TY - JOUR A1 - Grimm, Martin A1 - Gasser, Martin A1 - Bueter, Marco A1 - Strehl, Johanna A1 - Wang, Johann A1 - Nichiporuk, Ekaterina A1 - Meyer, Detlef A1 - Germer, Christoph T. A1 - Waaga-Gasser, Ana M. A1 - Thalheimer, Andreas T1 - Evaluation of immunological escape mechanisms in a mouse model of colorectal liver metastases N2 - Background: The local and systemic activation and regulation of the immune system by malignant cells during carcinogenesis is highly complex with involvement of the innate and acquired immune system. Despite the fact that malignant cells do have antigenic properties their immunogenic effects are minor suggesting tumor induced mechanisms to circumvent cancer immunosurveillance. The aim of this study is the analysis of tumor immune escape mechanisms in a colorectal liver metastases mouse model at different points in time during tumor growth. Methods: CT26.WT murine colon carcinoma cells were injected intraportally in Balb/c mice after median laparotomy using a standardized injection technique. Metastatic tumor growth in the liver was examined by standard histological procedures at defined points in time during metastatic growth. Liver tissue with metastases was additionally analyzed for cytokines, T cell markers and Fas/Fas-L expression using immunohistochemistry, immunofluorescence and RT-PCR. Comparisons were performed by analysis of variance or paired and unpaired t test when appropriate. Results: Intraportal injection of colon carcinoma cells resulted in a gradual and time dependent metastatic growth. T cells of regulatory phenotype (CD4+CD25+Foxp3+) which might play a role in protumoral immune response were found to infiltrate peritumoral tissue increasingly during carcinogenesis. Expression of cytokines IL-10, TGF-b and TNF-a were increased during tumor growth whereas IFN-g showed a decrease of the expression from day 10 on following an initial increase. Moreover, liver metastases of murine colon carcinoma show an up-regulation of FAS-L on tumor cell surface with a decreased expression of FAS from day 10 on. CD8+ T cells express FAS and show an increased rate of apoptosis at perimetastatic location. Conclusions: This study describes cellular and macromolecular changes contributing to immunological escape mechanisms during metastatic growth in a colorectal liver metastases mouse model simulating the situation in human cancer. KW - Krebs KW - colon carcinoma cells KW - carcinogenesis KW - human cancer Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-67899 ER - TY - JOUR A1 - Grimmig, Tanja A1 - Moench, Romana A1 - Kreckel, Jennifer A1 - Haack, Stephanie A1 - Rueckert, Felix A1 - Rehder, Roberta A1 - Tripathi, Sudipta A1 - Ribas, Carmen A1 - Chandraker, Anil A1 - Germer, Christoph T. A1 - Gasser, Martin A1 - Waaga-Gasser, Ana Maria T1 - Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer JF - International Journal of Molecular Sciences N2 - Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer. KW - tumor growth KW - TLR2 KW - TLR4 KW - TLR9 KW - pancreatic cancer KW - inflammation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165743 VL - 17 IS - 12 ER - TY - JOUR A1 - Ellgring, Johann Heinrich A1 - Seiler, S. A1 - Perleth, B. A1 - Gasser, T. A1 - Oertel, W. T1 - An integrated approach for the neurological and psychological support of Parkinson patients N2 - Introduction Although symptomatic therapy is available for Parkinson's disease, patients and relatives are faced with continuous severe psychological problems. These psychological problems include: 1. lack of emotional expression, 2. bradephrenia, 3. depression, 4. lack of motivation,S. social anxiety, 6. stress induced increase of symptoms. The first four of these may be at least in part due to the dopamine deficiency. However, even as part of the primary symptoms they have social and communicative impact for patients and relatives. Social anxiety and stress induced increase of symptoms on the other hand clearly result from an interaction of somatic and psychological factors. Social anxiety mainly develops in Parkinson I s disease as an indirect consequence of the motor symptoms. Patients are afraid of being negatively evaluated in the public, of receiving negative comments etc. Thus r social withdrawal increases and the improvement of neurological symptoms following drug treatment may not be fully exploited on the psychosocial level. Stress induced increase of motor symptoms is a commonly observed phenomenon in Parkinson's disease. Even minor stressors, mainly social in nature, can have extreme effects and may elicit or increase tremor or rigidity. A patient can be well in one moment, but unable to move in the next when being aware that he has to leave the house in an hour. Given this situation, patients and relatives have to develop strategies fo~ an emotional balance in the presence of a continuous confrontation with the direct and indirect consequences of the disease. A precondition for developing new psychologically based strategies is an optimwn medical treatment. The integrated approach for neurological and psychological support has the following goals: 1. improving medical treatment for the individual patient, 2. improving psychological coping and psychosocial adaptation for patients and relatives, and 3. evaluating and improving medical and psychological therapy. CONCLUSION Psychological intervention can provide considerable help for a substantial part of Parkinson patients. The main target is coping with stressful social situations. Relaxation and cognitive restructuring together with situational behavioral analysis and training of social skills specifically adapted to the disease are" the main strategies. Various problems remain open at the moment, like the maintenance of motivation which is especially critical for Parkinson patients. Parkins on 's disease is a neurological disease with a known pathological substrate and a therapy which is effective at least for several years on a symptomatic level. The symptoms are tightly connected with psychological emotional and cognitive processes. Moreover, patients and relatives have to cope with symptoms which strongly influence social interaction. And they have to cope together with this situation over a period of ten or twenty years. Thus not only for the patient but also for the health of the relatives, psychological aid is urgently needed. We suggest to integrate psychological approach into the neurological diagnosis and treatment. Y1 - 1990 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42456 ER - TY - JOUR A1 - Ellgring, Johann Heinrich A1 - Oertel, W. H. A1 - Ulm, G. A1 - Gasser, T. A1 - Perleth, B. A1 - Seiler, S. T1 - Partnership and depression in Parkinson's Disease N2 - In this study, the influence of partnership on depression and coping with Parkinson's disease has been investigated. Twentythree single female patients, 46 married patients (23 female, 23 male) with unimpaired partnership and 42 patients (21 female, 21 male) whose partnership had worsened since the onset of disease, were compared with regard to depression and self reported extent of psychosocial distress. Single female patients tended to have higher depression scores than patients in a stable partnership, especially in items concerning personal worthlessness and senselessness of life. Patients differed in the extent of distress concerning social behavior, psychological problems/anxiety and efficiency. Within the group of single female patients two subgroups emerged: (1) patients with low extent of distress in all aspects; (2) patients who were highly distressed by psychological problems and physical disability but weakly distressed from social interaction. Male and female patients living in a stable partnership reported only a generally low to moderate extent of distress. More than half of the male and female patients who reported an impairment of their relationship also had scores of moderate to severe depression. These patients also had the h~ghest extent of distress in each ofthe aspects assessed. The results are dicussed with regard to possible interactive effects ofthe disease, quality of the partnership and availability of coping strategies. KW - Depression KW - Parkinson's disease KW - Partnership KW - Psychological distress Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-42516 ER -