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Clinical Cancer Research Vol. 8, 2912-2923, September 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Reactive Stroma in Human Prostate Cancer

Induction of Myofibroblast Phenotype and Extracellular Matrix Remodeling1

Jennifer A. Tuxhorn, Gustavo E. Ayala, Megan J. Smith, Vincent C. Smith, Truong D. Dang and David R. Rowley2

Departments of Molecular and Cellular Biology [J. A. T., T. D. D., D. R. R.] and Pathology [G. E. A., M. J. S., V. C. S.] Baylor College of Medicine, Houston, Texas 77030

Purpose: Generation of a reactive stroma environment occurs in many human cancers and is likely to promote tumorigenesis. However, reactive stroma in human prostate cancer has not been defined. We examined stromal cell phenotype and expression of extracellular matrix components in an effort to define the reactive stroma environment and to determine its ontogeny during prostate cancer progression.

Experimental Design: Normal prostate, prostatic intraepithelial neoplasia (PIN), and prostate cancer were examined by immunohistochemistry. Tissue samples included radical prostatectomy specimens, frozen biopsy specimens, and a prostate cancer tissue microarray. A human prostate stromal cell line was used to determine whether transforming growth factor ß1 (TGF-ß1) regulates reactive stroma.

Results: Compared with normal prostate tissue, reactive stroma in Gleason 3 prostate cancer showed increased vimentin staining and decreased calponin staining (P < 0.001). Double-label immunohistochemistry revealed that reactive stromal cells were vimentin and smooth muscle {alpha}-actin positive, indicating the myofibroblast phenotype. In addition, reactive stroma cells exhibited elevated collagen I synthesis and expression of tenascin and fibroblast activation protein. Increased vimentin expression and collagen I synthesis were first observed in activated periacinar fibroblasts adjacent to PIN. Similar to previous observations in prostate cancer, TGF-ß1-staining intensity was elevated in PIN. In vitro, TGF-ß1 stimulated human prostatic fibroblasts to switch to the myofibroblast phenotype and to express tenascin.

Conclusions: The stromal microenvironment in human prostate cancer is altered compared with normal stroma and exhibits features of a wound repair stroma. Reactive stroma is composed of myofibroblasts and fibroblasts stimulated to express extracellular matrix components. Reactive stroma appears to be initiated during PIN and evolve with cancer progression to effectively displace the normal fibromuscular stroma. These studies and others suggest that TGF-ß1 is a candidate regulator of reactive stroma during prostate cancer progression.




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