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      A Cytokine-Based Neuroimmunologic Mechanism of Cancer-Related Symptoms

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          Abstract

          While many of the multiple symptoms that cancer patients have are due to the disease, it is increasingly recognized that pain, fatigue, sleep disturbance, cognitive dysfunction and affective symptoms are treatment related, and may lead to treatment delays or premature treatment termination. This symptom burden, a subjective counterpart of tumor burden, causes significant distress. Progress in understanding the mechanisms that underlie these symptoms may lead to new therapies for symptom control. Recently, some of these symptoms have been related to the actions of certain cytokines that produce a constellation of symptoms and behavioral signs when given exogenously to both humans and animals. The cytokine-induced sickness behavior that occurs in animals after the administration of infectious or inflammatory agents or certain proinflammatory cytokines has much in common with the symptoms experienced by cancer patients. Accordingly, we propose that cancer-related symptom clusters share common cytokine-based neuroimmunologic mechanisms. In this review, we provide evidence from clinical and animal studies that correlate the altered cytokine profile with cancer-related symptoms. We also propose that the expression of coexisting symptoms is linked to the deregulated activity of nuclear factor-kappa B, the transcription factor responsible for the production of cytokines and mediators of the inflammatory responses due to cancer and/or cancer treatment. These concepts open exciting new avenues for translational research in the pathophysiology and treatment of cancer-related symptoms.

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          Most cited references 52

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          NF-kappaB in cancer: from innocent bystander to major culprit.

          Nuclear factor of kappaB (NF-kappaB) is a sequence-specific transcription factor that is known to be involved in the inflammatory and innate immune responses. Although the importance of NF-KB in immunity is undisputed, recent evidence indicates that NF-kappaB and the signalling pathways that are involved in its activation are also important for tumour development. NF-kappaB should therefore receive as much attention from cancer researchers as it has already from immunologists.
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            A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man

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              The macrophage theory of depression.

               R.S. Smith (1991)
              Excessive secretion of macrophage monokines is proposed as the cause of depression. Monokines when given to volunteers can produce the symptoms necessary for the Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised (DSM-III-R) diagnosis of major depressive episode. Interleukin-1 (IL-1) can provoke the hormone abnormalities linked with depression. This theory provides an explanation for the significant association of depression with coronary heart disease, rheumatoid arthritis, stroke and other diseases where macrophage activation occurs. The 3:1 female/male incidence of depression ratio is accounted for by estrogen's ability to activate macrophages. The extraordinary low rate of depression in Japan is consistent with the suppressive effect of eicosapentanoic acid on macrophages. Fish oil is proposed as a prophylaxis against depression and omega-6 fat as a promoter. Infection, tissue damage, respiratory allergies and antigens found in food are some of the possible causes of macrophage activation triggering depression.
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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                1021-7401
                1423-0216
                2004
                August 2004
                20 August 2004
                : 11
                : 5
                : 279-292
                Affiliations
                aDepartment of Hematopathology, bDepartment of Symptom Research, cDepartment of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Tex., dMedical Writing Department, AmgenInc., Thousand Oaks, Calif., eDepartment of Pharmacology, Louisiana State University Medical School, Shreveport,La., fDepartment of Psychiatry, Emory University, Atlanta, Ga., and gDepartment of Neurology, Memorial Sloan-Kettering Cancer Center, New York, N.Y., USA; hLaboratory of Integrative Neurobiology, University of Bordeaux 2, Bordeaux, France; iDepartment of Anesthesia, McGill University, Montreal, Canada
                Article
                79408 Neuroimmunomodulation 2004;11:279–292
                10.1159/000079408
                15316238
                © 2004 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, References: 125, Pages: 14
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