Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer.

BACKGROUND Morphine stimulates angiogenesis and cancer progression in mice. We investigated whether morphine influences tumour onset, development, and animal model survival, and whether µ-opioid receptor (MOR), lymphangiogenesis, mast cell activation, and substance P (SP) are associated with the tumour-promoting effects of morphine. METHODS Transgenic mice with a rat C3(1) simian virus 40 large tumour antigen fusion gene which demonstrate the developmental spectrum of human infiltrating ductal breast carcinoma were used. Mice were treated at different ages with clinically relevant doses of morphine or phosphate-buffered saline to determine the effect on tumour development and progression, and on mouse survival. Tumours were analysed for MOR, angiogenesis, lymphangiogenesis, SP, and mast cell activation by immunofluorescent- or laser scanning confocal-microscopy. Cytokine and SP levels were determined by enzyme-linked immunosorbent assay. RESULTS Morphine did not influence tumour development when given before the onset of tumour appearance, but significantly promoted progression of established tumours, and reduced survival. MOR-immunoreactivity (ir) was observed in larger but not in smaller tumours. Morphine treatment resulted in increased tumour angiogenesis, peri-tumoural lymphangiogenesis, mast cell activation, and higher levels of cytokines and SP in tumours. SP-ir co-localized with mast cells and elsewhere in the tumours. CONCLUSIONS Morphine does not affect the onset of tumour development, but it promotes growth of existing tumours, and reduces overall survival in mice. MOR may be associated with morphine-induced cancer progression, resulting in shorter survival. Mast cell activation by morphine may contribute to increased cytokine and SP levels, leading to cancer progression and refractory pain.