Molecular Determinants of Ovarian Cancer Plasticity

Abstract

During development, the formation and remodeling of primary vascular networks occurs by vasculogenesis and angiogenesis. Recently, the term "vasculogenic mimicry" has been used by our laboratory and collaborators to reflect the embryonic-like ability of aggressive, but not nonaggressive, melanoma tumor cells to form a pattern of matrix-rich networks (containing channels) surrounding spheroids of tumor cells in three-dimensional culture, concomitant with their expression of vascular cell markers. Ovarian cancer is usually diagnosed as advanced stage disease in most patients when widespread metastases have already been established within the peritoneal cavity. In this study, we explored whether invasive ovarian carcinoma cells could engage in molecular vasculogenic mimicry reflected by their plasticity, compared with their normal cell counterparts. The data revealed that the invasive ovarian cancer cells, but not normal ovarian surface epithelial cells, formed patterned networks containing solid and hollow matrix channels when grown in three-dimensional cultures containing Matrigel or type I collagen, in the absence of endothelial cells or fibroblasts. Immunohistochemical analysis showed that matrix metalloproteinases (MMP)-1, -2, and -9, and MT1-MMP were discretely localized to these networks, and the formation of the networks was inhibited by treatment with MMP inhibitors. Furthermore, the RNase protection assay revealed the expression of multiple vascular cell-associated markers by the invasive ovarian cancer cells. In patient tumor sections from high-stage, high-grade ovarian cancers, 7 to 10% of channels containing red blood cells were lined by tumor cells. By comparison, all vascular areas in benign tumors and low-stage cancers were endothelial lined. These results may offer new insights and molecular markers for consideration in ovarian cancer diagnosis and treatment strategies based on molecular vascular mimicry by aggressive tumor cells.

Putting tumours in context

“…These vessels are believed to transport blood into the depths of the tumour 82,83 . This concept has now been well-characterized [84][85][86][87] and could represent a general component of tumour development 88 . To produce more selective antiangiogenic therapies, it might be necessary to combine detailed examinations of vasculogenic mimicry with existing models of tumour angiogenesis.…”

Metalloproteinases and their inhibitors in tumor angiogenesis

“…The MMP inhibitor Metastat prevented network formation but did not destroy preexisting networks. 103 Further evidence comes from work showing that laminin-5 g2 chain, MMP-1, -2, -9 and MT1-MMP are all upregulated in aggressive versus poorly aggressive melanoma cells. When the aggressive melanoma cells formed networks in vitro on collagen gels, these molecules were shown to be localized at the developing channels.…”

Tissue-type plasminogen activator has antiangiogenic properties without effect on tumor growth in a rat C6 glioma model

“…Among these is the ability of cancer cells to form 'vasculogenic' channels, also called 'vasculogenic mimicry' in the literature. [28][29][30][31][32][33] Although further studies would be needed to support this hypothesis, we previously described the in vitro potential of C6 cells to form vascular-like networks on Matrigel, which were resistant to angiostatin as well as to plasma treated with the combination of rtPA and captopril. 34 Figure 7 Tumor volume (mm 3 ).…”