Vasculogenic mimicry (VM) is a strategy used by tumors to ensure sufficient blood supply is brought to its cells through establishing new tumor vascularization. This process is similar to tumor angiogenesis; on the other hand vascular mimicry is unique in that this process occurs independent of endothelial cells. Vasculature is instead developed de novo by cancer cells, which under stress conditions such as hypoxia, express similar properties to stem cells, capable of differentiating to mimic the function of endothelial cells and form vasculature-like structures. The ability of tumors to develop and harness nearby vasculature is considered one of the hallmarks of cancer disease development and is thought to be closely linked to tumor invasion and metastasis. Vascular mimicry has been observed predominantly in aggressive and metastatic cancers and has been associated with negative tumor characteristics such as increased metastasis, increased tissue invasion, and overall poor outcomes for patient survival. Vascular mimicry poses a serious problem for current therapeutic strategies due to its ability to function in the presence of Anti-angiogenic therapeutic agents. In fact, such therapeutics have been found to actually drive VM formation in tumors, causing more aggressive and difficult to treat tumors to develop.
Overview Vascular mimicry was first discovered in 1999 by Maniotis et al. who identified blood supplying channels in melanoma that were composed entirely of tumor cell based structures. They found that cancer cells had taken on endothelial cell properties and were forming blood conducting vessels independent of normal angiogenesis pathways. This finding spurred interest within the research community to discover the cause of this pathway and its relevance to disease. Researchers have since discovered that VM is closely linked to several signaling pathways including vascular signaling, embryogenesis, and the hypoxic response.
Requirements for VM formation In order for new vasculature to form through VM, several requirements must be met. These generally include aberrant expression of VE-cadherin, as well as changes to the density and composition of the extracellular matrix. VE-cadherin is a transmembrane protein that is specifically expressed in endothelial cells to promote and maintain specific adhesion of endothelial cells critical to vascularization. However, aggressive and metastatic cancers have been found to have aberrant expression of VE-cadherin, allowing for formation of cancer cell specific vasculature. VE-cadherin also regulates inter-cellular signaling pathways which promote invasion of cancer cells into nearby and distal tissues, a major component of metastatic disease. VE-cadherin has also been linked to regulatory functions in cell proliferation, cell death, and the expression and function of VEGFRs.
Another major factor in the formation of VM in tumors is the adjustment of the extracellular matrix to promote vasculature formation. Aggressive tumors express elevated levels of proteins such as matrix metalloproteinases (MMPs), laminin5y2, and type-1 & 4 collagens. These glycoproteins secreted are into the ECM by cancer cells and act to clear space for new vessel formation, as well as promote recruitment and reorganization of cancer cells to form new blood conducting vessels.
Identification and classification Clinically, VM is diagnosed through immunohistochemistry (IHC) and Periodic acid-Schiff stain (PAS) of patient tumor biopsy. IHC staining identifies the expression of common biomarkers of endothelial cells such as CD31, while PAS staining marks the extracellular matrix for glycoproteins, laminin, proteoglycans, heparin sulfate and collagens, which are known to be a sign of VM. Clinicians diagnose a tumor as having VM by CD31-/PAS+ expressing blood conducting vessels, indicating that there are no endothelial cells but still vasculature present. Vascular mimicry may be divided into tubular and patterned matrix types. Tubular VM is characterized by channels surrounded by glycoprotein covered tumor cells where endothelial cells would normally sit. Patterned matrix type VM lacks the endothelial-like tumor cells and is instead tumor cells that are enveloped by PAS+ matrix/
Mechanisms and pathways
Epithelial-mesenchymal transition (EMT) EMT is thought to be one of the major drivers of VM in cancer. This is a mechanism through which cancer cells lose their epithelial properties resulting in a loss of cell-cell adhesion and a transition towards mesenchymal-like properties . EMT plays a diverse and essential role in adhesion, motility and morphology of cells under both normal and pathological conditions. When cells undergo EMT, they lose their polarity, ability to adhere to neighboring cells, and the tight contacts as result of losing expression of epithelial cell markers such as E-cadherin. Cells that have taken on mesenchymal properties are non-adherent, and thus promote invasion into nearby tissues. This process occurs normally in wound healing as well as embryonic development. This transition process has been identified to occur in cancer cells and drives metastasis and invasion into other tissues. EMT is associated with increasing and maintaining the VM in tumors through several pathways such as Twist transcription factor, and TGFB. Importantly to VM, the process of EMT results in the loss of E-cadherin, and the promotion of VE-cadherin transcription and expression, a critical factor in development of vascular mimicry. EMT is also implicated in promotion of stem-like properties in cancer cells.
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