activate the cancer because of its c-JUN connection which leads to Tumor Growth factor!
14. Viral penetration involves the Wnt
15. It controls cell morphology, migration, endocytosis and cell cycle progression (through Cdc42)

I have to stop to spare you!  Look, I have not started to talk about how it leads to Metastasis...I just have to stop.  The Wnt, a powerful pathway!

Researchers from the Memorial Sloan K. have confirmed the principle that reading phenomena at the cell membrane you could predict recurrence and prognosis of cancer. They looked at patients with stage I lung cancer (earliest stage) and could predict recurrence based on concentration of membrane receptors to IL 12 and IL7.  We know that increased Growth factor Receptor promote cancer cell in an autocrine fashion.  This finding seems to reinforce this knowledge.  We have discussed the GLYCOCALYX, activity of the Flipase/Flopase and other changes that may attract the Macrophage.  We also have shown that through the Caspase 8, membrane occurring phenomena could induce Apoptosis without nuclear involvement.
Focusing on membrane activity take you also to the Calmodulin and initiation of signal pathways.  All is happening at the membrane, and a focus at these changes is warranted!

APPROACHES TO CANCER CURE!

As we are moving forward to cancer cure, one realizes several facts

1.  Translational research reveals to us that Medical science is too much compartmentalized.
- Our biologists focus on giving us Molecular basis, chemistry basis to various organelles and even smaller molecules important in the patho-physiology, homeostasis, metabolism at cell level.
- Our Biotech and /or pharmaceutical companies focus on taking this information and developing localized therapeutic targets.  They operate under significant stress to be first and patented!
- Clinical researcher take these  target therapy into clinical trials
- Our Medical Oncologists await the results of clinical trial to use the drug and formulate patterns of treatments based on experience on broader population (Phase IV post market tracking).

At each step, necessary check and balances occur, but it is also true that information is lost, diluted or missed.  This slows down translational research results' implementation. An integrated approach will allow for faster pace of implementation.  We need a TRANSLATIONAL  ONCOLOGY CLINIC WHERE ALL GROUPS WILL SIT TOGETHER AND PRIORITIZE THE THINGS TO DO!

2. Cure is not going to be the same for every cancer.   The reason is in some cancers there are DRIVER Oncogenes, in others, there are DRIVER Pathways.  At least so far, evidence seems to suggest that the success in targeting steps in pathways seems more promising in hematologic malignancies then in treatment of solid tumors.  This impression may change as we move forward.  We are now seeing response rates of 70+ percent in lung cancer when the right driver oncogene is disabled.  This is new!

3. One of the major clinical differences between a basal cell cancer of the skin and  Melanoma is in their ability to spread and multiply.  And one cannot talk about multiplication without looking at events in the Podosomes where actin, paxillin, cortactin and integrin B are main events.  We are reviewing the literature to see what has been accomplished with these potential targets!  Many pathways start in the Podosome and a whole lot of Enzymes are also here!

4. ACTIN (closely liked to 2nd law) is the core of the cell Cytoskeleton and the nervous system of the cell.
What types of Microfilaments/Microtubule/Actin exist,  can some anti-Actin work better than others...? Its relationship with metabolism and physiology of CA++/Calmodulin?  This is important stuff for Brain tumors!
We are working hard at CRBCM!

THIORIDAZINE, A PHENOTHIAZINE WHICH IS AN INHIBITOR OF CALMODULIN WILL HAVE ANTITUMOR EFFECT AS DEMONSTRATED BY CANADIAN RESEARCHERS WHEN THEY DESCRIBED A 50 PERCENT DECREASE OF STEM CELLS.  WE AT CRBCM BELIEVE THIS EFFECT IS OF COURSE LINKED TO THE RELEASE OF CALCIUM IN THE CYTOSOL LEADING TO ENDONUCLEASE STIMULATION WITH THE RESULTING ATTACK ON DNA.
THE FACT IS THIS EFFECT WILL BE MORE ON MEMBRANE WHERE CALMODULIN IS MOSTLY LOCATED.  THEREFORE LIBERATION OF CALCIUM AFFECTS ELECTRICAL POLARITY AT THE MEMBRANE. TORSADE DE POINTE CAN RESULT AND HAD LED TO THE BANNING OF THIORIDAZINE IN CANADA.
THIORIDAZINE ACTS ALSO AS AN ANTIGROWTH FACTOR IN GENERAL. THIS FACT COULD CONTRIBUTE TO ITS ANTI-CANCER ACTIVITY.  IN OUR PREVIOUS NOTES, WE
HAD SUGGESTED ADDING THE ANTI-CALMODULIN TO AVASTIN AS A STRATEGY TO TREAT RECURRENT BRAIN TUMOR.