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.