Systemic Delivery of Oncolytic Adenoviruses Targeting Transforming Growth Factor-β Inhibits Established Bone Metastasis in a Prostate Cancer Mouse Model

Abstract We have examined whether Ad.sT?RFc and TAd.sT?RFc, two oncolytic viruses expressing soluble transforming growth factor-? receptor II fused with human Fc (sTGF?RIIFc), can be developed to treat bone metastasis of prostate cancer. Incubation of PC-3 and DU-145 prostate tumor cells with Ad.sT?RFc and TAd.sT?RFc produced sTGF?RIIFc and viral replication; sTGF?RIIFc caused inhibition of TGF-?-mediated SMAD2 and SMAD3 phosphorylation. Ad(E1-).sT?RFc, an E1? adenovirus, produced sTGF?RIIFc but failed to replicate in tumor cells. To examine the antitumor response of adenoviral vectors, PC-3-luc cells were injected into the left heart ventricle of nude mice. On day 9, mice were subjected to whole-body bioluminescence imaging (BLI). Mice bearing hind-limb tumors were administered viral vectors via the tail vein on days 10, 13, and 17 (2.5?1010 viral particles per injection per mouse, each injection in a 0.1-ml volume), and subjected to BLI and X-ray radiography weekly until day 53. Ad.sT?RFc, TAd.sT?RFc, and Ad(E1-).sT?RFc caused significant inhibition of tumor growth; however, Ad.sT?RFc was the most effective among all the vectors. Only Ad.sT?RFc and TAd.sT?RFc inhibited tumor-induced hypercalcemia. Histomorphometric and synchrotron micro-computed tomographic analysis of isolated bones indicated that Ad.sT?RFc induced significant reduction in tumor burden, osteoclast number, and trabecular and cortical bone destruction. These studies suggest that Ad.sT?RFc and TAd.sT?RFc can be developed as potential new therapies for prostate cancer bone metastasis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98454/1/hum%2E2012%2E040.pd

TGF-β Regulates DNA Methyltransferase Expression in Prostate Cancer, Correlates with Aggressive Capabilities, and Predicts Disease Recurrence

DNA methyltransferase (DNMT) is one of the major factors mediating the methylation of cancer related genes such as TGF-β receptors (TβRs). This in turn may result in a loss of sensitivity to physiologic levels of TGF-β in aggressive prostate cancer (CaP). The specific mechanisms of DNMT's role in CaP remain undetermined. In this study, we describe the mechanism of TGF-β-mediated DNMT in CaP and its association with clinical outcomes following radical prostatectomy.We used human CaP cell lines with varying degrees of invasive capability to describe how TGF-β mediates the expression of DNMT in CaP, and its effects on methylation status of TGF-β receptors and the invasive capability of CaP in vitro and in vivo. Furthermore, we determined the association between DNMT expression and clinical outcome after radical prostatectomy. We found that more aggressive CaP cells had significantly higher TGF-β levels, increased expression of DNMT, but reduced TβRs when compared to benign prostate cells and less aggressive prostate cancer cells. Blockade of TGF-β signaling or ERK activation (p-ERK) was associated with a dramatic decrease in the expression of DNMT, which results in a coincident increase in the expression of TβRs. Blockade of either TGF-β signaling or DNMT dramatically decreased the invasive capabilities of CaP. Inhibition of TGF-β in an TRAMP-C2 CaP model in C57BL/6 mice using 1D11 was associated with downregulation of DNMTs and p-ERK and impairment in tumor growth. Finally, independent of Gleason grade, increased DNMT1 expression was associated with biochemical recurrence following surgical treatment for prostate cancer.Our findings demonstrate that CaP derived TGF-β may induce the expression of DNMTs in CaP which is associated with methylation of its receptors and the aggressive potential of CaP. In addition, DNMTs is an independent predictor for disease recurrence after prostatectomy, and may have clinical implications for CaP prognostication and therapy

Personalized prostate cancer care: from screening to treatment

Unprecedented progress has been made in genomic personalized medicine in the last several years, allowing for more individualized healthcare assessments and recommendations than ever before. However, most of this progress in prostate cancer (PCa) care has focused on developing and selecting therapies for late-stage disease. To address this issue of limited focus, we propose a model for incorporating genomic-based personalized medicine into all levels of PCa care, from prevention and screening to diagnosis, and ultimately to the treatment of both early-stage and late-stage cancers. We have termed this strategy the "Pyramid Model" of personalized cancer care. In this perspective paper, our objective is to demonstrate the potential application of the Pyramid Model to PCa care. This proactive and comprehensive personalized cancer care approach has the potential to achieve three important medical goals: reducing mortality, improving quality of life and decreasing both individual and societal healthcare costs

Natural products and transforming growth factor-beta (TGF-β) signaling in cancer development and progression.

Actions of many herbal medicine products for cancer treatment are linked to an altered production of TGF-β in the target cells. An altered TGF-β production in the target cells will have profound effects on the patients. Therefore, it is important that we review the pros and cons of these products on cancer development and progression in terms of TGF-β signaling. It has been well established that TGF-β is growth inhibitory to benign cells or early stages of cancer cells but it is tumor promoting and metastatic for advanced malignancies. Further, many dietary components can alter gene-specific DNA methylation levels in systemic and in target tissues. Since TGF-β signaling in cancer is closely linked to the DNA methylation profiles, we also review the effect of dietary components on DNA methylation. In light of this knowledge, it is important to note that many natural products that can induce TGF-β production in the target cells may be beneficial in preventing cancer development but may be harmful for cancer patients, especially when they harbor advanced stage cancer. A discussion of the effect of herbal natural products on cancer can be divided into three categories. The first category of herbal medicine products will be those related to the induction of cancer as far as TGF-β is concerned. Since TGF-β is growth inhibitory and pro-apoptosis to benign cells, any herbal medication that can induce the production of TGF-β in the target cells will be beneficial to the patients. However, such herbal medicine may not necessarily be beneficial for patients with established and advanced cancer. The second category of herbal products will inhibit TGF-β signaling and will reduce TGF-β mediated growth promotion and metastasis in advanced cancers. For patients with established and advanced cancer, agents that can inhibit the production of TGF-β may also inhibit cancer growth and metastasis. Finally, the third category of herbal products has no impact on TGF-β signaling, such as lycopene

Natural products and transforming growth factor-beta (TGF-β) signaling in cancer development and progression.

Actions of many herbal medicine products for cancer treatment are linked to an altered production of TGF-β in the target cells. An altered TGF-β production in the target cells will have profound effects on the patients. Therefore, it is important that we review the pros and cons of these products on cancer development and progression in terms of TGF-β signaling. It has been well established that TGF-β is growth inhibitory to benign cells or early stages of cancer cells but it is tumor promoting and metastatic for advanced malignancies. Further, many dietary components can alter gene-specific DNA methylation levels in systemic and in target tissues. Since TGF-β signaling in cancer is closely linked to the DNA methylation profiles, we also review the effect of dietary components on DNA methylation. In light of this knowledge, it is important to note that many natural products that can induce TGF-β production in the target cells may be beneficial in preventing cancer development but may be harmful for cancer patients, especially when they harbor advanced stage cancer. A discussion of the effect of herbal natural products on cancer can be divided into three categories. The first category of herbal medicine products will be those related to the induction of cancer as far as TGF-β is concerned. Since TGF-β is growth inhibitory and pro-apoptosis to benign cells, any herbal medication that can induce the production of TGF-β in the target cells will be beneficial to the patients. However, such herbal medicine may not necessarily be beneficial for patients with established and advanced cancer. The second category of herbal products will inhibit TGF-β signaling and will reduce TGF-β mediated growth promotion and metastasis in advanced cancers. For patients with established and advanced cancer, agents that can inhibit the production of TGF-β may also inhibit cancer growth and metastasis. Finally, the third category of herbal products has no impact on TGF-β signaling, such as lycopene

Population-standardized genetic risk score: the SNP-based method of choice for inherited risk assessment of prostate cancer

Several different approaches are available to clinicians for determining prostate cancer (PCa) risk. The clinical validity of various PCa risk assessment methods utilizing single nucleotide polymorphisms (SNPs) has been established; however, these SNP-based methods have not been compared. The objective of this study was to compare the three most commonly used SNP-based methods for PCa risk assessment. Participants were men (n = 1654) enrolled in a prospective study of PCa development. Genotypes of 59 PCa risk-associated SNPs were available in this cohort. Three methods of calculating SNP-based genetic risk scores (GRSs) were used for the evaluation of individual disease risk such as risk allele count (GRS-RAC), weighted risk allele count (GRS-wRAC), and population-standardized genetic risk score (GRS-PS). Mean GRSs were calculated, and performances were compared using area under the receiver operating characteristic curve (AUC) and positive predictive value (PPV). All SNP-based methods were found to be independently associated with PCa (all P 0.05 for comparisons between the three methods), and all three SNP-based methods had a significantly higher AUC than family history (all P < 0.05). Results from this study suggest that while the three most commonly used SNP-based methods performed similarly in discriminating PCa from non-PCa at the population level, GRS-PS is the method of choice for risk assessment at the individual level because its value (where 1.0 represents average population risk) can be easily interpreted regardless of the number of risk-associated SNPs used in the calculation

Dietary Fatty Acids Correlate With Prostate Cancer Biopsy Grade and Volume in Jamaican Men

Jamaica has the highest incidence of prostate cancer in the world. Dietary fat is associated with prostate cancer. The Ω6 polyunsaturated fatty acids have been shown to stimulate prostate carcinogenesis and the Jamaican diet is rich in linoleic acid. We hypothesized positive correlations between Ω6 polyunsaturated fatty acid, prostate specific antigen and prostate biopsy pathology. A total of 148 men were enrolled in Kingston, Jamaica. Serum prostate specific antigen and erythrocyte membrane polyunsaturated fatty acids were analyzed. Men with prostate specific antigen 2.6 ng/ml or greater underwent biopsy. Histopathological and statistical analyses were performed on available data. Of the 54 men who underwent biopsy 24 had prostate cancer, 17 had a Gleason score of 7 or greater and 11 had a tumor volume of 50% or greater. There were significant positive correlations between linoleic acid and Gleason score (p = 0.009), and the linoleic acid-to-docosahexaenoic acid (Ω3) ratio and tumor volume (p = 0.03). There was a significant negative correlation between the arachidonic acid (Ω6)-to-docosapentanoic acid (Ω3) ratio and Gleason score (p = 0.04). Statistical correlations between prostate specific antigen and polyunsaturated fatty acids were inconsistent. The positive correlations between linoleic acid and Gleason score, and the linoleic acid-to-docosahexaenoic acid ratio and tumor volume support studies showing that Ω6 polyunsaturated fatty acids stimulate and Ω3 polyunsaturated fatty acids inhibit prostate cancer growth. The negative correlation between the arachidonic acid-to-docosapentanoic acid ratio and Gleason score supports studies that demonstrate increased metabolism of arachidonic acid in prostate cancer to form carcinogenic metabolites, namely prostaglandin E2. Our findings support the association between dietary fatty acids and prostate cancer, and they warrant further dietary and tissue studies in high risk populations