Hypoxia inducible factor signaling in breast tumors controls spontaneous tumor dissemination in a site-specific manner.

Hypoxia is a common feature in tumors and induces signaling that promotes tumor cell survival, invasion, and metastasis, but the impact of hypoxia inducible factor (HIF) signaling in the primary tumor on dissemination to bone in particular remains unclear. To better understand the contributions of hypoxia inducible factor 1 alpha (HIF1α), HIF2α, and general HIF pathway activation in metastasis, we employ a PyMT-driven spontaneous murine mammary carcinoma model with mammary specific deletion of Hif1α, Hif2α, or von Hippel-Lindau factor (Vhl) using the Cre-lox system. Here we show that Hif1α or Hif2α deletion in the primary tumor decreases metastatic tumor burden in the bone marrow, while Vhl deletion increases bone tumor burden, as hypothesized. Unexpectedly, Hif1α deletion increases metastatic tumor burden in the lung, while deletion of Hif2α or Vhl does not affect pulmonary metastasis. Mice with Hif1α deleted tumors also exhibit reduced bone volume as measured by micro computed tomography, suggesting that disruption of the osteogenic niche may be involved in the preference for lung dissemination observed in this group. Thus, we reveal that HIF signaling in breast tumors controls tumor dissemination in a site-specific manner.

Urogenital Lesions in Nonhuman Primates at 2 National Primate Research Centers.

Given their genetic and anatomic similarities to humans, nonhuman primates (NHPs) may serve as animal models for urogenital diseases of humans. The purpose of this study was to examine the frequency of spontaneous urogenital lesions occurring over a 30-year period at the Yerkes and Southwest National Primate Research Centers and to compare and contrast lesions occurring in Old World versus New World primates. Lesions occurring in the chimpanzee (Pan troglodytes), baboon (Papio spp.), rhesus macaque (Macaca mulatta), cynomolgus macaque (Macaca fascicularis), pig-tailed macaque (Macaca nemestrina), sooty mangabey (Cercocebus atys), common marmoset (Callithrix jacchus), cotton-top tamarin (Sanguinus oedipus), and squirrel monkey (Saimiri sciureus) are discussed. The most common lesions of the kidney were medullary amyloidosis, renal cysts, renal tubular degeneration, glomerulonephritis or glomerulopathy, nephritis, nephrocalcinosis, pyelonephritis, and hydronephrosis. Specific causes of renal tubular disease included pigmentary nephrosis and tubular lipidosis. Renal tumors, including renal adenoma and carcinoma, lymphoma, and nephroblastoma, were infrequent diagnoses in all species. Endometriosis was the most frequently diagnosed lesion of the female genital tract. Of the animals examined in this study, it was most frequent in Old World primates. Leiomyoma was the most common uterine tumor. Granulosa cell tumor was the most frequently observed neoplasm of the ovaries, followed by teratoma. Of animals included in the study, most ovarian tumors occurred in baboons. Neoplasms of the male reproductive tract included interstitial cell tumor, seminoma, penile squamous cell carcinoma, penile papilloma, and histiocytoma. In New World monkeys, renal lesions were reported more frequently than genital lesions.

Spontaneous Pituitary Adenomas in Squirrel Monkeys (Saimiri sciureus).

On postmortem examination, 2 geriatric captive male squirrel monkeys (Saimiri sciureus) were found to have pituitary masses that were unassociated with previous experimental manipulation. Both animals were euthanized due to apparently unrelated clinical reasons. Histopathology and immunohistochemical staining classified these tumors as thyrotrophic and corticotrophic pituitary adenomas. These cases represent the first reports of this tumor type in squirrel monkeys.

Marine fish oil is more potent than plant-based n-3 polyunsaturated fatty acids in the prevention of mammary tumors.

Marine-derived n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to inhibit mammary carcinogenesis. However, evidence regarding plant-based α-linolenic acid (ALA), the major n-3 PUFA in the Western diet, remains equivocal. The objective of this study was to examine the effect of lifelong exposure to plant- or marine-derived n-3 PUFAs on pubertal mammary gland and tumor development in MMTV-neu(ndl)-YD5 mice. It is hypothesized that lifelong exposure to n-3 PUFA reduces terminal end buds during puberty leading to delayed tumor onset, volume and multiplicity. It is further hypothesized that plant-derived n-3 PUFAs will exert dose-dependent effects. Harems of MMTV-FVB males were bred with wild-type females and fed either a (1) 10% safflower (10% SF, n-6 PUFA, control), (2) 10% flaxseed (10% FS), (3) 7% safflower plus 3% flaxseed (3% FS) or (4) 7% safflower plus 3% menhaden (3% FO) diet. Female offspring were maintained on parental diets. Compared to SF, 10% FS and 3% FO reduced (P<.05) terminal end buds at 6 weeks and tumor volume and multiplicity at 20 weeks. A dose-dependent reduction of tumor volume and multiplicity was observed in mice fed 3% and 10% FS. Antitumorigenic effects were associated with altered HER2, pHER-2, pAkt and Ki-67 protein expression. Compared to 10% SF, 3% FO significantly down-regulated expression of genes involved in eicosanoid synthesis and inflammation. From this, it can be estimated that ALA was 1/8 as potent as EPA+DHA. Thus, marine-derived n-3 PUFAs have greater potency versus plant-based n-3 PUFAs.

Antenatal exposure to the selective serotonin reuptake inhibitor fluoxetine leads to postnatal metabolic and endocrine changes associated with type 2 diabetes in Wistar rats.

HYPOTHESIS: 10-15% of women take antidepressant medications during pregnancy. A recent clinical study reported that the use of selective serotonin reuptake inhibitor antidepressants during pregnancy is linked with an increased risk of postnatal obesity. While obesity is often associated with fatty liver, dyslipidemia and inflammation, to date, the effects of perinatal exposure to SSRIs on these outcomes are unknown. METHODS: Female nulliparous Wistar rats were given vehicle (N=15) or fluoxetine hydrochloride (FLX 10mg/kg/d; N=15) orally for 2 weeks prior to mating until weaning. We assessed glucometabolic changes and hepatic pathophysiology in the offspring. RESULTS: Fluoxetine exposed offspring demonstrated altered glucose homeostasis without any alterations to beta cell mass. FLX-exposed offspring had a significant increase in the number of offspring with mild to moderate NASH and dyslipidemia. There was also increased inflammation of the liver in FLX-exposed offspring; males had significant elevations in TNFα, IL6 and monocyte chemoattractant protein 1 (MCP1), while female offspring had higher expression of TNFα, and increased macrophage infiltration (MCP1). LIMITATIONS: This is an animal study. Further research examining the metabolic outcomes of children exposed to antidepressants in utero are required, given the increase in childhood obesity and psychiatric medication use during pregnancy. CONCLUSION: These data demonstrate that fetal and neonatal exposure to FLX results in evidence of increased adiposity, fatty liver and abnormal glycemic control. Since these are all hallmarks of the metabolic syndrome, this raises concerns regarding the long term metabolic sequelae of fetal exposure to SSRIs in human populations.

The POZ-ZF transcription factor Kaiso (ZBTB33) induces inflammation and progenitor cell differentiation in the murine intestine.

Since its discovery, several studies have implicated the POZ-ZF protein Kaiso in both developmental and tumorigenic processes. However, most of the information regarding Kaiso's function to date has been gleaned from studies in Xenopus laevis embryos and mammalian cultured cells. To examine Kaiso's role in a relevant, mammalian organ-specific context, we generated and characterized a Kaiso transgenic mouse expressing a murine Kaiso transgene under the control of the intestine-specific villin promoter. Kaiso transgenic mice were viable and fertile but pathological examination of the small intestine revealed distinct morphological changes. Kaiso transgenics (Kaiso(Tg/+)) exhibited a crypt expansion phenotype that was accompanied by increased differentiation of epithelial progenitor cells into secretory cell lineages; this was evidenced by increased cell populations expressing Goblet, Paneth and enteroendocrine markers. Paradoxically however, enhanced differentiation in Kaiso(Tg/+) was accompanied by reduced proliferation, a phenotype reminiscent of Notch inhibition. Indeed, expression of the Notch signalling target HES-1 was decreased in Kaiso(Tg/+) animals. Finally, our Kaiso transgenics exhibited several hallmarks of inflammation, including increased neutrophil infiltration and activation, villi fusion and crypt hyperplasia. Interestingly, the Kaiso binding partner and emerging anti-inflammatory mediator p120(ctn) is recruited to the nucleus in Kaiso(Tg/+) mice intestinal cells suggesting that Kaiso may elicit inflammation by antagonizing p120(ctn) function.