The Evolution of Cooperation in the Tumor Microenvironment
This project is led by Dr. Ken Pienta at the Johns Hopkins University School of Medicine
This project raises new questions about tumorigenesis by studying cooperation through the sharing of diffusible products, with the aims of identifying the diffusible products shared by cancer cells to promote or inhibit growth, and utilizing the microhabitat patch (MPH) technology to study the interactions of cancer and host cells within a 3D microenvironment.
The evolution of cooperation has a well-established theoretical framework based on game theory. This approach has made valuable contributions to a wide variety of disciplines, including political science, economics, and evolutionary biology. Existing cancer theory suggests that individual clones of cancer cells evolve independently from one another, acquiring all of the genetic traits or hallmarks necessary to form a malignant tumor. It is also now recognized that tumors are heterotypic, with cancer cells interacting with normal stromal cells within the tissue microenvironment, including endothelial, stromal, and nerve cells. This tumor cell–stromal cell interaction in itself is a form of commensalism, because it has been demonstrated that these nonmalignant cells support and even enable tumor growth. We have added to this theory by regarding tumor cells as game players whose interactions with each other and host cells help to determine their Darwinian fitness. Our preliminary data demonstrates that tumor cells may promote proliferation of each other by means of diffusible products. This raises the possibility that neighboring cancer cells can help each other grow as well as protect each other from a set of host defenses that neither could survive alone. The data also demonstrates that cancer cells can have similar interactions with host myofibroblasts and endothelial cells. We believe that cooperation can evolve as byproduct of mutualism among genetically diverse tumor cells and / or host cells. The preliminary data also demonstrates examples of parasitism whereby one cancer clone grows at the expense of other clones. This hypothesis supplements, but does not supplant, the traditional view of carcinogenesis in which one clonal population of cells develops all of the necessary genetic traits independently to form a tumor. Cooperation through the sharing of diffusible products raises new questions about tumorigenesis and has implications for understanding observed phenomena, designing new experiments, and developing new therapeutic approaches.
Utilizing complementary 2-dimensional, 3-dimensional, and preclinical mouse models, we will demonstrate the existence of cooperative and parasitic systems in cancer for the first time. The demonstration of these systems opens up new avenues for research in many directions. New mathematical models can be developed for better prediction of cancer development and growth while simultaneously, new strategies for cancer therapy and prevention can be developed based on inhibition of shared resources.
These observations will be extended in the context of the following specific aims: Identifying the diffusible products shared by cancer cells to promote or inhibit growth; Utilizing the microhabitat patch (MPH) technology to study the interactions of cancer and host cells within a 3D microenvironment.