THE HORMONE OF HEALING AND HOPE
Surviving a cancer diagnosis and the treatment that follows requires overcoming significant emotional and physical hurdles. Even after a patient is cancer-free, he or she often continues to struggle with depression and anxiety from fear of cancer recurrence, and many also suffer from sleep disturbances. These ongoing challenges negatively impact well-being and quality of life, hindering a patient’s ability to fully flourish. Might contemplative practices help cancer survivors deal better with their mental and physical challenges to remain cancer free? In a recent study published in Integrative Cancer Therapies, Varela grantee David Lipschitz, MLI Fellow Yoshio Nakamura and colleagues at the University of Utah investigated the effects of two mind-body interventions on a number of physiological and psychological health outcomes in cancer survivors. This study used a strong experimental design, comparing three similar interventions to which participants were randomly assigned: mind-body bridging, mindfulness meditation, and a sleep education group as an active control. Below, David Lipschitz summarizes his Varela research project and its findings.
— Wendy Hasenkamp, Senior Scientific Officer
Mind–Body Interventions Affect Sleep and Oxytocin in Cancer Survivors
Oxytocin is a hormone produced in an area of the brain known as the hypothalamus, whose release activates a variety of brain regions resulting in many different functions, including birth (labor), breast feeding (lactation), maternal behavior, parental care, social bonding, affiliation (such as couples being together), and well-being. In recent studies in humans, oxytocin has been shown to be associated with increases in prosocial behaviors such as trust, altruism, generosity, cooperation and empathy. These various functions suggest that oxytocin may promote health by reducing stress and increasing calm/relaxed states, resulting in improved quality of life and well-being.
Given oxytocin’s stress-reducing and calming properties, and its capacity to increase well-being, its action may be relevant to those fighting cancer. We conducted a study to look at the effects of two mind-body therapies on changes in salivary oxytocin levels in a cancer survivor population with self-reported sleep disturbance. Investigating oxytocin in cancer survivors could be important, given cancer survivors’ high levels of distress, depression, and anxiety, as well as poor sleep, possibly due to the effects of cancer treatment and worries about cancer recurrence. In our study, we hypothesized that the mind-body therapies would increase oxytocin levels, which would be associated with improvements in sleep, increases in quality of life and well-being, and reduced stress.
The two sleep-focused mind–body interventions included mind–body bridging and mindfulness meditation, which were compared with a sleep hygiene education control program. Cancer survivors needed to be three months post-treatment (completed radiation, chemotherapy and/or surgery) to qualify for the study. Participants were randomly assigned to one of the three groups, each of which ended up having about 20 people. Before and after the interventions, we collected a number of validated self-report questionnaires (measuring sleep, depression, perceived stress, cancer-related quality of life, well-being, mindfulness, and self-compassion); we also collected saliva samples for oxytocin assessment from about 10 participants in each group. Each intervention was run over three sessions, once per week for three consecutive weeks. Saliva samples and the self-report measures were collected before the groups started (baseline), about one week after the final session (post-intervention), and at a two-month follow-up.
Overall, oxytocin levels did not differ between females and males and were not correlated with age. There were some indications in the baseline samples that oxytocin was negatively associated with sleep problems and depression (e.g., with less oxytocin, more sleep problems and depression were reported) and positively associated with cancer-related quality of life and well-being (e.g., with more oxytocin, greater quality of life and well-being were seen).
Regarding the effects of the mind-body therapies, after controlling for baseline differences among groups, post-treatment oxytocin levels were significantly higher in the mind–body bridging group as compared with those in the control group. For the self-reports, those in the mind–body bridging and mindfulness meditation groups showed greater reductions in sleep problems compared to controls, and in the mind–body bridging group, mindfulness and self-compassion increased to a greater extent than in controls.
These findings suggest that mind-body interventions may be particularly beneficial for cancer survivors to improve sleep and increase adaptive mental states. In addition, salivary oxytocin may be a reliable biological measure to assess the effects of mind–body therapies on health outcomes. More research is needed to further investigate the relationships between oxytocin and improved mental and physical health, but this work provides early evidence that increasing oxytocin levels using mind-body interventions might be one way of helping cancer survivors improve their chances of feeling better, by reducing their stress and anxiety levels—and in so doing, improving their chances of remaining cancer-free.
OXYTOCIN IN CANCER
Less is understood about the connection between oxytocin and cancer, partly due to lack of adequate research in this area. The first link of oxytocin to cancer was reported in 1984, when oxytocin was described to be structurally and genomically related to vasopressin, an endogenous hormone that is also secreted by the pituitary, and that in addition to its physiological functions has been found to constitute a biomarker of small-cell lung cancer. Furthermore, oxytocin and vasopressin are co-expressed in these cells, where they have been proposed to induce mitogenic effects. Oxytocin’s link to vasopressin and its potential role as a biomarker was subsequently proposed in 1990. Shortly thereafter, it was suggested that oxytocin may modulate growth in breast cancer, which was subsequently demonstrated. These observations have instigated additional research into oxytocin’s potential involvement in various forms of cancer.
Oxytocin in breast cancer
Interestingly, subsequent studies have shown that oxytocin in fact inhibits proliferation of breast cancer cell lines, such as MDA-MB231, MCF7, and T47D, as well as the canine mammary cell line CMT-U27, mouse mammary carcinoma cell line TS/A, and rat mammary carcinoma cell line D-R3230AC. This effect was shown to be mediated via the cyclic adenosine monophosphate protein kinase A in human cell lines. Importantly, anti-proliferative and tumor inhibitory properties were also observed in vivo in both rat and mouse experimental models, and attributed to both oxytocin and its analogue F314. Recently, it was suggested that exercise training, by inducing oxytocin secretion, may reduce the expression of specific signaling proteins involved in breast cancer.
Lactation has long been linked to a reduced risk of cancer, with research dating back to as early as the 1950’s. Worldwide, it has been shown that breastfeeding reduces the risk of both breast and uterine cancer, with prolonged durations of breastfeeding (usually involving multiple children breastfed) correlating with a progressive fall in the risks of both breast and uterine cancer. The relationship with uterine cancer might be related to the action of oxytocin as a paracrine and endocrine hormone in lactation. Nevertheless, while the relationship between oxytocin, lactation, and breastfeeding with reduced risk of breast and uterine cancer are all well documented individually, more research needs to be conducted to determine if the relationship between oxytocin, lactation, and breastfeeding with reduced breast and uterine cancer is causal. Elucidating such a connection may establish new therapeutic targets in cancer.
Oxytocin in ovarian cancer
In addition to breast and uterine cancer, the potential participation of oxytocin in the pathogenesis of other cancers in the reproductive system has been investigated. Oxytocin was found to inhibit the progression of ovarian carcinoma both in vitro and in vivo. Using cell viability, invasion, and migration assays, it was demonstrated that oxytocin inhibited proliferation, migration and invasion of ovarian cancer cells in vitro, and its administration also attenuated the dissemination of ovarian cancer using mean tumor burden as a measure. The same investigators had demonstrated in a previous study expression of the oxytocin receptor in various human ovarian carcinoma tissues and cell lines, and identified placental leucine aminopeptidase (P-LAP) as an oxytocin-degrading oxytocinase in certain adenocarcinoma tissues. This team of investigators, therefore, proposed that a system involving P-LAP and oxytocin plays a role in the regulation of human endometrial adenocarcinoma, in which P-LAP exerts a functionally positive impact on carcinoma cell growth by degrading suppressive peptides such as oxytocin. More recently, these effects have also been linked with a cross-talk network between oxytocin and the stress hormone cortisol, whereby oxytocin reversed the carcinogenic effects of cortisol via autophagy (cellular self-degradation). Interestingly, pertinent to the postulated connection between oxytocin and symptoms of autism, oxytocin and cancer have also demonstrated an inverse relationship in autistic children.
Oxytocin in the gastrointestinal tract
Oxytocin receptors are expressed throughout the gastrointestinal (GI) tract, but little is known about their function in the GI tract, especially in relation to cancer. Some studies have suggested a link between oxytocin and its receptor in GI-related cancers, such as esophageal, gastric, and pancreatic cancers. For example, some studies showed an inverse relationship between the duration of breastfeeding and risk of esophageal cancer, gastric cancer, and pancreatic cancer. In fact, Yu et al showed a 54% decreased risk of developing esophageal cancer in women who breastfed for over 12 mo.
Unpublished data from our laboratory shows that the messenger ribonucleic acid (mRNA) expression of oxytocin is twofold higher in PANC-1 (a human pancreatic cancer cell line highly unresponsive to the chemotherapeutic agents, gemcitabine and 5-FU) compared to L3.6pl (a highly responsive human pancreatic cancer cell line). We also found that oxytocin receptor protein expression is also higher in PANC-1 than in L3.6pl. Further, inhibition of the oxytocin receptor decreased cell proliferation of PANC-1 and L3.6pl cells. Our analysis of data from the cBioPortal database revealed that up to 5% of pancreatic cancer patients included in The Cancer Genome Atlas showed genetic alterations (primarily upregulation of mRNA expression) in oxytocin and its receptor. Patients with these alterations had poorer survival outcomes as compared to those without these alterations. These interesting data warrant further investigation on the molecular mechanisms implicating oxytocin and its receptor in pancreatic cancer and other GI cancers.
Oxytocin in prostate cancer
As a role for oxytocin in the regulation of prostate function is established, its potential involvement in the development of prostate cancer has been proposed. Data from over two decades ago implicated oxytocin in the pathophysiology of benign prostatic hyperplasia, where the peptide might contribute to both the physical enlargement and dynamic tone of the gland. More recently, immunohistochemical staining has detected oxytocin expression in stromal and epithelial cell lines and in tissue from patients with benign prostatic hyperplasia, which was significantly reduced in tissues of invasive prostate cancer in comparison to both benign prostatic hyperplasia tissues and normal human prostate epithelial cells. This inverse relationship might implicate a fall in oxytocin levels in progression of prostate cancer. Within the prostate, oxytocin has been shown to affect gland growth both directly and via its interaction with androgen metabolism, and oxytocin concentrations are positively correlated with androgens. Indeed, while in the absence of androgens oxytocin had no effect on prostate cancer cell lines (LNCaP and PC-3), in the presence of testosterone low oxytocin doses stimulated proliferation of PC-3 cells, supporting the notion that changes in levels of oxytocin in the prostate in aging and cancer may promote prostate epithelial cell proliferation. It is possible that increased levels of oxytocin might be involved in the mechanisms by which high ejaculation frequency is related to decreased risk of prostate cancer. This hypothesis needs to be further investigated.
Conversely, a different study recently revealed that oxytocin increased the expression of APPL1, a protein with the ability to interact with tumor suppressor proteins. In vitro studies showed that oxytocin increased prostate cancer cell proliferation, and expression of APPL1. Analysis of serum and tissue samples identified increased oxytocin levels in the serum of prostate cancer patients, and high expression of oxytocin and its receptor in prostate tissues collected from prostate cancer patients in comparison to those collected from patients without prostate cancer. The oxytocin receptor has also been implicated in the migration of prostate cancer cells, and possibly modulation of prostate cancer metastasis. Taken together, these observations of oxytocin in prostate cancer cells both in vivo and in vitro, suggest that oxytocin could serve as a prostate cancer biomarker.
Several explanations have been offered for the apparent differences in the data from different studies regarding the role of oxytocin in prostate cancer. One explanation is the notable difference in the numbers of participants involved in each study. Secondly, some of the studies included prostate cancer patients that had undergone neo-adjuvant therapy, which can affect oxytocin levels. Thirdly, oxytocin is likely to activate a wide range of signaling mechanisms to elicit variable cellular responses, possibly depending on the density or precise localization of the oxytocin receptor on the plasma membrane. This may also account for the dichotomy in the observations reported regarding the role of oxytocin in cancer. Clearly, additional studies are needed to elucidate the involvement of oxytocin and oxytocin receptor in progression or regression of human prostate cancer.