Emergence of metastatic hormone‐refractory disease in prostate cancer after anti‐androgen therapy

Lee, Edmund Chun Yu; Tenniswood, Martin

doi:10.1002/jcb.20040

Cited by 25 publications

(19 citation statements)

References 62 publications

(63 reference statements)

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“…16,17 Amplification of the AR gene was seen in approximately 20-30% of all HR tumors. [18][19][20][21][22][23] In addition, there was heterogeneity in the amplification seen within tumors.…”

Section: Amplification Of the Armentioning

confidence: 99%

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Rubin

2008

Modern Pathology

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The clinical dilemma today in the management of prostate cancer (PCA) is to distinguish men who need definitive treatment from men who have indolent disease. As demonstrated most recently by the randomized Scandinavian trial evaluating the benefit of prostatectomy over Watchful Waiting, surgery significantly decreased the risk of death from PCA. However, this same study also suggests that 19 men need to be treated to benefit one man. Given the high prevalence of the disease, the aging of the population, and the potential morbidity of treatment, the ability to distinguish aggressive from indolent forms of PCA is critical. Treatment for advanced PCA begins with androgen ablation, but eventually hormone-refractory (HR) PCA emerges. Novel therapies are in various stages of clinical trials, including kinase inhibitors, antisense oligonucleotides, and inhibitors of heat-shock proteins. The discovery of novel therapeutic approaches is an active area of clinical research. Eliminating HR PCA before it advances is a high priority in the biomarker field. Therefore, the development of molecular signatures of lethal PCA are critical. In addition, the recent discovery that a significant percentage of PCAs harbor a TMPRSS2-ETS gene fusion suggests that targeting either the ETS transcription factors or the fusion product may offer a novel approach to therapy. However, in 2007, the mainstay of treatment for advanced PCA remains androgen ablation therapy as originally introduced in the early 1940s.

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Section: Amplification Of the Armentioning

confidence: 99%

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Rubin

2008

Modern Pathology

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“…ADT can be achieved surgically by castration or pharmacologically by suppression of the pituitary-gonadal axis and/or antagonism of the androgen receptor (AR; refs. [17][18][19]. The response to ADT includes reduced tumor bulk and a variable pause in growth that can last several months or even years (19).…”

Section: Introductionmentioning

confidence: 99%

Roles for the Stem Cell–Associated Intermediate Filament Nestin in Prostate Cancer Migration and Metastasis

Kleeberger¹,

et al. 2007

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The intermediate filament protein Nestin identifies stem/ progenitor cells in adult tissues, but the function of Nestin is poorly understood. We investigated Nestin expression and function in common lethal cancers. Nestin mRNA was detected in cell lines from small cell lung, and breast cancers, and particularly elevated in cell lines derived from prostate cancer metastases. Whereas the androgen-independent lines PC3, 22RV1, and DU145 all expressed Nestin transcripts under standard culture conditions, the androgen-dependent line LnCaP expressed Nestin only on androgen withdrawal. We confirmed associations of Nestin expression, androgen withdrawal, and metastatic potential by immunohistochemical analysis of samples from 254 prostate cancer patients. Cytoplasmic Nestin protein was readily identifiable in prostate cancer cells from 75% of patients with lethal androgenindependent disease, even in cancer sampled from the prostate itself. However, Nestin expression was undetectable in localized androgen-deprived tumors and in metastases without prior androgen deprivation. To address its function, we reduced Nestin levels with short hairpin RNAs, markedly inhibiting in vitro migration and invasion in prostate cancer cells but leaving cell growth intact. Nestin knockdown also diminished metastases 5-fold compared with controls despite uncompromised tumorigenicity at the site of inoculation. These results specify a function for Nestin in cell motility and identify a novel pathway for prostate cancer metastasis. Activity of this pathway may be selected by the extraprostatic environment or, as supported by our data, may originate within the prostate after androgen deprivation. Further dissection of this novel Nestin migration pathway may lead to strategies to prevent and neutralize metastatic spread.

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“…The disease is initially androgen dependent, and androgen-deprivation therapy represents the firstline treatment for prostate cancer patients (20). After an initial remission, prostate carcinoma progresses toward a condition of hormone resistance, characterized by high proliferation rate, strong metastatic behavior, and refractoriness to classic chemotherapy (21). CLU level of expression has been found to be either downregulated (22)(23)(24) or up-regulated (25) in prostate cancer specimens.…”

Section: Introductionmentioning

confidence: 99%

Clusterin Isoforms Differentially Affect Growth and Motility of Prostate Cells: Possible Implications in Prostate Tumorigenesis

et al. 2007

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Besides a fully processed, secreted form of clusterin (sCLU), an alternative proapoptotic form of the protein targeting the nucleus (nCLU) was recently described. The possible differential roles played by the two clusterin forms in growth and motility of nonmalignant and malignant prostate cells are investigated here. sCLU or nCLU was transiently transfected in both androgen-independent prostate cancer cells (PC3 and DU 145) and immortalized prostate epithelial cells (PNT1A, a nontumoral control). Then, cell growth, motility, and cytoskeleton organization were studied. We found that (a) in PNT1A cells, both sCLU and nCLU significantly decreased cell proliferation and motility; (b) in PC3 and DU 145 cancer cells, only nCLU inhibited cell growth and migration, with sCLU being ineffective; and (c) the antimotility effect of nCLU was accompanied by a dramatic dismantling of the actin cytoskeleton. Moreover, transfection with ''full-length'' CLU cDNA produced both sCLU and nCLU in nonmalignant PNT1A cells, whereas only sCLU was found in cancer cells. Thus, CLU gene expression might play a crucial role in prostate tumorigenesis by exerting differential biological effects on normal versus tumor cells through differential processing of CLU isoforms in the two cell systems. We also found that nCLU binds to A-actinin, a key protein for the regulation of actin cytoskeleton, and that nCLU and A-actinin colocalize in the cytoplasm. Thus, the antimotility activity of nCLU and its ability to cause dismantling of the actin cytoskeleton seem to be mediated by its binding to A-actinin. [Cancer Res 2007; 67(21):10325-33]

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Emergence of metastatic hormone‐refractory disease in prostate cancer after anti‐androgen therapy

Cited by 25 publications

References 62 publications

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Roles for the Stem Cell–Associated Intermediate Filament Nestin in Prostate Cancer Migration and Metastasis

Clusterin Isoforms Differentially Affect Growth and Motility of Prostate Cells: Possible Implications in Prostate Tumorigenesis

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