Molecular determinants of ovarian cancer plasticity

During development, the formation and remodeling of primary vascular networ ks occurs by vasculogenesis and angiogenesis. Recently, the term "vasculo-g enic mimicry" has been used by our laboratory and collaborators to reflect the embryonic-like ability of aggressive, but not nonaggressive, melanoma t umor cells to form a pattern of matrix-rich networks (containing channels) surrounding spheroids of tumor cells in three-dimensional culture, concomit ant with their expression of vascular cell markers. Ovarian cancer is usual ly diagnosed as advanced stage disease in most patients when widespread met astases have already been established within the peritoneal cavity, in this study, we explored whether invasive ovarian carcinoma cells could engage i n molecular vasculogenic mimicry reflected by their plasticity, compared wi th their normal cell counterparts. The data revealed that the invasive ovar ian cancer cells, but not normal ovarian surface epithelial cells, formed p atterned 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 s howed that matrix metalloproteinases (MMP)-1, -2, and -9, and MT1-MMP were discretely localized to these networks, and the formation of the networks w as inhibited by treatment with MMP inhibitors, Furthermore, the RNase prote ction assay revealed the expression of multiple vascular cell-associated ma rkers 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 i n 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 mimic ry by aggressive tumor cells.