Exercise affects high-fat diet-stimulated breast cancer metastasis through irisin secretion by altering cancer stem cell properties.

Background: Regular physical activities reduce the growth of breast cancer, but research on the effects of steady exercise on metastasis and its mechanisms is limited. In this study, the effects of steady exercise on breast cancer metastasis and its possible mechanism were demonstrated. Methods: Experimental metastasis was induced after 8 weeks of steady exercise using a mouse model. Furthermore, one of the myokines, irisin, was studied to elucidate the effects of metastasis-regulating protein expression, and colony and sphere formation, which are cancer stem cell properties. Results: Low- and moderate-intensity exercise significantly reduced the number and volume of metastasized tumors. Among myokines, only irisin was significantly increased by steady exercise but decreased by a high-fat diet. In vitro studies, irisin significantly decreased the number of colonies and sphere formation. Irisin also inhibited cell migration and invasion and suppressed the malignancy of breast cancer cells by reducing the expression of vimentin, MMP-2, MMP-9, and HIF-1 and by increasing the expression of TIMP-1 and TIMP-2. Conclusion: Steady exercise modulates myokine secretions and among them, irisin suppresses breast cancer metastasis by decreasing self-renewal properties and invasion regulating protein expressions. Thus, regular exercise may be beneficial in the prevention of breast tumor metastasis.

Effects of Steady Low-Intensity Exercise on High-Fat Diet Stimulated Breast Cancer Progression Via the Alteration of Macrophage Polarization.

Physical inactivity and high-fat diet, especially high saturated fat containing diet are established risk factors for breast cancer that are amenable to intervention. High-fat diet has been shown to induce tumor growth and metastasis by alteration of inflammation but steady exercise has anti-tumorigenic effects. However, the mechanisms underlying the effects of physical activity on high-fat diet stimulated breast cancer initiation and progression are currently unclear. In this study, we examined how the intensity of physical activity influences high fat diet-stimulated breast cancer latency and progression outcomes, and the possible mechanisms behind these effects. Five-week-old female Balb/c mice were fed either a control diet or a high-fat diet for 8 weeks, and then 4T1 mouse mammary tumor cells were inoculated into the mammary fat pads. Exercise training occurred before tumor cell injection, and tumor latency and tumor volume were measured. Mice with a high-fat diet and low-intensity exercise (HFLE) had a longer tumor latency period, slower tumor growth, and smaller tumor volume in the final tumor assessment compared with the control, high-fat diet control (HFDC), and high-fat diet with moderate-intensity exercise (HFME) groups. Steady low- and moderate-intensity exercise had no effect on cell proliferation but induced apoptosis by activating caspase-3 through the alteration of Bcl-2, Bcl-xL, and Bax expression. Furthermore, steady exercise reduced M2 macrophage polarization in breast tumor tissue, which has been linked to tumor growth. The myokine, myostatin, reduced M2 macrophage polarization through the inhibition of the JAK-STAT signaling pathway. These results suggest that steady low-intensity exercise could delay breast cancer initiation and growth and reduce tumor volume through the induction of tumor cell apoptosis and the suppression of M2 macrophage polarization.

Expression and localization of COMMD1 proteins in human placentas from women with preeclampsia.

PURPOSE: Recently, COMMD1 has been identified as a novel interactor and regulator of hypoxia-inducible factor-1 and nuclear factor kappa B transcriptional activity. The goal of this study was to determine the difference of COMMD1 expression in the placentas of women with normal and preeclamptic (PE) pregnancies. MATERIALS AND METHODS: Immnoperoxidase and immunofluorescent staining for COMMD1 was performed on nine normal and nine severe PE placental tissues, and COMMD1 mRNA expression was quantified by quantitative reverse transcription polymerase chain reaction. RESULTS: The expression of mRNA of COMMD1 was significantly higher in the study group than in the control group. The immunoreactivity was higher especially in the syncytiotrophoblast of PE placentas than in the control group. CONCLUSION: This study demonstrated increased placental COMMD1 expression in women with severe preeclampsia compared to that found in women with normal pregnancies, and this finding might contribute to a better understanding of the pathophysiology of preeclampsia.

Expression of DJ-1 proteins in placentas from women with severe preeclampsia.

OBJECTIVE: Lately, DJ-1 has been identified as a novel mediator of hypoxia-induced cellular responses. The aim of this study was to determine the difference of DJ-1 expression in the placentas of women with normal and preeclamptic pregnancies. STUDY DESIGN: DJ-1 mRNA expression was quantified by quantitative reverse transcription polymerase chain reaction (RT-PCR). Also, immunoperoxidase and immunofluorescent staining for DJ-1 was performed on 11 normal and 12 preeclamptic placental tissues. RESULTS: The expression of mRNA of DJ-1 was significantly higher in the study group than in the control group. The immunoreactivity was especially higher in the syncytiotrophoblast of preeclamptic placentas compared to the control group. CONCLUSION: Overexpression of the DJ-1 protein in the placentas of severe PE patients is thought to be a causative or compensatory mechanism in response to hypoxia, and this finding might contribute to a better understanding of the pathophysiology of preeclampsia.

Transmission of Synucleinopathies in the Enteric Nervous System of A53T Alpha-Synuclein Transgenic Mice.

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by abnormal deposition of α-synuclein aggregates in many regions of the central and peripheral nervous systems. Accumulating evidence suggests that the α-synuclein pathology initiates in a few discrete regions and spreads to larger areas in the nervous system. Recent pathological studies of PD patients have raised the possibility that the enteric nervous system is one of the initial sites of α-synuclein aggregation and propagation. Here, we evaluated the induction and propagation of α-synuclein aggregates in the enteric nervous system of the A53T α-synuclein transgenic mice after injection of human brain tissue extracts into the gastric walls of the mice. Western analysis of the brain extracts showed that the DLB extract contained detergent-stable α-synuclein aggregates, but the normal brain extract did not. Injection of the DLB extract resulted in an increased deposition of α-synuclein in the myenteric neurons, in which α-synuclein formed punctate aggregates over time up to 4 months. In these mice, inflammatory responses were increased transiently at early time points. None of these changes were observed in the A53T mice injected with saline or the normal brain extract, nor were these found in the wild type mice injected with the DLB extract. These results demonstrate that pathological α-synuclein aggregates present in the brain of DLB patient can induce the aggregation of endogenous α-synuclein in the myenteric neurons in A53T mice, suggesting the transmission of synucleinopathy lesions in the enteric nervous system.

Gene profiling of colonic serrated adenomas by using oligonucleotide microarray.

PURPOSE: The serrated pathway has been proposed as an important concept explaining the colorectal carcinogenesis. However, the key molecules of the serrated pathway which contribute to the formation of serrated polyp are still poorly understood. To elucidate the molecular genetic basis of the serrated pathway, we performed an initial oligonucleotide microarray to analyze the gene expression pattern of patients with colonic serrated adenomas. METHODS: Oligonucleotide microarrays containing 3,096 genes were used to compare individual gene profiles of serrated adenoma samples (n = 5) and normal mucosal samples obtained from colon in patients by colonoscopy. Three genes were further investigated by means of quantitative reverse transcription polymerase chain reaction (RT-PCR) for validation. The Significance Analysis of Microarray (SAM) package method was used to identify differentially expressed genes. RESULTS: Compared with normal colonic mucosa tissue, 73 genes were upregulated at least twofold, and 51 genes were downregulated by at least 50% in serrated polyp samples (approximately 3.6% of genes evaluated) with a p-value of less than 0.05. Moreover, some of the gene expression patterns observed were similar to those of previously reported in colorectal cancer, suggesting reinforcement of tendency to malignancy. Three genes (TNFRSF10A, BENE, RARA) with strongly significant expression intensities in the oligonucleotide microarray results were validated by quantitative RT-PCR. TNFRSF10A had upregulated expression patterns while BENE, RARA had downregulated expression pattern. CONCLUSION: Although our report presents only preliminary results, we think they provide important data regarding serrated adenomas not only to better define the precise mechanism of genetic changes involved as the main member in serrated pathway of colorectal carcinogenesis but also to yield practical information for identifying optimized diagnostic modalities.