The Prostate 66:1664 ^1673 (2006) Prostate Cancer Metastasis: Role of the Host Microenvironment in Promoting Epithelial to Mesenchymal Transition and Increased Bone and Adrenal Gland Metastasis Jianchun Xu, 1 Ruoxiang Wang, 1 Zhi Hui Xie, 1 Valerie Odero-Marah, 1 Sen Pathak, 2 Asha Multani, 2 Leland W.K. Chung, 1 and Haiyen E. Zhau 1 * 1 Department of Urology, Molecular Urology and Therapeutics Program, Emory University School of Medicine, Atlanta,Georgia 2 Department of Cancer Biology and Laboratory Medicine, the University of Texas M. D. Anderson Cancer Center, Houston,Texas BACKGROUND. The ARCaP cell line was established from the ascites fluid of a patient with metastatic prostate cancer. This study characterized the host microenvironmental role in cancer progression, epithelial to mesenchymal transition (EMT), and bone and adrenal metastasis in parental ARCaP and its derived cell subclones. METHODS. Cytogenetic profiles, growth, migration, invasion, cellular interaction, drug sensitivities, and gene expression of ARCaP cell subclones were compared. In vivo gene expression, behavior, and metastasis of ARCaP subclones were analyzed by serial intracardiac injections into SCID mice. RESULTS. ARCaP E cells, with cobblestone morphology, underwent EMT through cellular interaction with host bone and adrenal gland. Lineage-derived ARCaP M cells, with spindle-shape fibroblastic morphology, exhibited decreased cell adhesion and increased metastasis to bone and adrenal gland. Cytogenetic analyses of parental and ARCaP subclones confirmed their clonality. CONCLUSIONS. ARCaP uniquely models the molecular basis of prostate cancer bone and adrenal metastases and epithelial to mesenchymal transition. Prostate 66: 1664–1673, 2006. # 2006 Wiley-Liss, Inc. KEY WORDS: organ-specific tropism; clonal interaction; cancer cell heterogeneity; animal model; cancer progression INTRODUCTION The diversity and heterogeneity of human prostate cancer cells is well appreciated. A broad spectrum of cancer cell behaviors include the ability to grow, invade surrounding normal tissues, and metastasize to distant organs [1–3]. Despite similarities in the histologic presentation of prostate cancers at the time of disease diagnosis, their clinical behaviors, including time to disease progression and metastasis, sensitivity to hormones, chemotherapy and radiation, and propen- sity to relapse still cannot be predicted with certainty [4 – 7]. Relevant models that could probe the phenotype, behavior, and progression of cancer cells are lacking, as well as appropriate methods and sensitive biomarkers that can diagnose disease and reliably predict its Abbreviations: ARCaP, androgen refractory cancer of the prostate; EMT, epithelial mesenchymal transition. *Correspondence to: Haiyen E. Zhau, PhD, Department of Urology, Molecular Urology and Therapeutics Program, Emory University School of Medicine, 1365B Clifton Rd. NE, Atlanta, GA 30322. E-mail: hzhau@emory.edu Received 17 February 2006; Accepted 16 May 2006 DOI 10.1002/pros.20488 Published online 10 August 2006 in Wiley InterScience (www.interscience.wiley.com). ß 2006 Wiley-Liss, Inc.