Perioperative psycho-behavioral stress promotes cancer metastasis beyond the impact of surgery: Neuroendocrine and tumor molecular mediating mechanisms

Clinically, the unique impact of perioperative distress on long-term cancer outcomes remains unclear and is thus overlooked medically. Operated cancer patients experience intertwined psychological and physiological stress, which are hard to disentangle. Therefore, herein we employed rodents to assess the specific impact of psycho-behavioral stress on cancer metastasis in the context of surgery and without it, and studied underlying neuroendocrine mechanisms and intratumoral transcriptional mediators. A tilt-light stress paradigm was employed along with surgery/tumor cell inoculation, using two mouse colorectal cancer models of liver metastases (MC38 C57BL/6, and CT26 BALB/c), and a rat mammary pulmonary metastases model (MADB106 F344). In the latter, we also assessed the efficacy of a glucocorticoid, a β-adrenergic, or a COX-2 inhibitor/antagonist (mifepristone, propranolol, or etodolac) in preventing the effects of stress. A 48-hour perioperative stress exposure, but not 24hr pre- or 24hr post-operative exposure, consistently increased the number of experimental metastases in all models, irrespective of the effects of surgery. Both mifepristone and propranolol, but not etodolac, prevented these effects. To better mimic the clinical setting, the 4T1 mammary cancer model of spontaneous metastases was used, along with six perioperative days of alternating stress. Perioperative stress increased metastasis, and a propranolol + etodolac regimen, as employed in recent clinical studies, abrogated pre-operative deleterious effects of stress on tumor epithelial-to-mesenchymal transition and other metastasis-related transcriptional activity. Overall, psycho-behavioral stress can uniquely contribute to metastatic progression through stress responses and malignant pro-metastatic transcriptional pathways. Thus, in cancer patients, managing perioperative distress may improve long-term cancer outcomes. • Forty-eight hr psycho-behavioral stress increased metastases in three rodent models (85 characters) • Stress increased metastasis independently of the impact of surgery (68 characters) • Mifepristone and propranolol each completely abolished the increase in metastases (84 characters) • Stress induced prometastatic tumoral transcriptional activity and EMT (72 characters) • A propranolol+etodolac regimen blocked stress-induced transcriptional perturbations (85 characters)