Short Communication
Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients

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Abstract

Noradrenergic pathways have been implicated in growth and progression of ovarian cancer. Intratumoral norepinephrine (NE) has been shown to increase with stress in an animal cancer model, but little is known regarding how tumor NE varies with disease stage and with biobehavioral factors in ovarian cancer patients. This study examined relationships between pre-surgical measures of social support, depressed mood, perceived stress, anxiety, tumor histology and tumor catecholamine (NE and epinephrine [E]) levels among 68 ovarian cancer patients. We also examined whether associations observed between biobehavioral measures and tumor catecholamines extended to other compartments. Higher NE levels were found in advanced stage (p = 0.006) and higher grade (p = 0.001) tumors. Adjusting for stage, grade, and peri-surgical beta blockers, patients with a perceived lack of social support had significantly higher tumor NE  = −0.29, p = 0.012). A similar trend was seen for social support and ascites NE (adjusting for stage, peri-surgical beta blockers and caffeine: β = −0.50, p = 0.075), but not for plasma NE. Other biobehavioral factors were not related to tumor, ascites, or plasma NE (p values >0.21). Tumor E was undetectable in the majority of tumors and thus E was not further analyzed. In summary, these results suggest that tumor NE provides distinct information from circulating plasma concentrations. Tumor NE levels were elevated in relationship to tumor grade and stage. Low subjective social support was associated with elevated intratumoral NE. As beta-adrenergic signaling is related to key biological pathways involved in tumor growth, these findings may have implications for patient outcomes in ovarian cancer.

Introduction

Clinical and epidemiologic studies have demonstrated positive associations between stress and cancer progression (Chida et al., 2008, Kroenke et al., 2006, Sprehn et al., 2009) although findings are inconsistent. A key component of the stress response involves activation of the sympathetic nervous system (SNS) and production of mediators such as the catecholamines norepinephrine (NE) and epinephrine (E), which arise both from the SNS and the adrenal medulla (McEwen, 2007). Animal-based research has shown that stress can increase levels of intratumoral NE (Shahzad et al., 2010) as well as NE in the ovary and organs that are typical metastatic sites for ovarian cancer such as spleen and omentum (Thaker et al., 2006). Beta-adrenergic signaling has been shown to enhance biological processes involved in cancer progression such as angiogenesis, invasion, and metastasis (Chakroborty et al., 2009, Sood et al., 2006, Sood et al., 2010, Thaker et al., 2006, Shahzad et al., 2010). NE and E have been shown to stimulate the production of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6), and pro-invasive molecules such as matrix metalloprotineases 2 and 9 (MMP2, MMP-9) from ovarian and other cancer cells, thus increasing the invasive and metastatic potential of these cells (Lutgendorf et al., 2003, Lutgendorf et al., 2008, Nilsson et al., 2007, Sood et al., 2006, Thaker et al., 2006, Yang et al., 2002, Yang et al., 2006). Beta-adrenergic signaling also promotes ovarian cancer cell survival by inhibiting anoikis, the normal process of apoptosis that occurs when cells are separated from the extracellular matrix (ECM) (Sood et al., 2010).

High levels of social isolation have been consistently associated with increased risk for morbidity and mortality, with statistical effect sizes comparable to those of standard health risk factors such as smoking, blood pressure, and obesity (House et al., 1988). Elevated catecholamine levels have been observed in individuals with low social support, chronic stress, and depression (Esler et al., 1982, Hamer et al., 2007, Hughes et al., 2004, Seeman and McEwen, 1996, Weiner, 1992). In patients with ovarian cancer, poor social support has also been linked to higher levels of angiogenic cytokines including VEGF and IL-6, both in peripheral blood and in the tumor micro-environment (Costanzo et al., 2005, Lutgendorf et al., 2002, Lutgendorf et al., 2008). We previously reported in a small sample of 10 ovarian cancer patients that those with poor social support and high depression had significantly higher levels of tumor (but not plasma) NE as compared to patients with high social support and low depression (Lutgendorf et al., 2009). These catecholamine patterns paralleled alterations in activity in tumor tissue of beta-adrenergically linked transcription control pathways mediating processes such as inflammation, metastatic capacity, and cell proliferation (Lutgendorf et al., 2009). Other than this small previous study, the relationship of psychosocial factors and tumor catecholamines has not been examined.

To address this knowledge gap, we examined associations between social support, depression, perceived stress and levels of NE and E in primary ovarian tumor tissue. We also examined the relationship between catecholamines and tumor stage and grade, which has not been previously characterized. Based on our previous work (Lutgendorf et al., 2009), we hypothesized that lower social support, greater depression and greater perceived stress would be associated with higher catecholamine levels in tumor tissue, but not in circulating blood.

Section snippets

Participants

Women over 18 years of age with a new diagnosis of a pelvic or abdominal mass suspected to be ovarian cancer were recruited. Inclusion was confirmed by histologic diagnosis of primary invasive epithelial ovarian, peritoneal, or fallopian tube cancer. Patients were excluded for primary cancer of another organ site, a non-epithelial ovarian tumor, an ovarian tumor of low malignant potential, use of systemic corticosteroid medication in the last 4 months, chronic use of beta-blockers, or

Participant characteristics

Table 1 presents demographic characteristics and mean catecholamine levels by compartment. There were no significant associations between age or health behaviors and NE in tumor tissue or peripheral blood (all p values >0.12). Caffeine consumption was associated with higher levels of ascites NE (p = .059), and therefore was treated as a covariate in analyses involving ascites NE. Pre-surgical anxiety was examined as a potential confound, but was not significantly related to catecholamines in any

Discussion

The key findings of this study are that intratumoral NE levels in primary ovarian carcinomas are linked to both disease severity and patient psychosocial characteristics. Tumor NE was elevated in patients with advanced stage disease and higher grade pathology. Independent of grade or stage, tumor NE levels were also higher in patients reporting lower perceived social support at the time of surgical resection. Similar patterns were seen for ascites NE although relationships did not reach

Conflict of interest statement

The authors have no conflict of interest.

Acknowledgments

Grant support: This research was funded in part by grants CA88293, CA104825 and CA104825 Suppl1, CA140933 (S.K.L.), CA109298, CA110793 and the U.T. MD Anderson Cancer Center Ovarian Cancer SPORE (#P50CA083639) (A.K.S.), CA116778 (S.C.).

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