HonCode

Go Back   HER2 Support Group Forums > Articles of Interest
Register Gallery FAQ Members List Calendar Search Today's Posts Mark Forums Read

Reply
 
Thread Tools Display Modes
Old 02-23-2007, 12:41 AM   #1
heblaj01
Senior Member
 
Join Date: Apr 2006
Posts: 543
Stem cells: root cause of all cancers & of resitance to all chemos?

http://www.esf.org/esf_pressarea_pag...ewsrelease=164

Cancer is a stem cell issue
heblaj01 is offline   Reply With Quote
Old 03-31-2007, 12:08 AM   #2
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Cancer Is A Stem Cell Issue

Tissue culture methods have made gene therapy and stem cell research possible. The ability to transfect cultured cells with DNA gene sequences has allowed us to assign functions to different genes and understand the mechanisms that activate or redress their function. By the 1960s, cell culture technology was well established in cancer research. The time was right for the interaction between cell biology and genetics that gave birth to molecular biology. Without cell culture, gene therapy and the use of stem cells to repopulate damaged organs would be beyond imagination.

The study of Cell Function Analysis tells us that even when the disease is the same type, different patients' tumors respond differently to the same agents. So it doesn't matter if there is a "target" molecule in the cell that the "targeted" drug is going after, if the drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, drug resistance is multifactorial.

Over the past few years, gene expression profiling has been suggested as the best or only way of determining ex vivo drug sensitivity. However, the clinical applicaton of these DNA content assays have been shown to correlate only with response and not survival. And due to almost all patients being treated with combination chemotherapy, this methodology cannot even be calibrated without the use of Cell Function Analysis. This analysis can actually integrate all the gene expression into one convenient test result.

In obtaining information from gene mutations (DNA content assays) and/or gene expression (RNA content) it must be realized that DNA structure is only important insofar as it predicts for RNA content, which is only important insofar as it predicts for protein content, which is only important insofar as it predicts for protein function, which is important only insofar as it predicts for cell response, which is only important insofar as it predicts for tumor response and function. In other words, it correlates only with response and not survival, in entirely retrospective (not prospective) studies.

What are the data supporting the use of testing DNA, RNA and Protein expression? Two retrospective studies from two Harvard-affiliated hospitals, showing response, but not survival advantages, with a grand total of twenty six correlations. And a subsequent study, presented in the July 14, 2005 issue of the New England Journal of Medicine from another laboratory that did not show correlations between gene mutations and patient survival (Volume 353:133-144 Number 2).

There is Cell Function Analysis (functional profiling) that shows data indicating a near doubling in the survival of patients with platinum resistant ovarian cancer, striking correlations between platinum activity and patient survival in previously-untreated ovarian cancer, and a comprehensive meta-analysis of scores of studies reporting response and survival correlations in thousands of patients.

Plus a recent study using an angiogenesis assay describing correlations between cell culture assay results and survival in patients with non-small cell lung cancer. These correlations were based on the actual assay results which had been reported, in real time, prospectively to the doctors who had ordered the assay laboratory tests. There were striking correlations between test results and patient survival, not just response.

Not only is cellular profiling a very important predictive test, but it is a unique tool for identifying newer, better drugs, testing drug combinations, and serving as a "gold standard" to develop new DNA, RNA, and protein-based tests of drug activity.

Source: Various Bio-Assay Labs

BMJ 2007;334(suppl_1):s18 (6 January), doi:10.1136/bmj.39034.719942.94

http://www.bmj.com/cgi/content/full/334/suppl_1/s18
gdpawel is offline   Reply With Quote
Old 09-18-2007, 11:05 PM   #3
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Epigenetics To Shape Stem Cell Future

Everyone hopes that one day stem cell-based regenerative medicine will help repair diseased tissue. Before then, it may be necessary to decipher the epigenetic signals that give stem cells their unique ability to self-renew and transform them into different cell types.

The hype over epigenetic research is because it opens up the possibility of reprograming cells. By manipulating epigenetic marks, cells can be transformed into other cell types without changing their DNA. It is simply a question of adding or removing the chemical tags involved.
Stem cells rely heavily on epigenetic signals. As a stem cell develops, chemical tags on the DNA or its surrounding histone proteins switch genes on or off, controlling a cell’s fate.

Epigenetics and stem cell biology are such clear strengths in the European research community. European labs are breaking ground in both the epigenetic and stem cell arenas. To build on this expertise and stimulate the exchange on novel technologies, the European Science Foundation organized the EuroSTELLS workshop.

Epigenetic research has benefited tremendously from genome technology, and work in the field is advancing at break-neck speed. “If you think that the first enzymes controlling histone methylation were found in 2001, the acceleration is tremendous,” says Robert Feil, a EuroSTELLS researcher based at the CNRS Institute of Molecular Genetics in Montpellier. “We are making good use of past investments in genome sequencing. In the next five years the technology will be ten times faster than it has been so far.”

New high-throughput approaches and refined analytical techniques promise to fill in some big gaps in understanding how epigenetic tags define a stem cell and how they can be manipulated. With this knowledge on board, researchers will be boosting the odds that one day stem cell therapies will reach the clinic.

EuroSTELLS is the European Collaborative Research (EUROCORES) programme on “Development of a Stem Cell Tool Box” developed by the European Science Foundation.

Source: European Science Foundation
gdpawel is offline   Reply With Quote
Old 09-18-2007, 11:09 PM   #4
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Scientists study cancer cell movement

There was a very interesting article on embryonic stem cells and cancer reported in the May 16, 2007 issue of Molecular Biology of the Cell. British scientists have made a breakthrough in understanding how cancers spread, which could lead to new methods of fighting the disease.

The University of Manchester study used embryonic stem cells to investigate how some tumors are able to migrate to other parts of the body, thus making cancer treatments more difficult.

Christopher M. Ward, the lead researcher, and colleagues studied a crucial change what makes cancer cells able to start moving and spread into other tissues. Known as the epithelial-mesenchymal transition, this crucial change was observed in the early embryo, theorizing that embryonic stem cells might undergo a similar process.

They have shown embryonic stem cells spontaneously change in a manner that is remarkably similar to the epithelial-mesenchymal transition. They lose the proteins that cells use to bind to each other and have other protein alterations that are characteristic of spreading cancer cells.

Studying such cells, researchers have identified a novel component of the transition process and expect to identify other factors involved in cancer cell spread, hopefully leading to new cancer therapies.

http://www.molbiolcell.org/cgi/repri...urcetype=HWCIT

Abstract

http://www.molbiolcell.org/cgi/conte...urcetype=HWCIT

gdpawel is offline   Reply With Quote
Old 09-18-2007, 11:10 PM   #5
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Understanding embryonic stem cells

Humans have 46 chromosomes: 23 come from the mother (egg); 23 from the father (sperm). An egg without a sperm has only 23 chromosomes; it must be "fertilized" by the sperm to be endowed with all the genetic information (carried on the DNA of the 46 chromosomes) required for life.

All cells in the body are derived from this one fertilized egg. All the cells have the same chromosomes; the same DNA. What makes cells different is that different parts of the DNA are active in different cells. This activity is controlled by the activity of proteins and RNA (two things which are derived from the information carried by DNA).

The fertilized egg is a stem cell, but it's not the only stem cell. The fertilized egg divides into two cells and then four cells and then 8 cells. A stem cell can give rise to all of the tissues and organs necessary to make a human being. At a certain point, however, the stem cell becomes a "committed" cell. It can no longer make a human being. It can only make a certain type of tissue.

The "first generation" embryonic stem cell method of making a stem cell is to take an egg from a woman and fertilize the egg with donor sperm (actually a bunch of eggs, as excess embryos are typically created in in vitro fertilization clinics at the same time; the excess eggs/embryos are stored in liquid nitrogen for possible latter use). The fertilized egg is allowed to divide several times in cell culture, resulting in a little ball of typically 4 - 16 stem cells; in effect, the earliest embryo.

But stem cells are now able to be created using a "second generation" embryonic stem cell technology. Take an adult skin cell; introduce a small number of genes which direct the "committed" adult skin cell to revert all the way back to an embryonic stem cell; potentially capable of not only being used for stem cell research, but potentially capable of developing into a human baby, given the proper growth conditions.

This "second generation" embryonic stem cell would have the same genetic material and the same capabilities as a "first generation" stem cell. It would be the same cell as it was at the time it was a newly fertilized egg. It would genetically be an identical twin; a clone of the original fertilized egg, in every sense of the word.

But the cells are the same. In one case, the cells are created by going forward (fertilizing an egg). In the other case, the cells are created by going backwards (introducing a handful of gene to reprogram the DNA of an adult cell, so that the cell reverts back to the state of a newly fertilized egg). But the cells potentially are the same, with the same potential for developing into a baby.

In point of fact, it may well be that the first cloned human baby will come from this "second generation" technology and not from the "first generation" technology which everyone worries about. By officially sanctioning research into this "second generation" technology, the critics of embryonic stem cell research may actually be lending their support to a technology which has the greater potential for being used for a purpose they condemn (the cloning of a human).

Well, here it is!

http://stemcells.alphamedpress.org/cgi/reprint/2007-0252v1.pdf


Last edited by gdpawel; 01-17-2008 at 06:04 PM.. Reason: update
gdpawel is offline   Reply With Quote
Old 09-19-2007, 03:39 AM   #6
R.B.
Senior Member
 
Join Date: Mar 2006
Posts: 1,843
Fascinating.

Will need reading more than once.

An we all start life female I read recently.

Thank you.
R.B. is offline   Reply With Quote
Old 09-21-2007, 11:04 PM   #7
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Some Cancer Cells Mimic Stem Cells To Survive Chemotherapy

Anti-cancer treatments often effectively shrink the size of tumors, but some might have an opposite effect, actually expanding the small population of cancer stem cells believed to drive the disease, according to findings presented in Atlanta, Georgia at the American Association for Cancer Research's second International Conference on Molecular Diagnostics in Cancer Therapeutic Development.

"Our experiments suggest that some treatments could be producing more cancer stem cells that then are capable of metastasizing, because these cells are trying to find a way to survive the therapy," said one of the study's investigators, Vasyl Vasko, M.D. Ph.D., a pathologist at the Uniformed Services University of the Health Sciences in Bethesda, Md.

"This may help explain why the expression of stem cell markers has been associated with resistance to chemotherapy and radiation treatments and poor outcome for patients with cancers including prostate, breast and lung cancers," Dr. Vasko said. "That tells us that understanding how to target these markers and these cells could prove useful in treating these cancers."

The cancer stem cell markers include Nanog and BMI1, both of which contribute to stem cells' defining ability to renew themselves and differentiate into different cell types, Dr. Vasko said. These same molecules are found in embryonic stem cells.

Researchers have recently debated the notion that some therapies are not capable of eradicating cancer because they do not target the cancer stem cells responsible for tumor development. To test this hypothesis, Dr. Vasko, along with scientists from the CRTRC Institute for Drug Development in San Antonio and from the Johns Hopkins University, set out to measure both stem cells markers and tumor volume before and after treatment in a mouse model.

They selected a rare form of cancer, mesenchymal chondrosarcoma (MCS), which has not been well described and for which there is no effective treatment. The researchers first determined that Nanog and BMI1 stem cell markers were more highly expressed in metastatic tumors compared to primary tumors. "This suggests that expression of the marker plays some role in development of metastasis," Dr. Vasko said.

They then applied various therapies -- from VEGF inhibitors such as Avastin to the proteasome inhibitor Velcade -- in mice implanted with human MSC, and analyzed the effects on tumors. Some of the treatments seemed to work, because they led to a dramatic decrease in the size of the tumors, Dr. Vasko said. But analysis of stem cell expression before and after treatment revealed that even as some anti-cancer treatments shrank tumors, they increased expression of Nanog and BMI1. "These treatments were not enough to completely inhibit tumor growth, and the cancer stem cell markers were still present," Dr. Vasko said.

Use of the agents Velcade and Docetaxel led to the most significant increase in stem cell markers within the treated tumor, while ifosfamide and Avastin inhibited expression of the markers in this cancer subtype.

"We hypothesize that the tumor escapes from chemotherapy by induction of stem cell marker expression," he said. "The small number of cells that survive the treatment could then generate another tumor that metastasizes."

Dr. Vasko doesn't know how this happens, but theorizes that "dying cells could secrete a lot of factors that induce expression of stem cell markers in other cancer cells. I think they are trying to survive and they use a mechanism from their experience of embryonic life."

If scientists understood the pathways cancer stem cells use to survive treatment or increase their ranks, then therapeutic targets could be developed, Dr. Vasko said. Some novel therapies are already being tested against cancer stem cells, he added.

Source: American Association for Cancer Research
gdpawel is offline   Reply With Quote
Old 09-22-2007, 04:16 AM   #8
R.B.
Senior Member
 
Join Date: Mar 2006
Posts: 1,843
Thank you for that very informative post.

RB
R.B. is offline   Reply With Quote
Old 12-09-2007, 03:54 PM   #9
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
To Evade Chemotherapy, Some Cancer Cells Mimic Stem Cells

http://www.aacr.org/home/public--med...ses.aspx?d=822

Using the CellSearch System techique that quantifies circulating tumor cells, researchers had shown that chemotherapy with Taxol causes a massive release of cells into the circulation, while at the same time reducing the size of the tumor, explaining that complete pathologic responses do not correlate well with improvements in survival.

Circulating tumor cells (CTCs) are cancer cells that have detached from solid tumors and entered the blood stream. This can begin the process of metastasis, the most life-threatening aspect of cancer. To metastasize, or spread cancer to other sites in the body, CTCs travel through the blood and can take root in another tissue or organ.

In this stem cell research, anti-cancer treatments often effectively shrink the size of tumors, but some might have the opposite effect, actually expanding the small population of cancer stem cells that then are capable of metastasizing.

Even before the advent of the CellSearch technique, it had been observed in "cell death" cell culture assays, that there was an increase in the number of metabolic activity of mitochondria of the surviving cells from Taxol therapy, even in cases where the majority of the cells are being killed by Taxol. It may indeed give clinical response (tumor shrinkage), however, these are mostly short-lived and relapses after a response are often dramatic.
gdpawel is offline   Reply With Quote
Old 12-09-2007, 05:43 PM   #10
StephN
Senior Member
 
StephN's Avatar
 
Join Date: Nov 2004
Location: Misty woods of WA State
Posts: 4,128
This is all SO interesting.
As a survivor who had a favorable outcome so far with Taxol combined with Navelbine and Herceptin, I often wonder what went right with me.

To quote from the last post:
"Even before the advent of the CellSearch technique, it had been observed in "cell death" cell culture assays, that there was an increase in the number of metabolic activity of mitochondria of the surviving cells from Taxol therapy, even in cases where the majority of the cells are being killed by Taxol. It may indeed give clinical response (tumor shrinkage), however, these are mostly short-lived and relapses after a response are often dramatic. "

The chemo combo I was on was part of a trial dubbed "Antimitotic," since each drug killed the cells at a different phase of division. If a cell as missed by one drug, there was a good chance the other drug would catch it. Seemed to be a good theory, but I know there is more to it than that.

Glad I have not followed the curve and "lapsed."
__________________
"When I hear music, I fear no danger. I am invulnerable. I see no foe. I am related to the earliest times, and to the latest." H.D. Thoreau
Live in the moment.

MY STORY SO FAR ~~~~
Found suspicious lump 9/2000
Lumpectomy, then node dissection and port placement
Stage IIB, 8 pos nodes of 18, Grade 3, ER & PR -
Adriamycin 12 weekly, taxotere 4 rounds
36 rads - very little burning
3 mos after rads liver full of tumors, Stage IV Jan 2002, one spot on sternum
Weekly Taxol, Navelbine, Herceptin for 27 rounds to NED!
2003 & 2004 no active disease - 3 weekly Herceptin + Zometa
Jan 2005 two mets to brain - Gamma Knife on Jan 18
All clear until treated cerebellum spot showing activity on Jan 2006 brain MRI & brain PET
Brain surgery on Feb 9, 2006 - no cancer, 100% radiation necrosis - tumor was still dying
Continue as NED while on Herceptin & quarterly Zometa
Fall-2006 - off Zometa - watching one small brain spot (scar?)
2007 - spot/scar in brain stable - finished anticoagulation therapy for clot along my port-a-catheter - 3 angioplasties to unblock vena cava
2008 - Brain and body still NED! Port removed and scans in Dec.
Dec 2008 - stop Herceptin - Vaccine Trial at U of W begun in Oct. of 2011
STILL NED everywhere in Feb 2014 - on wing & prayer
7/14 - Started twice yearly Zometa for my bones
Jan. 2015 checkup still shows NED
2015 Neuropathy in feet - otherwise all OK - still NED.
Same news for 2016 and all of 2017.
Nov of 2017 - had small skin cancer removed from my face. Will have Zometa end of Jan. 2018.
StephN is offline   Reply With Quote
Old 12-09-2007, 06:54 PM   #11
gdpawel
Senior Member
 
gdpawel's Avatar
 
Join Date: Aug 2006
Location: Pennsylvania
Posts: 1,080
Medicinal Food Meets Epigenetics

As one of the editors of the Journal of Medicinal Food, Dr. Robert Nagourney, Medical Director at Rational Therapeutics, Inc., in Long Beach, California and an instructor of Pharmacology at the University of California, Irvine School of Medicine, he was asked to review an article on the chemical activities of grape seed extracts. He wrote an editorial describing the interesting findings in this study and their biological relevance.

For many years, naturopaths and health-conscious individuals have recommended the consumption of grape seed extracts. Chemical analyses of grape seeds have provided a treasure trove of active ingredients including resveratrol, anthocyanins, pro-anthocyanins, and numerous terpenes. Many of these substances are potent antioxidants and there is reason to believe that they may have meaningful health benefits.

The most interesting aspect of this well-conducted analysis was the description of a wholly new mechanism of action for the substances found in grape seeds. What the authors found was that the chemical species in grape seed extracts influence gene expression through a process knows as histone acetylation. What makes this so interesting is the fact the histone acetylation is one of the fundamental regulators of genetic expression and a critical part of the new field of science known as epigenetics.

Epigenetics is the field of study that examines heritable attributes that are not incorporated into DNA sequence. These epi-phenomena take existing genes and determine whether or not they will actually be expressed. The reason that this is so important is that it shines a very bright light on the limitations of genomic analyses (studies that examine the DNA sequence in tissues). Clearly, if the consumption of foodstuffs (like grape seed) can alter gene expression then the use of genomic profiles to predict cellular behavior can only be viewed as highly simplistic.

Dr. Nagourney is continually impressed by the complexity of biology and is humbled when we consider the intersecting pathways that take us from gene to function.

http://www.liebertonline.com/doi/abs.../jmf.2010.9401

Last edited by gdpawel; 03-03-2011 at 06:32 AM.. Reason: revise
gdpawel is offline   Reply With Quote
Reply

Thread Tools
Display Modes

Posting Rules
You may not post new threads
You may not post replies
You may not post attachments
You may not edit your posts

BB code is On
Smilies are On
[IMG] code is On
HTML code is On

Forum Jump


All times are GMT -7. The time now is 12:14 AM.


Powered by vBulletin® Version 3.8.7
Copyright ©2000 - 2024, vBulletin Solutions, Inc.
Copyright HER2 Support Group 2007 - 2021
free webpage hit counter