Maternal Obesity, Cage Density, and Age Contribute to Prostate Hyperplasia in Mice.

Identification of modifiable risk factors is gravely needed to prevent adverse prostate health outcomes. We previously developed a murine precancer model in which exposure to maternal obesity stimulated prostate hyperplasia in offspring. Here, we used generalized linear modeling to evaluate the influence of additional environmental covariates on prostate hyperplasia. As expected from our previous work, the model revealed that aging and maternal diet-induced obesity (DIO) each correlated with prostate hyperplasia. However, prostate hyperplasia was not correlated with the length of maternal DIO. Cage density positively associated with both prostate hyperplasia and offspring body weight. Expression of the glucocorticoid receptor in prostates also positively correlated with cage density and negatively correlated with age of the animal. Together, these findings suggest that prostate tissue was adversely patterned during early life by maternal overnutrition and was susceptible to alteration by environmental factors such as cage density. Additionally, prostate hyperplasia may be acutely influenced by exposure to DIO, rather than occurring as a response to worsening obesity and comorbidities experienced by the mother. Finally, cage density correlated with both corticosteroid receptor abundance and prostate hyperplasia, suggesting that overcrowding influenced offspring prostate hyperplasia. These results emphasize the need for multivariate regression models to evaluate the influence of coordinated variables in complicated animal systems.

Maternal high-fat diet induces hyperproliferation and alters Pten/Akt signaling in prostates of offspring.

Developing recommendations for prostate cancer prevention requires identification of modifiable risk factors. Maternal exposure to high-fat diet (HFD) initiates a broad array of second-generation adult disorders in murine models and humans. Here, we investigate whether maternal HFD in mice affects incidence of prostate hyperplasia in offspring. Using three independent assays, we demonstrate that maternal HFD is sufficient to initiate prostate hyperproliferation in adult male offspring. HFD-exposed prostate tissues do not increase in size, but instead concomitantly up-regulate apoptosis. Maternal HFD-induced phenotypes are focally present in young adult subjects and greatly exacerbated in aged subjects. HFD-exposed prostate tissues additionally exhibit increased levels of activated Akt and deactivated Pten. Taken together, we conclude that maternal HFD diet is a candidate modifiable risk factor for prostate cancer initiation in later life.

Bves and NDRG4 regulate directional epicardial cell migration through autocrine extracellular matrix deposition.

Directional cell movement is universally required for tissue morphogenesis. Although it is known that cell/matrix interactions are essential for directional movement in heart development, the mechanisms governing these interactions require elucidation. Here we demonstrate that a novel protein/protein interaction between blood vessel epicardial substance (Bves) and N-myc downstream regulated gene 4 (NDRG4) is critical for regulation of epicardial cell directional movement, as disruption of this interaction randomizes migratory patterns. Our studies show that Bves/NDRG4 interaction is required for trafficking of internalized fibronectin through the "autocrine extracellular matrix (ECM) deposition" fibronectin recycling pathway. Of importance, we demonstrate that Bves/NDRG4-mediated fibronectin recycling is indeed essential for epicardial cell directional movement, thus linking these two cell processes. Finally, total internal reflectance fluorescence microscopy shows that Bves/NDRG4 interaction is required for fusion of recycling endosomes with the basal cell surface, providing a molecular mechanism of motility substrate delivery that regulates cell directional movement. This is the first evidence of a molecular function for Bves and NDRG4 proteins within broader subcellular trafficking paradigms. These data identify novel regulators of a critical vesicle-docking step required for autocrine ECM deposition and explain how Bves facilitates cell-microenvironment interactions in the regulation of epicardial cell-directed movement.