As we have discussed, in this and previous lectures, cancer metastasis remains a glaring, unmet clinical need. After decades of research, while we have many answers, we are still far away from our goal of understanding the underlying mechanisms related to metastatic growth. From escape of cancer cells from the primary tumor, to how cancer cells form tumors far away from the original tumor site. To answer these questions, and to frame new questions related to metastasis, our research group has turned to ecological science to use the findings in ecology to inform our research in cancer biology. Novel paradigms to better understand the metastatic process are necessary to first characterize each of the steps and mechanisms of metastatic. And second to instigate the development of new therapeutic strategies to treat metastatic disease. So as they grow, tumors fundamentally alter their environment disrupting the homeostasis of the host organ and eventually the patient as a whole. Lethality is the ultimate result of deregulated cell signaling and regulatory mechanisms, as well as inappropriate host cell recruitment, an activity that lead to the death of the patient. This has striking parallels to the frameworks of ecological biology. Here you can see a table showing how cancer can be compared to ecological concepts. You have multiple interacting ecosystems, which can be compared to organ systems, made up of many different species or cell types, existing within a larger biosphere or the body. Introduction of an invasive species or cancer, alters these homeostatic ecosystems inducing dispersal of individuals, metastasis, and eventually ecosystem collapse, or organ failure, and death. Ultimately, to metastasize, a cancer cell must move from its native ecosystem of the primary tumor. Dispersal, both in ecology and in cancer biology, is a high risk endeavor. The risks associated with movement have been described in the field of movement ecology and include decreased short term fitness of the emigrant. Or in this case cancer cell, loss of the ability replicate because once the cancer cell is moving it can no longer replicate while it's moving. Change in metabolism. Energy spent to transition to a migratory phenotype. It takes a lot of energy for a cell to move, unfamiliar and hostile environment, which has increased predation and ecology but also increased immune surveillance in cancer metastasis. And future risk of a hostile secondary site or no secondary environment at all. So this high level of risk means that individuals, or cancer cells, do not leave their native ecosystems unless the risks of remaining in the ecosystem are higher than the risks associated with dispersal. One of the major reasons why organisms vacate their native ecosystem is because conditions deteriorate rapidly due to outside forces influencing the ecosystem and eventually leading to ecosystem collapse. Here we show an example of a eutrophic watershed. That was instigated by pollution from fertilizer and untreated sewage. Pollution leads to invasive algae growth, increase algae proliferation and decay causes hypoxic, acidic and nutrient poor conditions. So non native organisms that survive in the harsh conditions are selected for. Native species go extinct or migrate to a secondary site. In this decoupled ecosystem, organisms must either disperse from the harsh conditions to find a more favorable secondary site or they go extinct. A similar mechanism is at play in the primary tumor ecosystem in a cancer patient. Unlike rapid ecological eutrophication, in a tumor the rapidly proliferating cancer cells form a tumor that both instigates and maintains the harmful so-called autoeutrophic environment. Eventually as the tumor outstrips the vasculature, normal ecosystem homeostasis is dismantled resulting in a hypoxic, acidic and nutrient poor habitat. What we have termed the cancer swamp. Like the selection for anaerobic decomposers of the ecological setting, these conditions select for cancer cells that thrive in the harsh conditions of the tumor and lead to extinction of native species, or normal cells. Eventually as overcrowding increases and oxygen, pH, and nutrient levels decrease, cancer cells are induced to leave the primary tumor as a metastatic cell. Research in our group is working to understand each of these steps, from the formation of the cancer swamp to the ecosystem influences that induce cells to eventually disperse from the primary site, with the goal of understanding this first critical step of the metastatic progression. In addition to the example I outlined here, we and others are applying ecological paradise to other components of cancer biology in order to gain new insight into the metastatic problem. For example, active research is using ecological models to study engineering of the tumor microenvironment, movement ecology of metastatic cells, so why they move and how they move. Ability of circulating tumor cells to survive in transit, which we talked about. Causes of the cytokine mediated syndromes, a major cause of death in cancer patients. And designs of novel ecotherapy drugs to dismantle cancer ecosystems. So in this lecture, we've discussed metastasis, we've defined metastasis, we've defined the TNM staging system, and metastasis' role in that, the metastatic cascade, and also novel paradigms that research groups are working on to try to find underlying mechanisms of metastasis. [MUSIC]
