The inflammatory microenvironment of the aging prostate facilitates cellular proliferation and hypertrophy

Abstract

Benign Prostatic Hypertrophy (BPH, also known as benign prostatic hyperplasia or benign prostatic enlargement), is one of the most common benign proliferative conditions associated with aging in men and is pathologically characterized by the proliferation of fibroblast/myofibroblast and epithelial cell types in the prostate. Previous studies from our laboratory have shown that the CXC-type chemokines, CXCL5 and CXCL12, are secreted by aging prostate stroma and promotes both proliferative and transcriptional responses from prostate epithelial cells. Using array-based gene expression profiling and quantitative reverse-transcriptase polymerase chain reaction, we now show that the transcriptome of the aging prostate stroma is characterized by the up-regulation of several genes that encode secreted inflammatory mediators, including secreted CXC-type chemokines (CXCL1, CXCL2, CXCL5, CXCL6, CXCL12), interleukins (IL11, IL33), and transcripts with cytokine homology (CYTL1). At the protein level, ELISA experiments demonstrated that CXCL1, CXCL5, and CXCL6 were secreted by primary prostate stromal fibroblasts explanted from aging prostate stroma. Dose-response assays confirmed that, like CXCL5 and CXCL12, CXCL1 and CXCL6 promote low-level proliferative responses from both prostate stromal fibroblasts and epithelial cells. Taken together, these data suggest that inflammatory mediators are secreted by prostatic stroma consequent to aging, that the levels of these mediators are sufficient to promote lowlevel increases in the proliferative rate of both epithelial and stromal fibroblast cell types. Moreover, these processes may account for the low-level, but cumulative, proliferation of both epithelial and fibroblastic/myofibroblastic cell types that characterizes the aging-associated development of benign prostatic hypertophy.

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.…”

“…Similarly, prostate fibroblasts in benign prostatic hyperplasia secrete cytokines and chemokines that support an inflammatory proliferative microenvironment [52]. At more advanced tumourigenic stages, CAFs facilitate trafficking of myeloid cells into metastasizing tumours: in a mammary carcinoma model of pulmonary metastasis, stromal-derived CCL2 recruits CD11b + Gr1 + Ly6c + inflammatory monocytes that support pulmonary metastasis [69].…”

“…Accumulation of senescent fibroblasts in tumours may be a result of the accelerated proliferation of CAFs or a response to extrinsic genotoxic stress caused by oxidative stress and high glucose in the tumour microenvironment [88]. In addition, increased presence of senescent fibroblasts in tumours may also be part of normal ageing of the tissue where tumourigenesis occurs [52]. While these senescent fibroblasts may be a minority in the tumour milieu, the acquisition of a senescence-associated secretory phenotype is another mechanism that turns fibroblasts into proinflammatory cells that have the ability to promote tumour progression.…”

Cytokine-like 1 Chemoattracts Monocytes/Macrophages via CCR2

“…CYTL1 expression was reportedly also significantly positively correlated with perfluoroalkyl and polyfluoroalkyl substances (16). Moreover, the aging prostate showed upregulation of CYTL1 and several inflammatory mediators (17).…”

Cancer Associated Fibroblasts Exploit Reactive Oxygen Species Through a Proinflammatory Signature Leading to Epithelial Mesenchymal Transition and Stemness

“…This complex communications network is pivotal to providing the appropriate microenvironment to support tumorigenesis, angiogenesis, and metastasis. Normal fibroblasts play a helpful role in maintaining epithelial homeostasis by suppressing proliferation of adjacent epithelia (2,3,43). After epithelial neoplastic transformation, CAFs undergo profound changes, promote tumor growth, induce angiogenesis, and recruit bone marrow-derived endothelial progenitor cells (1,30,31).…”