- Email: [email protected]
Gene expression changes and fatigue during IMRT in patients with head and neck cancer
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Abstracts / Brain, Behavior, and Immunity 49 (2015) e1–e50
Abstract # 1610 Psychosocial stress suppresses tumor progression in a murine model of spontaneous, metastatic breast cancer R.P. Dawes, D.K. Byun, E.B. Brown, K.S. Madden University of Rochester Medical Center, Neuroscience Graduate Program, 601 Elmwood Avenue, Rochester, NY 14642, United States Late-stage breast cancer remains an intractable problem, with 40,000 deaths annually in the United States. Pre-clinical evidence suggests psychosocial stress accelerates cancer progression. Notably, these studies feature injectable tumor models, often in immunocompromised animals exposed to prolonged stress. We have employed a model of spontaneous, metastatic breast cancer, MMTV-PyMT mice, to more closely mimic clinical disease progression. Mice were exposed to a combined stressor featuring chronic social isolation and acute restraint, which activated the hypothalamic-pituitary-adrenal (HPA)-axis and sympathetic nervous system (SNS). Stressed mice were socially isolated during premalignancy. Two weeks later, isolated mice were exposed to 3 days of 2-hour restraint. We hypothesized this stressor would exacerbate tumor progression. Instead, 2 weeks post-restraint, stressed mice had smaller tumors, reduced splenic/lung CD11b+Gr-1+ myeloid-derived suppressor cells, and reduced pro-tumor MMP-2 and TGF-beta1/2 in plasma exosomes. By 3 weeks post-restraint, HPA-axis and SNS activation were still apparent in stressed mice, but no alterations in tumor size, immune populations, exosomal proteins, or lung metastases were detected. Stress-induced reduction in tumor growth suggests an inhibitory neurohormonal pathway linking stress and cancer progression. Psychosocial stress exposure had no long-term impact on progression, despite evidence for an altered neurohormonal environment, suggesting receptor desensitization/resistance may compensate for elevated neurohormones. A deeper understanding of biobehavioral pathways in cancer progression is needed before targeting stress neuroendocrine signaling therapeutically. Funded in part by NCI Contract No. HHSN261200800001E. http://dx.doi.org/10.1016/j.bbi.2015.06.112
Abstract # 1611 Regional cerebral glucose metabolism in the insula during acute stress predicts increased post-stress pulmonary inflammation in asthma M.A. Rosenkranz, W.W. Busse, B.T. Christian, A.T. Higgins, R.J. Davidson University of Wisconsin-Madison, Center for Investigating Healthy Minds, Waisman Center, 1500 Highland Ave, Madison, WI 53705, United States Although psychological factors contribute to the frequency, severity, and burden of asthma symptoms, the role of the brain in the pathophysiology and treatment of this disease is largely unknown. To examine the neural mechanisms which may regulate airway inflammation in asthma, we used [18F]fluoro-deoxyglucose positron emission tomography (FDG-PET) to identify neural circuits that are active during performance of a social stress task or a matched control condition. Asthmatic subjects with either high or low levels of chronic life stress underwent both stress and control conditions. Fractional exhaled nitric oxide (FeNO) was collected at baseline, as well as hourly post-challenge, and provided a measure of airway inflammation. These data reveal that, in those with high levels of chronic stress, an acute stressor leads to elevated
post-stress FeNO levels relative to those with low chronic stress. In addition, increased regional glucose metabolism in the insular cortex predicts overall FeNO levels. This region of the insula is nearly identical to a region we identified in a previous study where activation following challenge with inhaled allergen predicted the increase in percentage of eosinophils in lung tissue 24 h later. These data corroborate previous evidence indicating a role for the insula in the interaction of emotion and inflammation in asthma and may lead to novel targets for future treatment. http://dx.doi.org/10.1016/j.bbi.2015.06.113
Abstract # 1612 An HDAC6 inhibitor for treatment of chemotherapy-induced peripheral numbness and pain in a mouse model K. Krukowski a, C.J. Heijnen a, O. Golonzhka b, T. Gutti a, M. Jarpe b, A. Kavelaars a a
University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, United States b Acetylon Pharmaceuticals, United States Neurotoxic side-effects of chemotherapy, including pain and numbness in hands and feet, frequently leads to dose reduction. This chemotherapy-induced peripheral neuropathy (CIPN) often persists long into survivorship and negatively affects quality of life. No drugs are available to prevent or treat CIPN and underlying mechanisms are only partially understood. Animal models for investigating chemotherapy-induced numbness are lacking. We have developed a tool for measuring numbness in mice; the adhesive removal task (ART). This task measures the time it takes an animal to show a behavioral response to an adhesive patch on its paw. We show that cisplatin induces mechanical hyperalgesia and impairs performance in the ART without altering general locomotor activity or motor coordination. Here we investigated the capacity of a specific histone deacetylase 6 (HDAC6) inhibitor to treat cisplatin-induced numbness and pain in mice. We show that the HDAC6 inhibitor, ACY-1083, effectively treats cisplatin-induced numbness. ACY-1083 also reverses existing cisplatin-induced mechanical hyperalgesia. ACY-1083 alone did not affect sensitivity to mechanical stimulation or performance in the ART. Analysis of cultured dorsal root ganglia revealed that cisplatin treatment decreased mitochondrial axonal transport, while co-culture with ACY-1083 attenuated this decrease. This is important because HDAC6 acts by deacetylating alpha-tubulin, which is thought to promote axonal transport. To our knowledge this is the first identified drug capable of treating already existing chemotherapy-induced numbness and pain. http://dx.doi.org/10.1016/j.bbi.2015.06.114
Abstract # 1613 Gene expression changes and fatigue during IMRT in patients with head and neck cancer C. Xiao a, J.J. Beitler b, K.A. Higgins b, J. Felger b, K. Conneely b, B. Dwivedi b, J. Kowalski b, D.W. Bruner b, A.H. Miller b a 1520 Clifton Road NE, Emory University, Atlanta, GA 30322, United States b Emory University, United States
Abstracts / Brain, Behavior, and Immunity 49 (2015) e1–e50
This study assessed changes in gene expression and their association with fatigue in head and neck cancer (HNC) patients receiving Intensity-Modulated Radiotherapy (IMRT). Consented patients were investigated pre- and 1-month post-IMRT. Fatigue was assessed by Multidimensional Fatigue Inventory-20. RNA was isolated from peripheral blood mononuclear cells and analyzed on Illumina Whole Genome BeadChips microarray. Forty non-metastatic HNC patients were enrolled; 70% received chemoIMRT. 1076 genes demonstrated expression changes from pre- to post-IMRT that were significantly correlated with changes in fatigue; 323 (30%) were up-regulated and 753 (70%) were down-regulated from pre- to post-IMRT. Gene enrichment analysis was performed using MetaCore/Cytoscape (FDR<0.01). Among top 200 genes, the top two biological pathways in up-regulated genes were related to IL6 regulation and Legionellosis in innate immune response. The top two biological pathways in down-regulated genes were related to thymic T cell selection and IL12 regulation in acquired immune response. Among top 200 up-regulated genes, the top network of transcription factors/receptors, such as RAGE, AP-1, and CREB1, was significantly over-represented for genes involved in body’s response to treatment-related stimuli. The second most significant network, including TLR, NFkB and its family, was significantly over-represented for genes involved in body’s immune and defense system. These findings suggest that fatigue is associated with expression changes in genes related to inflammation and immune response. Future large studies are needed to verify these findings. http://dx.doi.org/10.1016/j.bbi.2015.06.115
Abstract # 1615 The perioperative use of the sedative dexmedetomidine in cancer patients may have detrimental effects H. Lavon a, R. Krigman a, E. Elbaz a, L. Sorski a, P. Matzner a, L. Shaashua a, A. Benbenishty a, J.P. Cata b, V. Gottumukkala b, S. Ben-Eliyahu a a Sagol School of Neuroscience and, School of Psychological Studies, Tel Aviv University, Tel Aviv 69345, United States b Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, United States
Dexmedetomidine is a widely used sedative, which activates alpha-2 adrenoceptors and exerts analgesic, sympatholytic, and anxiolytic effects. Surgery and the perioperative period are known to promote cancer progression. Different surgical routines and anaesthetic techniques were shown to considerably impact cancer recurrence rates. Studies of the perioperative impact of dexmedetomidine on metastatic progression are scarce. Herein we investigated the acute effects of dexmedetomidine on tumor metastasis employing syngeneic CT26 colon cancer in BALB/C mice and MADB106 adenocarcinoma in F344 rats. Dexmedetomidine increased MADB106 lung tumor retention (LTR) dose-dependently (50–300 microg/kg/day), mostly through suppressing NK activity, as indicated through in vivo selective NK-depletion studies, and ex-vivo assessment of NK cytotoxicity. A single administration of dexmedetomidine also increased MADB106 lung metastases and CT26 liver metastases enumerated 3 weeks following inoculation. Kidney and brain MADB106 tumor retention were elevated by dexmedetomidine not through NK-related mechanisms. On the other hand, in the context of surgery and restraint stress, low doses of dexmedetomidine (20– 50 microg/kg/day) reduced MADB106 LTR. Last, we collected retrospective data in non-small cell lung cancer patients. The intraoperative use of dexmedetomidine was associated with reduced overall survival rates, an effect that was ascribed to cumulative doses greater than 100 microg/patient. Overall, the results warrant further
e29
exploration of mediating mechanisms of the effects of dexmedetomidine. Implications of the retrospective findings in patients to the clinical practice call for robust well designed studies. http://dx.doi.org/10.1016/j.bbi.2015.06.116
Abstract # 1616 Acute and innocuous CpG-C immune stimulation potentiates host resistance to hepatic metastases of colon cancer and protects against immunosuppressive effects of surgery L. Sorski, R. Melamed, H. Lavon, P. Matzner, E. Rosenne, S. Ben-Eliyahu The Sagol School of Neuroscience, School of Psychological Sciences, Tel Aviv University, Tel Aviv 69978, Israel Liver metastases are a major cause of cancer-related mortality. Marginating-hepatic (MH)-NK cells are strategically located in the liver sinusoids to physically interact and lyse circulating tumor cells. In cancer patients, the short peri-operative period is now recognized as critical in determining the progression of remaining malignant disease into established metastases. However, the benefits of immune stimulation have rarely been studied peri-operatively, given the short time frame and contraindications to surgery. To overcome these obstacles, we herein employed a new synthetic TLR-9 agonist, CpG-C, which has minimal adverse effects in rodents and humans. Our results indicated that a single pre-operative CpG-C administration tripled MH-NK cell numbers, and dramatically increased their per-cell NK cytotoxicity against the standard YAC-1 and the syngeneic CT26 colon cancer cell lines. Furthermore, CpG-C treatment protected mice from laparotomy-induced immune suppression, based on examining MH-NK cytotoxicity levels and several molecular markers of NK-cell function, including NKp46, CD49b, CD11b, and NKG2A. Importantly, this short and innocuous CpG-C treatment dramatically reduced the number of hepatic metastases developed 3-weeks following surgical inoculation of CT26 through the hepatic portal vein. These beneficial effects are mediated through activation of NK cells, as NK depletion by anti-asialo GM1 completely abrogated them. Overall, this approach is feasible in cancer patients, and may introduce a new peri-operative intervention to improve long-term cancer outcomes during the critical and unexploited peri-operative time frame. http://dx.doi.org/10.1016/j.bbi.2015.06.117
Abstract # 1617 Pre-existent anxiety symptoms is associated with modified behavioral response during endotoxemia J. Lasselin a,b, M. Lekander a,b,c, J. Axelsson a,b,c, B. Karshikoff a, H. Engler d, S. Elsenbruch d, J. Grigoleit d, S. Benson d a Karolinska Institutet, Department of Clinical Neuroscience – Division of Psychology, nobels väg 9, Solna, Stockholm, Sweden b Stockholm University, Stress Research Institute, Frescati Hagväg 16A, Stockholm, Sweden c Osher Center for Integrative Medicine, Karolinska Institutet, Scheeles väg 1, Solna, Stockholm, Sweden d Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, Essen, Germany
Abstracts / Brain, Behavior, and Immunity 49 (2015) e1–e50
Abstract # 1610 Psychosocial stress suppresses tumor progression in a murine model of spontaneous, metastatic breast cancer R.P. Dawes, D.K. Byun, E.B. Brown, K.S. Madden University of Rochester Medical Center, Neuroscience Graduate Program, 601 Elmwood Avenue, Rochester, NY 14642, United States Late-stage breast cancer remains an intractable problem, with 40,000 deaths annually in the United States. Pre-clinical evidence suggests psychosocial stress accelerates cancer progression. Notably, these studies feature injectable tumor models, often in immunocompromised animals exposed to prolonged stress. We have employed a model of spontaneous, metastatic breast cancer, MMTV-PyMT mice, to more closely mimic clinical disease progression. Mice were exposed to a combined stressor featuring chronic social isolation and acute restraint, which activated the hypothalamic-pituitary-adrenal (HPA)-axis and sympathetic nervous system (SNS). Stressed mice were socially isolated during premalignancy. Two weeks later, isolated mice were exposed to 3 days of 2-hour restraint. We hypothesized this stressor would exacerbate tumor progression. Instead, 2 weeks post-restraint, stressed mice had smaller tumors, reduced splenic/lung CD11b+Gr-1+ myeloid-derived suppressor cells, and reduced pro-tumor MMP-2 and TGF-beta1/2 in plasma exosomes. By 3 weeks post-restraint, HPA-axis and SNS activation were still apparent in stressed mice, but no alterations in tumor size, immune populations, exosomal proteins, or lung metastases were detected. Stress-induced reduction in tumor growth suggests an inhibitory neurohormonal pathway linking stress and cancer progression. Psychosocial stress exposure had no long-term impact on progression, despite evidence for an altered neurohormonal environment, suggesting receptor desensitization/resistance may compensate for elevated neurohormones. A deeper understanding of biobehavioral pathways in cancer progression is needed before targeting stress neuroendocrine signaling therapeutically. Funded in part by NCI Contract No. HHSN261200800001E. http://dx.doi.org/10.1016/j.bbi.2015.06.112
Abstract # 1611 Regional cerebral glucose metabolism in the insula during acute stress predicts increased post-stress pulmonary inflammation in asthma M.A. Rosenkranz, W.W. Busse, B.T. Christian, A.T. Higgins, R.J. Davidson University of Wisconsin-Madison, Center for Investigating Healthy Minds, Waisman Center, 1500 Highland Ave, Madison, WI 53705, United States Although psychological factors contribute to the frequency, severity, and burden of asthma symptoms, the role of the brain in the pathophysiology and treatment of this disease is largely unknown. To examine the neural mechanisms which may regulate airway inflammation in asthma, we used [18F]fluoro-deoxyglucose positron emission tomography (FDG-PET) to identify neural circuits that are active during performance of a social stress task or a matched control condition. Asthmatic subjects with either high or low levels of chronic life stress underwent both stress and control conditions. Fractional exhaled nitric oxide (FeNO) was collected at baseline, as well as hourly post-challenge, and provided a measure of airway inflammation. These data reveal that, in those with high levels of chronic stress, an acute stressor leads to elevated
post-stress FeNO levels relative to those with low chronic stress. In addition, increased regional glucose metabolism in the insular cortex predicts overall FeNO levels. This region of the insula is nearly identical to a region we identified in a previous study where activation following challenge with inhaled allergen predicted the increase in percentage of eosinophils in lung tissue 24 h later. These data corroborate previous evidence indicating a role for the insula in the interaction of emotion and inflammation in asthma and may lead to novel targets for future treatment. http://dx.doi.org/10.1016/j.bbi.2015.06.113
Abstract # 1612 An HDAC6 inhibitor for treatment of chemotherapy-induced peripheral numbness and pain in a mouse model K. Krukowski a, C.J. Heijnen a, O. Golonzhka b, T. Gutti a, M. Jarpe b, A. Kavelaars a a
University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, United States b Acetylon Pharmaceuticals, United States Neurotoxic side-effects of chemotherapy, including pain and numbness in hands and feet, frequently leads to dose reduction. This chemotherapy-induced peripheral neuropathy (CIPN) often persists long into survivorship and negatively affects quality of life. No drugs are available to prevent or treat CIPN and underlying mechanisms are only partially understood. Animal models for investigating chemotherapy-induced numbness are lacking. We have developed a tool for measuring numbness in mice; the adhesive removal task (ART). This task measures the time it takes an animal to show a behavioral response to an adhesive patch on its paw. We show that cisplatin induces mechanical hyperalgesia and impairs performance in the ART without altering general locomotor activity or motor coordination. Here we investigated the capacity of a specific histone deacetylase 6 (HDAC6) inhibitor to treat cisplatin-induced numbness and pain in mice. We show that the HDAC6 inhibitor, ACY-1083, effectively treats cisplatin-induced numbness. ACY-1083 also reverses existing cisplatin-induced mechanical hyperalgesia. ACY-1083 alone did not affect sensitivity to mechanical stimulation or performance in the ART. Analysis of cultured dorsal root ganglia revealed that cisplatin treatment decreased mitochondrial axonal transport, while co-culture with ACY-1083 attenuated this decrease. This is important because HDAC6 acts by deacetylating alpha-tubulin, which is thought to promote axonal transport. To our knowledge this is the first identified drug capable of treating already existing chemotherapy-induced numbness and pain. http://dx.doi.org/10.1016/j.bbi.2015.06.114
Abstract # 1613 Gene expression changes and fatigue during IMRT in patients with head and neck cancer C. Xiao a, J.J. Beitler b, K.A. Higgins b, J. Felger b, K. Conneely b, B. Dwivedi b, J. Kowalski b, D.W. Bruner b, A.H. Miller b a 1520 Clifton Road NE, Emory University, Atlanta, GA 30322, United States b Emory University, United States
Abstracts / Brain, Behavior, and Immunity 49 (2015) e1–e50
This study assessed changes in gene expression and their association with fatigue in head and neck cancer (HNC) patients receiving Intensity-Modulated Radiotherapy (IMRT). Consented patients were investigated pre- and 1-month post-IMRT. Fatigue was assessed by Multidimensional Fatigue Inventory-20. RNA was isolated from peripheral blood mononuclear cells and analyzed on Illumina Whole Genome BeadChips microarray. Forty non-metastatic HNC patients were enrolled; 70% received chemoIMRT. 1076 genes demonstrated expression changes from pre- to post-IMRT that were significantly correlated with changes in fatigue; 323 (30%) were up-regulated and 753 (70%) were down-regulated from pre- to post-IMRT. Gene enrichment analysis was performed using MetaCore/Cytoscape (FDR<0.01). Among top 200 genes, the top two biological pathways in up-regulated genes were related to IL6 regulation and Legionellosis in innate immune response. The top two biological pathways in down-regulated genes were related to thymic T cell selection and IL12 regulation in acquired immune response. Among top 200 up-regulated genes, the top network of transcription factors/receptors, such as RAGE, AP-1, and CREB1, was significantly over-represented for genes involved in body’s response to treatment-related stimuli. The second most significant network, including TLR, NFkB and its family, was significantly over-represented for genes involved in body’s immune and defense system. These findings suggest that fatigue is associated with expression changes in genes related to inflammation and immune response. Future large studies are needed to verify these findings. http://dx.doi.org/10.1016/j.bbi.2015.06.115
Abstract # 1615 The perioperative use of the sedative dexmedetomidine in cancer patients may have detrimental effects H. Lavon a, R. Krigman a, E. Elbaz a, L. Sorski a, P. Matzner a, L. Shaashua a, A. Benbenishty a, J.P. Cata b, V. Gottumukkala b, S. Ben-Eliyahu a a Sagol School of Neuroscience and, School of Psychological Studies, Tel Aviv University, Tel Aviv 69345, United States b Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, United States
Dexmedetomidine is a widely used sedative, which activates alpha-2 adrenoceptors and exerts analgesic, sympatholytic, and anxiolytic effects. Surgery and the perioperative period are known to promote cancer progression. Different surgical routines and anaesthetic techniques were shown to considerably impact cancer recurrence rates. Studies of the perioperative impact of dexmedetomidine on metastatic progression are scarce. Herein we investigated the acute effects of dexmedetomidine on tumor metastasis employing syngeneic CT26 colon cancer in BALB/C mice and MADB106 adenocarcinoma in F344 rats. Dexmedetomidine increased MADB106 lung tumor retention (LTR) dose-dependently (50–300 microg/kg/day), mostly through suppressing NK activity, as indicated through in vivo selective NK-depletion studies, and ex-vivo assessment of NK cytotoxicity. A single administration of dexmedetomidine also increased MADB106 lung metastases and CT26 liver metastases enumerated 3 weeks following inoculation. Kidney and brain MADB106 tumor retention were elevated by dexmedetomidine not through NK-related mechanisms. On the other hand, in the context of surgery and restraint stress, low doses of dexmedetomidine (20– 50 microg/kg/day) reduced MADB106 LTR. Last, we collected retrospective data in non-small cell lung cancer patients. The intraoperative use of dexmedetomidine was associated with reduced overall survival rates, an effect that was ascribed to cumulative doses greater than 100 microg/patient. Overall, the results warrant further
e29
exploration of mediating mechanisms of the effects of dexmedetomidine. Implications of the retrospective findings in patients to the clinical practice call for robust well designed studies. http://dx.doi.org/10.1016/j.bbi.2015.06.116
Abstract # 1616 Acute and innocuous CpG-C immune stimulation potentiates host resistance to hepatic metastases of colon cancer and protects against immunosuppressive effects of surgery L. Sorski, R. Melamed, H. Lavon, P. Matzner, E. Rosenne, S. Ben-Eliyahu The Sagol School of Neuroscience, School of Psychological Sciences, Tel Aviv University, Tel Aviv 69978, Israel Liver metastases are a major cause of cancer-related mortality. Marginating-hepatic (MH)-NK cells are strategically located in the liver sinusoids to physically interact and lyse circulating tumor cells. In cancer patients, the short peri-operative period is now recognized as critical in determining the progression of remaining malignant disease into established metastases. However, the benefits of immune stimulation have rarely been studied peri-operatively, given the short time frame and contraindications to surgery. To overcome these obstacles, we herein employed a new synthetic TLR-9 agonist, CpG-C, which has minimal adverse effects in rodents and humans. Our results indicated that a single pre-operative CpG-C administration tripled MH-NK cell numbers, and dramatically increased their per-cell NK cytotoxicity against the standard YAC-1 and the syngeneic CT26 colon cancer cell lines. Furthermore, CpG-C treatment protected mice from laparotomy-induced immune suppression, based on examining MH-NK cytotoxicity levels and several molecular markers of NK-cell function, including NKp46, CD49b, CD11b, and NKG2A. Importantly, this short and innocuous CpG-C treatment dramatically reduced the number of hepatic metastases developed 3-weeks following surgical inoculation of CT26 through the hepatic portal vein. These beneficial effects are mediated through activation of NK cells, as NK depletion by anti-asialo GM1 completely abrogated them. Overall, this approach is feasible in cancer patients, and may introduce a new peri-operative intervention to improve long-term cancer outcomes during the critical and unexploited peri-operative time frame. http://dx.doi.org/10.1016/j.bbi.2015.06.117
Abstract # 1617 Pre-existent anxiety symptoms is associated with modified behavioral response during endotoxemia J. Lasselin a,b, M. Lekander a,b,c, J. Axelsson a,b,c, B. Karshikoff a, H. Engler d, S. Elsenbruch d, J. Grigoleit d, S. Benson d a Karolinska Institutet, Department of Clinical Neuroscience – Division of Psychology, nobels väg 9, Solna, Stockholm, Sweden b Stockholm University, Stress Research Institute, Frescati Hagväg 16A, Stockholm, Sweden c Osher Center for Integrative Medicine, Karolinska Institutet, Scheeles väg 1, Solna, Stockholm, Sweden d Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, Essen, Germany