Purpose: Prostate cancer metastasis to secondary organs is considered an initial event in the development of hormone refractory disease and remains the major cause of death among prostate cancer patients. In this study, we investigated the role of fascin, a cytoskeleton actinb undling protein involved in the formation of filopodia and cell migration, in prostate cancer progression. Experimental Design: Fascin protein expression was examined by immunohistochemistry in a cohort of 196 patients with localized prostate cancer and across several stages of disease progression, including hormone refractory disease. Cellular changes were also assessed in vitro and in vivo in DU145 prostate cancer cell line using fascin gene silencing. Results: Fascin epithelial expression was significantly up-regulated in localized and hormone refractory prostate cancer compared with benign prostate tissue (P < 0.05). Furthermore, high fascin expression was associated with an increased rate of prostate-specific antigen recurrence following radical prostatectomy (P = 0.075), signifying more aggressive clinical course, thus supporting a function for fascin in prostate cancer progression. In cellular models, fascin gene silencing using small interfering RNA in the androgen-independent prostate cancer cell line DU145 decreased cell motility and invasiveness while increasing cell adhesive properties. In addition, fascin small interfering RNA^expressing DU145 cells implanted orthotopically in mouse prostate showed significantly decreased growth (P < 0.005) and drastically prevented the formation of lymph node metastases (P < 0.001) compared with their matched controls. Conclusions:Our data show a function of fascin in the regulation of prostate cancer progression and emphasize the importance of fascin as a prognostic marker for aggressive disease and as a potential therapeutic target for advanced androgen independent disease.Prostate cancer remains one of the most prevalent cancers and a major source for morbidity and mortality in the Western world (1 -4). In 2007, f219,000 new patients were diagnosed with prostate cancer causing about 27,000 cancer related deaths (5). Disease progression and the development of hormone refractory disease remain major causes of cancer related death.To significantly alter the disease course, improved ways to understand, diagnose, and treat aggressive forms of metastatic prostate cancer are needed.Tumor cell motility is the hallmark of invasion and an essential step in metastasis (6, 7). Understanding the molecular pathways involved in tumor cell motility and how the tumor microenvironment contributes to cell migration and metastasis is critical to developing improved therapeutic targets for the treatment of metastatic prostate cancer. Predicting disease progression is a major and significant step in identifying patients at increased risk for cancer specific death. Therefore, one goal in the diagnosis and treatment of men with prostate cancer is to develop tissue-based molecular tests to distinguish ind...

Malignant tumor cells invade surrounding normal tissue and disseminate to distant organs through a multistep and multifactorial process. In general, the acquisition of early autonomous motile property involves cell polarization toward blood and lymphatic vessels in response to chemotactic signals, cell cytoskeleton remodeling, and formation of cell plasma membrane protrusions. The latter are the site of dynamic turnover of multiple focal adhesion molecules, which allow formation of stable cellmatrix attachments near the leading edge of the protrusions, forward movement of the cell body, and disassembly of focal-matrix adhesions and retraction at the trailing edge. These processes are the driving force for early cancer cell migration and invasion.Central to the regulation of the cell migration cycle is the focal adhesion kinase (FAK) and its homologous FAKrelated proline-rich tyrosine kinase 2 (Pyk2).1 FAK and Pyk2 share 45% amino acid sequence homology with a

The process of primary cancer invasion of distant organs is multifactorial and multistep. Successful therapeutic management of invasive cancers remains hampered by the multitude of overlapping signaling pathways that initiate and drive cancer cell migration. A crucial early event by which cancer cells switch from localized to invasive states is initiated by the acquisition of autonomous motile properties; a process driven by dynamic assemblies and disassemblies of multiple focal adhesion, cytoskeleton and motor proteins. Several of the protein complexes involved are tightly regulated through posttranslational modifications and intermolecular collisions with partners that occur in a time- and space-dependent manner. These concerted mechanisms are essential for the regulation of cell shape, cell polarity, and cell motility and migration in response to chemotactic signals. This review summarizes the current knowledge in the field and potential clinical implications for molecular pathology and cancer therapeutics. It is not meant to be comprehensive; aspects related to basic signaling are not dealt with extensively in this review. However, the reader is referred to excellent reviews that provide coverage of these topics.