[MUSIC] Hi, I'm Haley Axelrod, and I work at The Brady Urological Institute at the John Hopkins School of Medicine. In this lecture of understanding cancer metastasis, we will focus on dormancy and secondary tumor growth. At the end of this lecture, you should be able to understand the theories behind why different cancer types metastasize to different organs. Be able to identify and describe the types of dormancy and describe the differences between quiescence and senescence. It is also important to be able to understand how dormancy contributes to cancer lethality, and on that same note, be able to think about strategies for targeting dormant cancer cells. In this section we will briefly cover metastatic homing of disseminated tumor cells. The major question here is why do different cancers metastasize to different organs? For example, why do prostate and breast cancer like to metastasize to the bone but stomach and colorectal cancer metastasize mainly to the liver? There are two theories around this. The first one is that the disseminated cells specifically and preferentially home to those sites as if they have an address. In the figure to the right, this is shown as a cell coming from the original tumor mass preferentially going to the liver where it develops a metastasis after some time. However, the cell does not home to the kidney or the bone. The second theory is that the disseminated tumor cell non-specifically homes to many different sites in the body, but can only survive or grow at certain sites because of a compatibility issue. This is depicted to the right where the disseminated cells are able to home to all three organs. But it is unable to survive in the kidneys and in the bone it will survive but not proliferate. In the liver, however, the cancer cell is able to establish a metastasis because the micro-environment is conducive to its proliferation. Thus this reflects the well known seed and soil hypothesis where, in order to survive and grow, a seed must fall on good soil. The seed and soil hypothesis is a very important one in the metastasis field. There are still many unknowns in this area and this is a major hypothesis that many researchers adhere to and try to prove. Thus the remainder of this lecture will be taught with this hypothesis in mind. This top quote reflects the main point of the hypothesis. When a plant goes to seed, its seeds are carried in all directions. But they can only live and grow if they fall on congenial soil. In this analogy, the seed is the disseminated cell that has reached the circulation. Here, like a seed can be carried in all directions by the wind, the cell may travel to many sites around the body by the blood and the lymph. Where it lands, the soil, is any of these sites in the body and is ultimately the organ site of the metastasis. The makeup of this site, the soil, consists of the cell types within that organ and their surrounding micro environment. This can be the extracellular matrix and any cytokines or secreted molecules that are present for the seed, or the cell, to interact with. Ultimately, this soil is either permissive or restrictive for the growth of the seed. And this is determined by the different factors in that organ site, since these will vary, depending on which organ the cancer cell landed. Now that the cell has reached the secondary site, what are its potential fates? Well, if the soil is not conducive for survival, the cell will die. This means that the microenvironment does not provide the proper pro-survival signals for the cancer cell to receive. Thus, a metastasis will never form. The second option of a disseminated tumor cell is for it to undergo proliferation right away, meaning that it has landed on fertile soil. It is then unable to grow into a mass which represents a metastasis. The last option is for the disseminated tumor cell to undergo dormancy, and this is neither death nor proliferation. The cell is alive but it is not proliferating, so it just sits at the secondary site. However, this cell does have the potential to proliferate at some point, meaning it has a potential to grow into a metastasis. This would not appear until years later, though, so dormancy is thought to be the reason for cancer occurrence after a patient seems to have already been cured. Dormancy will be the main focus of the remainder of this lecture. This is the end of the first section, and you should now have an understanding of why different cancer types metastasize to different organs. We've talked about two theories in which the seed and soil hypothesis is taken to be the most accepted explanation. Where cells may travel to many organs, but whether or not they're able to form a metastasis depends on the compatibility between the cell and the host site, or the seed and the soil.
