|Grant Number:||5R01CA140933-04 Interpret this number|
|Primary Investigator:||Lutgendorf, Susan|
|Organization:||University Of Iowa|
|Project Title:||Biobehavioral Influences and the Ovarian Tumor Microenvironment|
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.
Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth.
Authors: Armaiz-Pena GN, Gonzalez-Villasana V, Nagaraja AS, Rodriguez-Aguayo C, Sadaoui NC, Stone RL, Matsuo K, Dalton HJ, Previs RA, Jennings NB, Dorniak P, Hansen JM, Arevalo JM, Cole SW, Lutgendorf SK, Sood AK, Lopez-Berestein G
Source: Oncotarget, 2015 Feb 28;6(6), p. 4266-73.
Biobehavioral approaches to cancer progression and survival: Mechanisms and interventions.
Authors: Lutgendorf SK, Andersen BL
Source: Am Psychol, 2015 Feb-Mar;70(2), p. 186-97.
Diurnal cortisol and survival in epithelial ovarian cancer.
Authors: Schrepf A, Thaker PH, Goodheart MJ, Bender D, Slavich GM, Dahmoush L, Penedo F, DeGeest K, Mendez L, Lubaroff DM, Cole SW, Sood AK, Lutgendorf SK
Source: Psychoneuroendocrinology, 2015 Mar;53, p. 256-67.
EPub date: 2015 Jan 20.
Understanding inflammation, its regulation, and relevance for health: a top scientific and public priority.
Authors: Slavich GM
Source: Brain Behav Immun, 2015 Mar;45, p. 13-4.
EPub date: 2014 Oct 29.
Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer.
Authors: Wen Y, Graybill WS, Previs RA, Hu W, Ivan C, Mangala LS, Zand B, Nick AM, Jennings NB, Dalton HJ, Sehgal V, Ram P, Lee JS, Vivas-Mejia PE, Coleman RL, Sood AK
Source: Clin Cancer Res, 2015 Jan 15;21(2), p. 448-59.
EPub date: 2014 Nov 21.
Endogenous opioid system influences depressive reactions to socially painful targeted rejection life events.
Authors: Slavich GM, Tartter MA, Brennan PA, Hammen C
Source: Psychoneuroendocrinology, 2014 Nov;49, p. 141-9.
EPub date: 2014 Jul 18.
From childhood trauma to elevated C-reactive protein in adulthood: the role of anxiety and emotional eating.
Authors: Schrepf A, Markon K, Lutgendorf SK
Source: Psychosom Med, 2014 Jun;76(5), p. 327-36.
Focal adhesion kinase: an alternative focus for anti-angiogenesis therapy in ovarian cancer.
Authors: Stone RL, Baggerly KA, Armaiz-Pena GN, Kang Y, Sanguino AM, Thanapprapasr D, Dalton HJ, Bottsford-Miller J, Zand B, Akbani R, Diao L, Nick AM, DeGeest K, Lopez-Berestein G, Coleman RL, Lutgendorf S, Sood AK
Source: Cancer Biol Ther, 2014 Jul;15(7), p. 919-29.
EPub date: 2014 Apr 23.
Antagonism of tumoral prolactin receptor promotes autophagy-related cell death.
Authors: Wen Y, Zand B, Ozpolat B, Szczepanski MJ, Lu C, Yuca E, Carroll AR, Alpay N, Bartholomeusz C, Tekedereli I, Kang Y, Rupaimoole R, Pecot CV, Dalton HJ, Hernandez A, Lokshin A, Lutgendorf SK, Liu J, Hittelman WN, Chen WY, Lopez-Berestein G, Szajnik M, Ueno NT, Coleman RL, Sood AK
Source: Cell Rep, 2014 Apr 24;7(2), p. 488-500.
EPub date: 2014 Apr 3.
From stress to inflammation and major depressive disorder: a social signal transduction theory of depression.
Authors: Slavich GM, Irwin MR
Source: Psychol Bull, 2014 May;140(3), p. 774-815.
EPub date: 2014 Jan 13.
Out of Mind, Out of Sight: Unexpected Scene Elements Frequently Go Unnoticed Until Primed.
Authors: Slavich GM, Zimbardo PG
Source: Curr Psychol, 2013 Dec 1;32(4), p. null.
Non-cancer life stressors contribute to impaired quality of life in ovarian cancer patients.
Authors: Lutgendorf SK, Slavich GM, Degeest K, Goodheart M, Bender D, Thaker PH, Penedo F, Zimmerman B, Lucci J 3rd, Mendez L, Collins K, Sood AK
Source: Gynecol Oncol, 2013 Dec;131(3), p. 667-73.
EPub date: 2013 Oct 3.
Using the stress and adversity inventory as a teaching tool leads to significant learning gains in two courses on stress and health.
Authors: Slavich GM, Toussaint L
Source: Stress Health, 2014 Oct;30(4), p. 343-52.
EPub date: 2013 Aug 16.
Importance of adrenergic pathways in women's cancers.
Authors: Thaker PH, Sood AK, Ramondetta LM
Source: Cancer Biomark, 2013;13(3), p. 145-54.
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 3rd, Thaker PH, Mendez L, Sood AK, Slavich GM, Lutgendorf SK
Source: Cancer, 2013 Sep 1;119(17), p. 3234-41.
EPub date: 2013 Jun 24.
Src activation by ?-adrenoreceptors is a key switch for tumour metastasis.
Authors: Armaiz-Pena GN, Allen JK, Cruz A, Stone RL, Nick AM, Lin YG, Han LY, Mangala LS, Villares GJ, Vivas-Mejia P, Rodriguez-Aguayo C, Nagaraja AS, Gharpure KM, Wu Z, English RD, Soman KV, Shahzad MM, Zigler M, Deavers MT, Zien A, Soldatos TG, Jackson DB, Wiktorowicz JE, Torres-Lugo M, Young T, De Geest K, Gallick GE, Bar-Eli M, Lopez-Berestein G, Cole SW, Lopez GE, Lutgendorf SK, Sood AK
Source: Nat Commun, 2013;4, p. 1403.
Why stress is BAD for cancer patients.
Authors: Nagaraja AS, Armaiz-Pena GN, Lutgendorf SK, Sood AK
Source: J Clin Invest, 2013 Feb;123(2), p. 558-60.
EPub date: 2013 Jan 25.
Psychoneuroimmunology and cancer: a decade of discovery, paradigm shifts, and methodological innovations.
Authors: Green McDonald P, O'Connell M, Lutgendorf SK
Source: Brain Behav Immun, 2013 Mar;30 Suppl, p. S1-9.
EPub date: 2013 Jan 16.
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 MJ, Dahmoush L, Penedo F, Lucci JA 3rd, Ganjei-Azar P, Mendez L, Markon K, Lubaroff DM, Thaker PH, Slavich GM, Sood AK, Lutgendorf SK
Source: Brain Behav Immun, 2013 Mar;30 Suppl, p. S126-34.
EPub date: 2012 Aug 5.
Social influences on clinical outcomes of patients with ovarian cancer.
Authors: Lutgendorf SK, De Geest K, Bender D, Ahmed A, Goodheart MJ, Dahmoush L, Zimmerman MB, Penedo FJ, Lucci JA 3rd, Ganjei-Azar P, Thaker PH, Mendez L, Lubaroff DM, Slavich GM, Cole SW, Sood AK
Source: J Clin Oncol, 2012 Aug 10;30(23), p. 2885-90.
EPub date: 2012 Jul 16.
Neuroendocrine influences on cancer progression.
Authors: Armaiz-Pena GN, Cole SW, Lutgendorf SK, Sood AK
Source: Brain Behav Immun, 2013 Mar;30 Suppl, p. S19-25.
EPub date: 2012 Jun 21.
Sleep disturbance, cytokines, and fatigue in women with ovarian cancer.
Authors: Clevenger L, Schrepf A, Christensen D, DeGeest K, Bender D, Ahmed A, Goodheart MJ, Penedo F, Lubaroff DM, Sood AK, Lutgendorf SK
Source: Brain Behav Immun, 2012 Oct;26(7), p. 1037-44.
EPub date: 2012 Apr 21.
Paraneoplastic thrombocytosis in ovarian cancer.
Authors: Stone RL, Nick AM, McNeish IA, Balkwill F, Han HD, Bottsford-Miller J, Rupairmoole R, Armaiz-Pena GN, Pecot CV, Coward J, Deavers MT, Vasquez HG, Urbauer D, Landen CN, Hu W, Gershenson H, Matsuo K, Shahzad MM, King ER, Tekedereli I, Ozpolat B, Ahn EH, Bond VK, Wang R, Drew AF, Gushiken F, Lamkin D, Collins K, DeGeest K, Lutgendorf SK, Chiu W, Lopez-Berestein G, Afshar-Kharghan V, Sood AK
Source: N Engl J Med, 2012 Feb 16;366(7), p. 610-8.
Cognitive-behavioral stress management reverses anxiety-related leukocyte transcriptional dynamics.
Authors: Antoni MH, Lutgendorf SK, Blomberg B, Carver CS, Lechner S, Diaz A, Stagl J, Arevalo JM, Cole SW
Source: Biol Psychiatry, 2012 Feb 15;71(4), p. 366-72.
EPub date: 2011 Nov 16.
Biobehavioral factors and cancer progression: physiological pathways and mechanisms.
Authors: Lutgendorf SK, Sood AK
Source: Psychosom Med, 2011 Nov-Dec;73(9), p. 724-30.
EPub date: 2011 Oct 21.
Dopamine blocks stress-mediated ovarian carcinoma growth.
Authors: Moreno-Smith M, Lu C, Shahzad MM, Pena GN, Allen JK, Stone RL, Mangala LS, Han HD, Kim HS, Farley D, Berestein GL, Cole SW, Lutgendorf SK, Sood AK
Source: Clin Cancer Res, 2011 Jun 1;17(11), p. 3649-59.
EPub date: 2011 Apr 29.
Stress influences on anoikis.
Authors: Sood AK, Lutgendorf SK
Source: Cancer Prev Res (Phila), 2011 Apr;4(4), p. 481-5.
Cancer induces inflammation and depressive-like behavior in the mouse: modulation by social housing.
Authors: Lamkin DM, Lutgendorf SK, Lubaroff D, Sood AK, Beltz TG, Johnson AK
Source: Brain Behav Immun, 2011 Mar;25(3), p. 555-64.
EPub date: 2010 Dec 21.
Impact of stress on cancer metastasis.
Authors: Moreno-Smith M, Lutgendorf SK, Sood AK
Source: Future Oncol, 2010 Dec;6(12), p. 1863-81.