Epithelial Ovarian Cancer-Induced Angiogenic Phenotype of Human Omental Microvascular Endothelial Cells May Occur Independently of VEGF Signaling

Abstract

Epithelial ovarian cancer (EOC) metastasizes transcoelomically to the peritoneum and omentum, and despite surgery and chemotherapy, recurrent disease is likely. Metastasis requires the induction of proangiogenic changes in the omental microenvironment and EOC-induced omental angiogenesis is currently a key therapeutic target. In particular, antiangiogenic therapies targeting the vascular endothelial growth factor A (VEGFA) pathway are commonly used, although, with limited effects. Here, using human omental microvascular endothelial cells (HOMECs) and ovarian cancer cell lines as an in vitro model, we show that factors secreted from EOC cells increased proliferation, migration, and tube-like structure formation in HOMECs. However, EOC-induced angiogenic tube-like formation and migration were unaffected by inhibition of tyrosine kinase activity of VEGF receptors 1 and 2 (Semaxanib; SU5416) or neutralization of VEGFA (neutralizing anti-VEGFA antibody), although VEGFA165-induced HOMEC migration and tube-like structure formation were abolished. Proteomic investigation of the EOC secretome identified several alternative angiogenesis-related proteins. We screened these for their ability to induce an angiogenic phenotype in HOMECs, i.e., proliferation, migration, and tube-like structure formation. Hepatocyte growth factor (HGF) and insulin-like growth factor binding protein 7 (IGFBP-7) increased all three parameters, and cathepsin L (CL) increased migration and tubule formation. Further investigation confirmed expression of the HGF receptor c-Met in HOMECs. HGF- and EOC-induced proliferation and angiogenic tube structure formation were blocked by the c-Met inhibitor PF04217903. Our results highlight key alternative angiogenic mediators for metastatic EOC, namely, HGF, CL, and IGFBP-7, suggesting that effective antiangiogenic therapeutic strategies for this disease require inhibition of multiple angiogenic pathways.

c‐Met inhibition enhances chemosensitivity of human ovarian cancer cells

“…Although the underlying mechanism for the role of c-Met in DNA damage repair has not been well investigated, it has been proved that downstream signalling pathways of RTKs intersect with DNA repair mechanisms to regulate cellular response to chemotherapy, including such pathways as Ras/ Raf/MEK/MAPK, JAK-STAT and PI3K/AKT pathways. 19,20 Our data…”

“…Our results suggest that the chemosensitization effect of INCB28060 on SKOV3 and OVCAR‐3 cells was associated with increased level of γH2AX after chemotherapy, indicating that the inhibition of c‐Met leads to reduced DNA damage repair ability. Although the underlying mechanism for the role of c‐Met in DNA damage repair has not been well investigated, it has been proved that downstream signalling pathways of RTKs intersect with DNA repair mechanisms to regulate cellular response to chemotherapy, including such pathways as Ras/Raf/MEK/MAPK, JAK‐STAT and PI3K/AKT pathways . Our data show that c‐Met inhibitor INCB28060 could efficiently inhibit the phosphorylation of c‐Met, PI3K and AKT, which regulate DNA repair ability in ovarian cells.…”

PDK1 promotes ovarian cancer metastasis by modulating tumor-mesothelial adhesion, invasion, and angiogenesis via α5β1 integrin and JNK/IL-8 signaling

“…Currently, there is an active search for more target agents involved in angiogenesis 41 . Here, we have demonstrated that PDK1 induces IL-8, an angiogenic CXC chemokine highly expressed in ovarian cancers and ascites 42,43 .…”

Resistance to chemotherapy and anti-angiogenic therapy in ovarian cancer

“…Evidence suggests that mechanisms of resistance to anti-VEGF therapy might be mediated by tumour cells and by members of the tumour microenvironment [11,27,28]. Tumour hypoxia is a major molecular controller of an "angiogenic switch" that determines a time-restricted event during tumour progression in which the balance between pro-and anti-angiogenic factors tilts towards a pro-angiogenic outcome [27,29,30].…”