α2 Integrin-Dependent Suppression of Pancreatic Adenocarcinoma Cell Invasion Involves Ectodomain Regulation of Kallikrein-Related Peptidase-5

Previous reports demonstrate that the α 2-integrin ( α 2) mediates pancreatic ductal adenocarcinoma (PDAC) cell interactions with collagens. We found that while well-differentiated cells use α 2 exclusively to adhere and migrate on collagenI, poorly differentiated PDAC cells demonstrate reduced reliance on, or complete loss of, α 2. Since well-differentiated PDAC lines exhibit reduced in vitro invasion and α 2-blockade suppressed invasion of well-differentiated lines exclusively, we hypothesized that α 2 may suppress the malignant phenotype in PDAC. Accordingly, ectopic expression of α 2 retarded in vitro invasion and maintenance on collagenI exacerbated this effect. Affymetrix profiling revealed that kallikrein-related peptidase-5 (KLK5) was specifically upregulated by α 2, and reduced α 2 and KLK5 expression was observed in poorly differentiated PDAC cells in situ . Accordingly, well-differentiated PDAC lines express KLK5, and KLK5 blockade increased the invasion of KLK5-positive lines. The α 2-cytoplasmic domain was dispensable for these effects, demonstrating that the α 2-ectodomain and KLK5 coordinately regulate a less invasive phenotype in PDAC.