Research Day Book 2013 - College of Medicine - Florida Atlantic ...

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REFERENCES: Yang, X., Guo, Z., Sun, F., Li, W., Alfano, A., Shimelis, H., Qiu, Y. (2011). Novel membraneassociated androgen receptor splice variant potentiates proliferative and survival responses in prostate cancer cells. J Biol Chem, 286(41), 36152‐36160. doi: 10.1074/jbc.M111.265124 ABSTRACT TITLE: Pulmonary inflammation associated with chitinase‐3‐like‐1 molecule (CHI3L1) expression accelerates breast cancer metastasis to the lung AUTHORS: Stephania Libreros 1 , Ramon Garcia‐Areas 1 , Roberto Carrio 2 and Vijaya Iragavarapu‐ Charyulu 1 . Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL. DEPARTMENT: Biomedical Science Metastasis of a primary tumor to distant organs is the principal cause of mortality in patients with breast cancer. Recently, it was reported that asthmatic patients have a greater propensity to develop distant metastasis to the lung. Using a ragweed pulmonary inflammation model, we found that asthmatic mice implanted with 4T1 mammary tumors have a 5‐fold increase in formation of metastatic foci in their lungs compared to non‐asthmatic 4T1 mammary tumor‐bearing mice. Further, asthmatic tumor‐bearing mice showed accelerated tumor growth and shorter disease‐free survival. We have previously reported that Chitinase‐3 like‐1 protein (CHI3L1) expression is increased in mammary tumor‐bearing mice and that it induces production of prometastatic mediators, CCL2, CXCL2 and MMP‐9 by macrophages. Asthmatic patients have been reported to exhibit elevated levels of CHI3L1 in their lungs and circulation while in breast cancer patients these levels are further elevated. We found that the levels of CHI3L1 are higher in circulation and lungs of asthmatic mammary tumor‐bearers compared to mice with either asthma or tumor alone. It is unknown if exposure to high levels of CHI3L1 previous to tumorigenesis accelerates metastasis. We hypothesize that CHI3L1‐induced pulmonary inflammation generates the proper environment for recruiting circulating breast cancer cells as well as proinflammatory leukocytes (M2 macrophages and myeloid derived suppressors), resulting in increased rate of metastasis to the lung. Treatment of 4T1 asthmatic mammary tumor‐bearing mice with chitin microparticles, the ligand of CHI3L1, resulted in decreased levels of metastasis to the lung. These studies provide an understanding of the role of CHI3L1 and existing inflammation in accelerating metastasis, the major cause of death in breast cancer patients. ABSTRACT TITLE: Determination of levels and expression of IL‐1β, IL‐4, TNF‐α, IL‐10, and IFN‐γ in the lacrimal glands of a predisposed mouse model of Sjögren’s Syndrome (SS): the influence of sex hormones and genetic background in the pathogenesis of SS AUTHORS: Stefanie P.C. Czerwinski, Safinaz Mostafa, Ana Maria Azzarolo DEPARTMENT: Integrated Medical Science
BACKGROUND: Sjögren’s Syndrome (SS) is a chronic, inflammatory autoimmune disease affecting mostly the exocrine cells of lacrimal and salivary glands, leading to diminished secretory function and resulting in keratoconjunctivitis sicca (dry eye disease) and/or stomatitis sicca (dry mouth disease). Nevertheless, the exact etiology and mechanisms of SS remain unknown. SS has been diagnosed predominantly in postmenopausal women with the female to male ratio reaching 9:1, suggesting a role of ovarian sex hormones in the pathogenesis of SS. However, not all postmenopausal women develop SS, indicating the contribution of other factors such as a genetic background to the onset of SS. SS has also been characterized by the upregulation of several pro‐inflammatory cytokines in the lacrimal gland. However, the source and time course of the cytokine increase remain to be elucidated. We have been studying the disease progression using ovariectomized (OVX) NOD.B10.H2 b mice, which provide a model of menopause and genetic predisposition to SS. We have previously shown that lymphocytic infiltration followed by acinar cell apoptosis in the lacrimal gland significantly increased at 3, 7, 21 and 30 days after OVX, and this infiltration and apoptosis was prevented by physiological doses of 17β estradiol (E2) or dihydrotestosterone (DHT). OBJECTIVES: In this study, we investigated the time course of changes in the levels and expression of cytokines IL‐1β, IL‐4, TNF‐α, IL‐10 and IFN‐γ in the lacrimal glands of NOD.B10.H2 b mice following OVX. We also investigated whether treatment with E2 or DHT prevented the changes in cytokine levels and expression found after OVX. METHODS: Six weeks old NOD.B10.H2 b and C57BL/10 mice were sham operated, OVX, OVX+E2 or OVX+DHT for 3, 7, 21 and 30 days. At the end of each experimental time period, lacrimal glands were collected and processed for RNA analysis by rt‐qPCR and protein assays by ELISA to evaluate cytokine expression and concentrations of IL‐1β, IL‐4, TNF‐α, IL‐10 and IFN‐γ. RESULTS: A significant increase in the expression of IL‐1β, TNF‐α, and IL‐4 in the lacrimal glands of NOD.B10.H2 b mice was seen at 3, 7, 21, and 30 days after OVX as compared to sham operated animals, while a significant increase in the expression of IL‐10 was seen only at 7, 21, and 30 days after OVX. A significant but much smaller increase in expression of IL‐1β and IL‐4 was seen at only 7, 21, and 30 days after OVX in the lacrimal glands of C57BL/10 mice. No significant changes were observed for TNF‐α and IL‐ 10 at any of the experimental times. The cytokine levels of IL‐1β, TNF‐α, and IL‐4 were significantly increased at 3, 7, 21, and 30 days after OVX in the lacrimal glands of NOD.B10.H2 b mice as compared to sham operated animals. Significant increase in levels of IL‐10 was seen only at 21 and 30 days after OVX. No significant differences were observed in the levels of IL‐1β, TNF‐α, IL‐4, and IL‐10 for all treatment groups at all four experimental times in the lacrimal glands of C57BL/10 mice. Treatment with physiological doses of E2 or DHT at time of OVX prevented the increase in cytokine levels and expression in both strains. Both expression and levels of IFN‐γ remained undetected in both mouse strains for all experimental groups and times. CONCLUSIONS: The results of this study suggest ovarian sex hormones and genetic background seem to be necessary for the pathogenesis of SS. Furthermore, this study suggests that cytokines are key players in the etiology of SS. It has been previously reported that IL‐1 and TNF‐ may be involved in different pathways leading to the clinical manifestations of SS, including the activation of the transcription factor NF‐ B. NF‐B has been reported to be involved in the transcription of various inflammatory and pro‐apoptotic genes. Therefore, IL‐1 and/or TNF‐ mediated NF‐B activation could cause apoptosis and a persistent inflammatory reaction in the lacrimal glands of SS patients. Furthermore, the specific time frame of upregulation of each cytokine is crucial to the understanding of the exact disease mechanism. For instance, this
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Page 5 and 6: Research Day Posters
Page 7 and 8: 12. Investigation of cell stiffness
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Page 13 and 14: RESULTS: We find that DHKA blocks 8
Page 15 and 16: ut the association of N‐TIMP‐1
Page 17 and 18: BACKGROUND: Cardiomyopathy refers t
Page 19 and 20: esponse (IHR) gene database. The ov
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