Pancreatic ductal
adenocarcinoma (PDAC) is highly resistant to conventional
chemotherapy. The presence of both cellular and stromal
fibronectin (FN) and its interaction with
integrins is necessary for PDAC progression. We tested the efficacy of
endothelial monocyte-activating polypeptide II (
EMAP II) to inhibit PDAC progression and its ability to interfere with FN-
integrin angiogenesis signaling. In heterotopic PDAC
tumors EMAP II caused a significant reduction (>65%) in
tumor growth, accompanied by a >50 and 44% decrease in microvessel density and proliferative activity, respectively.
EMAP II therapy caused a 62 and 56% reduction in host and
tumor cell FN expression. Cultured PDAC cells expressed alphaVbeta3 and alpha5beta1
integrins. In vitro
EMAP II had limited antiproliferative effects on ASPC-1, but a pronounced antiproliferative effect on endothellial cells. 3D FN matrices increased ASPC-1 cell proliferation by >50%, and this induction was significantly blocked by alpha3, alpha5, alpha6 and
alphaV integrin funtional
blocking antibodies, while alpha1, alpha2 and alpha4
antibodies had no effect.
EMAP II also inhibited 3D FN-matrix induced ASPC-1 proliferation by >43% at 20 microM. These findings suggest that
EMAP II demonstrates significant antitumor activity against PDAC cells, and that this effect may be in part mediated through targeted interference with stromal FN-
integrin dependent PDAC cell proliferation.