Protease-activated receptor-1 is upregulated in reactive stroma of primary prostate cancer and bone metastasis.
BACKGROUND
Prostate cancer progression is partly facilitated by tumor-stroma interactions. We recently reported that protease-activated receptors (PAR-1 and PAR-2) are overexpressed in prostate cancer, and PAR-1 expression in peritumoral stroma is associated with biochemical recurrence. However, the nature of PAR expression in prostate tumor microenvironment is not fully understood. We therefore evaluated PAR-1 and PAR-2 expression in primary prostate cancer and bone metastasis.


METHODS
PAR-1 and PAR-2 expression in normal, primary prostate cancer and the corresponding bone metastatic tissues were examined by immunohistochemistry, and double-label immunohistochemistry with the use of additional markers.


RESULTS
PAR-1 was expressed in peritumoral stroma in the majority of primary cancer tissues (83%). Serial sections and double-label immunohistochemistry determined that these PAR-1 expressing stromal cells were predominantly myofibroblasts, the primary cell type in reactive stroma. Analysis of cancer glands revealed that PAR-1 expression was significantly increased in the reactive stroma around higher Gleason grade cancers. PAR-2 was predominantly expressed in the primary cancer cells as well as smooth muscle cells but not in reactive stroma. In bone metastasis, PAR-1 expression in cancer cells was elevated compared to the primary site from the same patient. In the bone reactive stroma, PAR-1 was present in vascular endothelial cells and fibroblasts, while both PAR-1 and PAR-2 were expressed in osteoblasts and osteoclasts.


CONCLUSIONS
In primary prostate cancer and bone metastasis, PAR-1 is upregulated in reactive stroma and PAR-2 is uniformly overexpressed in carcinoma cells, suggesting these receptors may play potentially different roles in prostate cancer development and metastasis.
Zhang
Xiaotun
X
Department of Urology, University of Washington, Seattle, Washington, USA.
Wang
Wenbin
W
True
Lawrence D
LD
Vessella
Robert L
RL
Takayama
Thomas K
TK
D000368:Aged; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D044463:Receptor, PAR-1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018709:Statistics, Nonparametric; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
D044463:Receptor, PAR-1; D044464:Receptor, PAR-2