Aberrant Transforming Growth Factor-β Activation Recruits Mesenchymal Stem Cells During Prostatic Hyperplasia

Abstract

Benign prostatic hyperplasia (BPH) is the overgrowth of prostate tissues with high prevalence in older men. BPH pathogenesis is not completely understood, but it is believed to be a result of de novo overgrowth of prostatic stroma. In this study, we show that aberrant activation of transforming growth factor‐β (TGF‐β) mobilizes mesenchymal/stromal stem cells (MSCs) in circulating blood, which are recruited for the prostatic stromal hyperplasia. Elevated levels of active TGF‐β were observed in both a phenylephrine‐induced prostatic hyperplasia mouse model and human BPH tissues. Nestin lineage tracing revealed that 39.6% ± 6.3% of fibroblasts and 73.3% ± 4.2% smooth muscle cells were derived from nestin+ cells in Nestin‐Cre, Rosa26‐YFPflox/+mice. Nestin+ MSCs were increased in the prostatic hyperplasia mice. Our parabiosis experiment demonstrate that nestin+ MSCs were mobilized and recruited to the prostatic stroma of wild‐type mice and gave rise to the fibroblasts. Moreover, injection of a TGF‐β neutralizing antibody (1D11) inhibits mobilization of MSCs, their recruitment to the prostatic stroma and hyperplasia. Importantly, knockout of TβRII in nestin+ cell lineage ameliorated stromal hyperplasia. Thus, elevated levels of TGF‐β‐induced mobilization and recruitment of MSCs to the reactive stroma resulting in overgrowth of prostate tissues in BPH and, thus, inhibition of TGF‐β activity could be a potential therapy for BPH. Stem Cells Translational Medicine 2017;6:394–404

Tumor‐infiltrating mesenchymal stem cells: Drivers of the immunosuppressive tumor microenvironment in prostate cancer?

“…Based upon these analytical and functional characteristics (Figure ), MSCs have been identified in radical prostatectomy tissue from men with prostate cancer in a systematic analysis of benign and malignant prostate tissue obtained from multiple donors representing different disease states and a wide range of age groups, from fetal development through adult death . Our group and others have demonstrated the in vivo recruitment of MSCs to prostate tissue from systemic sources using a variety of independent techniques, including transgenic chimeras, in vivo cell tracking methodologies, and tissue recombination models . This raises the question of whether MSCs are contributing to prostate cancer progression.…”

Targeting phenotypic heterogeneity in benign prostatic hyperplasia

“…Recent evidence suggests the presence of at least 4 different stromal cell types in the prostate (85). The contribution of each of these indigenous cell types to stromal hyperplasia is poorly understood, as is the contribution of mesenchymal stem cells recruited from outside the prostate (86). The different types of prostatic hyperplasia (i.e.…”

Association of anti‐inflammatory and antiangiogenic therapies negatively influences prostate cancer progression in TRAMP mice

“…TGF‐β is known as the main inducer of CAF/myofibroblast differentiation during reactive stroma development . Different authors also reported that TGF‐β regulates reactive stroma phenotype through angiogenesis induction, promoting vessel formation, tumor growth, and cancer progression .…”

“…62 TGF-β is known as the main inducer of CAF/myofibroblast differentiation during reactive stroma development. 15,82 Different authors also reported that TGF-β regulates reactive stroma phenotype through angiogenesis induction, promoting vessel formation, tumor growth, and cancer progression. 16,83,84 Thus, we hypothesized that an angiokinase inhibitor, such as nintedanib, would hamper TGF-β actions during stromal reaction.…”