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This research article is titled "Dclk1 distinguishes between tumor and normal stem cells in the
intestine" it was published by the Chiba lab at Kyoto University in Kyoto Japan in Nature
Genetics in January 2013.
When you think about cancer, you probably think about the tumor cell mass. And it is
indeed this cell mass that causes damage to the body. Cancer forms when a group of cells
(here in green) divides uncontrollably to produce "differentiated" cells (here in purple)
that no longer divide. These green dividing cells and these purple differentiated cells
form the tumor. And it is this tumor cell mass that we try to destroy with treatments
such as chemotherapy. However, to develop effective treatments, it's necessary for us
to understand where the tumor mass came from, where do these green dividing cells come from
and how did they get there? Some scientists have hypothesized that some cancers but NOT
ALL may be fueled by cells that resemble stem cells, which we call cancer stem cells, whereby
a few SLOWLY dividing cells produce these green cells that will divide at a very high
rate to make the tumor. other scientists think that the cells that are fueling the tumor
are the green ones that divide very rapidly and that there are no slowly dividing cancer
stem cells.
stem cells (both normal and cancer stem cells) have a few important characteristics: unlike
normal cells, stem cells :
- Divide indefinitely
- Can make more of themselves as well as
- Make non stem cells
So they are responsible for populating tissues and repopulating tissues in case of injury.
Some cancers (such as leukemias, breast, colon, pancreas cancers)have been found to contain
such cancer stem cells. So what does this mean for therapy? Most cancers are treated
with chemotherapy which kills cells that divide and make more cells.
Well, chemotherapy would efficiently kill the green dividing cells and eventually the
purple differentiated cells since they would not be replenished by the green cells. but
chemotherapy would not do a very good job at killing the cancer stem cells since they
don't divide very quickly. so the cancer stem cells would be resistant to chemotherapy.
So as you can see, a cancer that is fueled by cancer stem cells may initially respond
to chemotherapy but eventually the tumor would reappear due to the perseverance of cancer
stem cells. So to treat these types of cancers, it would be ideal to kill both the cells that
compose the mass of the tumor as well as the cancer stem cells that fuel the tumor volume.
The presence of these cancer stem cells in SOME cancers has been controversial among
scientists because they are very rare and it is hard to distinguish them from normal
stem cells. So scientists have been looking for a marker of cancer stem cells that would
distinguish them from normal stem cells, which we want to keep around.
The scientists of this article focused on a protein called Dclk1 that was thought to
mark normal stem cells but was also found in some cancer cells in the intestine. they
were curious to see which intestinal cells contain Dclk1?
So the scientists designed mice whose cells turned blue when Dclk1 was present and all
future cells that this cell produced also turned blue. The scientists induced this blue
color only for a short period of time to track what happens to the cells. using this technique,
scientists can determine where cells came from and if the cell is dividing, what kinds
of cells it produces just by looking at which cells turned blue. So the scientists focused
on the intestines of these mice. because the stem cells produce all of the cells that make
up the intestinal tissue, if a stem cell contains Dclk1 then the whole intestinal tissue will
be blue and this blue color will persist because the stem cell keeps dividing and making more
cells. but, on the other hand, if a differentiated purple cells contains Dclk1, ONLY those differentiated
purple cells will be blue since they are not dividing so no other cells in the intestine
will be blue and the blue color will not persist because the differentiated cell does not divide
and will eventually die off. So the question is: which cells will turn blue and will the
blue color persist?
So in a normal tissue, the scientists found that the cells that turned blue from Dclk1
presence were all of the differentiated cells represented in purple that did not divide
and the blue color did not persist. This means that in normal tissue, Dclk1 is not present
in stem cells, but in differentiated purple cells.
Next, the scientists wondered what kinds of cells contained the Dclk1 protein in intestinal
cancer. So they performed the same experiment looking at cells that contained Dclk1 in a
mouse that spontaneously develops intestinal cancer. In those tissues, over time, more
and more of the tumors turned blue until all of the tumors were blue! And importantly,
the tumors stayed blue for over 110 days! this suggested that Dclk1 was present in some
stem cell population that kept dividing and persisted over time. Because the normal tissue
around the tumor was not blue after 110 days, this meant that these stem cells were specific
to the cancer and were not present in normal tissue!!
They studied these Dclk1 cells a little closer and confirmed that they were dividing and
were present at the same position as normal stem cells but were only found in cancer tissue.
These tumor Dclk1 cells also contained markers of stem cells and other stem cell characteristics:
-they could divide indefinitely
- they could make more of themselves & produce differentiated purple cells of the intestine
So all of this information pointed to the fact that Dclk1 might be a marker of cancer
stem cells but NOT normal stem cells!
If this is true, then killing Dclk1 cells should be able to kill off the tumor because
we would be killing the cells that fuel the tumor. So the scientists did just that. when
they specifically killed Dclk1 cells using genetic approaches in the mouse with intestinal
cancer, the tumors shrunk until there was almost no tumor left. But the normal tissue
was for the most part normal since the normal stem cells are able to divide and repopulate
the intestinal tissue.
So what did this study show?
This study showed that a protein "Dclk1" plays two different roles in normal and cancer tissues:
in a normal tissue, Dclk1 is present in the differentiated cells that do not divide.
however, in a cancer, Dclk1 is present specifically in cancer stem cells
Because Dclk1 is not present in normal stem cells, killing Dclk1 cells, shrinks and in
some cases eliminates the tumor without affecting the normal surrounding tissue!
So what does this mean for you?
This study supports the existence of these cancer stem cells in intestinal cancer and,
even though much work needs to be done to confirm this finding in a human as well as
in other cancers , this article provides a promising therapeutic opportunity to target
these cancer stem cells! The next question will be: how do we kill Dclk1 cells? The authors
of this study used genetic manipulation in mice which is not feasible in humans. So the
next step will be to find a non invasive way of delivering a drug specifically to Dclk1
cells, or targeting them some other way. Also, it will be important to understand where these
cancer stem cells come from? do they come from differentiated cells or do they come
from normal stem cells?
By broadening our understanding of stem cells and the presence of cancer stem cells in a
variety of cancers, scientists are trying to understand not just a static picture of
a cancer but where it came from, how it got there and where it is likely to go as the
cells continuously evolve and change!