Putative prognostic epithelial-to-mesenchymal transition biomarkers for aggressive prostate cancer

Whiteland, Helen; Spencer-Harty, Samantha; Thomas, Daniel W.; Davies, Christopher; Morgan, Claire; Kynaston, Howard; Bose, P.; Fenn, Neil; Lewis, Paul D.; Bodger, Owen; Jenkins, S. A.; Doak, Shareen H.

doi:10.1016/j.yexmp.2013.07.010

Cited by 29 publications

(29 citation statements)

References 28 publications

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“…Furthermore, aberrant E-cadherin was significantly associated with advanced tumor stage, LN metastasis, and distant metastasis; therefore with poor prognosis. these results are hand in hand with Whiteland et al (25). Meng et al also reported that PC metastasis was inhibited in mice that received a high dose of zileuton, 5-lipoxygenase inhibitor, which restored normal expression of E-cadherin (31).…”

Section: Discussionmentioning

confidence: 53%

“…Moreover, aberrant E-cadherin expression of PC cases revealed shorter BPFS and therefore poor prognosis. these results are hand in hand with other investigators (22,25). Whiteland et al demonstrated that reduced E-Cadherin expression was linked to worse prognosis and poor diseasefree survival, where E-cadherin was the only EMt marker significantly associated with patients who died as a result of PC progression when its expression was lost (25).…”

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confidence: 60%

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Prognostic value of twist-1, e-cadherin and ezh2 in prostate cancer: an immunohistochemical study

Abdelrahman

Arafa²,

Ahmed³

2017

TJPATH

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Objective: there is an urgent need to identify molecular biomarkers rather than clinical markers to distinguish aggressive prostate cancer from the indolent majority for proper treatment and accurate prediction of prognosis. We aimed to investigate the immunohistochemical expression of epithelial-mesenchymal transition (EMt)-related molecules (twist-1 and E-cadherin) and the stem cell marker EZH2 in prostate cancer and to assess their ability to identify the high-risk patients, in a trial to explore their prognostic implications. Material and Method:Immunohistochemical expression of twist-1, E-cadherin and EZH2 in 50 specimens of prostate cancer and 20 cases of benign prostatic hyperplasia were studied. the relationship between their expression and the clinicopathological variables, biochemical recurrence, and biochemical progression-free survival were investigated. Results:Our results revealed that high twist-1, as well as high EZH2 expression, was strongly associated with higher pre-treatment PSa level, gleason score ≥7, advanced tumor stage, lymph node involvement, distant metastasis and biochemical progression. aberrant E-cadherin expression was significantly associated with higher pre-treatment PSa level, gleason score ≥7, advanced tumor stage, lymph node involvement, and distant metastasis. a significant positive correlation between twist-1 and EZH2 expression was found (p<0.001), while E-cadherin expression showed a negative correlation with both markers (p<0.001). a significant association was found between high twist-1, high EZH2& aberrant E-cadherin expression, and shorter biochemical progression-free survival.Conclusion: the high twist-1 expression, aberrant E-cadherin and high EZH2 expression in primary prostate cancer are considered as adverse prognostic markers of an aggressive tumor with high metastatic potential. assessment of their expression level would contribute to the accurate prediction of biochemical progression.

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Section: Discussionmentioning

confidence: 53%

mentioning

confidence: 60%

Prognostic value of twist-1, e-cadherin and ezh2 in prostate cancer: an immunohistochemical study

Abdelrahman

Arafa²,

Ahmed³

2017

TJPATH

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“…En el CaP se ha reportado asociación entre tumores con bajo índice de Gleason y patrón normal de Ecadherina, y su expresión reducida en tumores avanzados y con alto índice de Gleason, por lo que se la propone como un posible indicador de pronóstico (19,31,32,38). En estos tumores, a semejanza de lo observado en algunos procesos de desarrollo, hay neoexpresión de N-cadherina y expresión aberrante de otros tipos de cadherinas, lo que se asocia con mayor capacidad de invasión, debido a que las interacciones homotípicas entre N-cadherinas son más débiles que las interacciones entre E-cadherinas (15,16,33).…”

Section: Expresión De E-cadherina Y Transición Epitelial-mesenquimalunclassified

“…Este además participa en la inducción de la EMT en respuesta a la hipoxia (48,49). También se ha encontrado sobreexpresión de Snail en el CaP, con aumento progresivo desde el tejido benigno hasta las metástasis, asociado con índice alto de Gleason y mal pronóstico (29,32,50).…”

Section: Figura 3 Regulación Transcripcional Y Mecanismos Moleculareunclassified

“…Otros informan diferencia en el patrón de expresión de E-cadherina entre las micro y macrometástasis ganglionares lo cual puede ser evidencia del proceso de MET previamente descrito, indicando un mayor potencial metastásico, de modo que la evaluación de su expresión tendría implicaciones terapéuticas potenciales (71). También se ha informado pérdida de E-cadherina, aumento de Snail en el núcleo y sobreexpresión de vimentina en el citoplasma de las células tumorales, asociados con alto índice de Gleason y mal pronóstico; sin embargo, solo E-cadherina estuvo asociada con muerte por CaP (32). Otro trabajo reciente halló disminución significativa de la expresión de E-cadherina en el CaP comparado con el tejido adyacente, principalmente en el citoplasma, y se ha planteado la inhibición de la formación del complejo E-cadherina/β-catenina.…”

Section: Aplicación Clínicaunclassified

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Transición epitelial-mesenquimal en la progresión del adenocarcinoma prostático

Benedetti

Reyes

2015

iatreia

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RESUMENMundialmente, el adenocarcinoma prostático es el segundo cáncer diagnosticado en hombres y las metástasis son su principal complicación; se ha descrito la participación en su desarrollo de la transición epitelial-mesenquimal (TEM) proceso fundamental durante el desarrollo embrionario, la remodelación tisular y la cicatrización, que implica pérdida de las propiedades adhesivas y la polaridad epitelial y adquisición del fenotipo mesenquimal que aumenta la movilidad celular individual y permite el desarrollo de características invasivas. Este cambio en el comportamiento celular es mediado por una regulación molecular compleja en la que participa un gran número de vías de señalización, algunas actuando en forma independiente y otras interconectadas; la mayoría converge en el control de la expresión de la E-cadherina, cuya subregulación es el evento molecular clave en este proceso. Diversos estudios señalan una relación estrecha entre la TEM y el desarrollo y progresión de metástasis en carcinomas, pero ha sido menos ampliamente estudiada en el adenocarcinoma prostático. Los objetivos de esta revisión fueron: describir las bases moleculares y morfológicas de este proceso biológico y analizar la influencia de sus reguladores en la adquisición del fenotipo agresivo por las células tumorales, específicamente en lo que tiene que ver con la progresión del adenocarcinoma prostático. PALABRAS CLAVETransición epitelial-mesenquimal; Adhesión Celular; Metástasis; Adenocarcinoma Prostático SUMMARY Epithelial-mesenquimal transition in the progression of prostatic adenocarcinomaWorldwide, prostate adenocarcinoma is the second most frequently diagnosed cancer in men, and metastases are its most serious complication. The participation in its development of the epithelial-mesenchymal transition (EMT) has been described, a fundamental process during embryonic development, tissue remodeling and wound healing, which involves loss of

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The epithelial–mesenchymal transition regulators Twist, Slug, and Snail are associated with aggressive tumour features and poor outcome in prostate cancer patients

Børretzen

Gravdal

Haukaas

et al. 2021

The Journal of Pathology CR

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The prognostic importance of transcription factors promoting epithelial-mesenchymal transition (EMT) and angiogenesis has not been well explored in prostate cancer patients with long follow-up, nor the interplay between these factors. The objective of this study was to assess the individual protein expression and coexpression of Twist, Slug (Snai2), Snail (Snai1), and hypoxia-inducible factor-1 alpha (Hif-1α) in prostate cancer in relation to EMT, angiogenesis, hypoxia, tumour features, disease recurrence, and patient survival. Immunohistochemical staining was performed on tissue microarray sections from 338 radical prostatectomies with long follow-up. In addition, 41 cases of prostatic hyperplasia, 33 non-skeletal metastases, 13 skeletal metastases, and 33 castration-resistant prostate carcinomas were included. Our findings were validated in external gene expression data sets. Twist was overexpressed in primary prostate cancer and markedly reduced in distant metastases (p < 0.0005). Strong expression of Twist and Slug was associated with Hif-1α in localised prostate cancer (p ≤ 0.001), and strong Twist was associated with Hif-1α in castration-resistant carcinomas (p = 0.044). Twist, Slug, and increased Snail at the tumour stromal border were associated with vascular factors (p ≤ 0.045). Each of the three EMT-regulating transcription factors were associated with aggressive tumour features and shorter time to recurrence and cancer-specific death. Notably, the co-expression of factors demonstrated an enhanced influence on outcome. In the subgroup of E-cadherin low carcinomas, strong Slug was associated with shorter time to all end points and was an independent predictor of time to multiple end points, including cancer-specific death (hazard ratio 3.0, p = 0.041). To conclude, we demonstrate an important relation between EMT, hypoxia, and angiogenesis and a strong link between the investigated EMT regulators and aggressive tumour features and poor patient outcome in prostate cancer. Despite the retrospective nature of this long-term study, our findings could have a significant impact on the future treatment of prostate cancer, where tailored therapies might be directed simultaneously against epithelial-mesenchymal phenotypes, angiogenesis, and tumour hypoxia.

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Putative prognostic epithelial-to-mesenchymal transition biomarkers for aggressive prostate cancer

Cited by 29 publications

References 28 publications

Prognostic value of twist-1, e-cadherin and ezh2 in prostate cancer: an immunohistochemical study

Prognostic value of twist-1, e-cadherin and ezh2 in prostate cancer: an immunohistochemical study

Transición epitelial-mesenquimal en la progresión del adenocarcinoma prostático

The epithelial–mesenchymal transition regulators Twist, Slug, and Snail are associated with aggressive tumour features and poor outcome in prostate cancer patients

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