Development and Characterization of a Novel Congenic Rat Strain for Obesity and Cancer Research.

The association between a Western Diet and colon cancer suggests that dietary factors and/or obesity may contribute to cancer progression. Our objective was to develop a new animal model of obesity and the associated pathophysiology to investigate human cancer independent of dietary components that induce obesity. A novel congenic rat strain was established by introducing the fa allele from the Zucker rat into the Rowett Nude rat to generate a "fatty nude rat".

High-fat Western diet-induced obesity contributes to increased tumor growth in mouse models of human colon cancer.

Strong epidemiologic evidence links colon cancer to obesity. The increasing worldwide incidence of colon cancer has been linked to the spread of the Western lifestyle, and in particular consumption of a high-fat Western diet. In this study, our objectives were to establish mouse models to examine the effects of high-fat Western diet-induced obesity on the growth of human colon cancer tumor xenografts, and to examine potential mechanisms driving obesity-linked human colon cancer tumor growth.

PKCδ is activated in the liver of obese Zucker rats and mediates diet-induced whole body insulin resistance and hepatocyte cellular insulin resistance.

Insulin resistance can arise when pathological levels of free fatty acids (FFAs) and proinflammatory cytokines disrupt insulin signaling. Protein kinase C delta (PKCδ) is a FFA- and a proinflammatory cytokine-regulated protein kinase that is associated with inhibition of insulin signaling and action. To gain insight into the role of PKCδ in insulin resistance, PKCδ activation was studied in a genetic model of obesity-linked insulin resistance.

Lipid metabolism, oxidative stress and cell death are regulated by PKC delta in a dietary model of nonalcoholic steatohepatitis.

Steatosis, oxidative stress, and apoptosis underlie the development of nonalcoholic steatohepatitis (NASH). Protein kinase C delta (PKCδ) has been implicated in fatty liver disease and is activated in the methionine and choline-deficient (MCD) diet model of NASH, yet its pathophysiological importance towards steatohepatitis progression is uncertain. We therefore addressed the role of PKCδ in the development of steatosis, inflammation, oxidative stress, apoptosis, and fibrosis in an animal model of NASH.

Light at night activates IGF-1R/PDK1 signaling and accelerates tumor growth in human breast cancer xenografts.

Regulation of diurnal and circadian rhythms and cell proliferation are coupled in all mammals, including humans. However, the molecular mechanisms by which diurnal and circadian rhythms regulate cell proliferation are relatively poorly understood. In this study, we report that tumor growth in nude rats bearing human steroid receptor-negative MCF-7 breast tumors can be significantly accelerated by exposing the rats to light at night (LAN).

Inhibition of fatty acid transport and proliferative activity in tissue-isolated human squamous cell cancer xenografts perfused in situ with melatonin or eicosapentaenoic or conjugated linoleic acids.

Melatonin and eicosapentaenoic and 10t,12c-conjugated linoleic acids suppress the growth-stimulating effects of linoleic acid (LA) and its metabolism to the mitogenic agent 13-(S)-hydroxyoctadecadienoic acid (13-(S)-HODE) in established rodent tumors and human cancer xenografts. Here we compared the effects of these 3 inhibitory agents on growth and LA uptake and metabolism in human FaDu squamous cell carcinoma xenografts perfused in situ in male nude rats. Results demonstrated that these agents caused rapid inhibition of LA uptake, tumor cAMP content, 13-(S)-HODE formation, extracellular signal-regulated kinase p44/ p42 (ERK 1/2) activity, mitogen-activated protein kinase kinase (MEK) activity, and [3H]thymidine incorporation into tumor DNA.

Dietary fish oil deactivates a growth-promoting signaling pathway in hepatoma 7288CTC in Buffalo rats.

Dietary fish oil decreases growth of solid tumors in rodents. Mechanisms for this effect are not well defined. In rat hepatoma 7288CTC, short-term (1-2 h) treatment with eicosapentaenoic acid during perfusion in situ reduced fatty acid uptake and [(3)H]thymidine incorporation.

Human cancer xenograft perfusion in situ in rats: a new perfusion system that minimizes delivery time and maintains normal tissue physiology and responsiveness to growth-inhibitory agents.

We developed an artificial lung and catheter system for perfusing tissue-isolated tumors in situ that dramatically minimizes perfusate delivery time. Our investigations demonstrated that the circadian neurohormone melatonin (MLT), eicosapentaenoic acid (EPA), and conjugated linoleic acid (CLA) inhibit growth and metabolism in several rodent and human tumors. These anticancer agents function in a receptor-mediated manner to suppress tumor uptake of linoleic acid (LA), the principal tumor growth-promoting fatty acid, and its conversion to the mitogenic agent 13-hydroxyoctadecadienoic acid (13-HODE).

Melatonin-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats.

The increased breast cancer risk in female night shift workers has been postulated to result from the suppression of pineal melatonin production by exposure to light at night. Exposure of rats bearing rat hepatomas or human breast cancer xenografts to increasing intensities of white fluorescent light during each 12-hour dark phase (0-345 microW/cm2) resulted in a dose-dependent suppression of nocturnal melatonin blood levels and a stimulation of tumor growth and linoleic acid uptake/metabolism to the mitogenic molecule 13-hydroxyoctadecadienoic acid. Venous blood samples were collected from healthy, premenopausal female volunteers during either the daytime, nighttime, or nighttime following 90 minutes of ocular bright, white fluorescent light exposure at 580 microW/cm2 (i.

Differential inhibition of fatty acid transport in tissue-isolated steroid receptor negative human breast cancer xenografts perfused in situ with isomers of conjugated linoleic acid.

In established rodent tumors and human cancer cell lines, conjugated dienoic isomers of linoleic acid (CLA) suppress the growth-stimulating effects of linoleic acid (LA) and its metabolism to the mitogenic agent, 13-hydroxyoctadecadienoic acid (13-HODE). Here, we compared the effects of three CLA isomers on LA uptake and metabolism, and growth in human breast xenografts perfused in situ in female nude rats. The results demonstrated that two CLA isomers [10t, 12c-CLA>9t, 11t-CLA] caused a dose-dependent inhibition of LA uptake, cAMP content, 13-HODE formation, Erk 1/2 activity, and [(3)H]thymidine incorporation into tumor DNA; 9c, 11t-CLA showed no effect.