RESUMO
Obesity is associated with non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Obesity and metabolic abnormalities resulting in low-grade inflammation can increase the risk of developing NASH and HCC. NASH, a risk factor for HCC, is characterized by increased inflammation, lipid accumulation, and liver injury. Obesogenic proteins modulate signaling pathways that induce physiological changes including lipogenesis, ROS, and inflammation. Silibinin, a polyphenol in milk thistle seed, has been shown to have anti-inflammatory properties. Studies have yet to determine whether silibinin can be used to dissect the obesity-cancer link to delay progression of liver cancer. Using an in vitro model, sera from obese (OB), overweight (OW), or normal weight (NW) males (based on BMI) were used to determine the efficacy of silibinin to reduce the pro-tumorigenic properties of obesity. HepG2 cells were exposed to OB, OW, NW ± silibinin and tested for growth, ROS, lipogenesis, MMP-9, invasion and protein expression. Silibinin suppressed obesity-induced growth, ROS, lipogenesis, MMP-9, and cell invasion. These physiological changes corresponded with decreased FASN, IL-6, IL-1B, and phosphorylated Erk. We describe the differential effect of sera from OB, OW, and NW males on characteristics relevant for liver cancer and the potential use of silibinin to mitigate these effects.
Assuntos
Neoplasias Hepáticas/tratamento farmacológico , Obesidade/tratamento farmacológico , Silimarina/farmacologia , Índice de Massa Corporal , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Células Hep G2 , Humanos , Inflamação , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipogênese/efeitos dos fármacos , Neoplasias Hepáticas/complicações , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Obesidade/complicações , Sobrepeso/complicações , Sobrepeso/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Fatores de Risco , SilibinaRESUMO
Obesity is associated with a greater risk of prostate cancer mortality. However, the mechanisms connecting obesity to the progression of prostate cancer remain unknown. This study determined the impact of obesity on macrophage recruitment and tumor-associated macrophage (TAM) polarization in the prostate tumor microenvironment, since a high concentration of TAMs in tumors has been linked to progression in prostate cancer. We utilized an in vitro model in which pre-adipocytes, prostate cancer cells, and macrophages were exposed to sera from obese or nonobese men, or conditioned media generated under obese or nonobese conditions. Matrigel invasion chambers were used to assess macrophage recruitment in vitro, and immunohistochemical analysis evaluated recruitment in a PTEN knockout mouse model. qPCR was used to measure mRNA levels of CCL2, COX-2, IL-10, TGF-beta, VEGF-A, arginase-1, and MMP-9. PGE2 production was measured by ELISA. Obesity increased macrophage and TAM recruitment, and increased mRNA levels of TAM markers in macrophages. Similarly, obese conditions increased CCL2 and COX-2 expression, as well as PGE2 levels in prostate cancer cells. COX-2 inhibition resulted in lower expression of obesity-induced TAM markers. Our data suggest that obesity promotes macrophage infiltration into the prostate tumor microenvironment, and induces TAM polarization through the COX-2/PGE2 pathway.
Assuntos
Macrófagos/patologia , Obesidade/complicações , Neoplasias da Próstata/patologia , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Quimiocina CCL2/genética , Ciclo-Oxigenase 2/genética , Dinoprostona/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/patologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Comunicação Parácrina , Neoplasias da Próstata/metabolismoRESUMO
BACKGROUND: Obesity is associated with larger tumors, shorter time to PSA failure, and higher Gleason scores. However, the mechanism(s) by which obesity promotes aggressive prostate cancer remains unknown. We hypothesize that circulating factors related to obesity promote prostate cancer progression by modulating components of the metastatic cascade. METHODS: Male C57BL/6 mice (6 weeks) were fed an ad libitum diet-induced obesity (60% fat) or control diet (10% fat) for 12 weeks. Serum was collected, metabolic and inflammatory proteins were measured by an antibody array. Sera were used to measure, in vitro, characteristics of a metastatic phenotype. RESULTS: Comparable to obese men, obese sera contained higher levels or leptin, vascular endothelial growth factor, PAI-1, interleukin-6 (IL-6) and lower levels of testosterone. In prostate cells, serum was used to assess: proliferation, invasion, migration, epithelial-mesenchymal-transition (EMT) and matrix metalloproteinase (MMP) activity. LNCaP and PacMetUT1 cells exposed to obese sera increased proliferation, whereas PrEC and DU145 were unaffected. LNCaP, PacMetUT1 and DU145 cancer cells exposed to obese sera resulted in increased invasion, migration and MMP-9 activity. Prostate cancer cells exposed to obese sera showed increased vimentin, dispersion of e-cadherin and ß-catenin from the plasma membrane. CONCLUSION: We report, prostate cancer cells exposed to sera from obese mice increases proliferation, invasion, migration, MMP activity and induces changes in proteins critical for EMT.
