A three-dimensional and temporo-spatial model to study invasiveness of cancer cells by heregulin and prostaglandin E2.

To study the temporal expression of motile structures and protease activity during colon cancer cell invasion by heregulin-beta1 (HRG) and prostaglandin E2 (PGE2), we have developed a three-dimensional spatial model system. HRG and PGE2 each induced the formation of well-organized, three-dimensional structures with empty spaces in the center and stimulated the expression of urokinase plasminogen activator (uPA) with differential localization of membrane-bound uPA at the focal adhesion points and leading edges of the motile cells. A specific cyclooxygenase-2 inhibitor blocked the formation of three-dimensional luminal glandular structures induced by HRG but did not block those induced by PGE2. A specific antagonist of uPA receptor completely blocked the formation of these luminal glandular structures induced by PGE2 and HRG. These findings suggest that HRG-mediated increased invasiveness of colon cancer cells is augmented at least in part by induction of PGE2 and uPA, and this augmentation may involve the formation of three-dimensional invasive structures via the uPA pathway. In addition, the three-dimensional model system presented here may have a wider application to screen the effects of therapeutic compounds and biomolecules on different spatial aspects of colonic biology, including cell growth, motility, invasion, survival, and apoptosis.