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Dysplasia of human prostate CD133(hi) sub-population in NOD-SCIDS is blocked by c-myc anti-sense.

ABSTRACT: The CD133(hi) sub-population of prostate epithelial cells has been demonstrated to possess tumor-initiating capacity consistent with that of the cancer stem cell theory. However, the involvement of oncogenes such as c-myc has not been fully elucidated in the CD133(hi) sub-population.We have isolated primary prostate cell strains (IBC-10a) and immortalized them by transfection with hTERT. The in vitro and in vivo tumorigenic capacity of isolated CD133(hi) and CD133(lo) cells was evaluated with respect to c-myc expression using specific sense and anti-sense oligonucleotides.Freshly immortalized cells consisted of <3.3% CD133(hi)/CD24(hi) sub-population (SP). "Prostaspheres" generated from single CD133(hi) cells in the presence of EGF consisted of approximately 10% CD133(hi) SPs in 12-21 day cultures. A single Prostasphere generated from single CD133(hi) cells (6-10 cell stage at day 6 injected i.t.) produced dysplastic lesions in NOD-SCID mice (n = 4/5). Treatment of Prostaspheres from CD133(hi) SPs in vitro with c-myc or cyclin D1 anti-sense oligonucleotides totally blocked colony forming ability and growth. Furthermore, treatment of fully formed, 6-day Prostaspheres for 48 hr with c-myc anti-sense significantly reduced c-myc expression and their ability to generate lesions in NOD-SCIDs (n = 10 Prostaspheres injected i.t./mouse).These data demonstrate for the first time that a single CD133(hi) cell is competent to generate Prostaspheres in vitro and that CD133(hi) Prostaspheres require c-myc to grow and form dysplastic lesions in vivo.

SUBMITTER: Goodyear SM

PROVIDER: S-EPMC2720608 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Dysplasia of human prostate CD133(hi) sub-population in NOD-SCIDS is blocked by c-myc anti-sense.

Goodyear S M SM Amatangelo M D MD Stearns M E ME

The Prostate 20090501 7

<h4>Background</h4>The CD133(hi) sub-population of prostate epithelial cells has been demonstrated to possess tumor-initiating capacity consistent with that of the cancer stem cell theory. However, the involvement of oncogenes such as c-myc has not been fully elucidated in the CD133(hi) sub-population.<h4>Methods</h4>We have isolated primary prostate cell strains (IBC-10a) and immortalized them by transfection with hTERT. The in vitro and in vivo tumorigenic capacity of isolated CD133(hi) and CD ...[more]

PMID: 19143028

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Project description:BackgroundPreviously, we showed that carbohydrate restriction with calorie restriction slowed tumor growth in xenograft mouse prostate cancer models. Herein, we examined the impact of carbohydrate restriction without calorie restriction on tumor development within the context of diet-induced obesity in the Hi-Myc transgenic mouse model of prostate cancer.MethodsMice were randomized at 5 weeks of age to ad libitum western diet (WD; 40% fat, 42% carbohydrate; n=39) or ad libitum no carbohydrate ketogenic diet (NCKD; 82% fat, 1% carbohydrate; n=44). At age 3 or 6 months, mice were killed, prostates weighed and prostate histology, proliferation, apoptosis and macrophage infiltration evaluated by hematoxylin and eosin, Ki67, TUNEL and F4/80 staining, respectively. Body composition was assessed by DEXA, serum cytokines measured using multiplex, and Akt/mTOR signaling assessed by Western.ResultsCaloric intake was higher in the NCKD group, resulting in elevated body weights at 6 months of age, relative to the WD group (45 g vs 38g; P=0.008). Despite elevated body weights, serum monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-1α levels were lower in NCKD versus WD mice (P=0.046 and P=0.118, respectively), and macrophage infiltration was reduced in prostates of NCKD versus WD mice (P=0.028). Relative Akt phosphorylation and phospho-S6 ribosomal protein levels were reduced in prostates of NCKD versus WD mice. However, while mice randomized to NCKD had smaller prostates after adjustment for body weight at 3 and 6 months (P=0.004 and P=0.002, respectively), NCKD mice had higher rates of adenocarcinoma at 6 months compared to WD mice (100 vs 80%, P=0.04).ConclusionsDespite higher caloric intake and elevated body weights, carbohydrate restriction lowered serum MCP-1 levels, reduced prostate macrophage infiltration, reduced prostate weight, but failed to slow adenocarcinoma development. Together, these data suggest that although carbohydrate restriction within the context of obesity may reduce obesity-associated systemic inflammation and perhaps slow tumor growth, it is not sufficient to counteract obesity-associated tumor development.

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Dysplasia of human prostate CD133(hi) sub-population in NOD-SCIDS is blocked by c-myc anti-sense.

Publications

Dysplasia of human prostate CD133(hi) sub-population in NOD-SCIDS is blocked by c-myc anti-sense.

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