Heparin-binding
epidermal growth factor-like
growth factor (
HB-EGF) is involved in several biological processes including cell adhesion, invasion, and angiogenesis.
HB-EGF also plays a pivotal role in the progression of
ovarian cancer. To investigate the significance of
HB-EGF in peritoneal dissemination, we examined the roles of
HB-EGF in cell adhesion, invasion, and angiogenesis in
ovarian cancer. Through the suppression of
focal adhesion kinase and
EGF receptor activation, cell adhesive properties mediated by
integrin beta(1) were diminished by the inhibition of
HB-EGF expression. The reduction of
HB-EGF expression attenuated the chemotactic invasive ability and the expression of matrix
metalloprotease (MMP)-2 and
vascular endothelial growth factor (
VEGF), leading to the inhibition of cell invasion and angiogenesis. Suppression of the Snail family, which regulates the epithelial-mesenchymal transition, blocked the cell adhesion properties on extracellular matrices, the chemotactic invasive ability, and the expression of MMP9 and
VEGF through the reduction of
HB-EGF expression. The volume of
tumor burden in the peritoneal cavity was dependent on the expression of
HB-EGF. According to these results,
HB-EGF contributes to cell adhesion, invasion, and angiogenesis, which are integral to transcoelomic
metastasis in
ovarian cancer.
CRM197, an inhibitor of
HB-EGF, resulted in a significant decrease of
tumor burden in peritoneal dissemination, accompanied with a reduction in both cellular spreading, when assayed on an extracellular matrix, and invasive ability, when assayed in a chemotaxis chamber, as well as decreased expression of MMP9 and
VEGF. Thus,
HB-EGF is a mutual validating target in the peritoneal dissemination of
ovarian cancer, and
CRM197 may be useful as a
anticancer agent for advanced
ovarian cancer.