Epithelial-to-mesenchymal transition in prostate cancer: paradigm or puzzle?

Nauseef, Jones T.; Henry, Michael D.

doi:10.1038/nrurol.2011.85

Cited by 171 publications

(186 citation statements)

References 104 publications

(110 reference statements)

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“…(17). Of interest is the activation (via phosphorylation) of p42/44, which when stimulated by several stimuli including GFs contributes to the increased proliferation of tumor cells (10). Furthermore, activation of this pathway is also known to induce EMT in cancer cells (19).…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of tumor growth and metastasis by a self-therapeutic nanoparticle

Arvizo¹,

Saha²,

Wang³

et al. 2013

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

217

215

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Although biomedical applications of nanotechnology, which typically involve functionalized nanoparticles, have taken significant strides, biological characterization of unmodified nanoparticles remains underinvestigated. Herein we demonstrate that unmodified gold nanoparticles (AuNPs) inhibit the proliferation of cancer cells in a size-and concentration-dependent manner by abrogating MAPK-signaling. In addition, these AuNPs reverse epithelial-mesenchymal transition (EMT) in cancer cells by reducing secretion of a number of proteins involved in EMT, up-regulating E-Cadherin, and down-regulating Snail, N-Cadherin, and Vimentin. Inhibition of MAPK signaling and reversal of EMT upon AuNP treatment inhibits tumor growth and metastasis in two separate orthotopic models of ovarian cancer. Western blot analyses of tumor tissues reveal up-regulation of E-Cadherin and down-regulation of Snail and phospho-MAPK, confirming the reversal of EMT and inhibition of MAPK signaling upon AuNP treatment. The ability of a single selftherapeutic nanoparticle to abrogate signaling cascades of multiple growth factors is distinctive and purports possible medical applications as potential antitumor and antimetastatic agent.drug delivery | heparin-binding growth factors

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Section: Resultsmentioning

confidence: 99%

“…Repression of E-Cadherin (E-Cad) is the hallmark of EMT and occurs through transcriptional repressors such as Vimentin, Snail, Slug, Twist, etc. (8)(9)(10). Down-regulation of E-Cad expression by its transcriptional repressors through several compensatory and independent mechanisms poses a challenge for anti-EMT therapy (11)(12)(13).…”

mentioning

confidence: 99%

Inhibition of tumor growth and metastasis by a self-therapeutic nanoparticle

Arvizo¹,

Saha²,

Wang³

et al. 2013

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

217

215

View full text Add to dashboard Cite

show abstract

“…EMT is typically characterized by the loss of epithelial (i.e., CDH1) and the gain of mesenchymal (i.e., VIM, CDH2) markers expression (36). Several reports suggest that AR activation, as well as androgen deprivation therapy, may induce changes characteristic of EMT that may be involved in prostate cancer progression (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

Marín-Aguilera

Codony-Servat

Reig

et al. 2014

Molecular Cancer Therapeutics

138

112

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Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel þ androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-kB transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44 þ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44 þ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer. Mol Cancer Ther; 13(5); 1270-84. Ó2014 AACR.

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“…EMT has received considerable attention as a novel paradigm to explain the invasive behavior of cancer and its resistance to therapy (41), setting the stage for the search of specific inhibitors. However, due to the multifactorial aspect of EMT, simultaneous targeting of the underlying pathways should be considered to achieve meaningful efficacy.…”

Section: Discussionmentioning

confidence: 99%

Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways

Basu

Lettan

Damodaran

et al. 2014

Molecular Cancer Therapeutics

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Embryonic signaling pathways, in particular those mediated by Wnt and TGF-b, are known to play key roles in tumor progression through the induction of epithelial-mesenchymal transition (EMT). Their simultaneous targeting could therefore represent a desirable anticancer strategy. On the basis of recent findings that both Wnt and TGF-b-associated pathways are regulated by Hippo signaling in mammalian cells, we reasoned that targeting the latter would be more effective in inhibiting EMT. In a search for such inhibitors, we identified a small molecule (C19) with remarkable inhibitory activity not only against Hippo, but also against Wnt and TGF-b pathways. C19 inhibited cancer cell migration, proliferation, and resistance to doxorubicin in vitro, and exerted strong antitumor activity in a mouse tumor model. Mechanistically, C19 induced GSK3-b-mediated degradation of the Hippo transducer TAZ, through activation of the Hippo kinases Mst/Lats and the tumor suppressor kinase AMPK upstream of the degradation complex. Overall, this study identified C19 as a multi-EMT pathway inhibitor with a unique mechanism of action. The findings that both AMPK and Mst/Lats mediate the antitumor activity of C19 shed light on a potential cross-talk between metabolic and organ size control pathways in regulating cancer progression. By simultaneously targeting these two pathways, C19 may represent a new type of agents to suppress cancer progression and/or its recurrence.

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Epithelial-to-mesenchymal transition in prostate cancer: paradigm or puzzle?

Cited by 171 publications

References 104 publications

Inhibition of tumor growth and metastasis by a self-therapeutic nanoparticle

Inhibition of tumor growth and metastasis by a self-therapeutic nanoparticle

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways

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