Stress regulation of cancer progression through β-adrenergic signalling

Cancer is among the leading causes of death worldwide, with 90% of cancer-related deaths due to metastasis of the primary tumour. The progression of cancer involves a complex interaction between tumour cells and their microenvironment, prompting the need to not only consider the tumour cells, but also the patient as a whole in treatment. It is well accepted that chronic stress has a negative effect on the mental wellbeing of patients diagnosed with cancer. However, the physiological repercussions of chronic stress for the patient as a whole, and more specifically, its effect on the biology of a tumour have been largely overlooked. Fibres of the sympathetic system (SNS) innervate many major organ systems including sites of primary cancer and metastasis including lung, bone, lymph node and pancreas. Activation of SNS signalling either physiologically through stress or pharmacologically through β-agonism has been shown to alter the function of these organs. Additionally, evidence is accumulating that the tumour microenvironment is sensitive to changes in an individual’s response to behaviour, or response to the environment, and is supported by a several pre-clinical studies linking chronic stress-induced SNS activation to the progression of a number of cancers. These studies identify SNS stress signalling as a physiological regulator of cancer progression. However, the steps in the metastatic cascade that are sensitive to stress signalling the and molecular and cellular mechanisms underlying stress-enhanced cancer progression are yet to be defined. Using a restraint paradigm that has been shown to activate the SNS, this project investigates the effect of stress on early events in cancer progression. Due to the emerging importance of the tumour microenvironment on cancer progression, it is vital that orthotopic (natural position) models are used to recapitulate tumour-tumour microenvironment interactions. To study the effect of chronic stress on cancer progression we used various orthotopic models of breast cancer, and were one of the first to do so with pancreatic cancer. Longitudinal bioluminescence imaging was used to assess the effect of chronic stress on cancer progression and revealed chronic stress-induced SNS signalling promoted tumour cell dissemination to clinically relevant organs. Advanced fluorescence imaging revealed stress signalling modulated lymphatic function to drive the course of cancer. The use of xenograft models allowed for the analysis stress-induced changes in tumour cell and stromal cell-specific gene expression, providing further insight into the tumour-host interactions. In vitro invasion, proliferation and signalling assays also provided insight into the direct effect of β-adrenergic signalling on the contributions of tumour and stromal cell to metastasis. Pharmacological studies confirmed the important role of β-adrenergic signalling in stress-enhanced cancer progression. We support this with clinical evidence showing the presence of β-adrenergic receptors on patient tumour samples and providing evidence that β-blockade may be protective against the harmful effects of chronic stress on cancer outcome.