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 statistical significance, potentially due to the limited numbers of patients with ascites. Social support was not related to plasma catecholamines. Depression, generalized perceived stress, pre-surgical anxiety, and use of peri-surgical beta blockers were not associated with tumor NE. These findings extend our previous report of elevated tumor catecholamines accompanying biobehavioral risk factors in a small sample of ovarian cancer patients (Lutgendorf et al., 2009
). They also extend pre-clinical experiments demonstrating that behavioral stress increases intratumoral NE in an orthotopic mouse model of ovarian cancer (Shazad et al, 2010
), and also increases NE in organs that are typical metastatic sites for ovarian cancer (Thaker et al, 2006
). To the extent that the intratumoral catecholamine differences observed here affect biological pathways involved in tumor progression such as angiogenesis, invasion, anoikis, transcription pathway activation, etc. (Chakroborty et al., 2009
; Lutgendorf et al., 2009
; Sood et al., 2010
, Sloan et al., 2010
), the present results potentially shed light on relationships between psychosocial distress and increased risk of metastasis (Thaker et al., 2006
Although this study demonstrates that biobehavioral factors are related to tumor NE levels, the biological mechanisms underlying these effects will require further definition. There are direct connections from the central nervous system to the ovary via
the sympathetic nervous system (SNS), as well as neural feedback from the ovary to the hypothalamus (Aguado, 2002
). These connections influence the estrus cycle (Aguado, 2002
), but also may provide a neural pathway by which biobehavioral states could alter ovarian biology. Stress has been shown to upregulate the arborization of sympathetic neural fibers (e.g., in lymphoid organs) (Sloan, et al., 2008
), and stress-induced enhancement of tumor vascularization (Thaker et al., 2006
) may also increase innervation via
increased density of peri-vascular nerve fibers. In addition to conveying biobehavioral influences into the healthy ovary and ovarian cancer tissues, these dynamics could also establish a positive feedback loop for sympathetic activity and tumor growth. The basis for increased NE concentrations in ascites also remains to be determined, although increased spill-over from peri-vascular neuro-muscular junctions represents a plausible biological mechanism (Weiner, 1992
In pre-clinical models, catecholamines have been shown to enhance the expression of genes involved in angiogenesis (e.g., VEGF, IL6
) and tissue invasion (MMP2
) in ovarian and nasopharyngeal carcinoma cells (Nilsson et al., 2007
; Sood et al., 2006
; Yang et al., 2006
) and to directly activate angiogenesis promoting molecules such as signal transducer and activator of transcription factor-3 (STAT-3) which has downstream effects on cell proliferation, survival, and angiogenesis, as well as inhibition of apoptosis (Landen et al., 2007
). Catecholamines were also observed to protect tumor cells from anoikis by activating focal adhesion kinase (FAK), a protein tyrosine kinase that mediates physical attachment of cells to their ECM (Sood et al., 2010
). In animal models, catecholamines increase angiogenesis, invasion, tumor weight and number of nodules (Thaker et al., 2006
), and protect tumor cells from anoikis (Sood et al., 2010
). Beta adrenergic activation of the cAMP-PKA signaling pathway via the beta-2 adrenergic receptor appears to be the major pathway mediating these effects (Sood et al., 2010
; Thaker et al., 2006
). Additional signaling pathways are likely also affected by catecholamines but have not been fully characterized.
What accounts for the relationship of social isolation with tumor NE? Socially isolated individuals are thought to have less availability of stress-reducing interpersonal resources such as emotional or instrumental support which would normally serve to bolster active coping efforts and thereby reduce stress (Waite and Hughes, 1999
). Although effects on health have been thought to derive partially from the fact that social isolation often leads to stress or depression (Cacioppo, et al., 2006
), in our data it was social isolation and not stress or depression which was related to tumor catecholamines. The ability to elicit social support may be a stable individual difference characteristic (Smith and MacKenzie, 2006
) and perceived social isolation may thus reflect an ongoing state of stress vulnerability with concomitant SNS activation that is not necessarily represented in more localized measures of stressful life experience. Such an ongoing vulnerability may result in greater integrated accumulation of catecholamines over time.
It is notable that stronger relationships were seen between social support and tumor NE rather than plasma NE. This finding, along with the fact that there was not a relationship between levels of NE in plasma and tumor implies that catecholamines in peripheral circulation are likely not responsible for the bulk of the intratumoral catecholamine levels. These findings also suggest that direct neural linkages between the CNS and ovary may operate differently than the SNS dynamics giving rise to the plasma catecholamine signal. It is also possible that catecholamine accumulation may differ in these two compartments, as the hypoxic and acidic tumor environment may enhance preservation of catecholamines (Miki and Sudo, 1998
). Our data suggest that measurement of stress factors in cancer research should be performed in the compartment of interest and that extrapolation of circulating catecholamine measurements to the tumor microenvironment would be misleading.
Blood sampling was done in a private pre-surgical examination room most often after the patient had been sitting for at least 5 minutes waiting for a nurse. However, because this was a clinical setting, movement artifacts may have been introduced for some patients. Tumors were harvested for catecholamine levels approximately 2–3 hours later during surgery, potentially affecting direct comparisons between plasma and tumor catecholamine levels. Although use of peri-surgical beta blockers was not significantly related to levels of tumor NE, residual effects of this pharmacological intervention on results cannot be totally ruled out. No definitive causal conclusions can be drawn from this observational study.
Social isolation was associated with higher tumor NE among ovarian cancer patients. As beta-adrenergic signaling is related to key pathways involved in tumor growth, these findings may have implications for patient outcomes in ovarian cancer.