Stromal and epithelial networks: Temporal gene expression profiling during invasive neoplasia

Abstract

The interaction between tumor cells and the stromal microenvironment is a critical factor in cancer development and progression. A recent study from the Khavari group profiled the expression changes during progression to invasion in a Ras-inducible model of human epithelial neoplasia and used network modeling to analyze the molecular interactions. Human dermis was seeded with H-Ras- and IkappaBalpha-expressing keratinocytes then grafted on to immune-deficient mice. The epithelial and stromal gene expression profiles were captured during progression from quiescent epithelial tissue to in situ neoplasia to invasive neoplasia. A subset of these altered genes was compiled into a "core tumor progression signature" (CTPS), which was shown to have clinical relevance in several cancer types. Network modeling of the CTPS revealed highly interconnected "hubs", which was dominated by extracellular matrix-related genes, including beta(1) integrin. Targeting integrin beta(1) functionality reduced Ras-driven tumorigenesis in vivo and validated the network modeling strategy for predicting genes essential to neoplasia. By integrating temporal analysis of both the epithelial and stromal compartments with network modeling of molecular interactions, this work has described an effective strategy for identifying highly interconnected targets essential to tumor development.

Figure 1

Progression stages in human tissue neoplasia model. (A) Quiescent tissue, (B) Following Ras-IκBα induction in the epidermis in situ neoplasia develops, with loss of epidermal polarity and increased angiogenesis, followed by (C) epithelial invasion into the stroma and loss of basement membrane integrity. Figure design by Kristin E. Johnson.