Hematopoietic colony–stimulating factors mediate tumor-nerve interactions and bone cancer pain

Schweizerhof, Matthias; Stösser, Sebastian; Kurejová, Martina; Njoo, Christian; Gangadharan, Vijayan; Agarwal, Nitin; Schmelz, Martin; Bali, Kiran Kumar; Michalski, Christoph; Brugger, Stefan; Dickenson, Anthony H.; Simone, Donald A.; Kuner, Rohini

doi:10.1038/nm.1976

Cited by 177 publications

(193 citation statements)

References 33 publications

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“…Anti-GM-CSF mAbs may treat juvenile myelomonocytic leukemias (50) and epithelial cancers, which secrete GM-CSF that suppresses the immune response against cancer (51,52). These mAbs may also be useful in treating pain (53,54). The risk of causing IPAP with these therapeutic anti-GM-CSF mAbs is low because very small amounts of GM-CSF are necessary to mature alveolar macrophages, and IPAP is only caused by a critical threshold of autoantibodies against GM-CSF (33).…”

Section: Discussionmentioning

confidence: 99%

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang

Thomson

Allan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.

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Section: Discussionmentioning

confidence: 99%

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang

Thomson

Allan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…As a result, early-phase clinical trials targeting granulocyte/macrophage colony-stimulating factor and macrophage colony-stimulating factor have now commenced (reviewed in [160]. CSFs mediate tumour nerve interactions and bone cancer pain in a mouse model [161]. Local injection of GM-CSF causes hypersensitivity to mechanical and thermal stimuli and GM-CSF sensitizes nerves to mechanical stimuli and capsaicin in vitro and in vivo [161].…”

Section: Colony-stimulating Factorsmentioning

confidence: 99%

“…Local injection of GM-CSF causes hypersensitivity to mechanical and thermal stimuli and GM-CSF sensitizes nerves to mechanical stimuli and capsaicin in vitro and in vivo [161]. Specific membrane receptors are expressed and are functional on nociceptive afferents [161,162] and inhibition of G-CSF and GM-CSF signalling in vivo reduces tumour growth and nerve remodeling, and abrogates bone cancer pain [161].…”

Section: Colony-stimulating Factorsmentioning

confidence: 99%

Nociceptor Sensitization by Proinflammatory Cytokines And Chemokines

Kress¹

2010

TOPAINJ

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Cytokines are small proteins with a molecular mass lower than 30 kDa. They are produced and secreted on demand, have a short life span and only travel over short distances if not released into the blood circulation. In addition to the classical interleukins and the chemotactic chemokines, growth factors like VEGF or FGF and the colony stimulating factors are also considered cytokines since they have pleiotropic actions and regulatory function in the immune system. Despite the redundancy and pleiotropy of the cytokine network, specific actions of individual cytokines and endogenous control mechanisms have been identified. Particular local profiles of the classical proinflammatory cytokines are associated with inflammatory hypersensitivity and suggest an early involvement of TNFα, IL-1ß and IL-6. An increasing number of novel cytokines and the more recently discovered chemokines are being associated with pathological pain states. Besides acting as pro-or anti-inflammatory mediators increasing evidence indicates that cytokines act on nociceptors. Neurons within the nociceptive system express neuronal receptors and specifically bind cytokines or chemokines which regulate neuronal excitability, sensitivity to external stimuli and synaptic plasticity. A first step towards a more mechanistic and individual pain therapeutic strategy could be avoidance of hypersensitive pain processing by either neutralization strategies for the proalgesic cytokines or by shifting the balance in favour of antialgesic members of the cytokine-chemokine network.Keywords: Hypersensitivity, inflammatory pain, unrepathic pain, neuroimmune interaction. HYPERSENSITIVITY AND NOCICEPTOR SENSITI-ZATIONTissue injury and inflammation commonly cause hypersensitivity of the affected body region, so that normally painful stimuli become more painful (hyperalgesia), and those usually associated with nonnoxious sensations evoke pain (allodynia). The neural bases for these sensory phenomena have been explored most extensively using heat injury and experimental arthritis as models. Heat and/or mechanical hypersensitivity is observed after burns, inflammation, nerve lesion and malignant tumour growth. In models of peripheral inflammation hypersensitivity has been attributed to sensitization of myelinated (Adelta) and unmyelinated (C) primary sensory neurons [1] that normally respond to potentially tissue damaging (noxious) stimuli. Since the first report on primary afferent fibres that responded only to damaging stimulation of the skin and therefore were termed nociceptors [2] our knowledge on the function of these fibres and their association with pain has increased substantially. Detailed analyses of nociceptor function have been performed and strict criteria are available for phenotyping distinct classes of nociceptors in mice, rats and men [1,[3][4][5][6]. Nociceptors occupy a prominent functional position in fast information detection, transduction and transmission of potentially noxious stimuli. They can undergo plastic changes and nociceptor ...

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“…Neurotropins up regulate the tumor cells as well as the intratumoral nerves. Hematopoietic colony stimulating factors (G-CSF and GM-CSF) play a role in tumor-nerve interaction and most importantly tumor induced pain [20]. Myelin-associated glycoprotein (MAC, Siglec-4a) present on the nerve endings and laminin-5 on the tumor cells interact and facilitate PNI of tumor cells [21].…”

Section: Pathogenesismentioning

confidence: 99%