In vitro modelling of epithelial and stromal interactions in non-malignant and malignant prostates

Lang, Shona; Stower, Michael J.; Maitland, Norman J.

doi:10.1054/bjoc.1999.1029

Cited by 49 publications

(39 citation statements)

References 21 publications

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“…This invasive phenotype can be further augmented in the presence of stromal cells as a consequence of their high ECE-1 expression and ET-1 availability to the tumour. The role of stromal involvement during PC progression has been reported elsewhere (Lang et al, 2000), and this is consistent with recent observations that epithelial -stromal interactions are critical determinants of tumour cell behaviour. Ramaswamy et al (2003) compared the geneexpression profiles of metastatic adenocarcinomas with their primary counterparts and found that a considerable proportion of the refined geneexpression signature associated with metastasis was derived from the nonepithelial components of the tumour.…”

Section: Discussionsupporting

confidence: 91%

“…The invasion assay was performed essentially as described by Lang et al (2000). The following supplements were added, either alone or in combination, to both STO (stromal) cell (bottom well) and epithelial cell (top well) media: NEP (50 mg ml À1 ), thiorphan (1 mM), bradykinin (100 nM), ET-1 (10 nM) and the specific ECE inhibitor ECE-i (100 nM).…”

Section: Invasion Assaymentioning

confidence: 99%

“…More recently, studies have begun to document changes in the stromal environment surrounding the tumour ('reactive stroma') and its importance in promoting invasion, progression and metastasis (Tuxhorn et al, 2001). Human cancers have been found to generate a reactive stroma, which can promote tumorigenesis and influence epithelial cell invasion during in vitro modelling of prostate cancer invasion (Lang et al, 2000). Stromal cells derived from malignant prostate tissue can provide a greater stimulus for tumour cell invasion than their nonmalignant counterparts, but nonmalignant stromal cells can also influence the development and rate of human prostate tumorigenesis in mouse xenograft models (Tuxhorn et al, 2002).…”

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confidence: 99%

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Stromal–epithelial interactions influence prostate cancer cell invasion by altering the balance of metallopeptidase expression

et al. 2004

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Perturbations of stromal -epithelial interactions in the developing tumour can contribute to cancer invasion and metastasis. The structurally related metallopeptidases endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP) contribute sequentially to the synthesis and inactivation of ET-1, a mitogenic peptide that has been shown to affect tumour behaviour. This study has investigated the interaction between metastatic tumour epithelial cells, which lack NEP, and stromal cells, which we have shown to express ECE-1 (stromal -epithelial interactions), using Matrigel invasion chambers. The epithelial cell lines utilised in this study include androgen-sensitive LNCaP, androgen-independent PC-3, Du145 and recently established PNT-1a, PNT2-C2 and P4E6 prostate cell lines. Specific inhibition of endogenous ECE-1 activity in stromal cells reduced PC-3 and Du145 invasion by 70 and 50%, respectively. Addition of recombinant NEP to inactivate endogenous mitogenic peptides resulted in 50 and 20% reductions in invasion in PC-3 and Du145 cells, respectively. Neutral endopeptidase effects were reversed in the presence of thiorphan, a specific NEP inhibitor. Supplementation of defined media with bradykinin and ET-1 significantly increased PC-3 invasion by 40 and 50%, respectively. Du145 cell invasion increased by approximately 100% on adding ET-1. These studies implicate the metallopeptidases NEP and ECE-1 as mediators of prostate cancer invasion via a stromal/epithelial interaction.

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Section: Discussionsupporting

confidence: 91%

Section: Invasion Assaymentioning

confidence: 99%

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confidence: 99%

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Stromal–epithelial interactions influence prostate cancer cell invasion by altering the balance of metallopeptidase expression

et al. 2004

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“…The PC-3 cell line and cells derived from patients with CaP showed colonies and cells which appeared spiky and scattered whilst the PNT2-C2 cell line and cells derived from patients with BPH showed rounded colonies. This confirmed findings previously reported (Lang et al, 2000) which suggests a more motile and invasive nature of PC-3 and CaP derived epithelial cells. Regarding proteolytic enzyme production in BMS co-culture, we found that when cells derived from patients with CaP were grown in BMS co-culture, not only were the epithelial cells strongly stained for MMP-1, the stromal cells around the leading edge of the colony were also strongly positive.…”

Section: Discussionsupporting

confidence: 92%

Role of proteolytic enzymes in human prostate bone metastasis formation: in vivo and in vitro studies

et al. 2002

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Prostate cancers ability to invade and grow in bone marrow stroma is thought to be due in part to degradative enzymes. The formation of prostate skeletal metastases have been reproduced in vitro by growing co-cultures of prostatic epithelial cells in bone marrow stroma. Expression of urokinase plasminogen activator, matrix metalloproteinase 1 and 7 by prostatic epithelial cells were identified using immunocytochemistry. Also, in vivo tissue sections from human prostatic bone marrow metastases were stained. To establish the role of these enzymes on colony formation, inhibitory antibodies directed against urokinase plasminogen activator, matrix metalloproteinase 1 and matrix metalloproteinase 7 were added into primary prostatic epithelial cells and bone marrow stroma co-cultures. All prostatic epithelial cell cultures stained positively for matrix metalloproteinase 1, matrix metalloproteinase 7 and urokinase plasminogen activator. Generally prostatic epithelial cells derived from malignant tissues showed increased staining in comparison to epithelia derived from non-malignant tissue. In agreement with in vitro cocultures, the in vivo tissue sections of prostate bone marrow metastases showed positive staining for all three enzymes. Inhibition studies demonstrated that blocking matrix metalloproteinase 1, matrix metalloproteinase 7 and urokinase plasminogen activator function reduced the median epithelial colony area significantly in bone marrow stroma co-cultures in vitro. Using a human ex-vivo model we have shown that matrix metalloproteinase 1, matrix metalloproteinase 7 and urokinase plasminogen activator play an important role in the establishment of prostatic epithelial cells within bone marrow.

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“…12,13 Many research groups have also shown that a dynamic stromal-epithelial interaction plays a critical role in the progression and metastasis of PCa. [14][15][16][17][18][19][20] Growth factors play a central role in mediating the interactions between epithelial and stromal cells. 21 The stromal-epithelial interaction is also critical for mediating the effects of these molecules on epithelial cells.…”

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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In vitro modelling of epithelial and stromal interactions in non-malignant and malignant prostates

Cited by 49 publications

References 21 publications

Stromal–epithelial interactions influence prostate cancer cell invasion by altering the balance of metallopeptidase expression

Stromal–epithelial interactions influence prostate cancer cell invasion by altering the balance of metallopeptidase expression

Role of proteolytic enzymes in human prostate bone metastasis formation: in vivo and in vitro studies

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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