Vasculogenic mimicry

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Vasculogenic mimicry (VM) is a way some tumors get their own blood supply without using normal blood vessels. Instead of forming vessels with endothelial cells like usual blood vessels, cancer cells themselves create tube-like channels that carry blood. This happens especially in aggressive cancers and under stressful conditions like low oxygen.

How VM forms
- Cancer cells in VM turn on endothelial-like properties, including abnormal expression of VE-cadherin, a protein that helps cells stick together in blood vessels.
- The surrounding extracellular matrix (ECM) is remodeled by enzymes like matrix metalloproteinases (MMPs) and other proteins, creating space for new channels.
- Epithelial-mesenchymal transition (EMT) helps cancer cells lose tight cell-to-cell adhesion and gain movable, invasive traits, aiding VM.
- Cancer stem cells, Notch and Nodal signaling, and VEGF help drive VM by promoting endothelial-like behavior and plasticity in tumor cells.

Key signals and triggers
- Hypoxia (low oxygen) in tumors activates HIFs, which turn on VM-related genes such as VE-cadherin, Twist, Nodal, EphA2, VEGF, and VEGFRs.
- Other pathways, like NF-κB and Notch/Nodal signaling, also support VM and the stem-like qualities of cancer cells.

What VM looks like and how it’s found
- There are two main VM types: tubular VM, where channels are lined by tumor cells in place of endothelial cells; and patterned matrix VM, where tumor cells are surrounded by a PAS-positive matrix.
- VM is diagnosed in tissue samples by staining that shows CD31 (an endothelial marker) is negative and PAS staining marks the VM channels and surrounding matrix (CD31-/PAS+).

Clinical significance
- VM is linked to more invasion, more metastasis, and worse outcomes for patients.
- Tumors with VM often resist anti-angiogenic therapies, and some treatments that raise tumor hypoxia can unintentionally promote VM.
- A large analysis found that patients with VM-positive tumors had lower five-year survival (about 31%) compared with VM-negative tumors (about 56%), with even bigger differences in later-stage disease.

Cancers where VM has been noted
- Melanoma, including aggressive and metastatic cases.
- Breast cancer, especially triple-negative breast cancer (TNBC) and also HER2-positive types.
- Glioblastoma (a brain cancer) and other cancers like prostate cancer, renal cell carcinoma (RCC), and ovarian cancer.

Biomarkers and targets
- VM tumors often show markers such as VE-cadherin, VEGF, HIF-1α, Nodal, and components of the ECM like MMPs.
- Researchers are developing strategies to inhibit VM, though few VM-specific drugs are approved yet. Some existing compounds have shown VM-blocking effects in lab and animal studies.

In short, vasculogenic mimicry is a cancer strategy where tumor cells form blood-conducting channels on their own, helping tumors grow and spread even when traditional blood-vessel formation is blocked. It’s a marker of aggressiveness and treatment resistance, making VM a focus of ongoing research for better diagnostics and new therapies.