A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain.

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.

Postvoid residuals remain unchanged in patients with postoperative thoracic epidural analgesia after thoracotomy.

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.

Hematopoietic colony-stimulating factors: new players in tumor-nerve interactions.

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.

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

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.