In
colorectal cancer,
cyclooxygenase-2 (COX-2) overexpression in stromal cells induces angiogenesis through EP2
prostaglandin E2 receptor signaling. Cytoplasmic
phospholipase A2 (PLA2) alpha preferentially hydrolyses
arachidonic acid, which is the limiting substrate for
prostaglandin production, from membrane
phospholipids. We therefore investigated a possible relationship between cytoplasmic PLA2 and COX-2 overexpression in stromal cells, angiogenesis and
microsatellite instability in 48 human colorectal
adenocarcinomas. Cytoplasmic PLA2 and COX-2 expression in stromal cells and
vascular endothelial growth factor (
VEGF) expression in
tumor cells were evaluated by immunohistochemistry. Microvessel density was assessed in 10 x 400 fields after CD31 staining.
Microsatellite instability was evaluated by PCR and immunohistochemistry. A total of 16
tumors had
microsatellite instability. We found an overexpression of cytoplasmic PLA2 in superficial stromal cells. These cells corresponded to fibroblasts and myofibroblasts. There was an association between the number of cytoplasmic PLA2 and COX-2-expressing cells (P=0.006). Cytoplasmic PLA2-positive stromal cells usually also expressed COX-2. A high number of cytoplasmic PLA2-positive stromal cells was correlated with a high microvessel density (P=0.002), a strong
VEGF (P=0.01) and the absence of
microsatellite instability (P=0.001). The coordinate overexpression of cytoplasmic PLA2 and COX-2 in stromal cells could lead to an important
prostaglandin production. These results suggest that cytoplasmic PLA2 overexpression in these cells regulates COX-induced angiogenesis probably by providing
arachidonic acid, which is the limiting factor for
prostaglandin production. The lower number of cytoplasmic PLA2-positive stromal cells in
carcinomas with
microsatellite instability could be related to their lower microvessel density and
VEGF expression.