title: Evolution of tumor invasiveness: the adaptive tumor microenvironment landscape model.
abstract: Interactions between cancer cells and their microenvironment are crucial for promoting tumor growth and invasiveness. In the tumor adaptive landscape model, hypoxic and acidic microenvironmental conditions reduce the fitness of cancer cells and significantly restrict their proliferation. This selects for enhanced motility as cancer cells may evolve an invasive phenotype if the consequent cell movement is rewarded by proliferation. Here, we used an integrative approach combining a mathematical tumor adaptive landscape model with experimental studies to examine the evolutionary dynamics that promote an invasive cancer phenotype. Computer simulation results hypothesized an explicit coupling of motility and proliferation in cancer cells. The mathematical modeling results were also experimentally examined by selecting Panc-1 cells with enhanced motility on a fibroblast-derived 3-dimensional matrix for cells that move away from the unfavorable metabolic constraints. After multiple rounds of selection, the cells that adapted through increased motility were characterized for their phenotypic properties compared with stationary cells. Microarray and gene depletion studies showed the role of Rho-GDI2 in regulating both cell movement and proliferation. Together, this work illustrates the partnership between evolutionary mathematical modeling and experimental validation as a potentially useful approach to study the complex dynamics of the tumor microenvironment.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia 19111, USA.
authors.forename: Hyung-Ok
authors.initials: HO
authors.lastname: Lee
authors.forename: Ariosto S
authors.initials: AS
authors.lastname: Silva
authors.forename: Susanna
authors.initials: S
authors.lastname: Concilio
authors.forename: Yue-Sheng
authors.initials: YS
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Slifker
authors.forename: Robert A
authors.initials: RA
authors.lastname: Gatenby
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cheng
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003198:Computer Simulation; D017353:Gene Deletion; D020869:Gene Expression Profiling; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D059016:Tumor Microenvironment; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
chemical_list: D020730:Guanine Nucleotide Dissociation Inhibitors; D025521:Tumor Suppressor Proteins; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors