The Prostate 70:1672^1682 (2010) Role of Monocyte-Lineage Cells in Prostate Cancer Cell Invasion and Tissue Factor Expression Paul F. Lindholm, 1 * Yi Lu, 3 Brian P. Adley, 1 Tudor Vladislav, 3 Borko Jovanovic, 4 Neela Sivapurapu, 1 Ximing J. Yang, 1,2 and Andre ´ Kajdacsy-Balla 3 1 Department of Pathology,The Feinberg School of Medicine, Northwestern University,Chicago, Illinois 2 Robert H. Lurie Cancer Center, Prostate CancerTissue Core Facility,The Feinberg School of Medicine, Northwestern University,Chicago, Illinois 3 Department of Pathology,College of Medicine,University of Illinois,Chicago, Illinois 4 Department of Preventive Medicine and Bioinformatics Core,The Feinberg School of Medicine, Northwestern University,Chicago, Illinois BACKGROUND. Tissue factor (TF) is a cell surface glycoprotein intricately related to blood coagulation and inflammation. This study was performed to investigate the role of monocyte- lineage cells in prostate cancer cell TF expression and cell invasion. METHODS. Prostate cancer cell invasion was tested with and without added peripheral blood monocytes or human monocyte-lineage cell lines. TF neutralizing antibodies were used to determine the TF requirement for prostate cancer cell invasion activity. Immunohistochemistry was performed to identify prostate tissue CD68 positive monocyte-derived cells and prostate epithelial TF expression. RESULTS. Co-culture of PC-3, DU145, and LNCaP cells with isolated human monocytes significantly stimulated prostate cancer cell invasion activity. TF expression was greater in highly invasive prostate cancer cells and was induced in PC-3, DU145, and LNCaP cells by co-culture with U-937 cells, but not with THP-1 cells. TF neutralizing antibodies inhibited PC-3 cell invasion in co- cultures with monocyte-lineage U-937 or THP-1 cells. Prostate cancer tissues contained more CD68 positive cells in the stroma and epithelium (145  53/mm 2 ) than benign prostate (108  31/mm 2 ). Samples from advanced stage prostate cancer tended to contain more CD68 positive cells when compared with lower stage lesions. Prostatic adenocarcinoma demonstrated significantly increased TF expression compared with benign prostatic epithelium. CONCLUSIONS. This study shows that co-culture with monocyte-lineage cells induced prostate cancer cell invasion activity. PC-3 invasion and TF expression was induced in co-culture with U- 937 cells and partially inhibited with TF neutralizing antibodies. Prostate 70: 1672–1682, 2010. # 2010 Wiley-Liss, Inc. KEY WORDS: prostate cancer; monocytes; tissue factor; invasion INTRODUCTION Inflammation and infection contributes to the development of several gastrointestinal, head and neck and uterine cervical cancers and other cancer types [1–8]. The association of chronic inflammation and infection with prostate cancer has also been studied and a history of previous venereal infections has been epidemiologically linked to an increased risk of prostate cancer development [9]. In addition, areas of prostate inflammation have been found to occur in proximity with proliferating prostate epithelium, or Grant sponsor: Department of Defense New Investigator; Grant number: DAMD17-02-1-0162; Grant sponsor: National Cancer Institute Prostate; Grant number: P50-CA090386. Current address: Brian P. Adley, MD, Advocate Lutheran General Hospital, Park Ridge, IL. *Correspondence to: Paul F. Lindholm, Department of Pathology, The Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611. E-mail: p-lindholm@northwestern.edu Received 9 October 2010; Accepted 3 May 2010 DOI 10.1002/pros.21202 Published online 6 July 2010 in Wiley Online Library (wileyonlinelibrary.com). ß 2010 Wiley-Liss, Inc.