Friday, February 28, 2014

Work still to be done in survivors

One of the aspect of cancer treatment that remains to be clearly categorized in most cancers including our focus:Breast cancers, is how to best monitor survivors and separate them early in high risk for recurrence versus those who should expect longer remission.  So far we have concentrated purposely on monitoring recurrence by Xrays or checking bio-markers in the blood.  But genetic work could also help predict recurrence and may be suggest target therapy to be envisioned early.  ie OLOPADE et al:  "A new model of ovarian cancer tumor progression implicates aberrant FANCF promoter methylation that is associated with gene silencing and disruption of the Fanconi-anemia-BRCA pathway. Disruption of the pathway occurs de novo in ovarian cancers and may contribute to selective sensitivity to platinum salts."  (BRING BACK TO YOUR INTELLIGENCE THAT MANY DRUGS WORKS THROUGH EPIGENETIC EFFECTS AND NOT DNA CROSS-LINKING)

Although the disease can recur locally by increase of the original tumor size, most of the time the disease return in a metastatic fashion.  And when this occurs, there are many implications to be drawn.

Neoplastic transformation assumes acquisition of new functions to the cell.  One of the critical function is ability to metastasize, acquisition of MET1 amplification, activity at the Rho gene/RHOA/ROCK but also activity at Vimentin are important processes the cell has to go through to acquire these new functions.  These are just some of the aspects.....

Detection of cancer recurrence is as complex as the nature of the Neoplastic process itself!
1. There are activity at promoter genes, most of there activity are silencing of certain promoter genes through methylation. see implications of Methylation of such gene as TGF Beta, SMAD4 and even FBXO32, Cyclin D, 14.3.3. etc   (Aberrant Methylation)
2. Suppression of E-Cadherin which for some poise the cell for Migration.  If this occur through MSK1, it may also impact p38MAPK and restart tumor induced by the MAPK pathway amplification, and inducing VEGF induced migration of cells.   This phenomena could be worse in these disease when Anti-VEGF is not usually used (since we use Anti-VEGF only in certain diseases--if we continue to use clinical trial as our basis foe adoption of a treatment)
3.Coming back to methylation, it has been stricking that certain genes are not remarkably expressed in certain cancer cells. ie. "
"DAB2 mRNA is expressed in normal ovarian epithelial cells but is down-regulated or absent from ovarian carcinoma cell lines."wikipedia   This seems to involve somehow the SMAD
do remember "DAB2 has been shown to interact with C-src tyrosine kinase,[4] Cdk1,[5] Src,[4] LRP2,[6] DVL3,[7] PIN1,[5] MYO6,[8][9] DVL2,[7] DAB2IP,[10] Mothers against decapentaplegic homolog 3[11] and Mothers against decapentaplegic homolog 2.[11]" wikipedia

note many things please
attachment opportunity offered by C-Src
involvement of Cdk1 affecting cell proliferation and of course SMAD....   Terget therapy in mind!


Decreased expression of 14-3-3 sigma is associated with advanced disease in human epithelial ovarian cancer: its correlation with aberrant DNA methylation.

Akahira J1, Sugihashi Y   (READ THE ARTICLE)


WILSON ET AL "HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-beta induced pro-invasive and pro-metastatic gene signature."   MARKING THE IMPORTANCE OF TGF IN HER-2 POSITIVE CANCERS!

5.In BRCA-1 pt
we have already stress the importance of following PTPN2 as it impacts TGF, Paxillin, and mainly SHC1, the regulator of Apoptosis!

6. And if you are following Vimentin, weel check the AXL, decrease of RAB25, and the Integrin Beta subunit, these to gauge Epithelia-mesothelial transformation, an important step to acquisition of metastatic potential

well I stop here, survivors are deemed expensive because of this complexity and gene monitoring, weel we are not up to it yet, we chose head in the sand...And I am not talking yet about persistant of viral compounds that may also be important in metastatic potential in survivors.  What we need is a better organization of pouring info coming to us ...."sparsely-disconnected" .
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