FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2149804766> ?p ?o ?g. }

• W2149804766 endingPage "3191" @default.
• W2149804766 startingPage "3180" @default.
• W2149804766 abstract "Epidemiological studies have provided evidence suggesting an important role for diet and obesity in the development of cancer. Specifically, lipid nutrients of the diet have been identified as important regulators of tumor development and progression. In the present study, we have examined the role of dietary fat and cholesterol in the initiation and progression of prostate cancer using the well-characterized TRAMP mouse model. Consumption of a Western-type diet—that is, enriched in both fat and cholesterol—accelerated prostate tumor incidence and tumor burden compared to mice fed a control chow diet. Furthermore, we also show that this diet increased the extent and the histological grade of prostate tumors. These findings were confirmed by the presence of increased levels of protein markers of advanced tumors in prostates obtained from animals fed a Western-type diet compared to those obtained from control animals. Increased lung metastases in animals fed a Western-type diet were also observed. In addition, we found that with a Western diet, animals bearing tumors presented with reduced plasma cholesterol levels compared with animals fed a control diet. Finally, we show that tumors obtained from animals fed a Western-type diet displayed increased expression of the high-density lipoprotein receptor SR-BI and increased angiogenesis. Taken together, our data suggest that dietary fat and cholesterol play an important role in the development of prostate cancer. Epidemiological studies have provided evidence suggesting an important role for diet and obesity in the development of cancer. Specifically, lipid nutrients of the diet have been identified as important regulators of tumor development and progression. In the present study, we have examined the role of dietary fat and cholesterol in the initiation and progression of prostate cancer using the well-characterized TRAMP mouse model. Consumption of a Western-type diet—that is, enriched in both fat and cholesterol—accelerated prostate tumor incidence and tumor burden compared to mice fed a control chow diet. Furthermore, we also show that this diet increased the extent and the histological grade of prostate tumors. These findings were confirmed by the presence of increased levels of protein markers of advanced tumors in prostates obtained from animals fed a Western-type diet compared to those obtained from control animals. Increased lung metastases in animals fed a Western-type diet were also observed. In addition, we found that with a Western diet, animals bearing tumors presented with reduced plasma cholesterol levels compared with animals fed a control diet. Finally, we show that tumors obtained from animals fed a Western-type diet displayed increased expression of the high-density lipoprotein receptor SR-BI and increased angiogenesis. Taken together, our data suggest that dietary fat and cholesterol play an important role in the development of prostate cancer. According to cancer statistics published by the American Cancer Society, prostate cancer is the most frequently diagnosed cancer and the second-leading cause of cancer deaths among men in the United States (American Cancer Society, Cancer Facts & Figures 2010, http://www.cancer.org/Research/cancer-facts-and-figures-2010, last accessed October 15, 2010). There is strong evidence suggesting that genetic changes in epithelial cells of the prostate are almost inevitable with aging. Therefore, the prevalence of small, latent prostatic carcinomas is believed to be similar across many populations.1Hsing AW Devesa SS Trends and patterns of prostate cancer: what do they suggest?.Epidemiol Rev. 2001; 23: 3-13Crossref PubMed Scopus (222) Google Scholar However, marked geographic variation exists in the clinical incidence of prostate cancer, ranging from 2.3 per 100,000 men in China to 101 and 137 per 100,000 men in white and black Americans.2Hsing AW Tsao L Devesa SS International trends and patterns of prostate cancer incidence and mortality.Int J Cancer. 2000; 85: 60-67Crossref PubMed Scopus (699) Google Scholar Interestingly, the incidence of prostate cancer in Chinese and Japanese men increases substantially after migration to the United States.3Shimizu H Ross RK Bernstein L Yatani R Henderson BE Mack TM Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County.Br J Cancer. 1991; 63: 963-966Crossref PubMed Scopus (742) Google Scholar, 4Klassen AC Platz EA What can geography tell us about prostate cancer?.Am J Prev Med. 2006; 30: S7-S15Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Such differences may be attributable to the acquisition of more “Westernized” behaviors, such as change in diet, activity level, and/or use of substances such as tobacco and alcohol. Regarding the diet, migration of Asians to Western countries implies not only the consumption of more animal-based diets, but also a reduction in the consumption of a diet enriched in certain types of vegetables. In this case, consumption of phytochemicals has been demonstrated to potentially reduce cancer risk. These diets are enriched in polyphenols (found in green tea) and phytoestrogens (present in large quantities in soy products).5Wu AH Yu MC Tseng CC Hankin J Pike MC Green tea and risk of breast cancer in Asian Americans.Int J Cancer. 2003; 106: 574-579Crossref PubMed Scopus (227) Google Scholar From these observations stems the hypothesis that environmental factors, most likely present in the diet, may act as late stage promoters responsible for the transformation of the prostate tumor from a latent form into a more aggressive and clinically-apparent form.4Klassen AC Platz EA What can geography tell us about prostate cancer?.Am J Prev Med. 2006; 30: S7-S15Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Diet and obesity are now considered important risk factors for cancer development.6Cowey S Hardy RW The metabolic syndrome: a high-risk state for cancer?.Am J Pathol. 2006; 169: 1505-1522Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar, 7McMillan DC Sattar N McArdle CS ABC of obesity. Obesity and cancer.BMJ. 2006; 333: 1109-1111Crossref PubMed Google Scholar Experimental and epidemiological evidences have suggested that increased dietary fat intake may be associated with increased prostate cancer risk.8Pollard M Luckert PH Promotional effects of testosterone and high fat diet on the development of autochthonous prostate cancer in rats.Cancer Lett. 1986; 32: 223-227Abstract Full Text PDF PubMed Scopus (69) Google Scholar, 9Kolonel LN Nomura AM Cooney RV Dietary fat and prostate cancer: current status.J Natl Cancer Inst. 1999; 91: 414-428Crossref PubMed Scopus (208) Google Scholar, 10Michaud DS Augustsson K Rimm EB Stampfer MJ Willet WC Giovannucci E A prospective study on intake of animal products and risk of prostate cancer.Cancer Causes Control. 2001; 12: 557-567Crossref PubMed Scopus (178) Google Scholar, 11Sonn GA Aronson W Litwin MS Impact of diet on prostate cancer: a review.Prostate Cancer Prostatic Dis. 2005; 8: 304-310Crossref PubMed Scopus (142) Google Scholar However, as the literature on the topic has expanded, the fat–cancer association has become more tenuous, with recent important studies not confirming this association.12Crowe FL Key TJ Appleby PN Travis RC Overvad K Jakobsen MU Johnsen NF Tjonneland A Linseisen J Rohrmann S Boeing H Pischon T Trichopoulou A Lagiou P Trichopoulos D Sacerdote C Palli D Tumino R Krogh V Bueno-de-Mesquita HB Kiemeney LA Chirlaque MD Ardanaz E Sanchez MJ Larranaga N Gonzalez CA Quiros JR Manjer J Wirfalt E Stattin P Hallmans G Khaw KT Bingham S Ferrari P Slimani N Jenab M Riboli E Dietary fat intake and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition.Am J Clin Nutr. 2008; 87: 1405-1413PubMed Google Scholar Conversely, the specific dietary nutrients that may predispose to prostate cancer are not clear.13Gerber M Background review paper on total fat, fatty acid intake and cancers.Ann Nutr Metab. 2009; 55: 140-161Crossref PubMed Scopus (62) Google Scholar Several studies have demonstrated that cholesterol, a prominent lipid component of the Western diet, accumulates in solid tumors. In addition, cholesterol homeostasis is altered in the prostate with aging and during the transition to malignant tumors.14Swyer G The cholesterol content of normal and enlarged prostates.Cancer Res. 1942; 2: 372-375Google Scholar, 15Schaffner CP Prostatic cholesterol metabolism: regulation and alteration.Prog Clin Biol Res. 1981; 75A: 279-324PubMed Google Scholar, 16Hager MH Solomon KR Freeman MR The role of cholesterol in prostate cancer.Curr Opin Clin Nutr Metab Care. 2006; 9: 379-385Crossref PubMed Scopus (123) Google Scholar, 17Ettinger SL Sobel R Whitmore TG Akbari M Bradley DR Gleave ME Nelson CC Dysregulation of sterol response element-binding proteins and downstream effectors in prostate cancer during progression to androgen independence.Cancer Res. 2004; 64: 2212-2221Crossref PubMed Scopus (231) Google Scholar, 18Chen Y Hughes-Fulford M Human prostate cancer cells lack feedback regulation of low-density lipoprotein receptor and its regulator. SREBP2.Int J Cancer. 2001; 91: 41-45Crossref PubMed Scopus (135) Google Scholar, 19Porstmann T Griffiths B Chung YL Delpuech O Griffiths JR Downward J Schulze A PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP.Oncogene. 2005; 24: 6465-6481Crossref PubMed Scopus (340) Google Scholar Nevertheless, the investigation of a possible relationship between dietary and plasma cholesterol levels and tumor incidence has offered contradictory results. In some epidemiological studies, a significant positive correlation has been obtained between hypercholesterolemia and prostate cancer incidence.20Bravi F Scotti L Bosetti C Talamini R Negri E Montella M Franceschi S La Vecchia C Self-reported history of hypercholesterolaemia and gallstones and the risk of prostate cancer.Ann Oncol. 2006; 17: 1014-1017Crossref PubMed Scopus (60) Google Scholar Additional research has demonstrated statistically significant correlations between dietary cholesterol intake and cancer risk.21De Stefani E Mendilaharsu M Deneo-Pellegrini H Ronco A Influence of dietary levels of fat, cholesterol, and calcium on colorectal cancer.Nutr Cancer. 1997; 29: 83-89Crossref PubMed Scopus (32) Google Scholar, 22Horn-Ross PL Morrow M Ljung BM Diet and the risk of salivary gland cancer.Am J Epidemiol. 1997; 146: 171-176Crossref PubMed Scopus (51) Google Scholar, 23Jarvinen R Knekt P Hakulinen T Rissanen H Heliovaara M Dietary fat, cholesterol and colorectal cancer in a prospective study.Br J Cancer. 2001; 85: 357-361Crossref PubMed Scopus (128) Google Scholar Tumor progression may also be correlated with a progressive decrease in plasma cholesterol levels.24Rose G Shipley MJ Plasma lipids and mortality: a source of error.Lancet. 1980; 1: 523-526Abstract PubMed Scopus (216) Google Scholar In this case, it has been suggested that decreased plasma cholesterol levels may be a metabolic consequence of the tumor existence instead of a cause. In agreement with these hypotheses, recent studies have even suggested that statin treatment of hypercholesterolemia may be associated with reduced prostate cancer incidence.25Murtola TJ Tammela TL Maattanen L Huhtala H Platz EA Ala-Opas M Stenman UH Auvinen A Prostate cancer and PSA among statin users in the finnish prostate cancer screening trial.Int J Cancer. 2010; 127: 1650-1659Crossref PubMed Scopus (84) Google Scholar Taken together, these data suggest that increased plasma cholesterol levels may be a predisposing factor for cancer development. However, in later stages of cancer development, plasma cholesterol levels are reduced possibly because of an increased utilization by the developing tumors.26Iribarren C Reed DM Chen R Yano K Dwyer JH Low serum cholesterol and mortality. Which is the cause and which is the effect?.Circulation. 1995; 92: 2396-2403Crossref PubMed Scopus (112) Google Scholar In the present study, we have tested the hypothesis that increased dietary fat and cholesterol, and consequently, increased plasma cholesterol levels, may play an important role in prostate cancer onset and progression as well as in metastasis development. To evaluate this possibility, we have used the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which spontaneously develops prostate tumors. TRAMP male mice carry a transgene that allows the expression of the SV40 large T antigen under the control of a prostate-specific promoter (probasin). As a consequence, male TRAMP mice develop spontaneous multistage prostate cancer that exhibits both histological and molecular features similar to those observed in human prostate cancer cases. In this model, prostate cancer progresses from prostatic intraepithelial neoplasia (PIN) that is thought to be a precursor lesion, to adenocarcinoma. PIN is believed to lead to microinvasion, which subsequently results in frank invasion and metastatic disease.27Bostwick DG Brawer MK Prostatic intra-epithelial neoplasia and early invasion in prostate cancer.Cancer. 1987; 59: 788-794Crossref PubMed Scopus (456) Google Scholar, 28Kaplan-Lefko PJ Chen TM Ittmann MM Barrios RJ Ayala GE Huss WJ Maddison LA Foster BA Greenberg NM Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model.Prostate. 2003; 55: 219-237Crossref PubMed Scopus (366) Google Scholar Distant site metastases can be detected in male TRAMP mice as early as 12 weeks of age, and by 28 weeks of age a significant proportion of animals harbor prostate tumors that metastasize to the lymph nodes and lungs.29Greenberg NM DeMayo F Finegold MJ Medina D Tilley WD Aspinall JO Cunha GR Donjacour AA Matusik RJ Rosen JM Prostate cancer in a transgenic mouse.Proc Natl Acad Sci USA. 1995; 92: 3439-3443Crossref PubMed Scopus (1077) Google Scholar, 30Gingrich JR Barrios RJ Foster BA Greenberg NM Pathologic progression of autochthonous prostate cancer in the TRAMP model.Prostate Cancer Prostatic Dis. 1999; 2: 70-75Crossref PubMed Scopus (197) Google Scholar Antibodies and their sources were as follows: rabbit polyclonal anti-cyclin D1 was from NeoMarkers (Fremont, CA); mouse monoclonal anti-PCNA was from Santa Cruz Biotechnology, Inc. (Palo Alto, CA); rabbit polyclonal anti-SR-BI was from Novus Biologicals, Inc. (Littleton, CO); and rabbit anti-CD31 was from Abcam, Inc. (Cambridge, MA). All animals were housed and maintained in a barrier facility at the Kimmel Cancer Center at Thomas Jefferson University. Mice were kept on a 12-hour light/dark cycle with ad libitum access to food and water. Animal protocols used in this study were approved by the Institutional Animal Care and Use Committee from Thomas Jefferson University. TRAMP (transgenic adenocarcinoma of mouse prostate) mice expressing the SV40 large T-antigen under the control of the prostate specific rat probasin promoter were obtained from The Jackson Laboratory (Bar Harbor, ME). All mice used in this study were in the C57Bl/6J background. Transgenic males were distinguished from their non-transgenic littermates for the presence of the TRAMP transgene by PCR, as suggested by The Jackson Laboratory (Bar Harbor, ME). All TRAMP mice used in this study were hemizygous for the TRAMP transgene. For tumor studies, 8-week-old TRAMP males and their nontransgenic littermates were distributed into either a chow diet (regular chow diet containing 4.5% fat and 0.002% cholesterol (wt/wt), TestDiet) or a Western diet (typical Western-type diet containing 21.2% fat and 0.2% cholesterol (wt/wt), TestDiet) and sacrificed at 28 weeks of age. Carbohydrate content (50% and 48% for chow and Western diet, respectively) and energetic values (4.14 and 4.43 kcal/g for chow and Western diet, respectively) were similar between the two diets. The number of mice for each experimental group ranged from 17 to 19. At the time of sacrifice, total body weight and epididymal fat weight were determined for each mouse. The genitourinary (GU) tract including the bladder, seminal vesicles, ampulary gland, and prostate was excised en bloc and weighed. Whenever possible, the GU tract was further dissected under a dissecting microscope to excise the prostate individual lobes. Therefore, each pair of ventral, lateral, dorsal, and anterior lobes was microdissected and frozen in liquid nitrogen or fixed in 10% neutral buffered formalin. Whenever a gross tumor obscured the boundaries of the individual prostatic lobes and so that no individual isolation was possible, the whole tumor mass was dissected, weighed, and formalin-fixed for further histopathological analysis. Ventral and anterior prostate lobes dissected from male mice at 28 weeks of age were fixed with 10% neutral buffered formalin for 24 hours, transferred to 70% ethanol, dehydrated, and embedded in paraffin. Sections were cut at 5 μm, stained with hematoxylin and eosin, and evaluated by an experienced histopathologist without the knowledge of the mouse genotype or experimental group. Each prostatic lobe was graded as normal, prostatic intraepithelial neoplasia (PIN), well-differentiated adenocarcinoma (WD), moderately-differentiated adenocarcinoma (MD), and poorly-differentiated adenocarcinoma (PD) using a scale that had been previously established for TRAMP mice.28Kaplan-Lefko PJ Chen TM Ittmann MM Barrios RJ Ayala GE Huss WJ Maddison LA Foster BA Greenberg NM Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model.Prostate. 2003; 55: 219-237Crossref PubMed Scopus (366) Google Scholar, 30Gingrich JR Barrios RJ Foster BA Greenberg NM Pathologic progression of autochthonous prostate cancer in the TRAMP model.Prostate Cancer Prostatic Dis. 1999; 2: 70-75Crossref PubMed Scopus (197) Google Scholar Sections from 8 to 10 mice were analyzed for each experimental condition. Computer-assisted image analysis was performed using an Olympus BX51 System Microscope (Olympus Corp., Miami, FL) equipped with a Micropublisher 5.0 cooled CCD camera (QImaging Corp., Burnaby, BC). After removal of the GU tract, 28-week-old TRAMP male mice were injected with 2 ml of 10% neutral buffered formalin by tracheal cannulation to fix the inner spaces and inflate the lung lobes. Lungs were then excised and placed into formalin for 24 hours. The left lung of each animal was paraffin-embedded, sectioned at 50-μm intervals, and stained with hematoxylin and eosin. Lung metastasis were scored as the total number of metastatic foci (defined as a cluster of 10 or more cells) per lung, as we previously described.31Williams TM Medina F Badano I Hazan RB Hutchinson J Muller WJ Chopra NG Scherer PE Pestell RG Lisanti MP Caveolin-1 gene disruption promotes mammary tumorigenesis and dramatically enhances lung metastasis in vivo. Role of Cav-1 in cell invasiveness and matrix metalloproteinase (MMP-2/9) secretion.J Biol Chem. 2004; 279: 51630-51646Crossref PubMed Scopus (267) Google Scholar We analyzed the lungs obtained from 7 and 9 mice fed a chow or a Western diet, respectively. Paraffin-embedded ventral prostatic lobes were first deparaffinized by treatment with xylene and then rehydrated by passage through a graded series of ethanol. Antigen retrieval was performed by placing the slides in a sodium citrate buffer solution in a pressure cooker. Endogenous peroxidase activity was quenched by incubation in 3% H2O2. Slides were then washed with PBS, blocked with 10% normal goat serum (Vector Laboratories, Inc., Burlingame, CA) in PBS for 1 hour, and incubated with the primary antibody diluted in blocking solution overnight at 4°C. Sections were then incubated with a biotin-streptavidin detection system (LSAB2 System-HRP, Dako North America, Inc., Carpinteria, CA), and bound antibodies were visualized using 3,3′–diaminobenzidine (DAB) as a substrate. Finally, slides were washed in PBS, counterstained with hematoxylin, dehydrated, and mounted with coverslips. Sections from four TRAMP males fed either a chow or a Western-type diet were stained. Computer-assisted image analysis was performed using an Olympus BX51 System Microscope (Olympus Corp., Miami, FL) equipped with a Micropublisher 5.0-cooled CCD camera (QImaging Corp., Burnaby, BC). Plasma samples from TRAMP male mice and their nontrangenic littermates were obtained by tail bleeding at 8 (basal levels before distribution of the mice into the different diets) and 22 weeks of age, and by cardiac puncture after the mice had been sacrificed at 28 weeks of age. Total plasma cholesterol levels were determined using a colorimetric assay kit (Wako Chemicals USA, Inc., Richmond, VA). The number of mice in each experimental group ranged from 17 to 19. Lipoprotein profiles were determined by fast protein liquid chromatography (FPLC). Fasting plasma samples obtained from 10 mice in each group were pooled to obtain a total volume of 150 μl and loaded onto a Superose 6 column (GE Health care Bio-Sciences Corp., Piscataway, NJ) to achieve a total bed volume of 25 ml and a void volume of 7.5 ml. Plasma was passed through the column at a flow rate of 0.25 ml/min, and 0.5-ml fractions were collected. Total cholesterol content of each fraction was determined (Wako Chemicals USA, Inc., Richmond, VA) and plotted against elution volume. Values were reported as the mean ± SE. Comparisons between control and treated mouse samples were performed using the Student's t-test or by analysis of variance when appropriate. The number of mice used for each experiment was indicated in the corresponding figure legend. To directly assess the role of dietary fat and cholesterol on prostate tumor onset and progression, we fed 8-week-old TRAMP male mice with a chow diet (containing 4.5% fat and 0.002% cholesterol) or a Western diet (containing 21.2% fat and 0.2% cholesterol). On necropsy at 28 weeks, 33% (6 of 18 mice) of TRAMP mice fed a Western diet showed a grossly evident spherical prostate tumor. By contrast, the incidence of grossly-identifiable tumors in TRAMP mice fed a chow diet was only 17% (3 of 17 mice) (Figure 1A). Whenever present, prostate bulky tumors were carefully excised and weighed. Taking the total tumor weight per mouse into account, TRAMP mice fed a Western diet were shown to develop larger tumors with an average of 6.00 ± 2.09 g as compared to only 2.42 ± 1.17 g for mice fed a chow diet (Figure 1B). Figure 1C shows representative pictures of GU tracts corresponding to 28-week-old TRAMP males. Note the increased tumor size observed in the Western diet group. Histological examination of the prostate gross tumors revealed that all tumors were of high-grade and poorly differentiated adenocarcinomas (Figure 1D). However, in the majority (83 and 67% in the chow and the Western diet groups, respectively) of 28-week-old TRAMP males a bulky tumor was not present. In those cases, the weight of the whole GU tract was taken as an indirect measure of tumor volume, and then individual prostate lobes were excised and histologically examined. As expected, the GU weight in TRAMP mice was significantly greater than in the corresponding nontransgenic littermates in both chow and Western diet fed mice (P < 0.001) (Figure 2B). Interestingly, hyperplasia of the GU apparatus was significantly enhanced (1.77 ± 0.13 g versus 1.21 ± 0.09 g; P < 0.001) in mice fed a Western diet as compared to mice fed a chow diet (Figure 2B). Representative pictures of the different GU tracts are shown in Figure 2A. Taken together, these data indicate that consumption of a typical Western-type diet results in increased tumor incidence and burden, suggesting an important role for dietary fat and cholesterol in prostate tumor formation. In addition to following the tumor incidence and burden, we also examined whether dietary fat and cholesterol could affect tumor aggressiveness. Therefore, ventral and anterior prostatic lobes were obtained from each animal, dissected, sectioned, and histologically examined. Representative histological sections are shown for ventral (Figure 3) and anterior (Figure 4) prostates and for each experimental condition (n = 8–10 mice for each group). As expected, ventral (Figure 3A) and anterior (Figure 4A) lobes obtained from nontrangenic males were composed of prostatic glands embedded in a loose stroma. Glands were evenly distributed and regular in shape and size. They were lined by tall columnar cells and showed intraluminal projections with fibrovascular cores. Importantly, no histological differences were observed between ventral and anterior prostates obtained from non-transgenic mice fed a regular chow diet and those obtained from mice fed a Western-type diet (data not shown).Figure 4TRAMP mice fed a Western-type diet show more advanced anterior prostate carcinogenic lesions. Anterior prostate lobes of nontransgenic and TRAMP male mice fed a chow or a Western diet until 28 weeks of age were microdissected, fixed, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Representative histological images are shown of anterior prostates corresponding to nontransgenic littermates (A), TRAMP males fed a chow diet (B), and TRAMP males fed a Western diet (C). Images were taken at an original magnification of ×40. Each section was graded as normal (N), prostatic intraepithelial neoplasia (PIN), well-differentiated adenocarcinoma (WD), moderately differentiated adenocarcinoma (MD), and poorly differentiated adenocarcinoma (PD) using a scale that had been previously established for TRAMP mice. The percentage of mice in a given histopathological stage is represented (D). Nine TRAMP males fed a chow diet and eight TRAMP males fed a Western diet were examined. Scale bars = 50 μm.View Large Image Figure ViewerDownload Hi-res image Download (PPT) All ventral prostate sections corresponding to TRAMP mice fed a chow diet showed replacement of normal columnar epithelium by hyperchromatic cells forming multilayered groups (Figure 3B). These atypical cells displayed nuclear enlargement, crowding, and loss of polarity as typically seen in high-grade prostatic intraepithelial neoplasia (PIN) (Figure 3D). Most glands maintained regular outline, and there was no change in the surrounding stroma. By contrast, only 30% (3 of 10 mice) of the TRAMP males fed a Western diet were classified as being in the high-grade PIN stage, whereas 70% (7 of 10 mice) of the mice examined showed markedly distended glands and foci of invasion characterized by the presence of irregularly shaped small glands surrounded by desmoplastic stroma (Figure 3C). These prostate tumors were therefore classified as being in the moderately differentiated stage (Figure 3D). Regarding the anterior prostate analysis, partial replacement of normal columnar epithelium by atypical cells was observed in all of the TRAMP mice fed a chow diet (Figure 4B). By comparison, a higher architectural complexity and a higher replacement by high-grade PIN were observed in TRAMP mice fed a Western diet as compared with mice fed a chow diet (Figure 4C). Moreover, 25% of mice fed a Western diet showed bright eosinophilic secretion and signs of invasion that were not present in any of the mice fed the chow diet (Figure 4D). Therefore, consumption of a Western-type diet results in the worsening of the histological grade of prostate cancer. Cyclin D1 has been suggested as an appropriate protein marker for prostate tumorigenesis in TRAMP mice because its expression levels have been found to increase gradually concomitant to tumor progression.32Khor TO Yu S Barve A Hao X Hong JL Lin W Foster B Huang MT Newmark HL Kong AN Dietary feeding of dibenzoylmethane inhibits prostate cancer in transgenic adenocarcinoma of the mouse prostate model.Cancer Res. 2009; 69: 7096-7102Crossref PubMed Scopus (32) Google Scholar The expression level of cyclin D1 was therefore examined in the ventral prostates by immunohistochemistry. Confirming the aggravation of the prostate tumors, cyclin D1 expression was shown to be significantly more elevated in tumors obtained from TRAMP mice fed a Western diet compared to samples derived from TRAMP mice fed a chow diet (Figure 5A). We next examined the expression levels of the proliferating cell nuclear antigen (PCNA), a well characterized marker for cellular proliferation. Immunohistochemical analysis revealed an important increase in the number of PCNA-positive cells in the prostate of TRAMP mice fed a Western diet compared to those of mice fed a chow diet (Figure 5B). Because the ability of tumor cells to metastasize closely correlates with the pathological grade of the tumor, we also sought to determine whether the consumption of a typical Western-type diet could affect the development of metastases in TRAMP mice. We found that consumption of a Western diet resulted in significantly higher levels of pulmonary metastasis. Thus, 67% (6 of 9 mice) of TRAMP mice fed a Western diet demonstrated the presence of at least one metastatic focus, as compared with 43% (3 of 7 mice) in the group of mice fed a chow diet (Figure 6A). Importantly, control mice lacking the TRAMP transgene did not exhibit any lung metastasis. Furthermore, the number of metastases found in the left lung of each animal was 6.9 times higher in TRAMP mice fed a Western diet, with an average of 3 ± 1.04 metastatic foci versus 0.43 ± 0.2 foci found in the chow diet group (Figure 6B). Fasting plasma samples were collected from TRAMP males and their nontransgenic littermates at 8, 22, and 28 weeks. Consequently, total plasma cholesterol (Figure 7A) and lipoprotein levels (Figure 7, B and C) were determined before t" @default.
• W2149804766 created "2016-06-24" @default.
• W2149804766 creator A5016681558 @default.
• W2149804766 creator A5023663886 @default.
• W2149804766 creator A5055537625 @default.
• W2149804766 creator A5062666855 @default.
• W2149804766 creator A5075885063 @default.
• W2149804766 creator A5079594267 @default.
• W2149804766 creator A5083019927 @default.
• W2149804766 date "2010-12-01" @default.
• W2149804766 modified "2023-10-09" @default.
• W2149804766 title "A Western-Type Diet Accelerates Tumor Progression in an Autochthonous Mouse Model of Prostate Cancer" @default.
• W2149804766 cites W1488600094 @default.
• W2149804766 cites W1530875344 @default.
• W2149804766 cites W162561352 @default.
• W2149804766 cites W1964181861 @default.
• W2149804766 cites W1965762546 @default.
• W2149804766 cites W1966665490 @default.
• W2149804766 cites W1971740567 @default.
• W2149804766 cites W1974664586 @default.
• W2149804766 cites W1984750966 @default.
• W2149804766 cites W1988959205 @default.
• W2149804766 cites W1992177921 @default.
• W2149804766 cites W1997156303 @default.
• W2149804766 cites W1999575737 @default.
• W2149804766 cites W2001679453 @default.
• W2149804766 cites W2010057554 @default.
• W2149804766 cites W2021181403 @default.
• W2149804766 cites W2022733347 @default.
• W2149804766 cites W2034464608 @default.
• W2149804766 cites W2035030519 @default.
• W2149804766 cites W2040661984 @default.
• W2149804766 cites W2044087374 @default.
• W2149804766 cites W2045873744 @default.
• W2149804766 cites W2047057336 @default.
• W2149804766 cites W2051823539 @default.
• W2149804766 cites W2054913269 @default.
• W2149804766 cites W2060656087 @default.
• W2149804766 cites W2062113746 @default.
• W2149804766 cites W2067083587 @default.
• W2149804766 cites W2070783596 @default.
• W2149804766 cites W2075884509 @default.
• W2149804766 cites W2078107567 @default.
• W2149804766 cites W2084197013 @default.
• W2149804766 cites W2084541894 @default.
• W2149804766 cites W2087775316 @default.
• W2149804766 cites W2087797579 @default.
• W2149804766 cites W2088879795 @default.
• W2149804766 cites W2109998568 @default.
• W2149804766 cites W2110271263 @default.
• W2149804766 cites W2110527632 @default.
• W2149804766 cites W2117104576 @default.
• W2149804766 cites W2124839644 @default.
• W2149804766 cites W2132973959 @default.
• W2149804766 cites W2136522333 @default.
• W2149804766 cites W2142285790 @default.
• W2149804766 cites W2148733940 @default.
• W2149804766 cites W2155407519 @default.
• W2149804766 cites W2156818917 @default.
• W2149804766 cites W2157145517 @default.
• W2149804766 cites W2158174974 @default.
• W2149804766 cites W2167342921 @default.
• W2149804766 cites W2167970739 @default.
• W2149804766 cites W2171294131 @default.
• W2149804766 cites W4231953333 @default.
• W2149804766 cites W4233116228 @default.
• W2149804766 doi "https://doi.org/10.2353/ajpath.2010.100568" @default.
• W2149804766 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2993263" @default.
• W2149804766 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/21088217" @default.
• W2149804766 hasPublicationYear "2010" @default.
• W2149804766 type Work @default.
• W2149804766 sameAs 2149804766 @default.
• W2149804766 citedByCount "105" @default.
• W2149804766 countsByYear W21498047662012 @default.
• W2149804766 countsByYear W21498047662013 @default.
• W2149804766 countsByYear W21498047662014 @default.
• W2149804766 countsByYear W21498047662015 @default.
• W2149804766 countsByYear W21498047662016 @default.
• W2149804766 countsByYear W21498047662017 @default.
• W2149804766 countsByYear W21498047662018 @default.
• W2149804766 countsByYear W21498047662019 @default.
• W2149804766 countsByYear W21498047662020 @default.
• W2149804766 countsByYear W21498047662021 @default.
• W2149804766 countsByYear W21498047662022 @default.
• W2149804766 countsByYear W21498047662023 @default.
• W2149804766 crossrefType "journal-article" @default.
• W2149804766 hasAuthorship W2149804766A5016681558 @default.
• W2149804766 hasAuthorship W2149804766A5023663886 @default.
• W2149804766 hasAuthorship W2149804766A5055537625 @default.
• W2149804766 hasAuthorship W2149804766A5062666855 @default.
• W2149804766 hasAuthorship W2149804766A5075885063 @default.
• W2149804766 hasAuthorship W2149804766A5079594267 @default.
• W2149804766 hasAuthorship W2149804766A5083019927 @default.
• W2149804766 hasBestOaLocation W21498047661 @default.
• W2149804766 hasConcept C121608353 @default.
• W2149804766 hasConcept C126322002 @default.
• W2149804766 hasConcept C142724271 @default.
• W2149804766 hasConcept C143998085 @default.

• next