Functional Neoangiogenesis Imaging of Genetically Engineered Mouse Prostate Cancer Using Three-Dimensional Power Doppler Ultrasound
Jim W. XuanMichael BygraveHongyi JiangFatma ValiyevaJoy Dunmore‐BuyzeDavid W. HoldsworthJonathan I. IzawaGlenn BaumanMadeleine MoussaScott F. WinterNorman M. GreenbergJoseph L. ChinMaria DrangovaAaron FensterJames C. Lacefield
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Abstract We report the first application of high-frequency three-dimensional power Doppler ultrasound imaging in a genetically engineered mouse (GEM) prostate cancer model. We show that the technology sensitively and specifically depicts functional neoangiogenic blood flow because little or no flow is measurable in normal prostate tissue or tumors smaller than 2–3 mm diameter, the neoangiogenesis “switch-on” size. Vascular structures depicted by power Doppler were verified using Microfil-enhanced micro-computed tomography (micro-CT) and by correlation with microvessel distributions measured by immunohistochemistry and enhanced vascularity visualized by confocal microscopy in two GEM models [transgenic adenocarcinoma of the mouse prostate (TRAMP) and PSP94 gene-directed transgenic mouse adenocarcinoma of the prostate (PSP-TGMAP)]. Four distinct phases of neoangiogenesis in cancer development were observed, specifically, (a) an early latent phase; (b) establishment of a peripheral capsular vascular structure as a neoangiogenesis initiation site; (c) a peak in tumor vascularity that occurs before aggressive tumor growth; and (d) rapid tumor growth accompanied by decreasing vascularity. Microsurgical interventions mimicking local delivery of antiangiogenesis drugs were done by ligating arteries upstream from feeder vessels branching to the prostate. Microsurgery produced an immediate reduction of tumor blood flow, and flow remained low from 1 h to 2 weeks or longer after treatment. Power Doppler, in conjunction with micro-CT, showed that the tumors recruit secondary blood supplies from nearby vessels, which likely accounts for the continued growth of the tumors after surgery. The microsurgical model represents an advanced angiogenic prostate cancer stage in GEM mice corresponding to clinically defined hormone-refractory prostate cancer. Three-dimensional power Doppler imaging is completely noninvasive and will facilitate basic and preclinical research on neoangiogenesis in live animal models. [Cancer Res 2007;67(6):2830–9]Keywords:
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The healthy prostate contains the highest concentration of mobile zinc in the body. As this level decreases dramatically during the initial development of prostate cancer, in vivo detection of prostate zinc content may be applied for diagnosis of prostate cancer. Using 19 F ion chemical exchange saturation transfer magnetic resonance imaging (iCEST MRI) and TF-BAPTA as a fluorinated Zn-binding probe with micromolar sensitivity, we show that iCEST MRI is able to differentiate between normal and malignant prostate cells with a 10-fold difference in contrast following glucose-stimulated zinc secretion in vitro. The iCEST signal decreased in normal prostate cells upon downregulation of the ZIP1 zinc transporter. In vivo, using an orthotopic prostate cancer mouse model and a transgenic adenocarcinoma of the mouse prostate (TRAMP) model, a gradual decrease of >300 % in iCEST contrast following the transition of normal prostate epithelial cells to cancer cells was detected.
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Purpose To improve early diagnosis of prostate cancer to aid clinical decision‐making. Diffusion‐weighted magnetic resonance imaging (DW‐MRI) is sensitive to water diffusion throughout tissues, which correlates with Gleason score, a histological measure of prostate cancer aggressiveness. In this study the ability of DW‐MRI to detect prostate cancer onset and development was evaluated in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Materials and Methods T 2 ‐weighted and DW‐MRI were acquired using a 7T MR scanner, 200 mm bore diameter; 10 TRAMP and 6 C57BL/6 control mice were scanned every 4 weeks from 8 weeks of age until sacrifice at 28–30 weeks. After sacrifice, the genitourinary tract was excised and sectioned for histological analysis. Histology slides registered with DW‐MR images allowed for validation of DW‐MR images and the apparent diffusion coefficient (ADC) as tools for cancer detection and disease stratification. An automated early assessment tool based on ADC threshold values was developed to aid cancer detection and progression monitoring. Results The ADC differentiated between control prostate ((1.86 ± 0.20) × 10 −3 mm 2 /s) and normal TRAMP prostate ((1.38 ± 0.10) × 10 −3 mm 2 /s) ( P = 0.0001), between TRAMP prostate and well‐differentiated cancer ((0.93 ± 0.18) × 10 −3 mm 2 /s) ( P = 0.0006), and between well‐differentiated cancer and poorly differentiated cancer ((0.63 ± 0.06) × 10 −3 mm 2 /s) ( P = 0.02). Conclusion DW‐MRI is a tool for early detection of cancer, and discrimination between cancer stages in the TRAMP model. The incorporation of DW‐MRI‐based prostate cancer stratification and monitoring could increase the accuracy of preclinical trials using TRAMP mice. J. Magn. Reson. Imaging 2016;43:1207–1217.
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Abstract : Prostate cancer progresses from androgen-dependent to androgen-independent state. The androgen receptor (AR) isexpressed throughout progression. We would like to understand the AR role in this progression. Using lox-Cre methodology,we have generated mice in which AR function is abolished in the entire animal (ARKO) or tissue specific manner. We willgenerate mice with ARKO in prostate only or in different stages to be used to study prostate cancer progresses. Our Aimsfollow. 1: Generate mice lacking functional AR in prostate epithelium. 2: Generate inducible ARKO mouse line to be used todetermine potential effect of androgen in absence of AR on prostate growth/maintenance. 3: Determine AR role in prostatecancer development/progression by crossing ARKO mice with TRAMP mice to examine AR role in TRAMP induced prostatecancer and permit determination of points in prostate cancer requiring AR function. 4: Determine AR role in tumorigenicity ofandrogen-dependent and androgen-independent ARKO prostate cancer cell lines. The effect of AR loss in these cells will beexamined for ability to generate/promote tumors in mice. This year we generated mice with ARKO in the prostate epitheliumand will be able to continue the other aims in the proposal in the coming years.
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Abstract BACKGROUND Contrast enhanced imaging enables powerful, non‐invasive diagnostics, important for detection and staging of early prostate cancer. The uptake of contrast agent is increased in prostate cancer as compared to normal prostate tissue. To reveal the underlying physiological mechanisms, quantification of tissue components in pathology specimens may yield important information. Aim of this study was to investigate whether microvascularity is increased in prostate confined cancer (pT2). METHODS Radical prostatectomy specimens of 26 patients were selected for organ confined peripheral zone tumors which were restricted to one side of the prostate. Microvessels were visualized by immunohistochemistry against CD31. Specimens were scanned using a computer controlled microscope and scanning stage and vessels were recognized automatically. Pseudocolor mappings were produced showing number of vascular profiles (MVD), vascular area (MVA) and perimeter (MVP) in an overview of the entire prostate transection. MVD is a common measure for vascularity, whereas MVA represents the 3D vascular volume and MVP the perfused surface area. Mean, coefficient of variation and 75th percentile of these parameters were calculated automatically in manually indicated areas, consisting of the entire tumor area and the corresponding normal area in the contra lateral side of the prostate. RESULTS The mappings clearly indicate areas of increased vascularity in prostate transections. In tumor tissue an increase was found compared to normal tissue of 81%, 49%, and 62% for mean MVD, mean MVA and mean MVP, respectively ( P < 0.001 for all comparisons). In contrast, the heterogeneity in tumor vasculature was significantly decreased as compared to normal prostate ( P < 0.001). CONCLUSIONS Characteristics of microvasculature deviated significantly in pT2 prostate tumor as compared to normal tissue. Prostate 69: 62–69, 2009. © 2008 Wiley–Liss, Inc.
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Circumstantial evidence indicates that zinc may have an important role in the prostate. Total zinc levels in the prostate are 10 times higher than in other soft tissues. Zinc concentrations in prostate epithethial cancer cells are decreased significantly. Zinc supplementation for prevention and treatment of prostate cancer in humans has yielded controversial results. No studies have been reported in animal models to show the effect of zinc supplementation on prevention of prostate cancer, thus far. In this study, we have examined the effect of zinc supplementation on development of prostate cancer in a TRAMP mouse model. Results from our study indicate that dietary zinc plays an important role in prostate carcinogenesis. Tumor weights were significantly higher when the dietary zinc intake was either deficient or high in comparison to normal zinc intake level, suggesting that an optimal dietary zinc intake may play a protective role against prostate cancer. Further, our studies also showed decreased insulin-like growth factor (IGF)-1 and IGF-1/IGF binding protein-3 ratio in normal zinc-supplemented animals, suggesting that zinc may modulate IGF-1 metabolism in relation to carcinogenesis. We conclude that optimal prostate zinc concentration has a protective role against cancer.
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Using the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute and American total mortality rates, the authors calculated the probability at birth of having a diagnosis of prostate cancer within a man's life to be 8.8% and then subtracted the incidence of microscopic Stage A cancers too small to ever be clinically significant. This gave a final probability of 8%.Prostates were examined after 139 consecutive unselected cystoprostatectomies from patients with bladder cancers in whom it was unknown whether they had prostate cancer. Prostate cancer was found in 55 patients (40%); the volume of the largest cancer in each specimen was determined using histologic morphometry. The authors identified the 8% of these 139 cytoprostatectomy specimens with the largest volume of prostate cancer.The largest 11 of the 55 cancers represented 7.9% of the total 139 samples. These cancers ranged in volume from 0.5-6.1 ml, representing only 20% of all patients with prostate cancer.If the strong evidence is accepted that cancer progression is proportional to cancer volume, it was concluded that prostate cancers larger than 0.5 ml appear to correspond to the 8% of men who will be diagnosed with a clinically significant carcinoma, as derived previously. Conversely, those 80% of prostate cancers smaller than 0.5 ml probably are not likely to reach a clinically significant size in view of the long doubling time of this cancer.
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Proc Amer Assoc Cancer Res, Volume 47, 2006
4842
The purpose of these studies has been to use genetically engineered mouse (GEM) models to elucidate the molecular mechanisms whereby the IGF signaling axis contributes to the initiation and progression of prostate cancer. The rationale is based on strong epidemiological studies demonstrating that elevated serum IGF-I is associated with cancer risk and, in particular, prostate cancer risk. Indeed, in preliminary studies we demonstrated that the transformed prostate gland could produce IGF-1 and that expression of the IGF-1 receptor (IGF-1R) was reduced in metastatic lesions of intact and castrated TRAMP mice, supporting different roles for IGF-1 signaling in organ confined and disseminated disease. To further investigate the association between localized IGF-1R activity and prostate disease we generated a prostate-specific conditional IGF-1R knockout model using the Cre/LoxP strategy. Mice that express Cre recombinase in terminally differentiated prostate epithelial cells were crossed with mice carrying a LoxP modified IGF-1R allele and /or TRAMP. Using these mice we now demonstrate that (a) IGF-1R is required to maintain terminal differentiation of the prostate epithelium; (b) IGF-1R loss allows epithelial cells to proliferate; (c) proliferation following IGF-1R loss induces a cellular senescence rescue program likely regulated by p53 and (d) IGF-1R depletion or loss subsequent to malignant transformation does not inhibit but might in fact promote progression to more aggressive prostate cancer disease states. Therefore we now believe that IGF-1 action facilitates the genesis of prostate cancer by suppressing cellular senescence and apoptosis thereby allowing the epithelial cells to survive spontaneous transformation while still enforcing a strong differentiation block.
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Abstract The healthy prostate contains the highest concentration of mobile zinc in the body. As this level decreases dramatically during the initial development of prostate cancer, in vivo detection of prostate zinc content may be applied for diagnosis of prostate cancer. Using 19 F ion chemical exchange saturation transfer magnetic resonance imaging (iCEST MRI) and TF‐BAPTA as a fluorinated Zn‐binding probe with micromolar sensitivity, we show that iCEST MRI is able to differentiate between normal and malignant prostate cells with a 10‐fold difference in contrast following glucose‐stimulated zinc secretion in vitro. The iCEST signal decreased in normal prostate cells upon downregulation of the ZIP1 zinc transporter. In vivo, using an orthotopic prostate cancer mouse model and a transgenic adenocarcinoma of the mouse prostate (TRAMP) model, a gradual decrease of >300 % in iCEST contrast following the transition of normal prostate epithelial cells to cancer cells was detected.
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Aim To construct tissue microarrays (TMAs) that consisted of prostate tumours from the transgenic adenocarcinoma of mouse prostate (TRAMP) mice and non-transgenic murine prostates and to assess androgen receptor (AR) levels during progression of prostate cancer in TRAMP mice by immunohistochemistry.Methods Haematoxylin and eosin (H&E) sections from the ventral and dorso-lateral prostate lobes of non-transgenic, intact TRAMP and castrated TRAMP were used to demarcate regions of interest for TMAs construction. The samples on TMAs were used to evaluate AR expression using video image analysis (VIA).Results AR was expressed during cancer progression, but AR levels were reduced or absent in late stage disease. Furthermore, when AR levels were compared in tumours from intact and castrate animals, a significant increase in AR levels was observed following androgen ablation.Conclusion Similar to clinical prostate cancer, in the TRAMP model, prostate tumours evolve mechanisms to maintain AR expression and AR responsive gene pathways following castration to facilitate continued tumour growth. (Med J Indones 2010; 19:5-13)Keywords : androgen ablation therapy, tissue microarrays, haematoxylin and eosin, video image analysis
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