Role of stroma in carcinogenesis of the prostate

Cunha, Gerald R.; Hayward, Simon W.; Wang, Y. Z.

doi:10.1046/j.1432-0436.2002.700902.x

Cited by 262 publications

(232 citation statements)

References 92 publications

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“…Therefore, they represent a model useful for the analysis of receptor antagonist action independently of the receptor transcriptional activity. We are additionally interested in these cells since stromal cells, through a cross talk with epithelial cells, have a role in the development and carcinogenesis of both the prostate and the mammary gland (Coussens and Werb, 2002;Cunha et al, 2002). For this reason, interference of the inhibitory peptide in AR/Src complex assembled upon androgen or growth factor stimulation of fibroblasts might also affect the interactions between stromal and epithelial cells, and in such a way contribute to slow down cancer growth.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth

et al. 2007

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In human mammary and prostate cancer cells, steroid hormones or epidermal growth factor (EGF) trigger association of the androgen receptor (AR)-estradiol receptor (ER) (a or b) complex with Src. This interaction activates Src and affects the G1 to S cell cycle progression. In this report, we identify the sequence responsible for the AR/Src interaction and describe a 10 amino-acid peptide that inhibits this interaction. Treatment of the human prostate or mammary cancer cells (LNCaP or MCF-7, respectively) with nanomolar concentrations of this peptide inhibits the androgen-or estradiol-induced association between the AR or the ER and Src the Src/Erk pathway activation, cyclin D1 expression and DNA synthesis, without interfering in the receptor-dependent transcriptional activity. Similarly, the peptide prevents the S phase entry of LNCaP and MCF-7 cells treated with EGF as well as mouse embryo fibroblasts stimulated with androgen or EGF. Interestingly, the peptide does not inhibit the S phase entry and cytoskeletal changes induced by EGF or serum treatment of AR-negative prostate cancer cell lines. The peptide is the first example of a specific inhibitor of steroid receptordependent signal transducing activity. The importance of these results is highlighted by the finding that the peptide strongly inhibits the growth of LNCaP xenografts established in nude mice.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth

et al. 2007

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“…Stromal cells can affect BPH progression by regulating epithelial proliferation, apoptosis, and angiogenesis. 48,49 This mutual cross talk is mediated by cell surface protein, extracellular matrix, and soluble factors. 19,50 Aging and androgens are the two established risk factors for development of BPH.…”

Section: Discussionmentioning

confidence: 99%

Stromally Expressed c-Jun Regulates Proliferation of Prostate Epithelial Cells

Febbo

et al. 2007

The American Journal of Pathology

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Stromal-epithelial interactions play a critical role inBenign prostatic hyperplasia (BPH) is the most common age-related proliferative abnormality of the human prostate affecting elderly men throughout the world. Half of all men have BPH identifiable histologically by age 60, and by age 85 the prevalence is ϳ90%. 1 The excessive cell proliferation associated with BPH causes benign prostatic enlargement, bladder outlet obstruction, and lower urinary tract symptoms, which afflict the patients. 2 BPH is a histological diagnosis associated with both epithelial and stromal (fibroblasts and smooth muscle cells of prostate) hyperplasia. 3 Cellular alterations that include changes in proliferation, differentiation, apoptosis, and senescence in the epithelium and stroma are implicated in the pathogenesis of BPH. Medical treatments available to patients with BPH target both prostatic stromal and epithelial cells.Watchful waiting, pharmacological therapy, and surgery are three treatment modalities for BPH patients. Medical therapy is a long-term commitment for the patient. Surveys show that a large number of patients discontinue therapy, often because they perceive lack of efficacy and/or experience side effects. 4,5 We can accordingly improve our treatment of BPH by better targeted medical therapy to decrease the number of invasive therapies for this benign disease. Better alternative and improved therapies can be achieved by studying the normal and abnormal reciprocal cross talk between prostatic stromal and epithelial cells.Stromal-epithelial interactions play a critical role in the development and growth of the prostate gland and BPH. Cunha and colleagues 6 -8 have demonstrated that the stromal embryonic tissue is responsible for instructing the proper development of prostate epithelial cells. Tissue recombinants between embryonic urogenital sinus mesenchyme and adult prostatic tissue have demonstrated that the fetal mesenchyme can drive differentiation and growth of adult prostatic epithelial cells. 9 It has been proposed that BPH may be caused by reactivation of dormant embryonic growth in the adult stroma. 10 The proliferation of the stromal elements can stimulate the ingrowth of epithelial cells to produce a benign hyperplastic growth that is recognized

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“…Prostatic epithelial cells are dependent on androgen-responsive stromal cells for development, differentiation and survival. 11 Thus, alterations in the stromal microenvironment are sufficient to promote malignant transformation of human prostatic epithelial cells. When the non-tumourigenic human prostatic epithelial cell line BPH-1 was recombined with urogenital sinus mesenchyme (UGM) or stromal cells from PCa, BPH-1 cells were induced to undergo malignant transformation.…”

Section: Introductionmentioning

confidence: 99%

The differential effects of prostate stromal cells derived from different zones on prostate cancer epithelial cells under the action of sex hormones

Jiang

Han²,

Zhao³

et al. 2011

Asian J Androl

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It is well known that prostate cancer (PCa) occurs predominantly in the peripheral zone (PZ), whereas benign prostatic hyperplasia (BPH) typically develops in the transition zone. To identify possible mechanisms underlying zonal differences, we compared the effects of prostate stromal cells derived from the peripheral zone (PZsc) and the transition zone (TZsc) on a PCa epithelial cell line (PC3) in the presence of sex hormones. First, we observed that androgen receptor (AR) mRNA was more highly expressed in PZsc than TZsc when the cells were treated with dihydrotestosterone (DHT) and b-oestradiol (E2) (P,0.05). By ELISA, we looked for differences in the secretion of peptide growth factors from PZsc and TZsc. We found that keratinocyte growth factor (KGF) secretion increased with increasing concentrations of DHT (P,0.01) and was higher in PZsc than TZsc. Under treatment with DHT plus E2, PZsc secreted more transforming growth factor-b1 (TGF-b1) than TZsc, but this pattern was reversed when the cells were treated with E2 only. With increasing concentrations of DHT, insulin-like growth factor-1 (IGF-1) secretion increased in PZsc but decreased in TZsc. To further characterize the effects of PZsc and TZsc on PC3 cells, we developed a coculture model and performed MTT assays, Western blot analysis and real-time RT-PCR. We found that PZsc promoted PC3 cell proliferation and progression better than TZsc, particularly when treated with 10 nmol l 21 DHT plus 10 nmol l 21 E2. In conclusion, our data suggest that PZsc may have a greater capacity to induce PCa development and progression than TZsc via growth factors regulated by sex hormones. These findings provide possible mechanisms underlying zonal differences in prostate diseases, which may aid the search for novel therapeutic targets for PCa.

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Role of stroma in carcinogenesis of the prostate

Cited by 262 publications

References 92 publications

Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth

Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth

Stromally Expressed c-Jun Regulates Proliferation of Prostate Epithelial Cells

The differential effects of prostate stromal cells derived from different zones on prostate cancer epithelial cells under the action of sex hormones

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