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1.
Cancer Cell ; 27(6): 780-96, 2015 Jun 08.
Article in English | MEDLINE | ID: mdl-26058077

ABSTRACT

Cancer pain is a debilitating disorder and a primary determinant of the poor quality of life. Here, we report a non-vascular role for ligands of the Vascular Endothelial Growth Factor (VEGF) family in cancer pain. Tumor-derived VEGF-A, PLGF-2, and VEGF-B augment pain sensitivity through selective activation of VEGF receptor 1 (VEGFR1) expressed in sensory neurons in human cancer and mouse models. Sensory-neuron-specific genetic deletion/silencing or local or systemic blockade of VEGFR1 prevented tumor-induced nerve remodeling and attenuated cancer pain in diverse mouse models in vivo. These findings identify a therapeutic potential for VEGFR1-modifying drugs in cancer pain and suggest a palliative effect for VEGF/VEGFR1-targeting anti-angiogenic tumor therapies.


Subject(s)
Neoplasms/pathology , Pain/metabolism , Sensory Receptor Cells/metabolism , Vascular Endothelial Growth Factor Receptor-1/biosynthesis , Angiogenesis Inhibitors/pharmacology , Animals , Disease Models, Animal , Humans , Male , Mice , Mice, Inbred C57BL , Neoplasms/metabolism , Pain/drug therapy , Pain/pathology , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/pathology , Up-Regulation , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors
2.
Reg Anesth Pain Med ; 36(1): 46-50, 2011.
Article in English | MEDLINE | ID: mdl-21455089

ABSTRACT

BACKGROUND AND OBJECTIVES: We found in previous studies that thoracic epidural analgesia (TEA) after open renal surgery via lumbotomy significantly impaired bladder function with decreased detrusor contractility and increased postvoid residuals under urodynamic assessment. Here we evaluated the effect of TEA on bladder emptying in patients undergoing thoracotomy. METHODS: In a prospective, follow-up study, 13 men and 13 women with an International Prostate Symptom Score of less than 7 and with a postvoid residual of less than 100 mL underwent sonographic assessment of the postvoid residual the day before thoracotomy without TEA and 2 days postoperatively under TEA. The epidural catheter was inserted at level T4/5 or 5/6. Continuous epidural analgesia was maintained with a mixture of bupivacaine 1 mg/mL, epinephrine 2 µg/mL, and fentanyl 2 µg/mL. Primary outcome was the difference in postvoid residual before versus during TEA. RESULTS: The postvoid residual did not change significantly preoperatively and postoperatively in men (P = 0.09) and women (P = 0.18). However, a significant decrease in bladder capacity at strong desire to void and voided volumes was observed in women. Of the 3 male patients with an initial International Prostate Symptom Score of 3 or greater and less than 7, all developed a postvoid residual of greater than 100 mL and were older than 50 years. CONCLUSIONS: Most patients after thoracotomy had unchanged postvoid residuals under TEA. Our study design does not allow us to determine cause and effect or to make conclusions that are based on comparative, randomized data. However, our observations do yield a hypothesis-generating basis for future clinical trials.


Subject(s)
Adrenergic Agonists/administration & dosage , Analgesia, Epidural , Analgesics, Opioid/administration & dosage , Anesthetics, Combined/administration & dosage , Anesthetics, Local/administration & dosage , Pain, Postoperative/prevention & control , Thoracotomy/adverse effects , Urinary Bladder/drug effects , Urination Disorders/chemically induced , Urination/drug effects , Adolescent , Adrenergic Agonists/adverse effects , Adult , Aged , Aged, 80 and over , Analgesia, Epidural/adverse effects , Analgesics, Opioid/adverse effects , Anesthetics, Local/adverse effects , Bupivacaine/administration & dosage , Epinephrine/administration & dosage , Female , Fentanyl/administration & dosage , Follow-Up Studies , Humans , Male , Middle Aged , Pain Measurement , Pain, Postoperative/etiology , Prospective Studies , Switzerland , Time Factors , Treatment Outcome , Ultrasonography , Urinary Bladder/diagnostic imaging , Urinary Bladder/physiopathology , Urination Disorders/diagnostic imaging , Urination Disorders/physiopathology , Urodynamics , Young Adult
3.
J Mol Med (Berl) ; 89(4): 321-9, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21079906

ABSTRACT

A variety of cancers are accompanied by debilitating pain, which constitutes the primary reason for poor quality of life in cancer patients. There is an urgent demand for the development of specific mechanism-based therapies against cancer pain. Recently, important advances have been made in mechanisms contributing to cancer pain. A notable finding was that the tumor-derived hematopoietic growth factors, granulocyte- and granulocyte-macrophage-colony-stimulating factors (G-CSF/GM-CSF), subserve important functions in the generation of pain hypersensitivity in tumor-affected regions. In this context, their receptors were unexpectedly found on pain-sensing nerves and were observed to be functionally linked to nociceptive sensitization and tumor-induced pain. Here, we review evidence supporting a role for G-/GM-CSF in sensitization of pain-sensing nerves, the underlying signaling pathways and the cross-talk with other pronociceptive cytokines, peptides and modulators derived from immune cells, osteoclasts and tumor cells. These findings hold implications in the therapy of pain in disease states, such as cancer and rheumatoid arthritis.


Subject(s)
Neoplasms/physiopathology , Nociceptors/metabolism , Pain/physiopathology , Receptors, Granulocyte Colony-Stimulating Factor/metabolism , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Animals , Bone and Bones/metabolism , Bone and Bones/physiopathology , Humans , Inflammation/physiopathology , Neoplasms/complications , Pain/drug therapy , Pain/etiology , Signal Transduction
4.
Nat Med ; 15(7): 802-7, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19525966

ABSTRACT

Pain is one of the most severe and debilitating symptoms associated with several forms of cancer. Various types of carcinomas and sarcomas metastasize to skeletal bones and cause spontaneous bone pain and hyperalgesia, which is accompanied by bone degradation and remodeling of peripheral nerves. Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood. Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells and tumor cells. Here we report that receptors and signaling mediators of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) are also functionally expressed on sensory nerves. GM-CSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP release and caused sprouting of sensory nerve endings in the skin. Interruption of G-CSF and GM-CSF signaling in vivo led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain. The key significance of GM-CSF signaling in sensory neurons was revealed by an attenuation of tumor-evoked pain following a sensory nerve-specific knockdown of GM-CSF receptors. These results show that G-CSF and GM-CSF are important in tumor-nerve interactions and suggest that their receptors on primary afferent nerve fibers constitute potential therapeutic targets in cancer pain.


Subject(s)
Bone Neoplasms/physiopathology , Granulocyte Colony-Stimulating Factor/physiology , Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Pain, Intractable/etiology , Sensory Receptor Cells/physiology , Calcitonin Gene-Related Peptide/metabolism , Receptors, Granulocyte Colony-Stimulating Factor/physiology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Signal Transduction
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