The Role of Transforming Growth Factor-β–Mediated Tumor-Stroma Interactions in Prostate Cancer Progression: An Integrative Approach

Abstract

We have implemented a hybrid cellular automata model based on the structure of human prostate that recapitulates key interactions in nascent tumor foci between tumor cells and adjacent stroma. Model simulations show how stochastic interactions between tumor cells and stroma may lead to a structural suppression of tumor growth, modest proliferation, or unopposed tumor growth. The model incorporates key aspects of prostate tumor progression, including transforming growth factor-B (TGF-B), matrix-degrading enzyme activity, and stromal activation. It also examines the importance of TGF-B during tumor progression and the role of stromal cell density in regulating tumor growth. The validity of one of the key predictions of the model about the effect of epithelial TGF-B production on glandular stability was tested in vivo. These experimental results confirmed the ability of the model to generate testable biological predictions in addition to providing new avenues of experimental interest. This work underscores the need for more pathologically representative models to cooperatively drive computational and biological modeling, which together could eventually lead to more accurate diagnoses and treatments of prostate cancer. [Cancer Res 2009;69(17):7111-20]

Microenvironmental variables need to effect intrinsic phenotypic parameters of cancer stem cells to affect tumourigenicity

“…HCA models have been used to study cancer progression and evolutionary dynamics since they can integrate biological parameters and produce predictions affecting different spatial and time scales [17][18][19][20] . As shown in figure 2C cells are modelled in a discrete fashion on a 500x500 2-D lattice.…”

Prostate Cancer Stem Cells and Their Involvement in Metastasis

“…In prostate cancer, the TGF-β pathway has been reported as both a tumor suppressor and an oncogene (Basanta et al, 2009). …”

An explicit numerical scheme to efficiently simulate molecular diffusion in environments with dynamically changing barriers

“…Cellular systems contain static as well as dynamically changing excluded volumes, such as dividing cells or macromolecules [10,12,13]. Furthermore, we here assume that a membrane, which is impenetrable for diffusing polar molecules, such as ions and proteins, encloses the environment under consideration [7].…”

“…This issue is even more important in cellular systems, where excluded volumes often dynamically change their location in space. As a consequence, spatial structures are simplified and excluded volumes are frequently neglected in practice [13]. Explicit numerical schemes are closely related to cellular automata (CA) [24] and, thus, adapt better to discrete phenomena such as a heterogeneous spatial environment that includes dynamic excluded volumes.…”

“…In the next section, we present the capabilities of our approach using cell communication in cancer as an application (Section 4). Towards this end, we extend a previously published multiscale model [13] by reformulating the diffusion equation. This application highlights that, based on CADM, further information of a heterogeneous space, such as excluded volumes, can easily be included into such a model.…”