Grant Number:	1R01CA140933-01 Interpret this number
Primary Investigator:	Lutgendorf, Susan
Organization:	University Of Iowa
Project Title:	Biobehavioral Influences and the Ovarian Tumor Microenvironment
Fiscal Year:	2009

DESCRIPTION (provided by applicant): Ovarian cancer is the second most common gynecologic cancer. Because of low rates of survival for the majority of ovarian cancer patients, identification of factors contributing to tumor progression is of paramount importance. Epidemiologic studies have suggested an association between biobehavioral factors such as life stress, depression, and social support and cancer progression. This study examines a novel pathway that may underlie these links in ovarian cancer, specifically, the relationship of biobehavioral factors with resident macrophages within the tumor microenvironment. It is now acknowledged that the tumor microenvironment is critical in supporting or inhibiting tumor progression. We have previously reported associations of depression and low social support with a poorer cellular immune response in ovarian cancer patients in the tumor microenvironment. We have also demonstrated direct links between biobehavioral factors and cytokines supporting angiogenesis, the formation of new blood vessels that enhance tumor growth and progression. Macrophages are major components of the tumor microenvironment where they are predominantly converted from an anti-tumor phenotype to a pro-tumor phenotype and play a key role in supporting inflammation and tumor progression. However, little is known regarding whether biobehavioral factors influence tumor associated macrophages (TAM) and interactions between TAM and tumor cells in a way that favors tumor growth. Based on compelling preliminary data, we propose that biobehavioral influences on both TAM and tumor cells in the tumor microenvironment have significant effects on production of factors supporting tumor growth and progression. We focus on TAM because of their key role in the tumor microenvironment, and because of indications of macrophage sensitivity to stress factors in the cardiovascular literature and in our preliminary data. Thus, the overarching goal of this proposal is to examine pathways by which biobehavioral factors contribute to a permissive local environment for interactions between resident cells (TAM) and tumor cells that favor tumor growth in ovarian cancer. The proposed project will prospectively examine the relationship of biobehavioral factors (life stress, depression, and social support) and TAM products (inflammatory cytokines and tumor growth factors) in the tumor microenvironment in 206 ovarian cancer patients. Association of biobehavioral factors with upregulation of gene transcripts related to inflammation and proliferation in tumor cells will also be examined. Based on preliminary data we will examine the role of adrenergic signaling as a mediator in these relationships. To determine the clinical significance of these biological alterations, the investigation will assess progression-free and overall survival during the 24 months following diagnosis. Findings will have implications for innovative behavioral and pharmacological intervention strategies for ovarian cancer patients. PUBLIC HEALTH RELEVANCE: There has been very little research examining systemic effects on the tumor microenvironment. This research examines a novel pathway by which biobehavioral factors may contribute to a permissive milieu for tumor growth and disease progression in the tumor microenvironment among ovarian cancer patients. A clearer understanding of biobehavioral risk factors and pathways by which they operate is critical for identifying targets for psychosocial and pharmacological intervention for ovarian cancer patients who may be at risk.




Quality of life and survivorship in patients with low-grade ovarian cancer.
Authors: Lemieux M. , Telles R. , Goodheart M. , Dahmoush L. , Hagemann I. , Penedo F.J. , Nandakumar R. , Cole S.W. , Sood A.K. , Lutgendorf S.K. , et al. .
Source: Gynecologic Oncology, 2024-08-21 00:00:00.0; 190, p. 96-103.
EPub date: 2024-08-21 00:00:00.0.
PMID: 39173565
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Rural-urban disparities in psychosocial functioning in epithelial ovarian cancer patients.
Authors: Telles R. , Zimmerman M.B. , Thaker P.H. , Slavich G.M. , Ramirez E.S. , Zia S. , Goodheart M.J. , Cole S.W. , Sood A.K. , Lutgendorf S.K. .
Source: Gynecologic Oncology, 2024 May; 184, p. 139-145.
EPub date: 2024-02-02 00:00:00.0.
PMID: 38309031
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The biology of hope: Inflammatory and neuroendocrine profiles in ovarian cancer patients.
Authors: Lutgendorf S.K. , Telles R.M. , Whitney B. , Thaker P.H. , Slavich G.M. , Goodheart M.J. , Penedo F.J. , Noble A.E. , Cole S.W. , Sood A.K. , et al. .
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EPub date: 2023-12-09 00:00:00.0.
PMID: 38081436
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Biobehavioral factors predict an exosome biomarker of ovarian carcinoma disease progression.
Authors: Lutgendorf S.K. , Thaker P.H. , Goodheart M.J. , Arevalo J.M.G. , Chowdhury M.A. , Noble A.E. , Dahmoush L. , Slavich G.M. , Penedo F.J. , Sood A.K. , et al. .
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Biobehavioral Pathways and Cancer Progression: Insights for Improving Well-Being and Cancer Outcomes.
Authors: Chang A. , Sloan E.K. , Antoni M.H. , Knight J.M. , Telles R. , Lutgendorf S.K. .
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PMID: 35579197
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Rural residence is related to shorter survival in epithelial ovarian cancer patients.
Authors: Lutgendorf S.K. , Ramirez E. , Schrepf A. , Valentine M.C. , Charlton M. , Zimmerman M.B. , Goodheart M.J. , Zia S. , Sood A.K. , Thaker P.H. .
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EPub date: 2021-08-13 00:00:00.0.
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Chronic difficulties are associated with poorer psychosocial functioning in the first year post-diagnosis in epithelial ovarian cancer patients.
Authors: Garvin L. , Slavich G.M. , Schrepf A. , Davis L.Z. , Thaker P.H. , Goodheart M.J. , Cole S.W. , Sood A.K. , Lutgendorf S.K. .
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EPub date: 2021-04-01 00:00:00.0.
PMID: 33760306
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Positive Psychosocial Factors and Oxytocin in the Ovarian Tumor Microenvironment.
Authors: Cuneo M.G. , Szeto A. , Schrepf A. , Thaker P.H. , Goodheart M. , Cole S.W. , Sood A.K. , McCabe P.M. , Mendez A.J. , Lutgendorf S.K. .
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PMID: 34080583
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Epithelial-mesenchymal transition polarization in ovarian carcinomas from patients with high social isolation.
Authors: Lutgendorf S.K. , Penedo F. , Goodheart M.J. , Dahmoush L. , Arevalo J.M.G. , Thaker P.H. , Slavich G.M. , Sood A.K. , Cole S.W. .
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Oxytocin in the tumor microenvironment is associated with lower inflammation and longer survival in advanced epithelial ovarian cancer patients.
Authors: Cuneo M.G. , Szeto A. , Schrepf A. , Kinner E.M. , Schachner B.I. , Ahmed R. , Thaker P.H. , Goodheart M. , Bender D. , Cole S.W. , et al. .
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PMID: 31005045
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Life stress as a risk factor for sustained anxiety and cortisol dysregulation during the first year of survivorship in ovarian cancer.
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Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens.
Authors: Nagaraja A.S. , Dood R.L. , Armaiz-Pena G. , Kang Y. , Wu S.Y. , Allen J.K. , Jennings N.B. , Mangala L.S. , Pradeep S. , Lyons Y. , et al. .
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PMID: 29889660
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Sustained adrenergic signaling promotes intratumoral innervation through BDNF induction.
Authors: Allen J.K. , Armaiz-Pena G.N. , Nagaraja A.S. , Sadaoui N.C. , Ortiz T. , Dood R. , Ozcan M. , Herder D.M. , Haemerrle M. , Gharpure K.M. , et al. .
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PMID: 29661830
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Biobehavioral modulation of the exosome transcriptome in ovarian carcinoma.
Authors: Lutgendorf S.K. , Thaker P.H. , Arevalo J.M. , Goodheart M.J. , Slavich G.M. , Sood A.K. , Cole S.W. .
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EPub date: 2017-11-07 00:00:00.0.
PMID: 29112229
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Diurnal cortisol rhythms, fatigue and psychosocial factors in five-year survivors of ovarian cancer.
Authors: Cuneo M.G. , Schrepf A. , Slavich G.M. , Thaker P.H. , Goodheart M. , Bender D. , Cole S.W. , Sood A.K. , Lutgendorf S.K. .
Source: Psychoneuroendocrinology, 2017 Oct; 84, p. 139-142.
EPub date: 2017-06-30 00:00:00.0.
PMID: 28711723
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Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens.
Authors: Nagaraja A.S. , Dood R.L. , Armaiz-Pena G. , Kang Y. , Wu S.Y. , Allen J.K. , Jennings N.B. , Mangala L.S. , Pradeep S. , Lyons Y. , et al. .
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PMID: 28814667
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Quality of life among long-term survivors of advanced stage ovarian cancer: A cross-sectional approach.
Authors: Lutgendorf S.K. , Shinn E. , Carter J. , Leighton S. , Baggerly K. , Guindani M. , Fellman B. , Matzo M. , Slavich G.M. , Goodman M.T. , et al. .
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Changes in spiritual well-being and psychological outcomes in ovarian cancer survivors.
Authors: Davis L.Z. , Cuneo M. , Thaker P.H. , Goodheart M.J. , Bender D. , Lutgendorf S.K. .
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Effects Of Lifetime Stress Exposure On Mental And Physical Health In Young Adulthood: How Stress Degrades And Forgiveness Protects Health
Authors: Toussaint L. , Shields G.S. , Dorn G. , Slavich G.M. .
Source: Journal Of Health Psychology, 2016 Jun; 21(6), p. 1004-14.
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SSRI use and clinical outcomes in epithelial ovarian cancer.
Authors: Christensen D.K. , Armaiz-Pena G.N. , Ramirez E. , Matsuo K. , Zimmerman B. , Zand B. , Shinn E. , Goodheart M.J. , Bender D. , Thaker P.H. , et al. .
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Adrenergic Stimulation Of Dusp1 Impairs Chemotherapy Response In Ovarian Cancer
Authors: Kang Y. , Nagaraja A.S. , Armaiz-Pena G.N. , Dorniak P.L. , Hu W. , Rupaimoole R. , Liu T. , Gharpure K.M. , Previs R.A. , Hansen J.M. , et al. .
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Biobehavioral And Neuroendocrine Correlates Of Antioxidant Enzyme Activity In Ovarian Carcinoma
Authors: Bayer J.L. , Spitz D.R. , Christensen D. , McCormick M.L. , Farley D. , DeGeest K. , Damoush L. , Aust S. , Sood A.K. , Lutgendorf S.K. .
Source: Brain, Behavior, And Immunity, 2015 Nov; 50, p. 58-62.
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Pre-treatment Effects Of Peripheral Tumors On Brain And Behavior: Neuroinflammatory Mechanisms In Humans And Rodents
Authors: Schrepf A. , Lutgendorf S.K. , Pyter L.M. .
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Eudaimonic well-being and tumor norepinephrine in patients with epithelial ovarian cancer.
Authors: Davis L.Z. , Slavich G.M. , Thaker P.H. , Goodheart M.J. , Bender D.P. , Dahmoush L. , Farley D.M. , Markon K.E. , Penedo F.J. , Lubaroff D.M. , et al. .
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Clinical Impact Of Selective And Nonselective Beta-blockers On Survival In Patients With Ovarian Cancer
Authors: Watkins J.L. , Thaker P.H. , Nick A.M. , Ramondetta L.M. , Kumar S. , Urbauer D.L. , Matsuo K. , Squires K.C. , Coleman R.L. , Lutgendorf S.K. , et al. .
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Sympathetic Nervous System Regulation Of The Tumour Microenvironment
Authors: Cole S.W. , Nagaraja A.S. , Lutgendorf S.K. , Green P.A. , Sood A.K. .
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Sustained Adrenergic Signaling Leads To Increased Metastasis In Ovarian Cancer Via Increased Pge2 Synthesis
Authors: Nagaraja A.S. , Dorniak P.L. , Sadaoui N.C. , Kang Y. , Lin T. , Armaiz-Pena G. , Wu S.Y. , Rupaimoole R. , Allen J.K. , Gharpure K.M. , et al. .
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Understanding Inflammation, Its Regulation, And Relevance For Health: A Top Scientific And Public Priority
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Diurnal cortisol and survival in epithelial ovarian cancer.
Authors: Schrepf A. , Thaker P.H. , Goodheart M.J. , Bender D. , Slavich G.M. , Dahmoush L. , Penedo F. , DeGeest K. , Mendez L. , Lubaroff D.M. , et al. .
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Adrenergic Regulation Of Monocyte Chemotactic Protein 1 Leads To Enhanced Macrophage Recruitment And Ovarian Carcinoma Growth
Authors: Armaiz-Pena G.N. , Gonzalez-Villasana V. , Nagaraja A.S. , Rodriguez-Aguayo C. , Sadaoui N.C. , Stone R.L. , Matsuo K. , Dalton H.J. , Previs R.A. , Jennings N.B. , et al. .
Source: Oncotarget, 2015-02-28 00:00:00.0; 6(6), p. 4266-73.
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Differential Platelet Levels Affect Response To Taxane-based Therapy In Ovarian Cancer
Authors: Bottsford-Miller J. , Choi H.J. , Dalton H.J. , Stone R.L. , Cho M.S. , Haemmerle M. , Nick A.M. , Pradeep S. , Zand B. , Previs R.A. , et al. .
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Biobehavioral Approaches To Cancer Progression And Survival: Mechanisms And Interventions
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Source: The American Psychologist, 2015 Feb-Mar; 70(2), p. 186-97.
PMID: 25730724
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Immunotherapy Targeting Folate Receptor Induces Cell Death Associated With Autophagy In Ovarian Cancer
Authors: Wen Y. , Graybill W.S. , Previs R.A. , Hu W. , Ivan C. , Mangala L.S. , Zand B. , Nick A.M. , Jennings N.B. , Dalton H.J. , et al. .
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Endogenous Opioid System Influences Depressive Reactions To Socially Painful Targeted Rejection Life Events
Authors: Slavich G.M. , Tartter M.A. , Brennan P.A. , Hammen C. .
Source: Psychoneuroendocrinology, 2014 Nov; 49, p. 141-9.
PMID: 25086307
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Using The Stress And Adversity Inventory As A Teaching Tool Leads To Significant Learning Gains In Two Courses On Stress And Health
Authors: Slavich G.M. , Toussaint L. .
Source: Stress And Health : Journal Of The International Society For The Investigation Of Stress, 2014 Oct; 30(4), p. 343-52.
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Focal Adhesion Kinase: An Alternative Focus For Anti-angiogenesis Therapy In Ovarian Cancer
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From Childhood Trauma To Elevated C-reactive Protein In Adulthood: The Role Of Anxiety And Emotional Eating
Authors: Schrepf A. , Markon K. , Lutgendorf S.K. .
Source: Psychosomatic Medicine, 2014 Jun; 76(5), p. 327-36.
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From stress to inflammation and major depressive disorder: a social signal transduction theory of depression.
Authors: Slavich G.M. , Irwin M.R. .
Source: Psychological Bulletin, 2014 May; 140(3), p. 774-815.
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Antagonism Of Tumoral Prolactin Receptor Promotes Autophagy-related Cell Death
Authors: Wen Y. , Zand B. , Ozpolat B. , Szczepanski M.J. , Lu C. , Yuca E. , Carroll A.R. , Alpay N. , Bartholomeusz C. , Tekedereli I. , et al. .
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Non-cancer life stressors contribute to impaired quality of life in ovarian cancer patients.
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Source: Gynecologic Oncology, 2013 Dec; 131(3), p. 667-73.
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Out Of Mind, Out Of Sight: Unexpected Scene Elements Frequently Go Unnoticed Until Primed
Authors: Slavich G.M. , Zimbardo P.G. .
Source: Current Psychology (new Brunswick, N.j.), 2013-12-01 00:00:00.0; 32(4), .
PMID: 24363542
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¿-blockers: A New Role In Cancer Chemotherapy?
Authors: Nagaraja A.S. , Sadaoui N.C. , Lutgendorf S.K. , Ramondetta L.M. , Sood A.K. .
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PMID: 23919278
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Impact Of Cardiovascular Comorbidity On Ovarian Cancer Mortality
Authors: Shinn E.H. , Lenihan D.J. , Urbauer D.L. , Basen-Engquist K.M. , Valentine A. , Palmero L. , Woods M.L. , Patel P. , Nick A.M. , Shahzad M.M. , et al. .
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Sleep disturbance, distress, and quality of life in ovarian cancer patients during the first year after diagnosis.
Authors: Clevenger L. , Schrepf A. , Degeest K. , Bender D. , Goodheart M. , Ahmed A. , Dahmoush L. , Penedo F. , Lucci J. , Thaker P.H. , et al. .
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PMID: 23797955
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Biologic Effects Of Dopamine On Tumor Vasculature In Ovarian Carcinoma
Authors: Moreno-Smith M. , Lee S.J. , Lu C. , Nagaraja A.S. , He G. , Rupaimoole R. , Han H.D. , Jennings N.B. , Roh J.W. , Nishimura M. , et al. .
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Neuroendocrine Influences On Cancer Progression
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Source: Brain, Behavior, And Immunity, 2013 Mar; 30 Suppl, p. S19-25.
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Cortisol And Inflammatory Processes In Ovarian Cancer Patients Following Primary Treatment: Relationships With Depression, Fatigue, And Disability
Authors: Schrepf A. , Clevenger L. , Christensen D. , DeGeest K. , Bender D. , Ahmed A. , Goodheart M.J. , Dahmoush L. , Penedo F. , Lucci J.A. , et al. .
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Psychoneuroimmunology And Cancer: A Decade Of Discovery, Paradigm Shifts, And Methodological Innovations
Authors: Green McDonald P. , O'Connell M. , Lutgendorf S.K. .
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Depressive symptoms and cortisol variability prior to surgery for suspected endometrial cancer.
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Why Stress Is Bad For Cancer Patients
Authors: Nagaraja A.S. , Armaiz-Pena G.N. , Lutgendorf S.K. , Sood A.K. .
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