The functional role of reactive stroma in benign prostatic hyperplasia

Abstract

The human prostate gland is one of the only internal organs that continue to enlarge throughout adulthood. The specific mechanisms that regulate this growth, as well as the pathological changes leading to the phenotype observed in the disease benign prostatic hyperplasia (BPH), are essentially unknown. Recent studies and their associated findings have made clear that many complex alterations occur, involving persistent and chronic inflammation, circulating hormonal level deregulation, and aberrant wound repair processes. BPH has been etiologically characterized as a progressive, albeit discontinuous, hyperplasia of both the glandular epithelial and stromal cell compartments coordinately yielding an expansion of the prostate gland and clinical symptoms. Interestingly, the inflammatory and repair responses observed in BPH are also key components of general wound repair in post-natal tissues. These responses include altered expression of chemokines, cytokines, matrix remodeling factors, chronic inflammatory processes, altered immune surveillance and recognition, as well as the formation of a prototypical ‘reactive’ stroma which is similar to that observed across various fibroplasias and malignancies of a variety of tissue sites. Stromal tissue, both embryonic mesenchyme, and adult reactive stroma myofibroblasts, has been shown to exert potent and functional regulatory control over epithelial proliferation and differentiation as well as immunoresponsive modulation. Thus, the functional biology of a reactive stroma, within the context of an adult disease typified by epithelial and stromal aberrant hyperplasia, is critical to understand within the context of prostate disease and beyond. The mechanisms that regulate reactive stroma biology in BPH represent targets of opportunity for new therapeutic approaches that may extend to other tissue contexts. Accordingly, this review seeks to address the dissection of important factors, signaling pathways, genes, and other regulatory components that mediate the interplay between epithelium and stromal responses in BPH.

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…Moreover, a recent in vivo wound healing study linked mechanical forces to inflammatory activation of fibroblasts via focal adhesion kinase (FAK), a transducer of both inflammatory and physical signals: In a mouse model of hypertrophic scar formation, fibroblast-specific knockdown of FAK resulted in reduced inflammation and fibrosis, compared with control mice [50]. While not involving cancer, these studies indicate that changes in tissue architecture as a result of aberrant epithelial proliferation, an early neoplastic response, may result in activation of inflammatory signalling by stromal fibroblasts, a hypothesis supported by reports of inflammatory signalling by stromal fibroblasts in benign prostatic hyperplasia [50][51][52][53]. Taken together, it is reasonable to hypothesize that biomechanical forces applied by aberrant proliferation of transformed epithelial cells in incipient tumours may be one of the physiological signals that trigger pro-inflammatory signalling in resident tissue fibroblasts.…”

Metabolic syndrome and lower urinary tract symptoms: the role of inflammation

“…23 It should be noted that the association between prostate volume and hypertension resulted very close to the level of MetS significance (HR ¼ 1.962, 95% confidence interval: 0.996-3.864, P ¼ 0.055, see Figure 3), suggesting that this component may be a potential contributor for the growth of prostate volume, as reported by other Authors. 5,21,23 A wealth of recent epidemiological and histopatological studies have clearly indicated that prostate chronic inflammation is not only a common finding in BPH, 24,25 but also has a primary role in triggering prostatic cells overgrowth. 26,27 Potential causes for inflammation and immune dysregulation in the prostate include exposure to dietary factors, and metabolic variations.…”

Antiinflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells

“…Chronic intraprostatic inflammation and subsequent chronic tissue remodeling are determinant factors in the development and progression of prostatic diseases, including BPH (see Kramer et al (2007), Fibbi et al (2010b) and Schauer & Rowley (2011) for reviews). A possible hormonal basis for prostate inflammation is suggested by preclinical studies in animal models, demonstrating that hypogonadism induced surgically (Robinette 1988, Desai et al 2004, Quintar et al 2006, Meng et al 2011 or by HFD administration ) exacerbate prostate inflammation and that exogenous testosterone can counteract this effect.…”

“…Although primarily characterized by hyperproliferation of both stromal and epithelial cells, a wealth of recent epidemiological and histopatological studies have clearly evidenced that chronic inflammation is a common finding in BPH (see Kramer et al (2007), Fibbi et al (2010b) and Schauer & Rowley (2011) for reviews). Data from two large-scale studies have indicated that chronic inflammatory infiltrates are associated with higher prostatic volume, a higher risk of BPH progression, and acute urinary retention , Nickel et al 2007.…”

“…From a pathophysiological standpoint, these data suggest that chronic inflammation could have a causative effect on BPH/LUTS, rather than merely occurring in response to tissue remodeling. Accordingly, infiltration of chronically activated CD4 C T lymphocytes and secretion of inflammatory cytokines within the prostatic gland are considered a determinant factor in BPH pathogenesis (see Kramer et al (2007), Fibbi et al (2010b) and Schauer & Rowley (2011) for reviews).…”