Fascin regulates prostate cancer cell invasion and is associated with metastasis and biochemical failure in prostate cancer.

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 actin-bundling 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.

Focal adhesion kinase-related proline-rich tyrosine kinase 2 and focal adhesion kinase are co-overexpressed in early-stage and invasive ErbB-2-positive breast cancer and cooperate for breast cancer cell tumorigenesis and invasiveness.

Early cancer cell migration and invasion of neighboring tissues are mediated by multiple events, including activation of focal adhesion signaling. Key regulators include the focal adhesion kinase (FAK) and FAK-related proline-rich tyrosine kinase 2 (Pyk2), whose distinct functions in cancer progression remain unclear. Here, we compared Pyk2 and FAK expression in breast cancer and their effects on ErbB-2-induced tumorigenesis and the potential therapeutic utility of targeting Pyk2 compared with FAK in preclinical models of breast cancer. Pyk2 is overexpressed in tissues from early and advanced breast cancers and overexpressed with both FAK and epidermal growth factor receptor-2 (ErbB-2) in a subset of breast cancer cases. Down-regulation of Pyk2 in ErbB-2-positive, FAK-proficient, and FAK-deficient cells reduced cell proliferation, which correlated with reduced mitogen-activated protein kinase (MAPK) activity. In contrast, Pyk2 silencing had little impact on cell migration and invasion. In vivo, Pyk2 down-regulation reduced primary tumor growth induced by a metastatic variant of ErbB-2-positive MDA 231 breast cancer cells but had little effect on lung metastases in contrast to FAK down-regulation. Dual reduction of Pyk2 and FAK expression resulted in strong inhibition of both primary tumor growth and lung metastases. Together, these data support the cooperative function of Pyk2 and FAK in breast cancer progression and suggest that dual inhibition of FAK and Pyk2 is an efficient therapeutic approach for targeting invasive breast cancer.

Early stage cancer cell invasion: signaling, biomarkers and therapeutic targeting.

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.