There is an urgent reason to study stem cells: stem cells are at the heart of some, if not all, cancers. Mounting evidence implicates a clutch of rogue stem cells brandishing ‘epigenetic’ marks as the main culprits in cancer. Wiping out tumours for good, some biologists believe, depends on uprooting these wayward stem cells.
A team in the Netherlands has uncovered a key protein that could stop these stem cells from becoming malignant. “This is a hot topic in the cancer field,” Maarten van Lohuizen of The Netherlands Cancer Institute, Amsterdam told participants at a EuroSTELLS workshop, held in Montpellier, France, 23-24 January. “To be successful in cancer therapy you need to target these stem cells: they are intrinsically resistant to chemotherapy.”
Polycomb proteins have emerged as key players in cancer pathogenesis. They are powerful epigenetic regulators that normally silence genes without altering the cell’s DNA. Compounds that regulate polycomb could result in novel anticancer drugs that shrink malignant tissue, and prevent cancer recurrence, a common problem with most chemotherapies.
That tumours and stem cells have much in common has been known for many years. Both self-renew and both spawn many different types of cells. But only recently, new techniques have enabled biologists to identify stem cells buried in tumours.
Van Lohuizen has found that stem cells in cancerous tissues are locked in an immature state in which they carry on multiplying instead of maturing into specific tissues. “Some resistant cancer cells don’t listen to the ‘stop’ signal any more,” he explains. That stop sign is delivered by the polycomb proteins. They silence several genes at once by affecting the way the DNA is compacted into chromatin fibres, without altering the DNA sequence.
Normally, the main role of the polycomb complex is to repress genes during development or when stem cells are needed for tissue maintenance. But an aberrant polycomb spells trouble. In mice where polycomb proteins have been genetically disabled, van Lohuizen has seen that the cells become invasive and trigger cancerous growth. “This may be why gliomas are such lethal tumours, because these stem cells become highly migratory,” van Lohuizen points out.
The hunt is now on for therapeutic agents that target these budding cancer stem cells. The Dutch researcher is optimistic that used in combination with chemotherapy, such compounds will also prevent cancer reigniting after treatment. “We have to be very careful because [these compounds] will also regulate normal stem cell behaviour. It is a fine balance,” he noted.
EuroSTELLS is the European Collaborative Research (EUROCORES) programme on “Development of a Stem Cell Tool Box” developed by the European Science Foundation.
The European Science Foundation (ESF) provides a platform for its Member Organisations to advance European research and explore new directions for research at the European level.
Established in 1974 as an independent non-governmental organisation, the ESF currently serves 75 Member Organisations across 30 countries.
From a news release by European Science Foundation
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