RESUMEN
BACKGROUND: Previously, 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. METHODS: Mice 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. RESULTS: Caloric 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). CONCLUSIONS: Despite 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.
Asunto(s)
Adenocarcinoma/dietoterapia , Quimiocina CCL2/genética , Inflamación/dietoterapia , Obesidad/dietoterapia , Neoplasias de la Próstata/dietoterapia , Adenocarcinoma/etiología , Adenocarcinoma/genética , Adenocarcinoma/patología , Animales , Composición Corporal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Dieta Baja en Carbohidratos , Dieta Cetogénica , Ingestión de Energía , Humanos , Inflamación/genética , Inflamación/patología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , Ratones Transgénicos , Obesidad/complicaciones , Obesidad/genética , Obesidad/patología , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: Epidemiologic and laboratory evidence supports a role for cholesterol in prostate cancer (PC). Dietary saturated fat content impacts serum cholesterol levels. However, epidemiologic associations between saturated fat and PC aggressiveness are inconsistent. We hypothesized that high saturated fat intake would be associated with increased PC aggressiveness, and that statin use would modify this association. METHODS: Of 1854 PC cases in the North Carolina-Louisiana PC Project, 321 (17%) were classified as high aggressive (Gleason sum ⩾8, PSA>20 ng ml-1, or Gleason sum ⩾7 and clinical stage T3-4) or low/intermediate aggressive (all other cases). Using low/intermediate aggressive cases as the referent group, we examined the association between tertiles of total fat-adjusted saturated fat intake and high aggressive PC using logistic regression, overall and stratified by race and statin use. We examined total fat-adjusted polyunsaturated and monounsaturated fatty acids (PUFA and MUFA, respectively), trans fat and cholesterol intake in secondary analysis. RESULTS: High total fat-adjusted saturated fat intake was associated with an elevated odds ratio (OR) for aggressive PC (ORT3vsT1 1.51; 95% CI 1.10-2.06; P-trend=0.009), with an attenuated association in statin users (ORT3vsT1 1.16; 95% CI 0.67-2.01; P-trend=0.661) compared with non-users (ORT3vsT1 1.71; 95% CI 1.16-2.51; P-trend=0.053). High total fat-adjusted cholesterol intake was associated with aggressive PC in European Americans (ORT3vsT1 1.62; 95% CI 1.02-2.58; P-trend=0.056), but not African Americans (ORT3vsT1 0.92; 95% CI 0.60-1.42; P-trend=0.750). High total fat-adjusted PUFA was inversely associated with PC aggressiveness (ORT3vsT1 0.75; 95% CI 0.55-1.03), although this was not significant. No associations were found between total fat-adjusted MUFA or trans fat and PC aggressiveness. CONCLUSIONS: High total fat-adjusted saturated fat intake was associated with increased PC aggressiveness, with a suggestion of a stronger effect in men not using statins. The association between total fat-adjusted cholesterol intake and PC aggressiveness was most pronounced in European Americans.
Asunto(s)
Grasas de la Dieta , Ácidos Grasos , Conducta Alimentaria , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/patología , Adulto , Anciano , Biomarcadores de Tumor , Grasas de la Dieta/efectos adversos , Progresión de la Enfermedad , Ácidos Grasos/efectos adversos , Humanos , Louisiana/epidemiología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , North Carolina/epidemiología , Oportunidad Relativa , Vigilancia de la Población , Neoplasias de la Próstata/epidemiología , Factores SocioeconómicosRESUMEN
Epidemiologic studies report a protective association between non-steroidal anti-inflammatory drug (NSAID) use and hormone receptor-positive breast cancer risk, a finding consistent with NSAID-mediated suppression of aromatase-driven estrogen biosynthesis. However, the association between NSAID use and breast cancer-specific mortality is uncertain and it is unknown whether this relationship differs by hormone receptor status. This study comprised 935 invasive breast cancer cases, of which 490 were estrogen receptor (ER)-positive, enrolled between 1996 and 2001 in the Carolina Breast Cancer Study. Self-reported NSAID use in the decade prior to diagnosis was categorized by duration and regularity of use. Differences in tumor size, stage, node, and receptor status by NSAID use were examined using Chi-square tests. Associations between NSAID use and breast cancer-specific mortality were examined using age- and race-adjusted Cox proportional hazards analysis. Tumor characteristics did not differ by NSAID use. Increased duration and regularity of NSAID use was associated with reduced breast cancer-specific mortality in women with ER-positive tumors (long-term regular use (≥8 days/month for ≥ 3 years) versus no use; hazard ratio (HR) 0.48; 95 % confidence interval (CI) 0.23-0.98), with a statistically significant trend with increasing duration and regularity (p-trend = 0.036). There was no association for ER-negative cases (HR 1.19; 95 %CI 0.50-2.81; p-trend = 0.891). Long-term, regular NSAID use in the decade prior to breast cancer diagnosis was associated with reduced breast cancer-specific mortality in ER-positive cases. If confirmed, these findings support the hypothesis that potential chemopreventive properties of NSAIDs are mediated, at least in part, through suppression of estrogen biosynthesis.
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Antiinflamatorios no Esteroideos/administración & dosificación , Neoplasias de la Mama/mortalidad , Receptores de Estrógenos/metabolismo , Adulto , Anciano , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana Edad , North Carolina/epidemiología , Receptores de Estrógenos/genéticaRESUMEN
BACKGROUND: While epidemiologic studies suggest that metformin use among diabetics may decrease prostate cancer (PC) incidence, the effect of metformin use on PC outcome is unclear. We investigated the association between pre-operative metformin use, dose and duration of use and biochemical recurrence (BCR) in PC patients with diabetes who underwent radical prostatectomy (RP). METHODS: We conducted a retrospective cohort analysis within the Shared Equal Access Regional Cancer Hospital (SEARCH) database of 371 PC patients with diabetes who underwent RP. Time to BCR between metformin users and non-users, and by metformin dose and duration of use was assessed using multivariable Cox proportional analysis adjusted for demographic, clinical and/or pathologic features. Time to castrate-resistant PC (CRPC), metastases and PC-specific mortality were explored as secondary outcomes using unadjusted analyses. RESULTS: Of 371 diabetic men, 156 (42%) were using metformin before RP. Metformin use was associated with more recent year of surgery (P<0.0001) but no clinical or pathologic characteristics. After adjustment for year of surgery, clinical and pathologic features, there were no associations between metformin use (hazard ratio (HR) 0.93; 95% confidence interval (CI) 0.61-1.41), high metformin dose (HR 0.96; 95% CI 0.57-1.61) or duration of use (HR 1.00; 95% CI 0.99-1.02) and time to BCR. A total of 14 patients (3.8%) developed CRPC, 10 (2.7%) distant metastases and 8 (2.2%) died from PC. Unadjusted analysis suggested that high metformin dose vs non-use was associated with increased risk of CRPC (HR 5.1; 95% CI 1.6-16.5), metastases (HR 4.8; 95% CI 1.2-18.5) and PC-specific mortality (HR 5.0; 95% CI 1.1-22.5). CONCLUSIONS: Metformin use, dose or duration of use was not associated with BCR in this cohort of diabetic PC patients treated with RP. The suggestion that higher metformin dose was associated with increased risk of CRPC, metastases and PC-specific mortality merits testing in large prospective studies with longer follow-up.
Asunto(s)
Hipoglucemiantes/efectos adversos , Metformina/efectos adversos , Neoplasias de la Próstata/patología , Anciano , Bases de Datos Factuales , Diabetes Mellitus/tratamiento farmacológico , Estudios de Seguimiento , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Masculino , Metformina/administración & dosificación , Metformina/uso terapéutico , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Evaluación del Resultado de la Atención al Paciente , Prostatectomía , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/cirugía , Estudios RetrospectivosRESUMEN
Obesity has been associated with increased incidence and mortality of oesophageal and colorectal adenocarcinoma. Excess central adiposity may drive this association through an altered inflammatory milieu. Utilising a unique adipose tissue bioresource we aimed to determine the pro-tumour properties of visceral adipose tissue. Comparing subcutaneous and visceral adipose tissue depots, we observed significantly higher levels of VEGF and IL-6, along with significantly higher proportions of CD8(+) T cells and NKT cells in visceral adipose tissue. Significantly higher levels of VEGF were observed in the conditioned media from visceral adipose tissue of centrally obese compared to non-obese patients. We also report a significant increase in oesophageal and colorectal tumour cell proliferation following culture with conditioned media from visceral adipose tissue of centrally obese patients. Neutralising VEGF in the conditioned media significantly decreased tumour cell proliferation. This novel report highlights a potential mechanism whereby visceral adipose tissue from centrally obese cancer patients may drive tumour progression.
Asunto(s)
Grasa Intraabdominal/patología , Neoplasias/patología , Obesidad/patología , Grasa Subcutánea/patología , Adulto , Anciano , Anciano de 80 o más Años , Procesos de Crecimiento Celular/fisiología , Femenino , Humanos , Inflamación/patología , Masculino , Persona de Mediana Edad , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Visceral adipose tissue may fuel obesity-associated chronic inflammation and tumorigenesis. T cells may be important in visceral adipose tissue in driving inflammation, but they have not yet been characterized in patients with cancer. This study aimed to characterize T lymphocytes in visceral adipose tissue and peripheral blood from patients with oesophageal adenocarcinoma. METHODS: Omental fat was taken from 35 patients with oesophageal adenocarcinoma at the start of surgery. Flow cytometry was performed to assess T cell activation status and cytokine production in omentum and peripheral blood. RESULTS: A large population of lymphocytes was present in the omentum. Omental CD4(+) and CD8(+) T cells displayed significantly enhanced expression of the T cell activation markers CD69 (P < 0·001) and CD107a (CD8(+) T cells: P < 0·01), and significantly decreased CD62L expression (P < 0·05), compared with blood. Significantly higher proportions of CD45RO(+) T cells compared with CD45RA(+) T cells were present in omentum (P < 0·001 and P = 0·012 for CD4(+) and CD8(+) cells respectively). Interferon γ was the most abundant cytokine expressed by omental T cells, with a significantly higher level than in blood and subcutaneous adipose tissue (P < 0·01). CONCLUSION: Visceral adipose tissue is a rich source of activated proinflammatory CD4(+) and CD8(+) T cells. It may fuel chronic inflammation via T cell-mediated pathways.