Plasticity of ovarian cancer cell SKOV3ip and vasculogenic mimicry in vivo

Abstract

The aim of this study is to investigate the plasticity of human epithelial ovarian cancer cell SKOV3ip and formation of vasculogenic mimicry (VM) in vivo. SKOV3ip was transfected with lentiviral vector carrying green fluorescence protein (GFP). Female nude mice were implanted intraperitoneally with GFP-labled SKOV3ip. When the transplanted tumor reached a volume of approximately 1 cm(3), paraffin-embedded, formaldehyde-fixed tissue was prepared and stained with hematoxylin and eosin (H & E). Tumor tissues were also studied by electron microscopy and fluorescence microscopy. The results of H & E staining, electron microscopy, and fluorescence microscopy indicated SKOV3ip formed patterned networks with erythrocytes in them, in the absence of vascular epithelial cells, which was a sign that SKOV3ip engaged in VM in vivo. Expression of vascular epithelium marker CD31 was investigated by immunohistochemical staining, immunofluorescence assay, semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and flow cytometric analysis (FACS). Factor VIII and vascular endothelial growth factor (VEGF) were also analyzed by FACS. Weak and focal CD31 immunohistochemical staining was found along the channels of tumor cells. Immunofluorescence assay and RT-PCR demonstrated that CD31 was expressed in primary-cultured SKOV3ip. CD31 and Factor VIII, but not VEGF were detected in primary-cultured SKOV3ip by FACS. The present study has shown that human ovarian cancer cell line SKOV3ip may be able to express some specific markers of vascular epithelial cells and has plasticity to form VM in vivo. In the following study, we indicated that hypoxia-inducible factor (HIF)-1alpha inhibitor, rapamycin, could possibly prevent VM and phenotype transformation of SKOV3ip, reflected by down-regulating expression of CD31 and Factor VIII. HIF-1alpha protein expression correlated with CD31 and Factor VIII protein expression in SKOV3ip. These results indicated that VM might be associated with HIF-1alpha.

CD133 expression in circulating tumor cells from breast cancer patients: Potential role in resistance to chemotherapy

“…For example, rapamycin (an inhibitor of the mTOR pathway and VEGF), an FDA-approved angiogenesis inhibitor, that has specifically suppressed tumor cell VM coincident with a downregulation of vascular endothelial growth factor, matrix metalloproteinases, and Hypoxia-inducible factor 1. 50 Interruption of the metastatic cascade via the targeting of CTCs is a promising therapeutic approach. The availability of novel targeted anticancer treatments increased the interest of the molecular characterization of CTCs, in particular in nonmetastatic BC patients that are potentially curable.…”

Functional significance of VEGF-a in human ovarian carcinoma: Role in vasculogenic mimicry

“…There is no direct relationship between VM formation and VEGF-a. Cell functional studies provided evidence that the SKOV3 and OVCAR3 cells (these cell-lines have the ability to form VM in vivo 41 ), show the capability of invasion and migration; and VEGFa can markedly enhance the plasticity and increase the ability to engage in pipe-like structure formation when cultured on a threedimensional matrix. However, morphological observations show that the cells were closely packed, and no endothelial-like cell plasticity was found in EGF-treated group.…”

Mammalian target of rapamycin signaling is involved in the vasculogenic mimicry of glioma via hypoxia-inducible factor-1α

“…A recent study indicated that rapamycin acts as an HIF-1α inhibitor and prevents VM formation of human epithelial ovarian cancer in vivo (9). Researchers have reached a consensus that HIF-1α is a major cause of VM (reviewed in ref.…”