Methylation is an epigenetic process which often results in
the silencing of genes and for example in the case of hematologic cancers is
often the driver for loss of proper maturation of cells and to the
proliferation of blast cells. The MDS condition is a prime example. This
precursor of AML is often a result of hypermethylation which in turn can be
treated by demethylating drugs.
In PCa there is still a debate as regards to the cell types
initiating the process, luminal vs basal, and also the existence and
significance of the PCa stem cell. In a recent paper by Pellacani et al the
authors note[1]:
Prostate cancer (CaP) is mostly composed of luminal-like
differentiated cells, but contains a small subpopulation of basal cells
(including stem-like cells), which can proliferate and differentiate into
luminal-like cells. In cancers, CpG island hypermethylation has been associated
with gene downregulation, but the causal relationship between the two phenomena
is still debated. Here we clarify the origin and function of CpG island
hypermethylation in CaP, in the context of a cancer cell hierarchy and
epithelial differentiation, by analysis of separated basal and luminal cells
from cancers.
For a set of genes (including GSTP1) that are
hypermethylated in CaP, gene downregulation is the result of cell
differentiation and is not cancer specific. Hypermethylation is however seen in
more differentiated cancer cells and is promoted by hyperproliferation. These
genes are maintained as actively expressed and methylation-free in
undifferentiated CaP cells, and their hypermethylation is not essential for
either tumour development or expansion.
We present evidence for the causes and the dynamics of
CpG island hypermethylation in CaP, showing that, for a specific set of genes,
promoter methylation is downstream of gene downregulation and is not a driver
of gene repression, while gene repression is a result of tissue-specific
differentiation.
The observation is interesting since it differentiates
hypermethylation from cause to effect.
As stated in the article in Medical Express concerning the above
article, the writers note[2]:
Scientists at the University of York have discovered that
a process called 'methylation', previously thought to drive the development of
cancer, occurs in cells that are already cancerous. The findings mean therapies
aimed at reversing this process might not be effective against cancer stem
cells, allowing the cancer to return…The work, … reveals a major difference
between the cells normally treated in cancer and the underlying 'stem' cells.
The discussion of stem cells in PCa is something we have
examined for the past few years. There is as of yet no clear definitive
demonstration of such stem cells and even more so there is no description of
what a stem cell is especially as regards to any genetic changes. They
continue:
Dr Pellacani said: "To develop cancer, certain
proteins found in healthy cells need to be switched off”. Sometimes this is
caused by methylation - a process where DNA is changed to block instructions
for making a specific protein. "There are obvious differences in the
methylation of genes in prostate cancer cells and
non-cancer cells. This previously suggested that the process could be driving
the progression of cancer, and that this could be reversed by using specific
drugs, but our research has suggested that this may not be the case."
Methylation is a powerful and ubiquitous process. It has
only been understood as a significant epigenetic factor in the past decade and
even now is going through a steep learning curve. Methylation is often found in
cancer cells and like so many of the suggested genetic profiles one wonders if
it is cause, effect, or just correlative. One may even wonder if methylation is
some archaic attempt by the cells to deal with the genetic changes causing the
cancer. It is not yet clear just what the function may be.
The authors continue:
Prostate cancer is made up of two types of cell; rare
basal cells, including stem cells, from which the tumour is formed, and luminal
cells, which form the tumour mass. The team found that a change from basal to
luminal cells – a process called differentiation – is strongly linked to the
methylation difference, suggesting that the methylation in prostate cancer
cells is not the primary driving force for the cancer.
This is a strong statement which some may not fully agree
with. There have been many studies which we have reported on here that question
whether we have a basal or luminal cell origination of PCa. In fact one might
even imagine some other cell altogether. Yet the methylation factor in basal to
luminal change is interesting.
Dr Pellacani continued: "There are clear
implications for the effectiveness of new drugs currently being developed to
change the methylation pattern in cancers. At the moment we only treat a
proportion of the cells. By breaking the cancer down into its component cell
types, we get insights into why cancers come back after treatment. Only by
treating all the cells in a cancer will we approach long term treatment
or even cure." Professor Maitland and his team at the YCR Cancer Research
Unit achieved international recognition in 2005 when they were the first to
identify prostate cancer stem cells, which are
believed to be the 'root cause' of prostate cancer.
This discussion is of interest and it blends well with our
model of cancer cell propagation. The two observations are critical. They are:
(i) that there are various cancer cells characterized by specific gene
expressions or lack thereof, (ii) that there exists a cell called the stem cell
which has characteristics we have discussed at length. The hypermethylation,
and even hypomethylation, are but two characteristics of epigenetic changes. We
would also expect to see miRNA, lncRNA and the like to also play roles.
The problem still is; what cells are we profiling? Are we
profiling cells proliferating in the prostate or one which have already spread
elsewhere?
Overall this is an interesting and compelling report.
References
Pellacani, D et al, DNA hypermethylation in prostate cancer
is a consequence of aberrant epithelial differentiation and hyperproliferation,
Cell Death & Differentiation, (24 January 2014).
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