There are currently no effective therapies for metastatic prostate cancer because the molecular mechanisms that underlie the metastatic spread of primary prostate cancer are unclear. Transcription factor Stat3 is constitutively active in malignant prostate epithelium, and its activation is associated with high histological grade and advanced cancer stage. Progression of prostate cancer to metastatic disease is one of the key problems in the clinical management of prostate cancer.1 This is because there are currently no effective therapies for metastatic prostate cancer, and metastatic prostate cancer is the lethal form of the disease. Identification of the molecular changes that lead to formation of distant metastasis is critical for improvement of therapeutic interventions for metastatic prostate cancer and for development of strategies to prevent primary prostate cancer from metastasizing.Transcription factor Stat3 has been implicated in the promotion of growth and progression of prostate cancer. Stat3, which is both a cytoplasmic signaling molecule and a nuclear transcription factor, belongs to the sevenmember Stat gene family of transcription factors.2 Stat3 becomes active by phosphorylation of a specific tyrosine residue in the carboxy-terminal domain by a tyrosine kinase (pY705).3 Activation of Stat3 is supplemented by phosphorylation of a specific serine residue (S727).4 After phosphorylation, Stat3 homodimerizes and translocates to the nucleus where it binds to specific Stat3 response elements of target gene promoters to regulate transcription.3 Transcription factor Stat3 is constitutively active in clinical human prostate cancer, 5-9 and activation of Stat3 has been associated with advanced stage of prostate cancer. 5,9 Moreover, several reports implicate Stat3 in promotion of prostate cancer cell proliferation and inhibition of apoptosis. 5,10,11

The results of this TMA study confirm a dominant prognostic significance of Gleason grading and Ki67 LI in prostate cancer, as compared to a less pronounced role of Bcl-2, and p53. We identified syndecan-1 as a new prognostic factor and provide evidence for an androgen-dependent regulation of CD-10 expression.

Upregulation of clusterin levels following androgen ablation therapy may represent an adaptive cell survival response following apoptotic signals like androgen withdrawal. These findings support clusterin as a valid therapeutic target in strategies employing novel multimodality therapy for advanced prostate cancer.

The molecular mechanisms that promote progression of localized prostate cancer to hormone-refractory and disseminated disease are poorly understood. Prolactin (Prl) is a local growth factor produced in high-grade prostate cancer, and exogenously added Prl in tissue or explant cultures of normal and malignant prostate is a strong mitogen and survival factor for prostate epithelium.