Michaela G Cuneo1, Angela Szeto2, Andrew Schrepf3, Ellen M Kinner1, Benjamin I Schachner4, Raisa Ahmed4, Premal H Thaker5, Michael Goodheart6, David Bender7, Steve W Cole8, Philip M McCabe2, Anil K Sood9, Susan K Lutgendorf10, Armando J Mendez4. 1. Department of Psychological & Brain Sciences, University of Iowa, United States. 2. Department of Psychology, University of Miami, United States. 3. Department of Anesthesiology and Chronic Pain and Fatigue Research Center, University of Michigan, United States. 4. Diabetes Research Institute, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, United States. 5. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, United States. 6. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa, United States; Holden Comprehensive Cancer Center, University of Iowa, United States. 7. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa, United States. 8. Department of Medicine, Division of Hematology/Oncology and Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, United States. 9. Departments of Gynecologic Oncology, Cancer Biology and Center for RNA Interference and Noncoding RNA, University of Texas M.D. Anderson Cancer Center, United States. 10. Department of Psychological & Brain Sciences, University of Iowa, United States; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa, United States; Holden Comprehensive Cancer Center, University of Iowa, United States. Electronic address: susan-lutgendorf@uiowa.edu.
Abstract
BACKGROUND: Prior research demonstrates a protective role for oxytocin in ovarian cancer based on its anti-proliferative, anti-migratory, and anti-invasive effects in vitro and in vivo. However, the role of endogenous oxytocin has not been examined in ovarian cancer patients. Oxytocin also has anti-inflammatory properties that have not been examined in cancer. The purpose of this investigation was to examine relationships between endogenous oxytocin, tumor-associated inflammation (interleukin-6), and survival in advanced epithelial ovarian cancer patients. METHODS: Tumor microenvironment (ascites) and plasma oxytocin levels were analyzed via ELISA on extracted samples obtained from 79 patients. In vitro models were used to characterize oxytocin and oxytocin receptor expression in four ovarian cancer cell lines and to investigate direct anti-inflammatory effects of oxytocin on tumor cell secretion of interleukin-6. High and variable levels of oxytocin were observed in ascites, up to 200 times greater than in plasma. Higher levels of ascites oxytocin were associated with lower levels of systemic and tumor-associated interleukin-6, an inflammatory cytokine implicated in ovarian tumor progression. Oxytocin also attenuated interleukin-6 secretion from multiple ovarian tumor cell lines in vitro. Higher levels of ascites oxytocin were associated with a significant survival advantage and statistical mediation analyses suggested this effect was partially mediated by interleukin-6. CONCLUSIONS: These data identify a previously unacknowledged hormone in the ovarian tumor microenvironment and provide initial evidence that oxytocin has protective effects in ovarian cancer via anti-inflammatory mechanisms. Future studies should examine the therapeutic utility of oxytocin.
BACKGROUND: Prior research demonstrates a protective role for oxytocin in ovarian cancer based on its anti-proliferative, anti-migratory, and anti-invasive effects in vitro and in vivo. However, the role of endogenous oxytocin has not been examined in ovarian cancerpatients. Oxytocin also has anti-inflammatory properties that have not been examined in cancer. The purpose of this investigation was to examine relationships between endogenous oxytocin, tumor-associated inflammation (interleukin-6), and survival in advanced epithelial ovarian cancerpatients. METHODS:Tumor microenvironment (ascites) and plasma oxytocin levels were analyzed via ELISA on extracted samples obtained from 79 patients. In vitro models were used to characterize oxytocin and oxytocin receptor expression in four ovarian cancer cell lines and to investigate direct anti-inflammatory effects of oxytocin on tumor cell secretion of interleukin-6. High and variable levels of oxytocin were observed in ascites, up to 200 times greater than in plasma. Higher levels of ascitesoxytocin were associated with lower levels of systemic and tumor-associated interleukin-6, an inflammatory cytokine implicated in ovarian tumor progression. Oxytocin also attenuated interleukin-6 secretion from multiple ovarian tumor cell lines in vitro. Higher levels of ascitesoxytocin were associated with a significant survival advantage and statistical mediation analyses suggested this effect was partially mediated by interleukin-6. CONCLUSIONS: These data identify a previously unacknowledged hormone in the ovarian tumor microenvironment and provide initial evidence that oxytocin has protective effects in ovarian cancer via anti-inflammatory mechanisms. Future studies should examine the therapeutic utility of oxytocin.
Authors: Susan K Lutgendorf; Koen De Geest; David Bender; Amina Ahmed; Michael J Goodheart; Laila Dahmoush; M Bridget Zimmerman; Frank J Penedo; Joseph A Lucci; Parvin Ganjei-Azar; Premal H Thaker; Luis Mendez; David M Lubaroff; George M Slavich; Steven W Cole; Anil K Sood Journal: J Clin Oncol Date: 2012-07-16 Impact factor: 44.544
Authors: Aeson Chang; Erica K Sloan; Michael H Antoni; Jennifer M Knight; Rachel Telles; Susan K Lutgendorf Journal: Integr Cancer Ther Date: 2022 Jan-Dec Impact factor: 3.077
Authors: Michaela G Cuneo; Angela Szeto; Andrew Schrepf; Premal H Thaker; Michael Goodheart; Steve W Cole; Anil K Sood; Philip M McCabe; Armando J Mendez; Susan K Lutgendorf Journal: Psychosom Med Date: 2021-06-01 Impact factor: 3.864
Authors: C Sue Carter; William M Kenkel; Evan L MacLean; Steven R Wilson; Allison M Perkeybile; Jason R Yee; Craig F Ferris; Hossein P Nazarloo; Stephen W Porges; John M Davis; Jessica J Connelly; Marcy A Kingsbury Journal: Pharmacol Rev Date: 2020-10 Impact factor: 25.468