The reactive stroma microenvironment and prostate cancer progression

Abstract

Reactive stroma initiates during early prostate cancer development and coevolves with prostate cancer progression. Previous studies have defined the key markers of reactive stroma and have established that reactive stroma biology influences prostate tumorigenesis and progression. The stem/progenitor cells of origin and the mechanisms that regulate their recruitment and activation to myofibroblasts or carcinoma-associated fibroblasts are essentially unknown. Key regulatory factors have been identified, including transforming growth factor β, interleukin-8, fibroblast growth factors, connective tissue growth factor, wingless homologs-Wnts, and stromal cell-derived factor-1, among others. The biology of reactive stroma in cancer is similar to the more predictable biology of the stroma compartment during wound repair at sites where the epithelial barrier function is breached and a stromal response is generated. The coevolution of reactive stroma and the biology of how reactive stroma-carcinoma interactions regulate cancer progression and metastasis are targets for new therapeutic approaches. Such approaches are strategically designed to inhibit cancer progression by uncoupling the reactive stroma niche.

Figure 1. Cellular components of the human prostate gland

Secretory epithelial cells are situated on a basal lamina / basement membrane and secretes products into the acinar lumen. Basal cells and sparse neuroendocrine cells are also present in the epithelial compartment. The stromal compartment immediately surrounding the epithelial acini is complex, and consists of smooth muscle, trace fibroblasts, blood vessels, autonomic nerve fibers, inflammatory cells, and extracellular matrix components.

Figure 2. Stromal cell phenotypes and associated markers

Stromal cell populations found in the prostate gland and other epithelial-lined organs are distinguished based on their morphology and expression of marker proteins. Shown here are three major stromal cell types and associated markers used to identify them in the prostate gland. Importantly, these markers are not lineage-specific.

Figure 3. Prostate gland homeostasis and reactive stroma formation in cancer

The histopathologic changes in inflammatory conditions of the prostate (i.e. proliferative inflammatory atrophy or PIA) are similar to changes observed in wound repair. Similarly, prostate cancer can be viewed as an equivalent of chronic wounding with a prototypical reactive stroma response. It is hypothesized that the inflammatory cell populations recruited to lesions work coordinately with factors secreted by the carcinoma cells to generate a reactive stroma response. As cancer progresses, this reactive stroma co-evolves with foci of adjacent carcinoma. The net effect is likely to be tumor-promoting within the context of early and organ-confined disease.

Figure 4. Model of potential origin and regulators of reactive stroma

It is hypothesized that reactive stroma in prostate cancer may be derived from both bone marrow derived cells as well as non-marrow sources. The latter cell population is most likely tissue-resident mesenchymal/stromal stem cells or existing fibroblasts. Carcinoma-produced factors, including TGF-beta have the potential to reach and regulate the stromal compartment when the epithelial layer integrity and/or basement membrane integrity is disrupted during cancer progression.