Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance

Tanaka, Hiroshi; Kono, Evelyn A.; Tran, Chau P.; Miyazaki, Hideyo; Yamashiro, Joyce M.; Shimomura, Takeshi; Fazli, Ladan; Wada, Robert; Huang, Jiaoti; Vessella, Robert L.; An, Jaibin; Horvath, Steven; Gleave, Martin; Rettig, Matthew B.; Wainberg, Zev A.; Reiter, Robert E.

doi:10.1038/nm.2236

Cited by 288 publications

(284 citation statements)

References 26 publications

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“…The present study showed that CRPC tumors in which AR expression was elevated showed mesenchymal characteristics manifested by increased expression of mesenchymal markers, suggesting that CRPC tumors may have highly invasive and metastatic potential. This is supported by a recent report showing that N-cadherin is up-regulated in CRPC tissues (Tanaka et al 2010). As shown in this study, AR expression was elevated in invasive prostate cancer, which is consistent with a previous report showing that higher levels of AR expression is correlated with extraprostatic extension, seminal vesicle invasion, and lymph-node involvement in radical prostatectomy specimens (Li et al 2004).…”

Section: Discussionsupporting

confidence: 93%

Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer

Shiota¹,

Itsumi²,

Takeuchi³

et al. 2015

Endocrine-Related Cancer

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Although invasive and metastatic progression via the epithelial-mesenchymal transition (EMT) and acquisition of resistance to castration are both critical steps in prostate cancer, the molecular mechanism of this interaction remains unclear. In this study, we aimed to elucidate the interaction of signaling between castration resistance and EMT, and to apply this information to the development of a novel therapeutic concept using transforming growth factor-b (TGF-b) inhibitor SB525334 combined with androgen-deprivation therapy against prostate cancer using an in vivo model. This study revealed that an EMT inducer (TGF-b) induced full-length androgen receptor (AR) and AR variant expression. In addition, a highly invasive clone showed augmented full-length AR and AR variant expression as well as acquisition of castration resistance. Conversely, full-length AR and AR as well as Twist1 and mesenchymal molecules variant expression were up-regulated in castration-resistant LNCaP xenograft. Finally, TGF-b inhibitor suppressed Twist1 and AR expression as well as prostate cancer growth combined with castration. Taken together, these results demonstrate that Twist1/AR signaling was augmented in castration resistant as well as mesenchymal-phenotype prostate cancer, indicating the molecular mechanism of mutual and functional crosstalk between EMT and castration resistance, which may play a crucial role in prostate carcinogenesis and progression.

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Section: Discussionsupporting

confidence: 93%

Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer

Shiota¹,

Itsumi²,

Takeuchi³

et al. 2015

Endocrine-Related Cancer

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“…S7). Our results demonstrate that tumors driven by NICD1 in combination with kRas G12D , myrAKT, and Myc exhibit EMT features, a phenotype that may characterize invasive, poorly differentiated carcinoma (42)(43)(44)(45).…”

Section: Gene-expression Profiling Of Tumors Driven By Nicd1 In Combimentioning

confidence: 66%

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

Stoyanova

Riedinger

Lin

et al. 2016

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

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Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer.

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“…7e9 Hallmarks of EMT in PC include disruption of adherens junctions through down-regulation of E-cadherin, 2 concomitant with a development of a migratory phenotype and up-regulation of mesenchymal markers, such as N-cadherin, vimentin, and fibronectin. 10,11 Loss of E-cadherin results from mutations, DNA methylation, or silencing of E-cadherin promoter regions during transcription. 12,13 A predominant repressor of E-cadherin gene transcription and an inducer of N-cadherin expression during EMT is Twist1, 14e16 which belongs to the group of EMT transcription factors (Slug, Snail, Zeb1, and Zeb2).…”

mentioning

confidence: 99%

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

Talati

Ellsworth

et al. 2015

The American Journal of Pathology

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Active Stat5a/b predicts early recurrence and disease-specific death in prostate cancer (PC), which both typically are caused by development of metastatic disease. Herein, we demonstrate that Stat5a/b induces epithelial-to-mesenchymal transition (EMT) of PC cells, as shown by Stat5a/b regulation of EMT marker expression (Twist1, E-cadherin, N-cadherin, vimentin, and fibronectin) in PC cell lines, xenograft tumors in vivo, and patient-derived PCs ex vivo using organ explant cultures. Jak2-Stat5a/b signaling induced functional end points of EMT as well, indicated by disruption of epithelial cell monolayers and increased migration and adhesion of PC cells to fibronectin. Knockdown of Twist1 suppressed Jak2-Stat5a/beinduced EMT properties of PC cells, which were rescued by re-introduction of Twist1, indicating that Twist1 mediates Stat5a/b-induced EMT in PC cells. While promoting EMT, Jak2-Stat5a/b signaling induced stemlike properties in PC cells, such as sphere formation and expression of cancer stem cell markers, including BMI1. Mechanistically, both Twist1 and BMI1 were critical for Stat5a/b induction of stem-like features, because genetic knockdown of Twist1 suppressed Stat5a/b-induced BMI1 expression and sphere formation in stem cell culture conditions, which were rescued by re-introduction of BMI1. By using human prolactin knock-in mice, we demonstrate that prolactin-Stat5a/b signaling promoted metastases formation of PC cells in vivo. In conclusion, our data support the concept that Jak2-Stat5a/b signaling promotes metastatic progression of PC by inducing EMT and stem cell properties in PC cells. Most prostate cancer (PC)erelated deaths are because of development of metastatic disease. A central process in metastatic dissemination of PC is epithelial-to-mesenchymal transition (EMT), during which cancer cells attain more motile and invasive properties, invade through the basement membrane, and survive in systemic circulation. 1e3 Extravasation at distant organ sites is followed by adhesion of cancer cells to extracellular matrix proteins, such as fibronectin, 4e6 leading to formation of premetastatic niches and subsequent formation of macroscopic metastases. 7e9 Hallmarks of EMT in PC include disruption of adherens junctions through down-regulation of E-cadherin, 2 concomitant with a development of a migratory phenotype and up-regulation of mesenchymal markers, such as N-cadherin, vimentin, and fibronectin. 10,11 Loss of E-cadherin results from mutations, DNA methylation, or silencing of E-cadherin promoter

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Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance

Cited by 288 publications

References 26 publications

Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer

Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

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