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Beta-adrenergic activation of Epithelial-Mesenchymal Transition in ovarian cancer
Brain, Behavior, and Immunity 49 (2015) e1–e50
Contents lists available at ScienceDirect
Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi
Abstracts from the 2015 Annual PNIRS Meeting Abstract # 1508
Abstract # 1510
LPS increases pain sensitivity by decreased pain inhibition and increased insular activation B. Karshikoff a,b, K.B. Jensen a,b, M. Ingvar a,b, E. Kosek a,b, G. Kalpouzos c, A. Soop d, C. Olgart Höglund a,b,e, M. Lekander a,b,f, J. Axelsson a,b
Neuron-specific interleukin-1 receptor accessory protein (AcPb) modulates sleep- and wake-like states in vivo and in vitro P. Taishi, K. Jewett, A. Johnson, C.J. Davis, K. Quigley, S. Roy, J.M. Krueger
a
Karolinska Institutet, Dept. of Clinical Neuorscience, Stockholm, Sweden b Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden c ARC, Karolinska Institutet and Stockholm University, Sweden d CLINTEC, Karolinska Institutet, Stockholm, Sweden e Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden f Stress Research Institute, Stockholm University, Stockholm, Sweden We have shown that women are more prone to developing LPS-induced pain sensitivity than men, and that the descending endogenous pain inhibition is disrupted in women during experimental systemic inflammation. The aim of the present study was to investigate some of the central neural mechanisms underlying our previous findings. 51 participants (29 women) were injected with 0.6 ng/kg LPS or saline and went through a thumb-pressure pain fMRI paradigm 2 h after injection. As hypothesized, the subjects injected with LPS had decreased activity in the ventromedial prefrontal cortex and rostral anterior cingulate cortex (rACC), areas involved in descending pain inhibition. In addition, the LPS group had higher activity in the anterior insula, an area involved in medial/affective pain processing and interoception. These effects were not sex dependent. However, the male participants had overall stronger descending pain inhibition, reflected as a stronger rACC activity compared to women. It is possible that the more robust activation of descending pain inhibition rendered the men more resistant to the immune provocation, which may explain previously seen sex differences in LPS-induced pain sensitivity. Our findings give an indication to how the pain matrix is affected during a sickness response. The results strengthen the proposed link between systemic inflammation and weakened pain regulation in chronic pain disorders, and offers a possible mechanism underlying the female predominance in chronic pain disorders. http://dx.doi.org/10.1016/j.bbi.2015.06.026
Washington State University – Spokane, Spokane, WA 99202, United States Interleukin-1 beta (IL1) signals via its type I receptor (IL1R)-accessory protein (AcP) complex. In brain, an alternatively spliced isoform of AcP, AcPb, occurs in neurons. AcPb mRNA increases with sleep loss. Mice lacking AcPb, sleep less after sleep deprivation. Mature neuronal/glial cultures have a default sleep-like state. The sleep-like state becomes more wake-like with electrical stimulation as determined from: (a) action potential burstiness (BI for burstiness index), (b) synchronization of electrical potentials (SYN) and (c) slow wave (0.5–3.5 Hz) (SW) power; these parameters also characterize animal sleep. We cultured cortical cells from WT mice and AcPb knockout mice. After 10–12 days, stable spontaneous values of the BI, SYN and SW power emerged from the WT cells. Electrical stimulation reduced the BI, SYN and SW power values during and after (30 min) stimulation; 24 h later, homeostasis was evidenced by a rebound in BI, SYN and SW power values to higher than pre-stimulation baseline values. Cortical cells from AcPb knockout mice behaved differently. The emergence of the spontaneous sleep-like state was delayed and BI, SYN and SW power values were substantially lower. Electrical stimulation of WT cells reduced BI, SYN and SW power values whereas it was without effect on cultured AcPb cells. We conclude that such cultures are useful to define the genetic and molecular conditions necessary for emergence of network properties such as sleep. http://dx.doi.org/10.1016/j.bbi.2015.06.027
Abstract # 1511 Beta-adrenergic activation of Epithelial-Mesenchymal Transition in ovarian cancer S.K. Lutgendorf a, P.H. Thaker b, G.M. Slavich c, M.J. Goodheart a, D.P. Bender a, L. Dahmoush a, D.M. Lubaroff a, F. Penedo d, K. DeGeest e, J. Arevalo c, A.K. Sood f, S.W. Cole c
e2
Abstracts / Brain, Behavior, and Immunity 49 (2015) e1–e50
a Department of Psychology, University of Iowa, E11 Seashore Hall, Iowa City, IA 52242, United States b Washington University School of Medicine, United States c University of California Los Angeles, United States d Northwestern University, United States e Oregon Health and Science University, United States f University of Texas MD Anderson Cancer Center, United States
The Epithelial-Mesenchymal Transition (EMT) is a key process in cancer metastasis whereby epithelial cells lose their polarity and cell-to-cell adhesion, and undergo morphologic changes, giving them a mesenchymal phenotype that allows them to migrate and invade other tissues. Our previous research has shown that beta-adrenergic signaling stimulates pathways involved in ovarian tumor progression, but the underlying mechanisms are not fully understood. We performed genome-wide transcriptome profiling of advanced stage ovarian carcinomas from 98 patients and compared those above versus below the median split on tumor norepinephrine level (NE) (median: 1.05 pg/mg tumor). Patients were matched on age, BMI, cancer grade, stage, and histology. High-NE tumors showed increased expression of 694 genes by at least 25% and 124 by at least 50%. These included multiple genes related to EMT, as well as decreased expression of a variety of anti-metastatic genes. In ovarian cancer cell lines (SKOV3ip1 and HeyA8), exposure to stress-concentrations of NE increased transcription of SNAI2 and IL6, both of which regulate EMT. In an in vivo orthotopic mouse model of ovarian cancer, 3 weeks of restraint stress significantly decreased the epithelial marker E Cadherin, increased mesenchymal markers N Cadherin and Vimentin, and up-regulated EMT mediators Snai1, Snai2, and Twist1. These results identify an additional pathway by which beta-adrenergic signaling can promote ovarian cancer progression by stimulating EMT gene expression programs that mediate metastasis. http://dx.doi.org/10.1016/j.bbi.2015.06.028
Abstract # 1512 Effects of chronic social defeat on splenic chemokine expression and myeloid cell infiltration into the brain O. Ambree a, C. Ruland a, P. Zwanzger a,b, V. Arolt a, J. Alferink a,c a
University of Münster, Department of Psychiatry, Münster, Germany kbo-Inn-Salzach-Klinikum, Wasserburg am Inn, Germany c Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Germany b
Dysregulation of the innate immune response has frequently been described in stress-associated psychiatric disorders such as major depressive disorder (MDD). However the kinetics and cellular origin of cytokine and chemokine expression are not well understood. Aim of this study was to elucidate stress-induced changes in the immune response. After 2, 6, or 10 daily social defeats, animals were tested for social interaction behavior, expression levels of immune-related genes were assessed in brain and spleen tissues, and splenocytes and mononuclear cells isolated from the brain were analyzed by flow cytometry. Mice that developed social avoidance behavior showed a decreased expression of genes encoding C-C chemokines accompanied by a reduction in the percentages of activated T lymphocytes and reduced IFN-gamma expression levels in the spleens of defeated mice. Also, diminished percentages of CD4+FoxP3+ regulatory T cells and lower TGF-beta mRNA levels accumulated in the spleens of these animals. In contrast, enhanced percentages of CD45hiCD11b+ cells representing peripheral myeloid cells immigrated into the brain of defeated animals. In summary, stress induced social avoidance was accompanied by an altered
expression of CC chemokine genes and reduced T cell activation in the spleen, associated with an increased brain invasion of myeloid cells. Further studies will address the underlying molecular mechanisms, the cell types involved herein and in a translational approach the immune cell phenotype in patients with MDD. http://dx.doi.org/10.1016/j.bbi.2015.06.029
Abstract # 1513 Impaired ability of cortisol to regulate leukocyte homeostasis in response to stress in overweight and obese individuals C. McInnis a,b, M.V. Thoma a, D. Gianferante a, L. Hanlin a, X. Chen a, N. Rohleder a a Brandeis University, 415 South Street, Watham, MA 02453, United States b Boston University Medical Campus, United States
Rationale: Acute stress changes the composition of circulating leukocytes. The HPA axis regulates leukocyte trafficking by secreting the glucocorticoid (GC) cortisol. Correlations between cortisol and leukocytes have been used to index GC sensitivity, and GC-resistant individuals demonstrate attenuated correlations. We set out to determine whether overweight individuals display impaired GC sensitivity, as obesity is associated with inflammatory-mediated disease, potentially partially due to GC-resistance. Methods: We recruited n = 80 individuals and examined stress-induced changes in WBC, monocytes, lymphocytes and granulocytes before, 1, 30, 60 and 120 min after exposure to the Trier Social Stress Test (TSST). We calculated granulocyte-to-lymphocyte (G/L) ratios and monocyte-to-lymphocyte (M/L) ratios at 120 min post-TSST, and tested for relationships with cortisol responses. Results: Stress induced responses in cortisol, WBC, monocyte number, lymphocyte number and lymphocyte percentage (F’s > 8.6, p’s < 0.001), but not monocyte percentage, granulocyte number or granulocyte percentage (F’s < 1.5, p’s>0.23). Cortisol responses were marginally significantly correlated with lymphocyte percentage and number (r’s > 0.30, p’s < 0.10) in lean but not overweight individuals post-stress. Cortisol responses were significantly correlated with G/L ratio (r = 0.41, p = 0.03), and marginally significantly correlated with M/L ratio (r = 0.32, p = 0.09) post-stress in lean, but not overweight individuals. Conclusions: Taken together, results show that overweight individuals do not display expected relationships between cortisol responses and leukocytes, implicating GC resistance. This points to impaired ability of overweight and obese individuals to control immune activity, which might contribute to obesity-related pathophysiology. http://dx.doi.org/10.1016/j.bbi.2015.06.030
Abstract # 1515 A modified and cost effective method for hair cortisol analysis L. Xiang, I. Sunesara, K. Rehm, G.D. Marshall Jr. Univ of MS Med Ctr, Medicine, 2500 N State St, Jackson, MS 39216, United States To date, most studies have assessed cortisol levels using serum, saliva, or urine samples which provides a measurement of the cortisol concentration at a single time point. However, a single
Contents lists available at ScienceDirect
Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi
Abstracts from the 2015 Annual PNIRS Meeting Abstract # 1508
Abstract # 1510
LPS increases pain sensitivity by decreased pain inhibition and increased insular activation B. Karshikoff a,b, K.B. Jensen a,b, M. Ingvar a,b, E. Kosek a,b, G. Kalpouzos c, A. Soop d, C. Olgart Höglund a,b,e, M. Lekander a,b,f, J. Axelsson a,b
Neuron-specific interleukin-1 receptor accessory protein (AcPb) modulates sleep- and wake-like states in vivo and in vitro P. Taishi, K. Jewett, A. Johnson, C.J. Davis, K. Quigley, S. Roy, J.M. Krueger
a
Karolinska Institutet, Dept. of Clinical Neuorscience, Stockholm, Sweden b Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden c ARC, Karolinska Institutet and Stockholm University, Sweden d CLINTEC, Karolinska Institutet, Stockholm, Sweden e Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden f Stress Research Institute, Stockholm University, Stockholm, Sweden We have shown that women are more prone to developing LPS-induced pain sensitivity than men, and that the descending endogenous pain inhibition is disrupted in women during experimental systemic inflammation. The aim of the present study was to investigate some of the central neural mechanisms underlying our previous findings. 51 participants (29 women) were injected with 0.6 ng/kg LPS or saline and went through a thumb-pressure pain fMRI paradigm 2 h after injection. As hypothesized, the subjects injected with LPS had decreased activity in the ventromedial prefrontal cortex and rostral anterior cingulate cortex (rACC), areas involved in descending pain inhibition. In addition, the LPS group had higher activity in the anterior insula, an area involved in medial/affective pain processing and interoception. These effects were not sex dependent. However, the male participants had overall stronger descending pain inhibition, reflected as a stronger rACC activity compared to women. It is possible that the more robust activation of descending pain inhibition rendered the men more resistant to the immune provocation, which may explain previously seen sex differences in LPS-induced pain sensitivity. Our findings give an indication to how the pain matrix is affected during a sickness response. The results strengthen the proposed link between systemic inflammation and weakened pain regulation in chronic pain disorders, and offers a possible mechanism underlying the female predominance in chronic pain disorders. http://dx.doi.org/10.1016/j.bbi.2015.06.026
Washington State University – Spokane, Spokane, WA 99202, United States Interleukin-1 beta (IL1) signals via its type I receptor (IL1R)-accessory protein (AcP) complex. In brain, an alternatively spliced isoform of AcP, AcPb, occurs in neurons. AcPb mRNA increases with sleep loss. Mice lacking AcPb, sleep less after sleep deprivation. Mature neuronal/glial cultures have a default sleep-like state. The sleep-like state becomes more wake-like with electrical stimulation as determined from: (a) action potential burstiness (BI for burstiness index), (b) synchronization of electrical potentials (SYN) and (c) slow wave (0.5–3.5 Hz) (SW) power; these parameters also characterize animal sleep. We cultured cortical cells from WT mice and AcPb knockout mice. After 10–12 days, stable spontaneous values of the BI, SYN and SW power emerged from the WT cells. Electrical stimulation reduced the BI, SYN and SW power values during and after (30 min) stimulation; 24 h later, homeostasis was evidenced by a rebound in BI, SYN and SW power values to higher than pre-stimulation baseline values. Cortical cells from AcPb knockout mice behaved differently. The emergence of the spontaneous sleep-like state was delayed and BI, SYN and SW power values were substantially lower. Electrical stimulation of WT cells reduced BI, SYN and SW power values whereas it was without effect on cultured AcPb cells. We conclude that such cultures are useful to define the genetic and molecular conditions necessary for emergence of network properties such as sleep. http://dx.doi.org/10.1016/j.bbi.2015.06.027
Abstract # 1511 Beta-adrenergic activation of Epithelial-Mesenchymal Transition in ovarian cancer S.K. Lutgendorf a, P.H. Thaker b, G.M. Slavich c, M.J. Goodheart a, D.P. Bender a, L. Dahmoush a, D.M. Lubaroff a, F. Penedo d, K. DeGeest e, J. Arevalo c, A.K. Sood f, S.W. Cole c
e2
Abstracts / Brain, Behavior, and Immunity 49 (2015) e1–e50
a Department of Psychology, University of Iowa, E11 Seashore Hall, Iowa City, IA 52242, United States b Washington University School of Medicine, United States c University of California Los Angeles, United States d Northwestern University, United States e Oregon Health and Science University, United States f University of Texas MD Anderson Cancer Center, United States
The Epithelial-Mesenchymal Transition (EMT) is a key process in cancer metastasis whereby epithelial cells lose their polarity and cell-to-cell adhesion, and undergo morphologic changes, giving them a mesenchymal phenotype that allows them to migrate and invade other tissues. Our previous research has shown that beta-adrenergic signaling stimulates pathways involved in ovarian tumor progression, but the underlying mechanisms are not fully understood. We performed genome-wide transcriptome profiling of advanced stage ovarian carcinomas from 98 patients and compared those above versus below the median split on tumor norepinephrine level (NE) (median: 1.05 pg/mg tumor). Patients were matched on age, BMI, cancer grade, stage, and histology. High-NE tumors showed increased expression of 694 genes by at least 25% and 124 by at least 50%. These included multiple genes related to EMT, as well as decreased expression of a variety of anti-metastatic genes. In ovarian cancer cell lines (SKOV3ip1 and HeyA8), exposure to stress-concentrations of NE increased transcription of SNAI2 and IL6, both of which regulate EMT. In an in vivo orthotopic mouse model of ovarian cancer, 3 weeks of restraint stress significantly decreased the epithelial marker E Cadherin, increased mesenchymal markers N Cadherin and Vimentin, and up-regulated EMT mediators Snai1, Snai2, and Twist1. These results identify an additional pathway by which beta-adrenergic signaling can promote ovarian cancer progression by stimulating EMT gene expression programs that mediate metastasis. http://dx.doi.org/10.1016/j.bbi.2015.06.028
Abstract # 1512 Effects of chronic social defeat on splenic chemokine expression and myeloid cell infiltration into the brain O. Ambree a, C. Ruland a, P. Zwanzger a,b, V. Arolt a, J. Alferink a,c a
University of Münster, Department of Psychiatry, Münster, Germany kbo-Inn-Salzach-Klinikum, Wasserburg am Inn, Germany c Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Germany b
Dysregulation of the innate immune response has frequently been described in stress-associated psychiatric disorders such as major depressive disorder (MDD). However the kinetics and cellular origin of cytokine and chemokine expression are not well understood. Aim of this study was to elucidate stress-induced changes in the immune response. After 2, 6, or 10 daily social defeats, animals were tested for social interaction behavior, expression levels of immune-related genes were assessed in brain and spleen tissues, and splenocytes and mononuclear cells isolated from the brain were analyzed by flow cytometry. Mice that developed social avoidance behavior showed a decreased expression of genes encoding C-C chemokines accompanied by a reduction in the percentages of activated T lymphocytes and reduced IFN-gamma expression levels in the spleens of defeated mice. Also, diminished percentages of CD4+FoxP3+ regulatory T cells and lower TGF-beta mRNA levels accumulated in the spleens of these animals. In contrast, enhanced percentages of CD45hiCD11b+ cells representing peripheral myeloid cells immigrated into the brain of defeated animals. In summary, stress induced social avoidance was accompanied by an altered
expression of CC chemokine genes and reduced T cell activation in the spleen, associated with an increased brain invasion of myeloid cells. Further studies will address the underlying molecular mechanisms, the cell types involved herein and in a translational approach the immune cell phenotype in patients with MDD. http://dx.doi.org/10.1016/j.bbi.2015.06.029
Abstract # 1513 Impaired ability of cortisol to regulate leukocyte homeostasis in response to stress in overweight and obese individuals C. McInnis a,b, M.V. Thoma a, D. Gianferante a, L. Hanlin a, X. Chen a, N. Rohleder a a Brandeis University, 415 South Street, Watham, MA 02453, United States b Boston University Medical Campus, United States
Rationale: Acute stress changes the composition of circulating leukocytes. The HPA axis regulates leukocyte trafficking by secreting the glucocorticoid (GC) cortisol. Correlations between cortisol and leukocytes have been used to index GC sensitivity, and GC-resistant individuals demonstrate attenuated correlations. We set out to determine whether overweight individuals display impaired GC sensitivity, as obesity is associated with inflammatory-mediated disease, potentially partially due to GC-resistance. Methods: We recruited n = 80 individuals and examined stress-induced changes in WBC, monocytes, lymphocytes and granulocytes before, 1, 30, 60 and 120 min after exposure to the Trier Social Stress Test (TSST). We calculated granulocyte-to-lymphocyte (G/L) ratios and monocyte-to-lymphocyte (M/L) ratios at 120 min post-TSST, and tested for relationships with cortisol responses. Results: Stress induced responses in cortisol, WBC, monocyte number, lymphocyte number and lymphocyte percentage (F’s > 8.6, p’s < 0.001), but not monocyte percentage, granulocyte number or granulocyte percentage (F’s < 1.5, p’s>0.23). Cortisol responses were marginally significantly correlated with lymphocyte percentage and number (r’s > 0.30, p’s < 0.10) in lean but not overweight individuals post-stress. Cortisol responses were significantly correlated with G/L ratio (r = 0.41, p = 0.03), and marginally significantly correlated with M/L ratio (r = 0.32, p = 0.09) post-stress in lean, but not overweight individuals. Conclusions: Taken together, results show that overweight individuals do not display expected relationships between cortisol responses and leukocytes, implicating GC resistance. This points to impaired ability of overweight and obese individuals to control immune activity, which might contribute to obesity-related pathophysiology. http://dx.doi.org/10.1016/j.bbi.2015.06.030
Abstract # 1515 A modified and cost effective method for hair cortisol analysis L. Xiang, I. Sunesara, K. Rehm, G.D. Marshall Jr. Univ of MS Med Ctr, Medicine, 2500 N State St, Jackson, MS 39216, United States To date, most studies have assessed cortisol levels using serum, saliva, or urine samples which provides a measurement of the cortisol concentration at a single time point. However, a single