Developmental and Hormonal Regulation of Transforming Growth Factor-α and Epidermal Growth Factor Receptor Gene Expression in Isolated Prostatic Epithelial and Stromal Cells*

Itoh, Naoki; Patel, Urvashi; Skinner, Michael K.

doi:10.1210/endo.139.3.5821

Cited by 28 publications

(6 citation statements)

References 34 publications

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“…Amphiregulin (AREG)/EGFR was identified as the most significant autocrine ligand–receptor interaction in LSC med cells. AREG is one of the over-expressed genes of the LSC med cell signature [ 5 ], and the EGFR pathway has been reported to promote both prostatic cell proliferation [ 43 , 44 ] and stemness [ 45 , 46 , 47 ]. These findings support this pathway as a relevant autocrine regulator of LSC med cells in vivo.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells

Baurès

Lombardi

Martino

et al. 2022

Cancers

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Background: The molecular and cellular mechanisms that drive castration-resistant prostate cancer (CRPC) remain poorly understood. LSCmed cells defines an FACS-enriched population of castration-tolerant luminal progenitor cells that has been proposed to promote tumorigenesis and CRPC in Pten-deficient mice. The goals of this study were to assess the relevance of LSCmed cells through the analysis of their molecular proximity with luminal progenitor-like cell clusters identified by single-cell (sc)RNA-seq analyses of mouse and human prostates, and to investigate their regulation by in silico-predicted growth factors present in the prostatic microenvironment. Methods: Several bioinformatic pipelines were used for pan-transcriptomic analyses. LSCmed cells isolated by cell sorting from healthy and malignant mouse prostates were characterized using RT-qPCR, immunofluorescence and organoid assays. Results: LSCmed cells match (i) mouse luminal progenitor cell clusters identified in scRNA-seq analyses for which we provide a common 15-gene signature including the previously identified LSCmed marker Krt4, and (ii) Club/Hillock cells of the human prostate. This transcriptional overlap was maintained in cancer contexts. EGFR/ERBB4, IGF-1R and MET pathways were identified as autocrine/paracrine regulators of progenitor, proliferation and differentiation properties of LSCmed cells. The functional redundancy of these signaling pathways allows them to bypass the effect of receptor-targeted pharmacological inhibitors. Conclusions: Based on transcriptomic profile and pharmacological resistance to monotherapies that failed in CRPC patients, this study supports LSCmed cells as a relevant model to investigate the role of castration-tolerant progenitor cells in human prostate cancer progression.

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Section: Resultsmentioning

confidence: 99%

Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells

Baurès

Lombardi

Martino

et al. 2022

Cancers

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“…10). These genes included receptors, growth factors and extracellular matrix components that could be important to the cell-cell communication that is necessary for normal prostate function 18,20,21 (Fig. 9, Supplemental Tables S10 and S11).…”

Section: Discussionmentioning

confidence: 99%

“…In the current study, transgenerational changes to the epigenome of ventral prostate epithelial and stromal cells are characterized in F3 generation rats after ancestral vinclozolin exposure, compared to controls. Stromal-epithelial cell interactions are critical for normal prostate development and function, so abnormal interactions can lead to prostate diseases, including cancer 17–21 . The transgenerational epigenetic changes investigated in the current study involve changes to DNA methylation that have previously been associated with ancestral toxicant exposures in germ cells 22,23 and somatic cells 24,25 .…”

Section: Introductionmentioning

confidence: 99%

Environmental Toxicant Induced Epigenetic Transgenerational Inheritance of Prostate Pathology and Stromal-Epithelial Cell Epigenome and Transcriptome Alterations: Ancestral Origins of Prostate Disease

Klukovich

Nilsson

Sadler‐Riggleman

et al. 2019

Sci Rep

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Prostate diseases include prostate cancer, which is the second most common male neoplasia, and benign prostatic hyperplasia (BPH), which affects approximately 50% of men. The incidence of prostate disease is increasing, and some of this increase may be attributable to ancestral exposure to environmental toxicants and epigenetic transgenerational inheritance mechanisms. The goal of the current study was to determine the effects that exposure of gestating female rats to vinclozolin has on the epigenetic transgenerational inheritance of prostate disease, and to characterize by what molecular epigenetic mechanisms this has occurred. Gestating female rats (F0 generation) were exposed to vinclozolin during E8-E14 of gestation. F1 generation offspring were bred to produce the F2 generation, which were bred to produce the transgenerational F3 generation. The transgenerational F3 generation vinclozolin lineage males at 12 months of age had an increased incidence of prostate histopathology and abnormalities compared to the control lineage. Ventral prostate epithelial and stromal cells were isolated from F3 generation 20-day old rats, prior to the onset of pathology, and used to obtain DNA and RNA for analysis. Results indicate that there were transgenerational changes in gene expression, noncoding RNA expression, and DNA methylation in both cell types. Our results suggest that ancestral exposure to vinclozolin at a critical period of gestation induces the epigenetic transgenerational inheritance of prostate stromal and epithelial cell changes in both the epigenome and transcriptome that ultimately lead to prostate disease susceptibility and may serve as a source of the increased incidence of prostate pathology observed in recent years.

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“…Although androgen ablation isinitiallyasuccessfulantitumor treatment,prostatetumours usually,in time,overcome androgen blockadeand develop ahormone-unresponsivephenotype with resistancetotherapy.EGF and TGF-α arepotentmitogensplaying aregulatory roleinthe proliferation of prostatecancercells bothinprostategland (2,7,9) and in metastasestolymph nodes and medullary bone (24,46).Thus,EGF and TGF-α maypromoteprostatecellmetastasis (1,7,47,48). Consequently,interruption of receptor-linked proteintyrosinekinasesignalingcan beconsidered asapotentialstrategyforthe effectiveinhibition of tumour metastasis (49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

“…Prostatecarcinoma(PCa)i spredominantlyatumorof older men:itmaybesurgicallytreated and cured when localized;initiallyitisfrequentlyr esponsivetoanti-androgens.Epidermal growthf actor(EGF)and transforming growthf actor-alpha (TGF-α )h aveabout 35%sequenceh omologyand bind tothe same cellsurfacereceptors (1). EGF isgenerallys ecreted by bothnormaland malignantcells,while TGF-α ispredominantly produced byt umorcellst hrough autocrine mechanisms (2). EGFR(erbB-1) isa170 kDa trans-membrane phosphoglycoprotein overexpressed in severalsolid tumours,including prostate cancer (3)(4)(5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Epidermal growth factor modulates prostate cancer cell invasiveness regulating urokinase-type plasminogen activator activity

Festuccia

Angelucci²,

Gravina³

et al. 2005

Thromb Haemost

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Urokinase-type plasminogen activator receptor (uPAR) and Epidermal Growth Factor Receptor (EGFR) are ubiquitous receptors involved in the control of a variety of cellular processes frequently found altered in cancer cells. The EGFR has been recently described to play a transduction role of uPAR stimuli, mediating uPA-induced proliferation in highly malignant cells that overexpress uPAR. We compared the uPA production, the presence of uPAR, AR, EGFR and Her2 with the chemotaxis and the Matrigel invasion in ten human PCa cell lines and observed that: (1) the levels of Her2, but not of EGFR, as well as the uPA secretion, cell motility and Matrigel invasion were statistically higher in AR negative than in AR positive PCa cells; (2) the uPA secretion and uPA Rexpression were positively related to Matrigel invasion; (3) the EGF was able to stimulate chemotaxis and Matrigel invasion in a dose-dependent manner; (4) the EGF-induced cell migration was statistically higher inAR negative than in AR positive cells with a similar increase with respect to basal value (about 2.6 fold); (5) the Matrigel invasion was statistically higher in AR negative than in AR positive PCa cells also if the increment of Matrigel invasion after EGF treatment was statistically higher in AR positive respect to AR negative cells; (6) the EGF induced uPA secretion and its membrane uptake through the increment of uPAR; and (7) these effects were blocked by EGFR/Her2 tyrosine kinase inhibitors with IC(50) lower than those needed to inhibit cell proliferation and required PI3K/Akt, MAPK and PI-PLC activities as verified by inhibition experiments. These enzymatic activities were regulated in different manners in PTEN positive and negative cells. In fact, the inhibition of PI3K blocked the EGF-induced invasiveness in PTEN positive cells but not in PTEN negative cells, in which PI3K activity was not influenced by EGFR/Her2 activation, whereas the inhibition of MAPK was able to block the invasive phenomena in both cell types. Taken together, our data suggest that the blockade of EGFR could attenuate the invasive potential of PCa cells. In addition, considering that the EGFR expression is related to higher Gleason grade of PCa and that EGFR levels are increased after anti androgenic therapy, this therapeutic approach could slow down the metastasis formation which represents the most dramatic event of PCa progression.

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Developmental and Hormonal Regulation of Transforming Growth Factor-α and Epidermal Growth Factor Receptor Gene Expression in Isolated Prostatic Epithelial and Stromal Cells*

Cited by 28 publications

References 34 publications

Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells

Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells

Environmental Toxicant Induced Epigenetic Transgenerational Inheritance of Prostate Pathology and Stromal-Epithelial Cell Epigenome and Transcriptome Alterations: Ancestral Origins of Prostate Disease

Epidermal growth factor modulates prostate cancer cell invasiveness regulating urokinase-type plasminogen activator activity

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