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Stem Cell Niche | Signaling pathways and Cell differentiation
#2
Prostate cancer and stem cells

The original article in this thread outlines the features of stem cell niches throughout the body. As mentioned in the article, if self- renewal of stem cells continued uncontrolled, the result would be rapid tumour development. Many cancers contain cancer stem-like cell (CSC) subpopulations within the heterogeneous population of cells that make up a tumour. The original article in the thread mentioned the prostate as an example and pointed out that the prostate gland contains a stem cell niche in the basal layer, proximal to the urethra.

Many studies have linked disease progression, recurrence and treatment failures to the CSC subpopulation. Recent studies on prostate cancer have focused on this in an attempt to identify potential new therapeutic avenues. Different signalling intermediates and pathways have been the focus of these studies, for example the transcription factor Myc and the hedgehog pathway. Techniques such as RNA interference have been employed and delivery methods including nanoparticles explored.

For example, a study using RNA interference approaches with noncoding promoter-associated RNA (paRNA) focused on silencing transcription of transcription factor Myc, which has a central function in stem cell biology and in human cancers. Myc was silenced in CSC in cell culture and in xenograft models of human prostate cancer. The fraction of CSCs in the cell population was reduced, leading to reduced self-renewal, tumour initiation and metastases. Myc silencing altered the stem cell phenotype and induced senescence. Prostate tumour development was greatly reduced. Thus Myc was identified as a potential target in reducing the tumour initiation potential of CSCs, particularly via a RNA inhibition-based strategy.

The original article in this thread mentions the hedgehog signalling pathway, which has also been examined in recent studies to identify potential prostate cancer therapies. In this case, HPMA copolymer-cyclopamine conjugate was used a delivery system for cyclopamine, which blocks the hedgehog signalling pathway. Selectivity of this conjugate toward CSCs was confirmed in human prostate cancer epithelial cells, RC-92a/hTERT cells by measurement of stem cell marker expression and prostasphere culture and by observation of reduced CSC viability.

Dual functional nanoparticles were employed in another study which could be delivered in a targeted manner using a single-chain prostate CSC antigen antibody. The core of the nanoparticles contained poly(D,L-lactic-co-glycolic acid), docetaxel and superparamagnetic iron oxide nanocrystals (SPIONs) ) with a multilayer shell formed by poly(allylamine hydrochloride) and two different sized poly(ethylene glycol) molecules. Drug release profiles showed drug could be delivered in a controlled manner in vitro to PC3 cells, resulting in increased anti-tumour activity due to the release of the docetaxel and SPIONs and enhanced magnetic resonance imaging. In vivo mouse studies on nude mice with PC3M xenografts, the nanoparticles stopped or even reversed tumour growth and increased the lifespan of the mice.

Thus there are many promising avenues of research for prostate cancer therapy but only the future will tell how applicable these methods will be in human cancer.

Sources

CIVENNI, G. et al., 2013. RNAi-mediated silencing of Myc transcription inhibits stem-like cell maintenance and tumorigenicity in prostate cancer. Cancer research,

GAO, X. et al., 2012. Prostate stem cell antigen-targeted nanoparticles with dual functional properties: in vivo imaging and cancer chemotherapy. International Journal Of Nanomedicine, 7, pp. 4037-4051

ZHOU, Y., YANG, J. and KOPECEK, J., 2012. Selective inhibitory effect of HPMA copolymer-cyclopamine conjugate on prostate cancer stem cells. Biomaterials, 33(6), pp. 1863-1872
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RE: Stem Cell Niche | Signaling pathways and Cell differentiation - by mtwalsh01 - 10-03-2013, 06:08 AM
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