In this next section, we'll take a look at some of the properties of dormant cancer cells. The first property of dormant cells is that they have decreased cellular activity. By this we are referring to RNA and protein synthesis and decreased metabolic activity. This is because a dormant cell is not dividing, so there's no reason for it to gear up to produce more cellular components for a potential daughter cell. Also because the cell's not dividing, by default it does not express the proteins needed to progress in the cell cycle. The second property is that dormant cancer cells are thought to be stem like. Meaning they share the features of a stem cell. Like I've mentioned earlier, stem cells are also maintained in a quiescent state until they are needed. Thus, they must have the ability to self renew and for more stem cells, as the cancer cells must eventually re-enter the cycle if it is going to form a metastasis. It also is hypothesized that cancer stem cells are the cells that initiate a tumor, eluding to their self renewal potential. This is the same idea of a dormant cell being the precursor to a metastasis. Additionally there is some evidence that DTCs can specifically inhabit the stem cell niche of the secondary host site such as prostate cancer that has been shown to inhabit the bone marrow stem cell niche. A dormant cancer cell also may be able to create a stem-like niche around itself at the secondary site. The figure to the right depicts a cancer stem cell niche in the green circle limiting the number of cancer stem cells through regulating their quiescence, while cancer cells without stem-like properties in the middle are able to propagate away from the niche. Dormant cancer cells are also more resistant to therapy. This is especially true for standard chemotherapies that target the cell's proliferation machinery to cause cell death, which wouldn't be effective on a cell that is not proliferating. Also since quiescence can be induced by stress response mechanisms, this inherently makes them more resistant to therapies as these mechanisms are put into place to protect the cell. Interestingly, there is some evidence that certain therapies can actually induce dormancy in the cells that survive. Perhaps by initiating stress response mechanisms. As we just discussed in the previous slide, dormant cancer cells are more stem-like, and normal stem cells and cancer stem cells have been shown to be more resistant to therapies. This is especially bad in cancer considering the self renewal potential of stem sells and stem like cells because they will always be able to propagate more progeny. This is why designing therapeutics targeting dormant stem cell properties may be more effective as depicted in the figure to the right. If only chemotherapy is used, it will kill the non-cancer stem cells by since the stem-like cells have survived, they can repopulate. However, if a dormant cancer cell or cancer stem cell specific therapy is used, it will eliminate the source for a new tumor to grow and ultimately the tumor will regress and will not be able to come back. As I've mentioned earlier, dormant cancer cells are clinically undetectable. This is the major reason why we are still trying to understand dormancy and how and when it arises. And as a reason why there's such thing as cancer recurrence. Our current clinical tests are not able to precisely detect these rare cells. None of the imaging technologies that are used to find cancer such as MRI, CT, PET Scan, or x-ray are able to pick up the small populations of cells. Biopsies to diagnosis a primary tumor can be taken because the tumor is large enough and the location is known. But we can't just take small samples of every organ, and expect to find individual cells or small colonies of cells to look for disseminated disease. The most promising test to find residual cancer is probably a blood test. If there are residual cancer cells somewhere in the body, there are most likely some of them traveling in the blood at any certain time, and tests are being developed to capture these individual cells. This still will not tel you which organs they are coming from or going to, but it will at least inform us that cancer is still present. Because none of our current standard clinical tests are sensitive enough, we are still unable to detect the residual cancer. In the bone scan to the right, cancer is shown in black spots. This patient clearly has residual cancer, but at this stage the cancer has already grown significantly. However if this skin came up without any evidence of cancer, we would still not be able to tell if there were dormant residual cells. The ability to detect these cells will be crucial in efforts to cure cancer by preventing lethal metastases all together. A fifth property of dormant cancer cells is that they're actually in a benign state. If you think about what fundamental property defines cancer, it is the ability to evade cell cycle checkpoints that control proliferation. Since dormant cells are not proliferating, they cannot lead to a cancer mass. Cancer ultimately becomes lethal when the mass of cancer cells leads to tissue damage, extreme pain or cachexia to name a few. Therefore, if we were able to maintain the dormant state of residual cancer cells, the patient would absolutely not die of cancer. To get a better sense of this, the picture shows a single DTC int he liver of a patient. No matter what organ it is in it does not have the ability to cause enough trauma to kill an entire patient. Lastly and importantly, dormant cancer cells are difficult to study in the lab. The implications of this are that it will take a long time before we can get a fuller grasp on the concepts around dormancy, and how to therapeutically target it. To give some idea of this, a lot of cancer research is done using cell line models. And in order to continually use a cell line, it must be proliferating to reduce more cells. It would be great if we could only use a few cells for every experiment if they are dormant but standard and cheap experimental assays require a millions of cells that you just won't be able to obtain if they are not proliferating. A way around this is to be able to induce dormancy of proliferating cells, but because dormancy is so hard to study, we still don't know the perfect recipe for inducing quiescence and at the same time making sure that those cells are not actually senescent or dead. Where the field has probably made the most ground is by using animal models. But these are expensive in terms of money, time, and labor. Finally they are poorly defined universal positive markers for quiescence cells. I told of you about some of them earlier, but in reality this are still being contested. They're a much better marker than assays to detect proliferating cells. To conclude the section, we have talked about six different but related properties of dormant cells. By now you should be able to think about why cells would want to go dormant, what factors can induce dormancy, and in the next section, we'll talk about why dormant cancer cells are a problem.
