Abstract # 3082 Sympathetic-inflammatory responses in operated nude mice prevent transformation into dormancy of human breast cancer metastases: Multiple mediating mechanisms through immunity and tumor secretion of IL-6, IL-8, and VEGF

• Published in: Brain, behavior, and immunity Vol. 76; p. e13
• Main Authors: Haldar, R., Shaashua, L., Rosenne, E., Sloan, E., Ben-Eliyahu, S.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.02.2019
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2018.11.211

Surgery-induced excess release of catecholamines and prostaglandins can facilitate metastatic progression. Here, we took advantage of highly-sensitive bioluminescent imaging of LUC2-labeled MDA-MB-231HM human breast cancer cells to study early phases of spontaneous metastasis in nude mice. Orthotopic MDA-MB-231H M primary-tumor (PT) was induced, and its removal, with or without an additional laparotomy, was studied. Surprisingly, PT removal alone markedly reduced metastatic signaling, and induced long-lasting metastatic dormancy, partly through the elimination of PT-secreted factors, eight of which we identified as potentially promoting metastasis. Laparotomy prevented dormancy, while perioperative β-adrenergic and COX-2 inhibition (employing propranolol + etodolac) restored metastatic dormancy, suggesting mediating impacts of adrenergic-inflammatory responses on secretion of these eight factors. Indeed, in vitro studies indicated that epinephrine and prostaglandin-E2 additively increased MDA-MB-231HM secretion of three of the eight factors, IL-6, IL-8, and VEGF, effects that (i) lasted long after the removal of epinephrine and prostaglandin-E2, and (ii) were blocked by specific antagonists. Exploring additional mediating mechanisms by using in vivo depletion of NK cells and NOD/SCID mice, we found that NK cells restrict metastatic progression in this model. Given the established in vivo suppression of NK activity by surgery-induced adrenergic and prostanoid responses, NK-suppression is a potential additional mediator of the prevention of metastatic dormancy by laparotomy. Overall, dormancy-related processes may mediate deleterious effects of laparotomy through multiple mechanisms, including neuroendocrine, immunological, and tumor secreted factors.