Search

The use of complementary therapies by patients with cancer has become increasingly prevalent; as a result, oncology nurses find themselves needing to understand those therapies and the evidence-based support for their use. This article describes the integrative use of the biofield therapy healing touch in conjunction with the chemoradiation received by patients with cervical cancer (stages IB1 to IVA) as reported in a 2010 research study. Findings indicated effects on the immune response and depression in healing touch recipients compared to patients receiving relaxation or standard care. Specifically, healing touch recipients demonstrated a minimal decrease in natural killer cell cytotoxicity over the course of treatment, whereas the cytotoxicity of patients receiving relaxation therapy and standard care declined sharply during radiation. Healing touch recipients also showed decreases in depressed mood compared to relaxation therapy and standard care recipients. The findings suggest that appropriate integration of complementary modalities into oncology care can enhance the impact of conventional care by putting patients in the best condition to use their innate healing resources.

Purpose: Increased adrenergic activity in response to chronic stress is known to promote tumor growth by stimulating the tumor microenvironment. The focus of the current study was to determine whether dopamine, an inhibitory catecholamine, could block the effects of chronic stress on tumor growth., Experimental Design: Expression of dopamine receptors (DR1-DR5) was analyzed by reverse transcriptase-PCR and by Western blotting. In vitro effects of dopamine on cell viability, apoptosis, and migration were examined. For in vivo therapy, murine and human DR2-siRNAs were incorporated into chitosan nanoparticles (CH-NP)., Results: In this model of chronic stress, tumoral norepinephrine levels remained elevated whereas dopamine levels were significantly decreased compared with nonstressed animals. Daily restraint stress resulted in significantly increased tumor growth in both immunodeficient (SKOV3ip1 and HeyA8) and immunocompetent (ID8) ovarian cancer models. This increase was completely blocked with daily dopamine treatment. Dopamine treatment also blocked the stress-induced increase in angiogenesis. Endothelial and ovarian cancer cells expressed all dopamine receptors except for the lack of DR3 expression in ovarian cancer cells. DR2 was responsible for the inhibitory effects of dopamine on tumor growth and microvessel density as well as the stimulatory effect on apoptosis, as the DR2 antagonist eticlopride reversed these effects. Dopamine significantly inhibited cell viability and stimulated apoptosis in vitro. Moreover, dopamine reduced cyclic AMP levels and inhibited norepinephrine and vascular permeability factor/VEGF-induced Src kinase activation., Conclusions: Dopamine depletion under chronic stress conditions creates a permissive microenvironment for tumor growth that can be reversed by dopamine replacement., (©2011 AACR.)

It long has been suspected that psychosocial factors affect cancer development and progression. Although the connections between stress and cancer causation are not strong, epidemiologic and clinical studies have provided strong links between cancer progression and several stress-related factors including chronic stress, depression, and social isolation. Recent molecular and biological studies have identified specific signaling pathways that influence cancer growth and metastasis. In particular, stress hormones can have a significant impact on protecting cancer cells from undergoing the anoikis form of programmed cell death, thus, providing a mechanistic advantage for metastasis. This review provides an overview of the relationship between psychosocial factors and the avoidance of anoikis by cancer cells., (©2011 AACR.)

Considerable data demonstrate a high prevalence of depressive symptoms in cancer patients. This study introduces an experimental model to examine the effect of tumor on depressive-like behavior. Female C57BL/6 mice were injected i.p. with syngeneic ID8 ovarian carcinoma. Experiment 1 measured sucrose intake before and after tumor incubation to assess the effect of tumor on anhedonic depressive-like behavior. Experiment 2 examined effects of tumor and social housing on anhedonia and a second depressive-like behavior, tail suspension test (TST) immobility. Systemic proinflammatory and antiinflammatory cytokines were measured following each experiment. Additional behaviors assessed the specificity of tumor's effect on depressive-like behavior. Tumor caused a reduction in sucrose intake relative to baseline and control levels (P<.05). Moreover, individually-housed tumor-bearing mice exhibited a lower sucrose preference than group-housed tumor-bearing or control mice in either housing condition (P<.05). Although tumor-bearing mice exhibited less locomotion than controls (P<.001), there was no significant effect of tumor on TST immobility. Tumor caused higher levels of systemic proinflammatory and antiinflammatory cytokines and smaller body weight (P<.05), but appetite and motor capacity were not significantly affected. Statistical mediation analysis showed that circulating interleukin-6 partially mediated the effect between tumor and home cage locomotion (P<.01) but not between tumor and sucrose intake. It is concluded that tumor elicits anhedonic depressive-like behavior in a murine model of ovarian cancer. This may have important implications for etiology of depression in the clinical cancer setting., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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 (β=-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., (Copyright © 2010 Elsevier Inc. All rights reserved.)

This review focuses on the contributions of stress-related behavioral factors to cancer growth and metastasis and the biobehavioral mechanisms underlying these relationships. Behavioral factors that are important in modulation of the stress response and the pivotal role of neuroendocrine regulation in the downstream alteration of physiologic pathways relevant to cancer control, including the cellular immune response, inflammation, and tumor angiogenesis, invasion, and cell signaling pathways are described. Consequences for cancer progression and metastasis, as well as quality of life, are delineated. Behavioral and pharmacologic interventions with the potential to alter these biobehavioral pathways for patients with cancer are discussed., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Following the end of adjuvant treatment, breast cancer survivors must cope with uncertainty related to the possibility of recurrence and the loss of the 'safety net' treatment provides. This study examined breast cancer survivors' efforts to manage uncertainty by making lifestyle changes, such as improvement in diet and exercise. We further investigated the role of women's common-sense beliefs about their cancer, as described by Leventhal's self-regulation theory, in explaining post-treatment changes., Method: At 3 weeks and 3 months post-treatment, 79 women who received adjuvant chemotherapy and/or radiation therapy for stages 0-III breast cancer (mean age=55 years) completed assessments of changes in health practices and other behaviors. Participants also completed measures of beliefs about the causes, course, personal control, and consequences of their cancer., Results: Survivors reported behavior changes directed toward improving physical, emotional, and spiritual well-being. Results further indicated that women who believed their cancer had more severe consequences and those who attributed the development of cancer or the prevention of recurrence to health behaviors or stress were most likely to report improvement in diet or physical activity and reduction in alcohol use or stress., Conclusions: Findings suggest that breast cancer survivors are poised to make lifestyle changes after treatment ends, creating an opportune time for health promotion interventions. Understanding women's cancer beliefs could help guide the development of tailored, proactive interventions to improve the health and well-being of breast cancer survivors., (Copyright © 2010 John Wiley & Sons, Ltd.)

The influence of psychosocial factors on the development and progression of cancer has been a longstanding hypothesis since ancient times. In fact, epidemiological and clinical studies over the past 30 years have provided strong evidence for links between chronic stress, depression and social isolation and cancer progression. By contrast, there is only limited evidence for the role of these behavioral factors in cancer initiation. Recent cellular and molecular studies have identified specific signaling pathways that impact cancer growth and metastasis. This article provides an overview of the relationship between psychosocial factors, specifically chronic stress, and cancer progression.

A growing number of studies indicate that chronic stress can accelerate tumor growth due to sustained sympathetic nervous system activation. Our recent findings suggest that chronic stress is associated with increased IL8 levels. Here, we examined the molecular and biological significance of IL8 in stress-induced tumor growth. Norepinephrine (NE) treatment of ovarian cancer cells resulted in a 250-300% increase in IL8 protein and 240-320% increase in its mRNA levels. Epinephrine treatment resulted in similar increases. Moreover, NE treatment resulted in a 3.5-4-fold increase in IL8 promoter activity. These effects were blocked by propranolol. Promoter deletion analyses suggested that AP1 transcription factors might mediate catecholamine-stimulated up-regulation of IL8. siRNA inhibition studies identified FosB as the pivotal component responsible for IL8 regulation by NE. In vivo chronic stress resulted in increased tumor growth (by 221 and 235%; p < 0.01) in orthotopic xenograft models involving SKOV3ip1 and HeyA8 ovarian carcinoma cells. This enhanced tumor growth was completely blocked by IL8 or FosB gene silencing using 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoliposomes. IL8 and FosB silencing reduced microvessel density (based on CD31 staining) by 2.5- and 3.5-fold, respectively (p < 0.001). Our findings indicate that neurobehavioral stress leads to FosB-driven increases in IL8, which is associated with increased tumor growth and metastases. These findings may have implications for ovarian cancer management.

Patients receiving chemoradiation for cervical cancer are at risk for distress, chemoradiation-related side-effects, and immunosuppression. This prospective randomized clinical trial examined effects of a complementary therapy, Healing Touch (HT), versus relaxation training (RT) and usual care (UC) for (1) supporting cellular immunity, (2) improving mood and quality of life (QOL), and (3) reducing treatment-associated toxicities and treatment delay in cervical cancer patients receiving chemoradiation. Sixty women with stages IB1 to IVA cervical cancer were randomly assigned to receive UC or 4 ×/weekly individual sessions of either HT or RT immediately following radiation during their 6-week chemoradiation treatment. Patients completed psychosocial assessments and blood sampling before chemoradiation at baseline, weeks 4 and 6. Multilevel regression analyses using orthogonal contrasts tested for differences between treatment conditions over time. HT patients had a minimal decrease in natural killer cell cytotoxicity (NKCC) over the course of treatment whereas NKCC of RT and UC patients declined sharply during chemoradiation (group by time interaction: p = 0.018). HT patients showed greater decreases in two different indicators of depressed mood (CES-D depressed mood subscale and POMS depression scale) compared to RT and UC (group by time interactions: p<0.05). No between group differences were observed in QOL, treatment delay, or clinically-rated toxicities. HT may benefit cervical cancer patients by moderating effects of chemoradiation on depressed mood and cellular immunity. Effects of HT on toxicities, treatment delay, QOL, and fatigue were not observed. Long-term clinical implications of findings are not known., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Multiple alterations in circadian rhythms have been observed in cancer patients, including the diurnal rhythm of the adrenal hormone cortisol. Diurnal cortisol alterations have been associated with cancer-related physiological processes as well as psychological stress. Here we investigate alterations in diurnal cortisol rhythm in ovarian cancer patients, and potential links with depression, life stress, and functional disability., Methods: Women (n = 177) with suspected ovarian cancer completed questionnaires and collected salivary cortisol 3× daily for 3 consecutive days before surgery. One hundred women were subsequently diagnosed with ovarian cancer and 77 with benign disease. In addition, healthy women (n = 33) not scheduled for surgery collected salivary cortisol at the same time points., Results: Ovarian cancer patients demonstrated significantly elevated nocturnal cortisol (P = .022) and diminished cortisol variability (P = .023) compared with women with benign disease and with healthy women (all P values <.0001). Among ovarian cancer patients, higher levels of nocturnal cortisol and less cortisol variability were significantly associated with greater functional disability, fatigue, and vegetative depression, but not with stress, distress, or depressed affect. There were no significant associations between functional or psychological variables and diurnal cortisol in women with benign disease., Conclusions: Nocturnal cortisol and cortisol variability show significant dysregulation in ovarian cancer patients, and this dysregulation was associated with greater functional disability, fatigue, and vegetative depression. These findings suggest potential hypothalamic-pituitary-adrenal involvement in functional disability in ovarian cancer, and may have implications for disease progression., (© 2010 American Cancer Society.)

Whereas evidence for the role of psychosocial factors in cancer initiation has been equivocal, support continues to grow for links between psychological factors such as stress, depression, and social isolation and progression of cancer. In vitro, in vivo, and clinical studies show that stress- related processes can impact pathways implicated in cancer progression, including immuno-regulation, angiogenesis, and invasion. Contributions of systemic factors, such as stress hormones to the crosstalk between tumor and stromal cells, appear to be critical in modulating downstream signaling pathways with important implications for disease progression. Inflammatory pathways may also be implicated in fatigue and other factors related to quality of life. Although substantial evidence supports a positive effect of psychosocial interventions on quality of life in cancer, the clinical evidence for efficacy of stress-modulating psychosocial interventions in slowing cancer progression remains inconclusive, and the biobehavioral mechanisms that might explain such effects are still being established. This article reviews research findings to date and outlines future avenues of research in this area.

Chronic stress is associated with hormonal changes that are known to affect multiple systems, including the immune and endocrine systems, but the effects of stress on cancer growth and progression are not fully understood. Here, we demonstrate that human ovarian cancer cells exposed to either norepinephrine or epinephrine exhibit lower levels of anoikis, the process by which cells enter apoptosis when separated from ECM and neighboring cells. In an orthotopic mouse model of human ovarian cancer, restraint stress and the associated increases in norepinephrine and epinephrine protected the tumor cells from anoikis and promoted their growth by activating focal adhesion kinase (FAK). These effects involved phosphorylation of FAKY397, which was itself associated with actin-dependent Src interaction with membrane-associated FAK. Importantly, in human ovarian cancer patients, behavioral states related to greater adrenergic activity were associated with higher levels of pFAKY397, which was in turn linked to substantially accelerated mortality. These data suggest that FAK modulation by stress hormones, especially norepinephrine and epinephrine, can contribute to tumor progression in patients with ovarian cancer and may point to potential new therapeutic targets for cancer management.

To identify genetic factors that interact with social environments to impact human health, we used a bioinformatic strategy that couples expression array-based detection of environmentally responsive transcription factors with in silico discovery of regulatory polymorphisms to predict genetic loci that modulate transcriptional responses to stressful environments. Tests of one predicted interaction locus in the human IL6 promoter (SNP rs1800795) verified that it modulates transcriptional response to beta-adrenergic activation of the GATA1 transcription factor in vitro. In vivo validation studies confirmed links between adverse social conditions and increased transcription of GATA1 target genes in primary neural, immune, and cancer cells. Epidemiologic analyses verified the health significance of those molecular interactions by documenting increased 10-year mortality risk associated with late-life depressive symptoms that occurred solely for homozygous carriers of the GATA1-sensitive G allele of rs1800795. Gating of depression-related mortality risk by IL6 genotype pertained only to inflammation-related causes of death and was associated with increased chronic inflammation as indexed by plasma C-reactive protein. Computational modeling of molecular interactions, in vitro biochemical analyses, in vivo animal modeling, and human molecular epidemiologic analyses thus converge in identifying beta-adrenergic activation of GATA1 as a molecular pathway by which social adversity can alter human health risk selectively depending on individual genetic status at the IL6 locus.

Purpose: The effects of reproductive hormones on ovarian cancer growth are not well understood. Here, we examined the effects of estrous cycle variation and specific reproductive hormones on ovarian cancer growth., Experimental Design: We investigated the role of reproductive hormones in ovarian cancer growth using both in vivo and in vitro models of tumor growth., Results: In vivo experiments using the HeyA8 and SKOV3ip1 ovarian cancer models showed that tumor cell inoculation during proestrus significantly increased tumor burden (251-273%) compared with injection during the estrus phase. Treatment of ovariectomized mice with 17beta-estradiol resulted in a 404% to 483% increase in tumor growth compared with controls. Progestins had no significant effect, but did block estrogen-stimulated tumor growth. Tumors collected from mice sacrificed during proestrus showed increased levels of vascular endothelial growth factor (VEGF) and microvessel density compared with mice injected during estrus. HeyA8, SKOV3ip1, and mouse endothelial (MOEC) cells expressed estrogen receptor alpha and beta and progesterone receptor at the protein and mRNA levels, whereas 2774 ovarian cancer cells were estrogen receptor-negative. In vitro assays showed that 17beta-estradiol significantly increased ovarian cancer cell adhesion to collagen in estrogen receptor-positive, but not in estrogen receptor-negative cells. Additionally, 17beta-estradiol increased the migratory potential of MOEC cells, which was abrogated by the mitogen-activated protein kinase (MAPK) inhibitor, PD 09859. Treatment with 17beta-estradiol activated MAPK in MOEC cells, but not in HeyA8 or SKOV3ip1 cells., Conclusion: Our data suggest that estrogen may promote in vivo ovarian cancer growth, both directly and indirectly, by making the tumor microenvironment more conducive for cancer growth.

Purpose: Surgical stress has been suggested to facilitate the growth of preexisting micrometastases as well as small residual tumor postoperatively. The purpose of this study was to examine the effects of surgical stress on ovarian cancer growth and to determine underlying mechanisms responsible for increased growth., Experimental Design: To mimic the effects of surgery, we did a laparotomy or mastectomy under isoflurane inhalation on athymic nude mice 4 days after i.p. tumor cell injection. Propranolol infusion via Alzet pumps was used to block the influence of sympathetic nervous system activation by surgical stress., Results: In both HeyA8 and SKOV3ip1 models, the mice in the laparotomy and mastectomy groups had significantly greater tumor weight (P < 0.05) and nodules (P < 0.05) compared with anesthesia only controls. There was no increase in tumor weight following surgery in the beta-adrenergic receptor-negative RMG-II model. Propranolol completely blocked the effects of surgical stress on tumor growth, indicating a critical role for beta-adrenergic receptor signaling in mediating the effects of surgical stress on tumor growth. In the HeyA8 and SKOV3ip1 models, surgery significantly increased microvessel density (CD31) and vascular endothelial growth factor expression, which were blocked by propranolol treatment., Conclusion: These results indicate that surgical stress could enhance tumor growth and angiogenesis, and beta-blockade might be effective in preventing such effects.

Purpose: To determine whether uncertainty of the diagnosis after large-core breast biopsy (LCBB) adversely affects biochemical stress levels., Materials and Methods: This study was institutional review board approved and HIPAA compliant, and all patients gave written informed consent. One hundred fifty women aged 18-86 years collected four salivary cortisol samples per day for 5 days after LCBB. t Tests were used to compare diurnal cortisol slopes among three groups: patients who did not have a final diagnosis (uncertain group), patients who knew they had cancer (known malignant group), and patients who knew they had benign disease (known benign group)., Results: Women learned their diagnosis on days 1-6 (mean, day 2.4) after LCBB. Analysis was truncated at day 5, when the data from a sufficient number of patients from each group were available for meaningful analysis: 16 patients from the known malignant group, 37 from the known benign group, and 73 from the uncertain group, which totaled 126 patients. The mean cortisol slope for the women with an uncertain diagnosis (-0.092 ln [microg/dL]/hr; 95% confidence interval [CI]: -0.113 ln [microg/dL]/hr, -0.072 ln [microg/dL]/hr) was significantly flatter (less desirable) than that for the women who learned that they had benign disease (-0.154 ln [microg/dL]/hr; 95% CI: -0.197 ln [microg/dL]/hr, -0.111 ln [microg/dL]/hr; P = .014) but not significantly different from that for the women who learned that they had malignant disease (-0.110 ln [microg/dL]/hr; 95% CI: -0.147 ln [microg/dL]/hr, -0.073 ln [microg/dL]/hr; P = .421)., Conclusion: Uncertainty about the final diagnosis after LCBB is associated with substantial biochemical distress, which may have adverse effects on immune defense and wound healing. Results indicate the need for more rapid communication of biopsy results., (RSNA, 2009)

Background: Research suggests that glucose levels in cancer patients may be an important prognostic indicator. In ovarian tumors, increased expression of glucose transporter 1 (GLUT1), a transmembrane protein responsible for glucose uptake, is related to shorter survival time in ovarian cancer patients. This study tested the hypothesis that higher presurgical glucose levels predict shorter disease-specific survival time and time to recurrence in ovarian cancer patients., Methods: Nonfasting plasma glucose levels were determined for 74 patients with ovarian cancer at the time of their presurgical consultation and for 125 ovarian cancer patients in an independent validation set. Survival time and time to recurrence (disease-free interval [DFI]) were ascertained from medical records. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) for survival time and DFI in relation to glucose level, adjusting for body mass index (BMI), stage, grade, and cytoreduction as appropriate., Results: Higher glucose levels were associated with shorter survival times in univariate analyses (HR, 1.88; P = .05). Multivariate analysis adjusting for stage showed that higher glucose levels were associated with shorter survival times (HR, 2.01; P = .04) and DFI (HR, 2.32; P = .05). In the validation set, higher glucose levels were associated with shorter survival times (HR, 2.01; P = .02) and DFI (HR, 2.48; P = .001) in univariate analysis, although glucose was not independent of the effect of cytoreduction when predicting survival time in this latter set., Conclusions: These findings contribute to mounting evidence that glucose levels have prognostic value in ovarian carcinoma., ((c) 2009 American Cancer Society.)

Motivated by previous indications that beta-adrenergic signaling can regulate tumor cell gene expression in model systems, we sought to determine whether similar dynamics occur in primary human ovarian cancer. DNA microarray analyses of 10 ovarian carcinomas identified 266 human transcripts that were differentially expressed in tumors from patients with elevated biobehavioral risk factors (high depressive symptoms and low social support) relative to grade- and stage-matched tumors from low-risk patients. Promoter-based bioinformatic analyses indicated increased activity of several beta-adrenergically-linked transcription control pathways, including CREB/ATF, NF-kappaB/Rel, STAT, and Ets family transcription factors. Consistent with increased beta-adrenergic signaling, high biobehavioral risk patients also showed increased intra-tumor concentrations of norepinephrine (but no difference in plasma norepinephrine). These data show that genome-wide transcriptional profiles are significantly altered in tumors from patients with high behavioral risk profiles, and they identify beta-adrenergic signal transduction as a likely mediator of those effects.

Clinical and animal studies now support the notion that psychological factors such as stress, chronic depression, and lack of social support might promote tumor growth and progression. Recently, cellular and molecular studies have started to identify biological processes that could mediate such effects. This review provides a mechanistic understanding of the relationship between biological and behavioral influences in cancer and points to more comprehensive behavioral and pharmacological approaches for better patient outcomes.

Purpose: Stromal cells in the tumor microenvironment, such as macrophages, play an active role in tumor growth and angiogenesis. However, little is known about relationships of biobehavioral factors with angiogenic cytokines and matrix metalloproteinases (MMP) produced by stromal cells. This study examined distress, MMPs, and angiogenic cytokines in ovarian cancer patients and in vitro., Experimental Design: Patients suspected of ovarian cancer completed preoperative questionnaires. At surgery, 56 were confirmed to have epithelial ovarian cancer. Tumor samples were analyzed for macrophage (CD68(+)) and tumor cell levels of MMP-2, MMP-9, and vascular endothelial growth factor. In vitro stimulation of isolated macrophage cells by the stress hormones norepinephrine and cortisol was done to assess effects on MMP-9., Results: Depressed patients showed significant elevations of MMP-9 in CD68(+) cells, adjusting for stage (P<0.0001). Patients with higher levels of current stress (P=0.01), life stress over the last 6 months (P=0.004), and general negative affect (P=0.007) also showed significantly greater MMP-9 in CD68(+) cells. In contrast, higher social support was associated with lower levels of MMP-9 (P=0.023) and vascular endothelial growth factor (P=0.036) in tumor cells. In vitro analyses showed that macrophage MMP-9 production could be directly enhanced (up to a 2-fold increase) by the stress hormones norepinephrine and cortisol., Conclusions: Ovarian cancer patients with elevated depressive symptoms, chronic stress, and low social support showed elevations in MMP-9 in tumor-associated macrophages. Direct in vitro enhancement of stromal MMP-9 production by stress hormones was also shown. These findings may have implications for patient outcomes in ovarian cancer.

The adaptive immune response of ovarian cancer patients has been linked to survival, and is known to be impaired in the tumor microenvironment. Little is known about relationships between biobehavioral factors such as depressed mood and anxiety and the adaptive immune response in ovarian cancer. Thirty-seven patients with epithelial ovarian cancer and 14 patients with benign ovarian neoplasms completed psychosocial questionnaires pre-surgery. Lymphocytes from peripheral blood, tumor, and ascites (fluid around the tumor), were obtained on the day of surgery. Expression of the Type-1 cytokine interferon-gamma (IFN gamma), and the Type-2 cytokine interleukin-4 (IL-4) by T-helper (CD4(+)) and T-cytotoxic (CD8(+)) cells was measured under autologous tumor-stimulated, polyclonally-stimulated, or unstimulated conditions. Links with mood were examined. Among cancer patients, marked elevations in unstimulated and tumor-stimulated Type-2 responses were seen, particularly in ascites and tumor-infiltrating lymphocytes (P values<0.01). With polyclonal stimulation, lymphocytes from all compartments expressed elevated Type-1 cytokines (P values<0.014). Depressed and anxious mood were both associated with significantly lower ratios of polyclonally-stimulated CD4(+) cells producing IFN gamma (TH(1) cells) vs. IL-4 (TH(2) cells) in all compartments (depressed mood: P=0.012; anxiety: P=0.038) and depressed mood was also related to lower ratios of polyclonally-stimulated CD8(+) cells producing IFN gamma (TC(1)) vs. IL-4 (TC(2)) (P=0.035). Although effects of polyclonal stimulation should be generalized with caution to the in vivo immune response, findings suggest that depressed and anxious mood are associated with greater impairment of adaptive immunity in peripheral blood and in the tumor microenvironment among ovarian cancer patients.

Purpose: Defects in the antigen processing machinery (APM) may provide tumor cells with a mechanism to escape immune recognition. The purpose of this study is to determine the clinical significance of APM component down-regulation and tumor-infiltrating T cells in ovarian carcinoma., Experimental Design: After institutional review board approval, tumor samples from 150 patients with invasive epithelial ovarian cancers were examined for TAP1, TAP2, tapasin, HLA class I heavy chain (HLA-HC), beta 2 microglobulin, and T-cell (CD3+ and CD8+) tumor infiltration using immunohistochemistry., Results: The majority of tumors had either heterogeneous or positive expression of TAP1, TAP2, HLA-HC, and beta 2 microglobulin (66.7%, 73.3%, 70.7%, and 63.3%, respectively), except tapasin for which 58% of the tumors lacked expression. Furthermore, 67% and 88% of the lesions possessed intratumoral and peritumoral CD3+ or CD8+ cells, respectively. The majority of APM component expression examined was significantly associated with both intratumoral and peritumoral T-cell infiltration (P < 0.05). The expression of APM components and the presence of intratumoral T-cell infiltrates were significantly associated with improved survival (all P < or = 0.01); however, peritumoral T-cell infiltrates did not significantly affect survival (P = 0.33). APM component down-regulation (P < 0.001), lack of intratumoral T-cell infiltrates (P = 0.03), and suboptimal cytoreduction (P < 0.001) were independent prognostic markers for death from ovarian carcinoma., Conclusion: The negative effect of APM component down-regulation by itself and in combination with absent intratumoral T-cell infiltration on the survival of patients with ovarian carcinoma implies a role for immune escape in addition to immunosurveillance in the clinical course of disease.

Background: Interleukin-8 (IL-8) is a proangiogenic cytokine that is overexpressed in many human cancers. We investigated the clinical and biologic significance of IL-8 in ovarian carcinoma using human samples and orthotopic mouse models., Methods: Tumor expression of IL-8 was assessed by immunohistochemistry among ovarian cancer patients (n = 102) with available clinical and survival data. We examined the effect of IL-8 gene silencing with small interfering RNAs incorporated into neutral liposomes (siRNA-DOPCs), alone and in combination with docetaxel, on in vivo tumor growth, angiogenesis (microvessel density), and tumor cell proliferation in mice (n = 10 per treatment group) bearing orthotopic taxane-sensitive (HeyA8 and SKOV3ip1) and taxane-resistant (SKOV3ip2.TR) ovarian tumors. All statistical tests were two-sided., Results: Of the 102 cancer specimens, 43 (42%) had high IL-8 expression and 59 (58%) had low or no IL-8 expression; high IL-8 expression was associated with advanced tumor stage (P = .019), high tumor grade (P = .031), and worse survival (median survival for patients with high vs low IL-8 expression: 1.62 vs 3.79 years; P < .001). Compared with empty liposomes, IL-8 siRNA-DOPC reduced the mean tumor weight by 32% (95% confidence interval [CI] = 14% to 50%; P = .03) and 52% (95% CI = 27% to 78%; P = .03) in the HeyA8 and SKOV3ip1 mouse models, respectively. In all three mouse models, treatment with IL-8 siRNA-DOPC plus the taxane docetaxel reduced tumor growth the most compared with empty liposomes (77% to 98% reduction in tumor growth; P < .01 for all). In the HeyA8 and SKOV3ip1 models, tumors from mice treated with IL-8 siRNA-DOPC alone had lower microvessel density than tumors from mice treated with empty liposomes (HeyA8: 34% lower, 95% CI = 32% to 36% lower [P = .002]; SKOV3ip1: 39% lower, 95% CI = 34% to 44% lower [P = .007]). Compared with empty liposomes, IL-8 siRNA-DOPC plus docetaxel reduced tumor cell proliferation by 35% (95% CI = 25% to 44%; P < .001) and 38% (95% CI = 28% to 48%; P < .001) in the HeyA8 and SKOV3ip1 models, respectively., Conclusions: Increased IL-8 expression is associated with poor clinical outcome in human ovarian carcinoma, and IL-8 gene silencing decreases tumor growth through antiangiogenic mechanisms.

Psychosocial factors are known to be associated with properties of both NK cells and T cells in cancer patients. Less is known about the relationship between psychosocial factors and NKT cells, a rare group of lymphocytes that have known relevance for tumor control. We examined four psychosocial factors and percentage and number of CD3+CD56+ NKT cells, CD3-CD56+ NK cells, and CD3+CD56- T cells in peripheral blood lymphocytes (PBL), ascites, and tumor of 35 ovarian cancer patients and 28 patients with benign pelvic masses. Patients awaiting surgery for a suspected cancerous mass completed questionnaires and gave a pre-surgical blood sample. Ascites and tumor were taken during surgery. After lymphocyte isolation, subpopulations were analyzed by flow cytometry. Benign and cancer patients did not differ on PBL subpopulations. Among cancer patients, NKT cell percentage was significantly higher in tumor and ascites than in PBL; T cell percentage was significantly higher in PBL than tumor. NKT, NK, and T cell number were significantly higher in peripheral blood than in ascites. Positive reframing was related to significantly higher NKT cell percentage and number in PBL. Social support was related to significantly higher NKT cell percentage in tumor. Vigor was related to significantly higher NKT cell percentage in PBL. Total mood disturbance was not related to NKT cell percentage or number. No significant relationships were found between psychosocial factors and NK cell percentage and number and T cell percentage and number. Given the anti-tumor activity of CD3+CD56+ cells, these relationships may have relevance for cancer control.

Supportive conversations may facilitate adjustment among cancer patients early in treatment. However, little is known about how cancer discussion is related to adjustment among long-term survivors of cancer or how gender differences may influence associations between cancer discussion and adjustment. The purpose of this study was to examine possible moderator effects of gender on associations between cancer discussions and adjustment among survivors of breast or prostate cancer. Eighty-eight breast and 88 prostate cancer patients were matched by years post-surgery and stage of cancer and completed measures of cancer discussion frequency, quality of life, and depression. Breast and prostate cancer patients differed on what cancer-related threats were discussed most frequently. In addition, among breast, but not prostate cancer patients, frequent cancer discussion was associated with higher depression and lower quality of life. Frequent discussion of cancer may be an indication of poorer adjustment among breast cancer patients at nearly four years post-surgery. The nature and context of cancer discussions may be important determinants of whether cancer discussions relate to adaptive versus maladaptive outcomes.

Clinical and anecdotal findings suggest that the completion of cancer treatment may be marked by heightened distress and disrupted adjustment. The present study examined psychological adjustment during the 3 months following treatment among 89 women with stages 0-III breast cancer. Participants completed measures of depression, cancer-related anxiety, cancer concerns, and quality of life at three time points: during treatment, 3 weeks following the end of treatment, and 3 months post-treatment. Post-treatment scores were suggestive of good psychological adjustment among the majority of women. Moreover, distress did not increase following treatment; longitudinal analyses showed no significant changes in depression or recurrence worry, while intrusive thoughts decreased, and quality of life improved. Younger age predicted greater distress across measures. A history of depression or anxiety predicted greater depressive symptomatology, while more extensive treatment predicted greater cancer-related anxiety. Despite the lack of distress endorsed on general depression and anxiety indices, participants reported moderate distress associated with cancer-related concerns, including physical problems, fear of cancer recurrence, and resuming normal life. In sum, while breast cancer survivors demonstrate good adjustment on general distress indices following treatment, some women are at risk for sustained distress. Moreover, significant cancer-related concerns are prevalent and may be important intervention targets.

There is growing evidence that chronic stress and other behavioral conditions are associated with cancer pathogenesis and progression, but the mechanisms involved in this association are poorly understood. We examined the effects of two mediators of stress, norepinephrine and epinephrine, on the activation of signal transducer and activator of transcription-3 (STAT3), a transcription factor that contributes to many promalignant pathways. Exposure of ovarian cancer cell lines to increasing concentrations of norepinephrine or epinephrine showed that both independently increased levels of phosphorylated STAT3 in a dose-dependent fashion. Immunolocalization and ELISA of nuclear extracts confirmed increased nuclear STAT3 in response to norepinephrine. Activation of STAT3 was inhibited by blockade of the beta1- and beta2-adrenergic receptors with propranolol, and by blocking protein kinase A with KT5720, but not with the alpha receptor blockers prazosin (alpha1) and/or yohimbine (alpha2). Catecholamine-mediated STAT3 activation was not inhibited by pretreatment with an anti-interleukin 6 (IL-6) antibody or with small interfering RNA (siRNA)-mediated decrease in IL-6 or gp130. Regarding the effects of STAT3 activation, exposure to norepinephrine resulted in an increase in invasion and matrix metalloproteinase (MMP-2 and MMP-9) production. These effects were completely blocked by STAT3-targeting siRNA. In mice, treatment with liposome-incorporated siRNA directed against STAT3 significantly reduced isoproterenol-stimulated tumor growth. These studies show IL-6-independent activation of STAT3 by norepinephrine and epinephrine, proceeding through the beta1/beta2-adrenergic receptors and protein kinase A, resulting in increased matrix metalloproteinase production, invasion, and in vivo tumor growth, which can be ameliorated by the down-regulation of STAT3.

Recent studies have demonstrated that chronic stress promotes tumor growth, angiogenesis, and metastasis. In ovarian cancer, levels of the pro-angiogenic cytokine, interleukin 6 (IL-6), are known to be elevated in individuals experiencing chronic stress, but the mechanism(s) by which this cytokine is regulated and its role in tumor growth remain under investigation. Here we show that stress hormones such as norepinephrine lead to increased expression of IL-6 mRNA and protein levels in ovarian carcinoma cells. Furthermore, we demonstrate that norepinephrine stimulation activates Src tyrosine kinase and this activation is required for increased IL-6 expression. These results demonstrate that stress hormones activate signaling pathways known to be critical in ovarian tumor progression.

Objectives: The sympathetic nervous system and hypothalamic-pituitary-gonadal axis are involved in the pathophysiology of benign prostatic hyperplasia (BPH). The sympathetic nervous system and hypothalamic-pituitary-gonadal axis are also highly reactive to psychological stressors, yet associations between prostate function and reactivity to a psychological stressor have not been examined using standardized psychological stress paradigms. The objective of this study was to examine the associations between psychological stress reactivity and BPH disease parameters., Methods: A total of 83 men diagnosed with BPH completed a standardized laboratory stress task, yielding measures of blood pressure, testosterone, and cortisol reactivity. Links were examined between stress reactivity (as indicated by changes in blood pressure, testosterone, and cortisol during the stress task) and measures of BPH disease, including prostate volume, postvoid residual bladder volume, urine flow rate, self-reported lower urinary tract symptoms, and impact and bother scores., Results: In equations controlling for BPH medications, body mass index, and age, greater diastolic blood pressure reactivity was associated with a greater transition zone volume (P <0.001), greater total prostate gland volume (P <0.05), greater postvoid residual bladder volume (P <0.05), more severe lower urinary tract symptoms (P <0.001), and greater impact scores (P <0.05). Greater cortisol reactivity was associated with greater bother (P <0.05) and impact (P <0.001) scores., Conclusions: Physiologic reactivity to a standardized laboratory stressor is associated with objective and subjective BPH disease parameters. These findings contribute to growing data suggesting that stress conditions could be associated with the development or aggravation of prostatic disease.

Purpose: Curcumin, a component of turmeric, has been shown to suppress inflammation and angiogenesis largely by inhibiting the transcription factor nuclear factor-kappaB (NF-kappaB). This study evaluates the effects of curcumin on ovarian cancer growth using an orthotopic murine model of ovarian cancer., Experimental Design: In vitro and in vivo experiments of curcumin with and without docetaxel were done using human ovarian cancer cell lines SKOV3ip1, HeyA8, and HeyA8-MDR in athymic mice. NF-kappaB modulation was ascertained using electrophoretic mobility shift assay. Evaluation of angiogenic cytokines, cellular proliferation (proliferating cell nuclear antigen), angiogenesis (CD31), and apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) was done using immunohistochemical analyses., Results: Curcumin inhibited inducible NF-kappaB activation and suppressed proliferation in vitro. In vivo dose-finding experiments revealed that 500 mg/kg orally was the optimal dose needed to suppress NF-kappaB and signal transducers and activators of transcription 3 activation and decrease angiogenic cytokine expression. In the SKOV3ip1 and HeyA8 in vivo models, curcumin alone resulted in 49% (P = 0.08) and 55% (P = 0.01) reductions in mean tumor growth compared with controls, whereas when combined with docetaxel elicited 96% (P < 0.001) and 77% reductions in mean tumor growth compared with controls. In mice with multidrug-resistant HeyA8-MDR tumors, treatment with curcumin alone and combined with docetaxel resulted in significant 47% and 58% reductions in tumor growth, respectively (P = 0.05). In SKOV3ip1 and HeyA8 tumors, curcumin alone and with docetaxel decreased both proliferation (P < 0.001) and microvessel density (P < 0.001) and increased tumor cell apoptosis (P < 0.05)., Conclusions: Based on significant efficacy in preclinical models, curcumin-based therapies may be attractive in patients with ovarian carcinoma.

Behavioral processes have long been suspected to influence many health processes including effects on cancer. However, mechanisms underlying these observations are not fully understood. Recent work has demonstrated that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden, and a more invasive pattern of ovarian cancer growth in an orthotopic mouse model. These effects are mediated primarily through the beta(2) adrenergic receptor (ADRB2) activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway. Additionally, tumors in stressed animals have increased vascularization and enhanced expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) -2 and -9. In this review, we highlight the importance of the neuroendocrine stress response in tumor biology and discuss mechanisms by which the beta-adrenergic receptors on ovarian cancer cells enhance angiogenesis and tumor growth.

Objectives: To examine the specificity and sensitivity of the inflammatory markers histamine, methylhistamine, and interleukin-6 (IL-6) in the urine of patients with interstitial cystitis compared with that in healthy controls., Methods: A total of 40 women with interstitial cystitis and 29 healthy controls collected 24-hour urine samples. During the 24 hours before urine collection, all participants refrained from consuming foods and medications that could contain bioactive amines. Methylhistamine and histamine were measured using radioimmunoassay kits and were normalized to urinary creatinine levels; IL-6 was measured using enzyme-linked immunosorbent assay. The data were analyzed by t tests, logistic regression analysis, and receiver operating characteristics., Results: IL-6 and histamine were significantly greater in the patients with interstitial cystitis than in the controls (P = 0.0003 and P = 0.038, respectively). The methylhistamine levels were also greater in the patients with interstitial cystitis than in the controls, but the results did not reach significance (P = 0.063). Using a combination of IL-6 and methylhistamine/creatinine, cutoff points were established. Using these cutoff points, the sensitivity was 70.0%, specificity 72.4%, positive predictive value 77.8%, and negative predictive value 63.6%., Conclusions: All three markers--histamine, methylhistamine, and IL-6--were greater in the patients with interstitial cystitis than in the controls. A combination of methylhistamine and IL-6 could be used as a sensitive and specific marker for interstitial cystitis.

In an investigation of the assessment and construct validity of stress-related growth, community-dwelling women (N = 163) wrote essays about the impact of a stressful life event that had occurred in the previous few years and completed the Posttraumatic Growth Inventory (PTGI). Independent ratings of growth in the essays were positively correlated with PTGI scores, suggesting that endorsement of growth on questionnaires can be substantiated by personal accounts. There was no relation between reports of growth on the PTGI and socially desirable responding or negative mood. Higher PTGI scores were associated with greater positive mood and greater depth of processing in the essays. These findings support the validity of stress-related growth as a construct and its assessment via questionnaire., (Copyright 2006 APA, all rights reserved.)

Purpose: Focal adhesion kinase (FAK) plays a critical role in ovarian cancer cell survival and in various steps in the metastatic cascade. Based on encouraging in vitro results with FAK silencing, we examined the in vivo therapeutic potential of this approach using short interfering RNA (siRNA) in the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC)., Experimental Design: Therapy experiments of FAK siRNA with or without docetaxel were done using human ovarian cancer cell lines SKOV3ip1, HeyA8, and HeyA8MDR in nude mice. Additional experiments with a cisplatin-resistant cell line (A2780-CP20) were also done. Assessments of angiogenesis (CD31), cell proliferation (proliferating cell nuclear antigen), and apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) were done using immunohistochemical analysis., Results: A single dose of FAK siRNA-DOPC was highly effective in reducing in vivo FAK expression for up to 4 days as assayed by Western blot and immunohistochemical analysis. Therapy experiments were started 1 week after injection of the ovarian cancer cells. Treatment with FAK siRNA-DOPC (150 mug/kg twice weekly) reduced mean tumor weight by 44% to 72% in the three cell lines compared with the control group (Ps < 0.05 for HeyA8, A2780-CP20, and SKOV3ip1). When FAK siRNA-DOPC was combined with docetaxel, there was even greater reduction in mean tumor weight in all models (all Ps < 0.05). Similar results were observed in combination with cisplatin. Treatment with FAK siRNA-DOPC plus docetaxel resulted in decreased microvessel density, decreased expression of vascular endothelial growth factor and matrix metalloproteinase-9, and increased apoptosis of tumor-associated endothelial cells and tumor cells., Conclusions: Taken together, these findings suggest that FAK siRNA-DOPC plus docetaxel or platinum might be a novel therapeutic approach against ovarian cancer.

Stress can alter immunological, neurochemical and endocrinological functions, but its role in cancer progression is not well understood. Here, we show that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway by the beta(2) adrenergic receptor (encoded by ADRB2). Tumors in stressed animals showed markedly increased vascularization and enhanced expression of VEGF, MMP2 and MMP9, and we found that angiogenic processes mediated the effects of stress on tumor growth in vivo. These data identify beta-adrenergic activation of the cAMP-PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth. These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.

The current study examined the use of engagement and avoidant coping strategies among advanced-stage gynecologic cancer patients who were facing the long-term stressors of extensive chemotherapy and advanced disease. Patients were compared to a reference group of early-stage patients who had received more limited treatment. Compared to the reference group, extensively-treated women more frequently utilized both engagement and avoidant strategies including active coping, seeking social support, and mental disengagement. Use of engagement coping strategies such as active coping and seeking social support were not significantly related to quality of life or mood. However, avoidant coping strategies, including disengagement and cognitive avoidance, were strongly associated with poorer well-being and more distressed mood. Moreover, relationships between coping and quality of life differed between the extensively-treated patients and patients in the limited treatment reference group. The use of avoidance and seeking instrumental support were associated with poorer outcomes among extensively-treated patients but not among the limited treatment group. Results of the current study suggest that coping patterns and outcomes may be more pronounced among cancer patients contending with severe disease and extensive treatment and that avoidant coping strategies may be particularly detrimental with respect to these patients' mood and quality of life., (Copyright 2005 John Wiley & Sons, Ltd.)

Objectives: To examine the relationships between symptoms and cystoscopic findings in women newly diagnosed with interstitial cystitis who had not previously received treatment., Methods: Twelve newly diagnosed and not previously treated women with interstitial cystitis completed a bladder symptom questionnaire the day before undergoing cystoscopy, hydrodistension, and biopsy. The daily voiding frequency was reported. Cystoscopic findings were converted to a numerical scale, and the data were analyzed using Pearson correlations., Results: Pain symptoms had consistent positive correlations with the cystoscopic findings. An increase in pain with bladder filling was associated with inflammation (P = 0.011), ulceration, and smaller bladder capacity. Pain relief after voiding correlated with smaller bladder capacity (P = 0.019), hematuria, and total cystoscopic score. Pain intensity in the urethra was related to ulceration and hematuria, and pain in the lower abdomen was related to a smaller bladder capacity (P = 0.047), glomerulations, and a larger total cystoscopic score. Daytime frequency correlated negatively with most cystoscopic findings, and nocturnal frequency had a positive relationship with most cystoscopic findings and was significantly associated with a smaller bladder capacity (P = 0.010). Urgency showed no strong associations with any cystoscopic findings., Conclusions: In patients with untreated interstitial cystitis, a strong correlation between pain and cystoscopic findings was observed. The differences between our results and those of previous studies that found no relationship between symptom reports and cystoscopic findings suggest possible effects of treatment on pain perception and therapeutic influence on cystoscopic findings.

Objective: Docetaxel causes cell death through induction of apoptosis; however, cell death characteristics for docetaxel have not yet been fully elucidated. We examined the role of focal adhesion kinase (FAK) cleavage in docetaxel-mediated apoptosis., Methods: FAK degradation after treatment with docetaxel was determined in both taxane-sensitive (HeyA8 and SKOV3) and taxane-resistant (HeyA8-MDR and SKOV3-TR) ovarian cancer cell lines by Western blot analysis. Cell growth was determined with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. FAK-targeting small interfering RNA (siRNA) was used to decrease FAK expression. Apoptosis and caspase activity were determined using commercially available kits., Results: SKOV3 and HeyA8 cell lines were both sensitive to docetaxel (IC50 levels, 1-6.2 nmol/L), whereas the SKOV3-TR and HeyA8-MDR cells were resistant (IC50>or=250 nmol/L for both). Docetaxel induced high rates of apoptosis in SKOV3 and HeyA8 cells (84% and 66% apoptosis, respectively) but minimal apoptosis (5-8%) in SKOV3-TR and HeyA8-MDR cells. Similarly, FAK was cleaved in SKOV3 and HeyA8 cells in response to docetaxel treatment but unchanged in the resistant cells. Caspase-3 and caspase-8 activity also increased significantly in docetaxel-treated SKOV3 and HeyA8 cells but not in the taxane-resistant cells. DEVD-fmk (caspase-3 blocker) was able to block both FAK cleavage and apoptosis mediated by docetaxel in SKOV3 and HeyA8 cells. FAK siRNA transfection resulted in 70% to 90% decrease in FAK levels in all cell lines within 72 hours. FAK silencing augmented docetaxel-mediated growth inhibition (5- to 8-fold increase) and apoptosis in both of the taxane-sensitive and taxane-resistant cell lines., Conclusions: Docetaxel induces FAK cleavage, mediated through activation of caspase-3, in taxane-sensitive ovarian cancer cells but not in taxane-resistant cells. The absence of FAK degradation may contribute to cell survival in taxane-resistant cells. FAK silencing promotes the in vitro efficacy of docetaxel in both taxane-sensitive and taxane-resistant cell lines and may serve as a novel therapeutic approach.

Extract: The perspective that cancer may be causally linked to stress has a long history. In 200 AD, Galen proposed that melancholic women were more susceptible to cancer than women who were sanguine. Rigorous examinations of related observations have lagged over the ensuing centuries. More recently, epidemiologic studies have shown that psychologic and social characteristics (e.g., chronic stress and negative life events, social isolation and support, socioeconomic burden, and emotional processes) might be associated with differential cancer incidence, progression, and mortality. The biologic mechanisms (e.g., signaling pathways) that may account for such observations are being discovered through the convergence of relevant molecular, cellular, and clinical data. In this article, we review the clinical and experimental evidence regarding the effects of stress on tumor development, growth, and progression. Within this context, we define "stress" as an external event ("stressor") or perception of such events that engender psychologic and physiologic changes ("stress responses") designed to approach, avoid, or defend against the external event.

Purpose: Psychosocial stress has been related to impaired immunity in cancer patients. However, the extent to which these relationships exist in immune cells in the tumor microenvironment in humans has not been explored. We examined relationships among distress, social support, and natural killer (NK) cell activity in ovarian cancer patients in peripheral-blood mononuclear cells (PBMC), ascitic fluid, and tumor-infiltrating lymphocytes (TIL)., Patients and Methods: Patients awaiting surgery for a pelvic mass suspected of being ovarian cancer completed psychological questionnaires and gave a presurgical sample of peripheral blood. Samples of tumor and ascites were taken during surgery, lymphocytes were then isolated, and NK cytotoxicity and percentage were determined. The final sample, which was confirmed by surgical diagnosis, included 42 patients with epithelial ovarian cancer and 23 patients with benign masses., Results: Peripheral NK cell activity was significantly lower among ovarian cancer patients than in patients with benign masses. Among ovarian cancer patients, NK cytotoxicity in TIL was significantly lower than in PBMC or ascitic fluid. Social support was related to higher NK cytotoxicity in PBMC and TIL, adjusting for stage. Distress was related to lower NK cytotoxicity in TIL. A multivariate model indicated independent associations of both distress and social support with NK cell activity in TIL., Conclusion: Psychosocial factors, such as social support and distress, are associated with changes in the cellular immune response, not only in peripheral blood, but also at the tumor level. These relationships were more robust in TIL. These findings support the presence of stress influences in the tumor microenvironment.

Background: Relations among psychological stress, depression, social support, and interleukin-6 (IL-6, a proinflammatory cytokine) have been documented in humans and animals. Because elevated IL-6 is associated with a poorer prognosis among ovarian cancer patients and has been implicated in the metastasis of ovarian cancer, the current study examined relations between psychosocial factors and IL-6 among women with advanced-stage ovarian cancer., Methods: Sixty-one ovarian cancer patients completed assessments of social support, distressed mood, and quality of life before surgery. Peripheral blood was drawn preoperatively, and the plasma was assayed for IL-6. Ascites samples were also assayed for IL-6 for a subset of patients., Results: Both IL-6 levels and distressed mood were elevated among patients. After statistically adjusting effects of age and disease stage, social attachment was associated with lower levels of IL-6 in peripheral blood (P = 0.03), whereas poorer health-related quality of life was associated with higher IL-6 (P values ranged from 0.01 to 0.03 on different measures). This pattern of relations was also found in the ascites. Moreover, IL-6 levels in peripheral blood plasma correlated significantly with IL-6 in the ascites (P < 0.001), suggesting that peripheral IL-6 reflects IL-6 levels at the site of the tumor., Conclusions: Results suggest that social support may play a protective role with respect to IL-6 elevations, and IL-6 may be an independent marker of health-related quality of life among ovarian cancer patients. Processes involving IL-6 represent possible pathways by which behavioral factors may contribute to disease outcomes among women with ovarian cancer.

Natural killer (NK) cells are essential for healthy aging. NK cell activation is controlled by MHC class I-specific CD94/NKG2 receptors and killer immunoglobulin-like receptors (KIR). To assess NK cytotoxic function in isolation from MHC receptor engagement, we measured the ability of purified NK cells to kill mouse P815 target cells in the presence of anti-CD16 mAb. CD16-mediated cytotoxicity did not change with age, indicating that NK activation and cytotoxic granule release remained functional. We then investigated MHC class I receptor expression on NK cells. There was an age related decrease in CD94 and NKG2A expression and a reciprocal age related increase in KIR expression. NKG2A expression also declined with age on CD56(+) T cells. CD94/NKG2A receptor function was proportional to expression, indicating that NK cell inhibitory signaling pathways were intact. NKG2A and KIR expression were complementary, suggesting that CD94/NKG2A function could substitute for inhibitory KIR function during polyclonal NK cell development in both young and elderly adults. The distinct roles of CD94/NKG2A and KIR receptors suggest that shifting MHC class I receptor expression patterns reflect age related changes in NK cell and CD56(+) T cell turnover and function in vivo.

Chronic distress has been associated with alterations in natural killer (NK) cell and T cell percentages and function. NK cells express inhibitory and stimulatory receptors that regulate cytotoxicity and cytokine secretion. T cells and T cells expressing CD56 (NKT cells) also express these NK-associated receptors, which are thought to serve the same function. The objective of this study was to examine the relationship between distress and expression of NK-associated receptors on NK cells, T cells, and NKT cells. Using multicolor flow cytometry and validated questionnaires, we studied twenty-nine healthy adults with a bimodal age spread. Whereas distress was related to significantly lower percentages of CD3(+) T cells, it was related to significantly higher percentages of NKT cells. Distress was associated with significantly higher percentages of T cells expressing NK-associated receptors including CD94 and KIR. In contrast, distress was associated with significantly lower percentages of NK cells bearing KIR (GL183) receptors. Our findings suggest a possible role for NK-associated receptors in distress-related alterations in lymphocyte maturation, trafficking, or activity.

Background: Previous research has indicated that older adults with severe life stress show attenuated immune responses to influenza vaccination. Associations among mood, optimism, stress, and the in vitro cytokine response to influenza virus and vaccine were evaluated in 18 healthy older adults with low to moderate life stress., Methods: Peripheral blood mononuclear cells were stimulated in cultures with 1999-2000 influenza vaccine viruses (A/Beijing/262/95, A/Sydney/5/97, and B/Yamanashi/166/98) and the 2000-2001 trivalent vaccine (containing A/New Caledonia/20/99, A/Panama/2007/99, and B/Yamanashi/166/98). The levels of T-helper type 1 (interleukin-2 and interferon-gamma) and type 2 (interleukin-10) cytokines were measured in culture supernatants., Results: Stress, age, and current health practices were unrelated to cytokine production. Older adults reporting greater anger, fatigue, confusion, and total mood disturbance had poorer cytokine responses to live virus and vaccine stimulation. In contrast, older adults who reported greater vigor and those who were more optimistic had greater cytokine responses to both live virus and vaccine. These relationships were largely unaffected by medications or health conditions., Conclusions: These findings suggest that among older adults, even mild to moderate mood disturbance is associated with an attenuated cellular immune response to live influenza virus and vaccine.

This study prospectively examined the relationship between religious attendance, interleukin-6 (IL-6) levels, and mortality rates in a community-based sample of 557 older adults. Attending religious services more than once weekly was a significant predictor of lower subsequent 12-year mortality and elevated IL-6 levels (> 3.19 pg/mL), with a mortality ratio of.32 (95% confidence interval [CI] = 0.15,0.72; p <.01) and an odds ratio for elevated IL-6 of.34 (95% CI = 0.16, 0.73, p <.01), compared with never attending religious services. Structural equation modeling indicated religious attendance was significantly related to lower mortality rates and IL-6 levels, and IL-6 levels mediated the prospective relationship between religious attendance and mortality. Results were independent of covariates including age, sex, health behaviors, chronic illness, social support, and depression. Findings are consistent with a role for IL-6 in processes mediating the relationship between religious attendance and mortality., (((c) 2004 APA, all rights reserved))