282 increased expression of SRC-3 in PCa correlates signiﬁ- cantly with pAkt levels in PCa specimens as well as increased proliferation and reduced apoptosis [22, 23]. In addition, SRC-3 stimulates cellular motility by activating focal adhesion kinase signaling and invasion by activating AR, AP1 and PEA3 dependent expression of matrix metalloproteinases 2 and 13 [23]. Inﬂammation As men age, circulating levels of inﬂammatory cytokines, including IL-6, tumor necrosis factor a (TNF-a) and interleukin-1b (IL-1b), increase along with PCa incidence [1, 24]. Particular focus has been on IL-6, since IL-6 has been shown to potentiate AR function. Regions of focal atrophic prostatic epithelium in aging men are common and are often associated with inﬂammation. These lesions, termed proliferative inﬂammatory atrophy (PIA), typically display increased epithelial proliferation, are associated with PIN and proposed to be precursors of PCa [24]. In benign prostate epithelium, IL-6 is expressed in basal cells, but in PIN and PCa its expression is detected in the secretory epithelium [25]. The highest circulating levels of IL-6 are observed in patients with CRPC and metastatic disease [26]. Increased IL-6 levels are associated with markers of PCa progression and poor prognosis such as androgen independent growth, resistance to chemothera- peutic drugs and neuroendocrine differentiation. In vitro studies show that IL-6 can both inhibit and promote the proliferation of AR expressing LNCaP PCa cells depending on the cellular context and ligand availability [26, 27]. IL-6 activates ligand independent AR activity via STAT3 and overexpression of IL-6 can protect LNCaP cells from growth arrest and apoptosis induced by androgen starvation [27]. One of the major conduits of inﬂammation is the NF-jB (nuclear factor kappa-light-chain-enhancer of activated B cells) family of transcription factors. Elevated NF-jB activity in primary PCas is associated with poor prognosis and reduced time to biochemical recurrence [28]. Contin- uous activation of the NF-jB pathway in vivo inhibits prostate regression following castration, maintains nuclear AR and sustains epithelial proliferation [28]. In human PCa cell lines, NF-jB signaling interferes with cell cycle arrest and apoptosis mediated by androgen deprivation and stimulates AR ligand independent transcriptional activity and recruitment of coactivators such as p300 [29]. Inter- estingly, processing the NF-jB family member p100 to produce p52 requires STAT3, a downstream signaling target of IL-6 and conversely IL-6 is a NF-jB target. Therefore, prostatitis and PCa associated inﬂammation likely aid in the development and progression of PCa by modulating AR function. 123 World J Urol (2012) 30:279–285 AR, reactive stroma, and PCa progression In the normal stroma, AR stimulates secretion of paracrine factors that regulate the proliferation and survival of the epithelium. The stromal compartment of the prostate undergoes signiﬁcant changes with PCa progression and both expansion and loss of the stroma signals poorer prognosis [30]. Recent studies indicate that reduced perit- umoral expression of stromal AR is associated with nega- tive clinical parameters and signiﬁcantly earlier relapse following radical prostatectomy [31]. Loss of stromal AR likely promotes cancer progression through deregulation of stromal factors required for normal growth and differenti- ation of the epithelium. In PCa, stroma often becomes reactive characterized by a reduction in well differentiated smooth muscle cells and increased deposition of extracel- lular matrix and collagen ﬁbrils. Patients who have more than 85% of intra-tumoral reactive stroma are at 17.13 times higher risk of biochemical recurrence [32]. Reactive stroma promotes invasion and metastasis of PCa. A number of stromal paracrine factors have been implicated in PCa, including transforming growth factor b (TGF-b), which is known to cross-talk with the AR. TGF-b and AR signaling cooperate to maintain the differentiated state of the stroma in the benign prostate. In the normal prostate, stromal TGF-b signaling is anti-proliferative, pro-apoptotic and enhances differentiation of the luminal epithelium. In malignant epithelial cells, AR suppresses TGF-b receptor II (TbR-II) transcription and reduces TGF-b1 driven apoptosis [33]. Furthermore, AR impedes TGF- b1 sig- naling in the epithelium through direct interaction and transcriptional suppression of SMAD3 [33]. These data suggest that AR action in malignant epithelial cells pro- vides a growth advantage by suppressing TGF mediated pathways. Therefore, androgen ablation therapies, which suppress epithelial AR mediate proliferation, also likely suppress beneﬁcial stromal AR activity and contribute to the progression and establishment of CRPC. Metastatic dissemination It is becoming evident that tumor dissemination occurs early in PCa development. The ﬁrst wave of cancer cell shedding occurs during primary tumor growth. The abun- dance of circulating tumor cells (CTC) is predictive of patient prognosis [34]. CTC analysis revealed that these cells have the same TMPSS2-ERG fusion status as primary tumor but increased heterogeneity of AR levels and PTEN loss [35], suggesting that these alterations may be sub- sequent to the fusion event. If indeed TMPRSS2-ERG fusion occurs early in tumorigenesis, its expression is then signiﬁcantly increased by AR signaling. Overexpression of