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Microenvironmental Independence Associated with Tumor Progression

¹ Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida and Departments of ² Cancer Biology and ³ Medicine, Vanderbilt University, Nashville, Tennessee

Requests for reprints: Alissa M. Weaver, Vanderbilt University School of Medicine, 771 PRB, 23rd and Pierce Avenues, Nashville, TN 37232-6840. Phone: 615-936-3529; Fax: 615-936-2911; E-mail: alissa.weaver{at}vanderbilt.edu or Alexander R.A. Anderson, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33629. Phone: 813-745-6119; Email: alexander.anderson{at}moffitt.org.

Tumor-microenvironment interactions are increasingly recognized to influence tumor progression. To understand the competitive dynamics of tumor cells in diverse microenvironments, we experimentally parameterized a hybrid discrete-continuum mathematical model with phenotypic trait data from a set of related mammary cell lines with normal, transformed, or tumorigenic properties. Surprisingly, in a resource-rich microenvironment, with few limitations on proliferation or migration, transformed (but not tumorigenic) cells were most successful and outcompeted other cell types in heterogeneous tumor simulations. Conversely, constrained microenvironments with limitations on space and/or growth factors gave a selective advantage to phenotypes derived from tumorigenic cell lines. Analysis of the relative performance of each phenotype in constrained versus unconstrained microenvironments revealed that, although all cell types grew more slowly in resource-constrained microenvironments, the most aggressive cells were least affected by microenvironmental constraints. A game theory model testing the relationship between microenvironment resource availability and competitive cellular dynamics supports the concept that microenvironmental independence is an advantageous cellular trait in resource-limited microenvironments. [Cancer Res 2009;69(22):8797–806]

Key Words: mathematical modeling • tumor microenvironment • tumor progression