Abstract 2884: Tumor-driven eutrophication of the tumor ecosystem selects for cancer cell clones that overcome evolutionary inertia leading to increased metastatic capacity
Authors: Sarah R. Amend, Kenneth Pienta
Journal: Cancer Research (2015)

Abstract Cancer biology has striking parallels to the ecological frameworks of conservation biologists: multiple ecosystems (tumor sites) within a larger biosphere (body), interacting species (cell types), resource cycling (cell signaling and metabolism), and ultimate ecosystem collapse. While tumor heterogeneity is typically attributed to intrinsic genetic instability, we propose that it is due to the evolution of cancer cells under the selection of ecological pressures in the tumor ecosystem. Like any ecosystem, a healthy organ requires balanced feedback mechanisms to respond dynamically to small perturbations. Small disturbances result in a robust ecosystem, such as immunity following viral infection. In contrast, the native ecosystem is unable to recover from catastrophic perturbation such as an invasive species: cancer. Invasive species are inherent ecosystem engineers that alter their habitat and modify resource availability. As a tumor grows, it consumes high levels of nutrients and oxygen and increases the local concentration of cellular waste, analogous to the ecological process of eutrophication associated with polluted swamps. The “cancer swamp” is a hypoxic, acidic, and nutrient-poor habitat. This ecosystem engineering alters the selective pressure and subsequent adaptation of the cancer cells. According to evolutionary inertia, while all cancer cells have the capacity to attain metastatic traits, an unchanged trait will remain unchanged (stasis) and a trait undergoing a change will maintain that change (thrust) unless an external force acts upon it. We hypothesize that the cancer swamp provides the external force to instigate evolutionary thrust by exerting selective pressure to promote the generation of clones with high metastatic capacity. To test this, mice will be inoculated with epithelial prostate cancer cells (PC3-Epi) or prostate cancer cells that have undergone EMT and display increased metastatic capacity (PC3-EMT). At time points prior to, during the establishment of, and after formation of the cancer swamp, tumors will be excised and cells exiting the primary tumor into the circulation will be assessed. We expect that PC3-Epi cells will have a greater than 1:1 ratio of migrating cells : primary tumor burden and that the migrating cells will become more EMT-like as the cancer swamp evolves and the tumor cells overcome evolutionary stasis. Because the PC3-EMT cells have already attained evolutionary thrust towards a metastatic phenotype, we expect migrating tumor cells to be unaffected by the pressures of the growing cancer swamp. Using ecological models to understand cancer biology introduces new avenues for therapy and metastatic prediction. Conservation biology provides several promising strategies that can be adapted to treat cancer including ecological traps, invasive species management, and land use restoration of the cancer swamp. Citation Format: Sarah R. Amend, Kenneth Pienta. Tumor-driven eutrophication of the tumor ecosystem selects for cancer cell clones that overcome evolutionary inertia leading to increased metastatic capacity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2884. doi:10.1158/1538-7445.AM2015-2884