Abstract
Vasculogenic mimicry (VM) describes a process by which cancer cells establish an alternative perfusion pathway in an endothelial cell-free manner. Despite its strong correlation with reduced patient survival, controversy still surrounds the existence of an in vitro model of VM. Furthermore, many studies that claim to demonstrate VM fail to provide solid evidence of true hollow channels, raising concerns as to whether actual VM is actually being examined. Herein, we provide a standardized in vitro assay that recreates the formation of functional hollow channels using ovarian cancer cell lines, cancer spheres and primary cultures derived from ovarian cancer ascites. X-ray microtomography 3D-reconstruction, fluorescence confocal microscopy and dye microinjection conclusively confirm the existence of functional glycoprotein-rich lined tubular structures in vitro and demonstrate that many of structures reported in the literature may not represent VM. This assay may be useful to design and test future VM-blocking anticancer therapies.
Highlights
Cancer cells within a tumor require a blood supply containing oxygen and nutrients in order to grow beyond a few millimeters[1,2,3]
Many strategies have been postulated to explain this phenomenon[5]. One of these strategies involves a phenotypic switch in certain cells within a tumor that modify their morphology to form a network of fluid-conducting tubular structures, establishing an angiogenesis-independent alternative perfusion pathway into the tumor, a process known as vasculogenic mimicry (VM)[6]
During the following years clinical studies unequivocally demonstrated the existence of VM in human tumor biopsies and in in vivo experimental settings using Periodic Acid Schiff (PAS) staining along with an absence of EC markers in blood containing vessel-like structures within tumors[16, 18]
Summary
Cancer cells within a tumor require a blood supply containing oxygen and nutrients in order to grow beyond a few millimeters[1,2,3]. Many strategies have been postulated to explain this phenomenon[5] One of these strategies involves a phenotypic switch in certain cells within a tumor that modify their morphology to form a network of fluid-conducting tubular structures, establishing an angiogenesis-independent alternative perfusion pathway into the tumor, a process known as vasculogenic mimicry (VM)[6]. It was originally described in uveal melanoma[7], many studies have demonstrated VM in a variety of malignancies including skin melanoma, lung, gastric, and colorectal cancers[8]. We demonstrate that tubular structures are present in in vitro cultures and are capable of conducting fluids
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