The Effects of Aging on the Molecular and Cellular Composition of the Prostate Microenvironment

Abstract

BackgroundAdvancing age is associated with substantial increases in the incidence rates of common diseases affecting the prostate gland including benign prostatic hyperplasia (BPH) and prostate carcinoma. The prostate is comprised of a functional secretory epithelium, a basal epithelium, and a supporting stroma comprised of structural elements, and a spectrum of cell types that includes smooth muscle cells, fibroblasts, and inflammatory cells. As reciprocal interactions between epithelium and stromal constituents are essential for normal organogenesis and serve to maintain normal functions, discordance within the stroma could permit or promote disease processes. In this study we sought to identify aging-associated alterations in the mouse prostate microenvironment that could influence pathology.Methodology/Principal FindingsWe quantitated transcript levels in microdissected glandular-adjacent stroma from young (age 4 months) and old (age 20–24 months) C57BL/6 mice, and identified a significant change in the expression of 1259 genes (p<0.05). These included increases in transcripts encoding proteins associated with inflammation (e.g., Ccl8, Ccl12), genotoxic/oxidative stress (e.g., Apod, Serpinb5) and other paracrine-acting effects (e.g., Cyr61). The expression of several collagen genes (e.g., Col1a1 and Col3a1) exhibited age-associated declines. By histology, immunofluorescence, and electron microscopy we determined that the collagen matrix is abundant and disorganized, smooth muscle cell orientation is disordered, and inflammatory infiltrates are significantly increased, and are comprised of macrophages, T cells and, to a lesser extent, B cells.Conclusion/SignificanceThese findings demonstrate that during normal aging the prostate stroma exhibits phenotypic and molecular characteristics plausibly contributing to the striking age associated pathologies affecting the prostate.

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.…”

Adiponectin inhibits oxidative stress in human prostate carcinoma cells

“…It is caused by an imbalance between the production of reactive oxygen species (ROS) and their detoxification by enzymes, such as catalase and manganese superoxide dismutase (MnSOD). OS related to age, 15 inflammation and nutrition, 16 as well as exposure to androgens, 17 leads to pro-carcinogenic events, in particular accumulation of oxidative DNA damage. Likewise, it has been suggested that compared with normal subjects or patients with BPH, PC patients have a systemic imbalance in their OS/anti-oxidant status.…”

Increased Infiltrated Macrophages in Benign Prostatic Hyperplasia (BPH)

“…Bianchi-Frias et al quantified transcription levels in microdissected glandular-adjacent stroma from young (age 4 months) and old (age 20 -24 months) C57BL/6 mice, and identified macrophages, as well as inflammation-associated genes CCL8, CCL12, CCL5, and CCL7, were significantly increased in the aged prostatic stroma (45), suggesting that macrophages could play an important role in promoting chemokine induction and prostatic stroma expansion.…”