ABSTRACT
Brain metastases from mammary adenocarcinoma constitute the chief cause of morbidity and mortality. Some evidence suggests that stress may contribute to disease progression and metastases. Here we show that acute restraint stress (30 min) induces statistically significant increase in brain metastases of systemically administered luciferase-tagged 4T1-BR-3P mouse mammary adenocarcinoma cells as evidenced by the total brain-associated photons from 5.6 × 10(7) photons in unstressed controls to 1.7 × 10(8) photons in C57BL/6 (p = 0.0018) and from 7.6 × 10(7) to 2.1 × 10(7) photons in BALB/c (p = 0.004) mice. Acute stress may increase metastases by disrupting the blood-brain-barrier (BBB), through release of corticotropin-releasing-hormone (CRH) activating perivascular brain mast cells.
Subject(s)
Adenocarcinoma/pathology , Brain Neoplasms/pathology , Brain Neoplasms/secondary , Breast Neoplasms/pathology , Restraint, Physical/adverse effects , Animals , Blood-Testis Barrier/physiopathology , Brain , Cell Line, Tumor , Corticotropin-Releasing Hormone/metabolism , Diagnostic Imaging/methods , Disease Models, Animal , Female , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred C57BL , PhotonsABSTRACT
Metastases continue to be the chief cause of morbidity and mortality for many tumors, including brain metastases of lung and mammary adenocarcinoma. Stress appears to increase metastases, but the mechanism is not understood. Recent evidence suggests that local inflammation is conducive for cancer growth and a unique immune cell, the mast cell, accumulates in the stroma surrounding tumors and is critically located at the blood-brain-barrier (BBB). Mast cells express receptors for and can be stimulated by corticotropin-releasing hormone (CRH), secreted under stress, to release mediators such as histamine, IL-8, tryptase and vascular endothelial growth factor (VEGF), which disrupt the BBB permitting metastases. Stress and mast cells could serve as new targets for drug development to prevent brain metastases, especially since CRH receptor antagonists and brain mast cell inhibitors have recently been developed.
