Date of Award

8-4-2010

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Jose Costa, MD

Abstract

Competition among cells has long been recognized as an important part of the evolutionary process of tissue leading up to the development of cancer. However, the role of cellular cooperation in cancer has been largely ignored. In this work, we investigated the role of cooperation in early tumor progression using a mathematical and agent-based modeling approach. We hoped to learn whether cooperation between cells in spatially organized tissue has a significant role in hastening tumor development, and to uncover general principles governing such cooperation. We focused on the early stages of tumor development given the critical importance of this time period and since we hypothesized that cooperation will have its greatest influence during these early phases. In our model, stem cells were placed into an array of 50 x 20 cell patches, with each patch carrying a maximum of 64 cells. The stem cells' potential to replicate or leave the stem cell compartment through apoptosis or differentiation were governed by modified versions of the Lotka-Volterra equation of ecology. The cells could also acquire mutations in two oncogenes and three tumor suppressor genes. We explored two different cooperation strategies, one in which a cell could acquire the ability to send a cooperative signal that improved the fitness of its immediate neighbors, and one in which a cell could acquire the ability to take advantage of a cooperative signal already in the environment. Cooperation could be acquired through mutation or assigned in advance. We ran simulations of the model in MATLAB. We found that cooperation is a very robust property. Once a small number of cooperative cells is introduced into a cell population, they rapidly proliferate to the point of being the major constituent of the cell population. Cooperation leads to an increased growth rate of the aggregate cell population, with the growth rate rising in parallel with the cooperative cell fraction. Interestingly, cooperation does not seem to have an effect on cell heterogeneity, counter to what we initially suspected. We also found that cooperative cells have a wider spatial influence than non-cooperating cells. The cooperative cells or their descendant are, on average, present in more patches than corresponding non-cooperative cells at each point in time. Further analysis showed that cooperation is particularly important in the very early pre-tumor stage, when tissue is morphologically and histologically normal, and during times of extensive cell death, such as when tissue experiences necrosis, repeated bouts of inflammation, or cancer treatment. In conclusion, we found that cooperation may play an important role in early tumor progression that is complementary to the competitive interactions among cells that are driven by mutations in tumor suppressors and oncogenes. Cooperation may also be a critical force during later stages of tumor progression when there is significant cell turnover. Our results have implications for cancer prevention and tumor therapeutic strategies.

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