Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Tumour-microenvironment interaction: the effect of analgesics. (#145)

Banafsheh Afshar Imani 1 , Peter J cabot 1 , Marie-Odile Parat 1
  1. University of Queensland, Woolloongabba, Qld, Australia
Surgery is the mainstay of breast cancer treatment; however, there are concerns about the possible effect of the anaesthetic regimen including analgesic medications on postoperative tumour recurrence and metastasis. A proposed contributor to tumour recurrence is the existence of micrometastases at the time of surgery. Whether these small malignant foci could lead to new tumours is determined in part by their microenvironment. This includes non-malignant cells such as macrophages and endothelial cells and the extracellular matrix (ECM). We hypothesized that perioperative analgesic drugs could modulate the interaction between tumour and non-tumour cells and thus affect the growth and invasiveness of micrometastases. In a mouse syngeneic breast cancer model we observed a dramatic increase in serum levels of the two ECM proteolytic enzymes, matrix metalloproteinase-9 (MMP-9) and urokinase-like plasminogen activator (uPA) as well as tissue inhibitor of metalloproteinase (TIMP)-1 in tumour-bearing mice. The tumour and its surrounding tissue differentially contributed to the overproduction of these enzymes. In in vitro co-culture models, direct contact between tumour cells and either macrophages or endothelial cells resulted in a surge of proteolytic enzymes MMP-9, MMP-2 and uPA as well as TIMPs. In these models, we examined the effect of two opioid analgesics widely used in the perioperative period, morphine and fentanyl and two non-steroidal anti-inflammatory drugs, aspirin and ketorolac, on the production of proteases and their inhibitors. Exposure to aspirin and ketorolac caused significant decrease in MMP-9, MMP-2 and uPA levels and treatment with morphine and fentanyl increased the level of TIMP-1. The results of our study suggest that the interactions between breast tumour cells, macrophages and endothelial cells induce changes in ECM degrading potential and that short-term exposure to analgesic drugs, commonly used in anaesthetic regimens, could modulate this interaction by either reducing the level of the enzymes or increasing their endogenous inhibitors.