Immunohistochemical determination of age related proliferation rates in normal and benign hyperplastic human prostates

Claus, Siegfried; Wrenger, M.; Senge, Theodor; Schulze, Harald

doi:10.1007/bf00296825

Cited by 39 publications

(21 citation statements)

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“…Expansion of the stromal compartment can occur in BPH [Claus et al, 1993] and growth of a prostatic adenoma has been proposed to be the result of aberrant expression or activity of unknown prostatic growth factors [McKeehan, 1991;Cunha, 1994;Freeman et al, 1996]. An interesting possibility is that HB-EGF plays a role in hyperplastic growth of interstitial smooth muscle and undifferentiated fibroblasts.…”

Section: Discussionmentioning

confidence: 97%

Heparin-binding EGF-like growth factor in the human prostate: Synthesis predominantly by interstitial and vascular smooth muscle cells and action as a carcinoma cell mitogen

et al. 1998

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Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an activating ligand for the EGF receptor (HER1/ErbB1) and the high-affinity receptor for diphtheria toxin (DT) in its transmembrane form (proHB-EGF). HB-EGF was immunolocalized within human benign and malignant prostatic tissues, using monospecific antibodies directed against the mature protein and against the cytoplasmic domain of proHB-EGF. Prostate carcinoma cells, normal glandular epithelial cells, undifferentiated fibroblasts, and inflammatory cells were not decorated by the anti-HB-EGF antibodies; however, interstitial and vascular smooth muscle cells were highly reactive, indicating that the smooth muscle compartments are the major sites of synthesis and localization of HB-EGF within the prostate. In marked contrast to prostatic epithelium, proHB-EGF was immunolocalized to seminal vesicle epithelium, indicating differential regulation of HB-EGF synthesis within various epithelia of the reproductive tract. HB-EGF was not overexpressed in this series of cancer tissues, in comparison to the benign tissues. In experiments with LNCaP human prostate carcinoma cells, HB-EGF was similar in potency to epidermal growth factor (EGF) in stimulating cell growth. Exogenous HB-EGF and EGF each activated HER1 and HER3 receptor tyrosine kinases and induced tyrosine phosphorylation of cellular proteins to a similar extent. LNCaP cells expressed detectable but low levels of HB-EGF mRNA; however, proHB-EGF was detected at the cell surface indirectly by demonstration of specific sensitivity to DT. HB-EGF is the first HER1 ligand to be identified predominantly as a smooth muscle cell product in the human prostate. Further, the observation that HB-EGF is similar to EGF in mitogenic potency for human prostate carcinoma cells suggests that it may be one of the hypothesized stromal mediators of prostate cancer growth.

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Section: Discussionmentioning

confidence: 97%

Heparin-binding EGF-like growth factor in the human prostate: Synthesis predominantly by interstitial and vascular smooth muscle cells and action as a carcinoma cell mitogen

et al. 1998

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“…Over the years, the question of whether or not proliferation plays the main role in the development of BPH has been raised. Claus et al (20) reported that enlargement of the prostate was associated with an increase of its weight, but that there was no significant correlation between proliferation rate and prostate weight. In the present study, we observed some proliferation in the prostatic epithelium but none in the stroma in BPH tissue.…”

Section: Discussionmentioning

confidence: 99%

A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia

Alonso-Magdalena

Brössner

Reiner

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

149

127

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Benign prostatic hyperplasia (BPH) is usually described as a pathological proliferation of prostatic fibroblasts/myofibroblasts and epithelial cells. In the present study of BPH samples, we have made a morphological and immunohistochemical study of BPH prostatic sections using markers of proliferation, apoptosis, hormone receptors, and TGF-␤ signaling. We found no evidence of proliferation in the stroma but in the epithelium of some ducts; 0.7% of the basal and 0.4% of luminal cells were positive for Ki67 and PCNA. Androgen receptor and estrogen receptor beta (ER␤)1 and ER␤cx were abundant in both stromal and epithelial compartments but cells expressing ER␣ were very rare. What was very common in all BPH samples was the following: (i) regions of the ductal epithelium where the epithelial cells did not express E-cadherin, had lost their polarization, and become spindle shaped (the nuclei of these cells were strongly positive for pSmad 3 and Snail); and (ii) regions where the walls of the blood vessels were extremely thick and there was loss of endothelial layer. Loss of E-cadherin, increased pSmad 3, and high expression of Snail are all characteristic of epithelial-mesenchymal transition (EMT). We conclude that BPH is not a disease of prostatic stromal proliferation but rather of accumulation of mesenchymal-like cells derived from the prostatic epithelium and the endothelium. TGF-␤ is thought to play a key role in EMT. Our data suggests that TGF-␤/Smad should be considered as targets for treatment of BPH.proliferation ͉ TGF beta signaling

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“…The volume of the transition zone can nearly double by age 55–60 [2, 6]. Cell proliferation is greatly elevated in BPH compared to normal equivalent tissue regions: epithelial cell proliferation was 9-fold higher, while stromal cell proliferation was 37-fold higher, in a retrospective study [10]. Prostate epithelial proliferation results in enlarged glandular nodules (Figure 2), whereas stromal proliferation produces a more diffuse hyperplasia with elevated matrix production, such as collagen type I [11], typical of a pro-fibrotic lesion.…”

Section: Benign Prostatic Hyperplasia and The Reactive Phenotypementioning

confidence: 99%

The functional role of reactive stroma in benign prostatic hyperplasia

2011

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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.

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Immunohistochemical determination of age related proliferation rates in normal and benign hyperplastic human prostates

Cited by 39 publications

References 13 publications

Heparin-binding EGF-like growth factor in the human prostate: Synthesis predominantly by interstitial and vascular smooth muscle cells and action as a carcinoma cell mitogen

Heparin-binding EGF-like growth factor in the human prostate: Synthesis predominantly by interstitial and vascular smooth muscle cells and action as a carcinoma cell mitogen

A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia

The functional role of reactive stroma in benign prostatic hyperplasia

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