 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 is 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 and like 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 and 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 rapidly. So the cancer stem cells would be resistant to chemotherapy. 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 it was also found in some cancer cells in the intestine, so 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 turn 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 cells keep dividing. But on the other hand, if a differentiated purple cell 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 this blue color persist? In a normal tissue, the scientists found that the cells that turned blue from DCLK1 presence were all of the differentiated cells that did not divide, represented in purple, and the blue color did not persist. This means that in normal tissue, DCLK1 is not present in stem cells, instead is present in differentiated purple cells. Next, the scientists wondered what kinds of cells contained 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. 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 they were only found in cancer. 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, and they could 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 a 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 were 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, or in other cells 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, 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.