Clinical implications of neuroendocrine differentiation in prostate cancer

Nelson, Eric; Cambio, Angelo J.; Yang, Joy C.; Ok, Joon Ha; Lara, Primo N.; Evans, Christopher P.

doi:10.1038/sj.pcan.4500922

Cited by 89 publications

(87 citation statements)

References 91 publications

(107 reference statements)

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“…Such neuroendocrine cells may convert CaP cells to a dependence on survival signals through Gprotein coupled receptors and growth factor receptors upstream of Akt, bypassing the usual androgen receptor signaling. 26 These data cumulatively provide a rationale for Akt inhibition as a therapeutic paradigm in CaP.…”

Section: Alterations Of Akt Activity In Capmentioning

confidence: 96%

“…Although Akt itself may not be directly involved in causing this transition, some of these pathways signal through Akt. 3,26 For example, emergence of a neuroendocrine phenotype in CaP may be important in disease progression. Such neuroendocrine cells may convert CaP cells to a dependence on survival signals through Gprotein coupled receptors and growth factor receptors upstream of Akt, bypassing the usual androgen receptor signaling.…”

Section: Alterations Of Akt Activity In Capmentioning

confidence: 99%

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Inhibition of Akt pathways in the treatment of prostate cancer

Nelson

Evans

Mack

et al. 2007

Prostate Cancer Prostatic Dis

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Akt is a serine/threonine kinase mediating multiple intracellular pathways involved in prostate cancer (CaP) biology. Increased understanding of the molecular mechanisms of Akt activation and signaling have led to the development of an increasing number of Akt inhibitors. These biologic agents demonstrate activity against a wide range of cancers in preclinical studies. Clinical studies of Akt inhibition in CaP are in progress, including agents such as celecoxib, perifosine and genistein. How best to integrate Akt inhibitors with standard CaP therapy or select patients most likely to benefit is the subject of ongoing research.

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Section: Alterations Of Akt Activity In Capmentioning

confidence: 96%

Section: Alterations Of Akt Activity In Capmentioning

confidence: 99%

Inhibition of Akt pathways in the treatment of prostate cancer

Nelson

Evans

Mack

et al. 2007

Prostate Cancer Prostatic Dis

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“…The major type of neuroendocrine cells contain serotonin, thyroid-stimulating hormone and chromogranin A. Neuroendocrine cells are terminally differentiated, post-mitotic cell types that are androgen-insensitive (Bui and Reiter, 1999) and can also express neuropeptide Y. Immunoreactivity to neuropeptide Y was demonstrated in up to 75% of CaP, suggesting a role in growth and progression of CaP (Ruscica et al, 2007). These differentiated cell populations can become more prominant in CaP with changes in number, histology and function (Nelson et al, 2007;Schalken and van Leenders, 2003) suggesting a regulatory role and demonstrating the plasticity of the differentiation program even in CaP. Mitogenic and oncogenic activities have also been demonstrated, for example expression of vascular endothelial growth factor (VEGF) leading to angiogenesis.…”

Section: Prostate Architecturementioning

confidence: 99%

“…Mitogenic and oncogenic activities have also been demonstrated, for example expression of vascular endothelial growth factor (VEGF) leading to angiogenesis. M a n u s c r i p t 5 Some neuroendocrine cells can also express somatostatin and even PSA (Nelson et al, 2007).…”

Section: Prostate Architecturementioning

confidence: 99%

Androgen receptor signalling in prostate: Effects of stromal factors on normal and cancer stem cells

Berry

Maitland

Collins

2008

Molecular and Cellular Endocrinology

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Please cite this article as: Berry, P.A., Maitland, N.J., Collins, A.T., Androgen receptor signalling in prostate: effects of stromal factors on normal and cancer stem cells, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe prostate gland is the most common site for cancer in males within the developed world. Androgens play a vital role in prostate development, maintenance of tissue function and pathogenesis of prostate disease. The androgen receptor signalling pathway facilitates that role in both the epithelial compartment and in the underlying stroma. Stroma is a key mediator of androgenic effects upon the epithelium and can regulate both the fate of the epithelial stem cell and potentially the initiation and progression of prostate cancer. Different groups of growth factors are expressed by stroma, which control proliferation, and differentiation of prostate epithelium demonstrating a critical role for stroma in epithelial growth and homeostasis. Paracrine stromal proteins may offer the possibility to control tumour stem cell growth and could permit prostate-specific targeting of both therapies and of androgenresponsive proteins. The effect of 5-dihydrotestosterone, the more potent metabolite of testosterone, on expression of androgen regulated genes in stroma from benign prostatic hyperplasia is a key mediator of epithelial cell fate. Global gene expression arrays have recently identified new candidate genes in androgen responsive stroma, some of which have androgen receptor binding sites in their promoter regions. Some of these genes have direct androgen receptor binding ability.

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“…Tumor cells present at this stage are usually extremely resistant to conventional therapies and finally metastasize. 3 Yet, research efforts during the last 50 years have not improved significantly the life expectancy of PCa patients. 4 Adult prostate gland possesses basal (proliferating) cells, secretory (luminal) cells and the less abundant (<0.1%) neuroendocrine (NE) cells.…”

mentioning

confidence: 99%

Upregulation of manganese superoxide dismutase (SOD2) is a common pathway for neuroendocrine differentiation in prostate cancer cells

Quiros

Sáinz

Hevia

et al. 2009

Intl Journal of Cancer

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Despite improvements in diagnosis of advanced prostate cancer (PCa), treatment is not efficient and 5-year survival is still low. Initially, the less abundant of cell types, neuroendocrine cells (NE), are involved in regulatory process but their physiological role is not fully understood. Among others, an increase in NE cells along with tumor progression has been commonly reported but their role in tumorigenesis or the molecular mechanisms of transdifferentiation is still a matter of debate. We have used human PCa cells (LNCaP) induced to differentiate to NE cells with several stimuli: androgen withdrawal, cyclic AMP or treatment with the antioxidant pineal hormone melatonin. PCa patients' specimens were also analyzed by western blotting and by immunocytochemistry. NE-like LNCaP cells express high levels of mitochondrial superoxide dismutase (MnSOD/SOD2) in addition to NE markers. MnSOD upregulation is mediated by NFjB transcription factor, mainly through p65 translocation into the nuclei. More importantly, overexpression of MnSOD induces the rise of NE-markers in LNCaP cells, showing that MnSOD upregulation might be instrumental for NE differentiation in PCa cells. Furthermore, MnSOD is highly expressed in advanced tumors of patients' when compared with control, nonpathological samples or with low-grade tumors, along with the presence of synaptophysin, a common NE marker. Also, fluorescence immunohistochemical analysis revealed that MnSOD colocalizes with NE markers in most of NE cells observed in PCa specimens. The present findings indicate that MnSOD is essential for NE transdifferentiation and mediates in part the differentiation process, which appears also to be critical in vivo. ' 2009 UICC

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Clinical implications of neuroendocrine differentiation in prostate cancer

Cited by 89 publications

References 91 publications

Inhibition of Akt pathways in the treatment of prostate cancer

Inhibition of Akt pathways in the treatment of prostate cancer

Androgen receptor signalling in prostate: Effects of stromal factors on normal and cancer stem cells

Upregulation of manganese superoxide dismutase (SOD2) is a common pathway for neuroendocrine differentiation in prostate cancer cells

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