AbstractOvarian cancer (OC) is the deadliest type of gynaecologic cancer predominantly of the epithelial subtype (EOC). Despite advances in treatments, relapse and dissemination are very likely to occur after remission. The heterogenous nature, complex immunosuppressive environment and the chronic inflammation promoting dysbiosis/oncobiosis are characteristics of OC and imply poor prognosis. Disparities in the outcomes of current therapies warrant new therapeutic strategies that are clinically effective and less invasive.
Diagnosis, relapse, and treatment of cancers are often stressful experience associated with mental and physical comorbidities. Cortisol is released in response to stress and strong evidence shows that prolonged release of cortisol can influence tumour biology and immunity. Although these effects are currently under debate as to whether cortisol promotes or inhibits ovarian tumour growth.
Our enhanced understanding of the gut microbiome and its pivotal role in the immune and brain development and function led to growing interest in their role in treating or preventing immune and neuroendocrine-mediated pathologies such as cancer and chronic stress. Therefore, probiotics are of interest because of their potential anti-tumour effect and their role in promoting positive mental health outcomes. Hence the name ‘psychobiotics’.
This study aims to first examine the effects of cortisol and psychological stress on ovarian cancer immunity, and to probe underlying mechanisms. Secondly, to investigate the anti-tumour effect of the probiotic Escherichia Coli Nissle 1917 (EcN) as a possible complementary therapy in OC metastasis. A 3D-ovarian cell culture (spheroids) model and a syngeneic female C57BL/6j mouse model for OC were used to investigate the impact of stress on anti-tumour immunity. Metastatic nodules, tumour burden and immune signature were assessed to probe an underlying mechanism. Gamma-H2AX immunofluorescence assay was applied to examine DNA damage in splenocytes of stressed mice.
Restraint stress (RS) significantly reduced overall mice weight at 4 weeks and the activation of splenic dendritic cells (DCs) at 2 weeks. Furthermore, restraint stress significantly increased DNA damage in splenocytes of stressed mice as large and compact spheroids were observed in the spheroids splenocytes co-cultures. This was verified in vitro using ex vivo T lymphocytes treated with pharmacological concentration of cortisol (10μM). EcN reduced tumour burden potentially through downregulation of Toll Like Receptor 4 (TLR-4) and upregulation of IL-23. But it did not reduce tumour burden in stressed mice. In summary, stress negatively impacted the anti-tumour immunity at an early stage of OC and EcN did not provide protection against the stress-induced negative effects in OC metastasis.
|Date of Award
|Melanie Flint (Supervisor) & Nadia Terrazzini (Supervisor)