Modeling stromal-epithelial interactions in disease progression

Abstract

The role of tumor stroma in progression to malignancy has become the subject of intense experimental and clinical interest. The stromal compartment of organs is composed of all the non-epithelial cell types and maintains the proper architecture and nutrient levels required for epithelial and, ultimately, organ function. The composition of the reactive stroma surrounding tumors is vastly different from normal stromal tissue. Stromal phenotype can be correlated with, and predictive of, disease recurrence. In addition, the stroma is now seen as a legitimate target for therapeutic intervention. Although much has been learned about the role of the stromal compartment in development and disease in recent years, a number of key questions remain. Here we review how some of these questions are beginning to be addressed using new models of stromal-epithelial interaction.

Figure 1

Trichrome staining of mouse prostate (left), human prostate (center), and tissue recombination xenografting of human prostate epithelia and inductive fetal rat urogenital mesenchyme under the kidney capsule (right). The balance of smooth muscle (red fibers) and collagen (blue) in human prostate stroma is more closely modeled using human cells in tissue recombination xenografting than in mouse transgenic models.

Figure 2

Modeling stromal heterogeneity in vivo. Left: H&E immunostaining of a three month tissue recombination graft under the kidney (K) capsule of a SCID mouse shows glandular formation of human prostate epithelia (G), smooth muscle differentiation of rat urogenital mesenchyme (SM), and human prostate fibroblasts (hPF) expressing GFP, which can be identified in a serial section using immunohistochemistry (right panel).

Figure 3

Schematic sequence of proposed events in prostate cancer progression modeled with normal human prostate epithelia and stromal cell lines and inductive mesenchyme (rUGM).