Vasculogenic mimicry

[5] Vascular mimicry was first discovered in 1999 by Maniotis et al. who identified blood supplying channels in malignant melanoma that were composed entirely of tumor cell based structures.

[7] 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.

[6] Clinically, VM is diagnosed through immunohistochemistry (IHC) and Periodic acid-Schiff stain (PAS) of patient tumor biopsy.

[2] 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.

EMT plays a diverse and essential role in adhesion, motility and morphology of cells under both normal and pathological conditions.

[12][13] 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.

This theory states that tumors arise from a small subpopulation of cancer cells which have the ability to self-renew as well as differentiate.

CSCs have been linked to driving VM formation predominantly through the secretion of VEGF, which is a well establish regulator or VE-cadherin expression.

Notch function remains active in adult tissues and is an essential signaling pathway in stem cell differentiation, including the formation of vasculature.

Notch modulates Nodal activation during embryonic stages during the establishment of positionality of specific cells in the embryo.

[16] To circumvent this problem, tumors utilize a diverse set of pathways to promote various angiogenesis strategies as well as vasculogenic mimicry.

[16] The location of HRE sites on the genome varies among cancer cell types, however hypoxia based signaling has been found to activate VM related genes including VE-cadherin, COX-2, Twist, Nodal, EphA2, VEGF-A, and VEGR-1.

[9] Vascular mimicry provides tumors with a strategy to resist anti-angiogenic therapies, which have been shown to actually increase VM formation in patients due to the hypoxia these treatments induce.

[9] Melanoma is an aggressive skin cancer which has been shown to utilize both angiogenesis and vascular mimicry to drive metastasis and also increase treatment resistance.

Prostate cancer with VM has been shown to occur in patients with overall more aggressive disease including higher Gleason scores, and more metastatic and lymph node formation.

Despite a strong initial response to chemotherapy, the majority of these patients will see disease recurrence as well as develop resistance to available chemotherapeutic strategies.

[20] The use of Anti-angiogenic compounds in ovarian cancer has met with limited success largely due to the availability of VM signaling pathways in aggressive tumors.

Due to poor strategies for early detection, ovarian cancer is generally caught at later stages of disease and thus difficult to treat.

Vascular mimicries (indicated by arrows) in melanoma A) H&E stain B) PanMelanoma cocktail stain.
The structure of tumor blood vessels formed through the known tumor angiogenesis pathways. Vasculogenesis , sprouting angiogenesis, Intussusceptive angiogenesis , vessel co-option, and both vascular mimicry tubular and patterned matrix types are shown.
Visual representation of vascular mimicry formation under hypoxic conditions. EET (A subtype of EMT) drives cancer cells to take on endothelial-like properties to form vasculature.
The transition of tumors from angiogenesis to vascular mimicry under hypoxic conditions
The major signaling pathways involved in vasculogenic mimicry. Vascular signaling (purple), Stem cell signaling (blue), and Hypoxia (green) are the major pathways shown.
Left: the relationship between breast cancer cell stemness, vasculogenic mimicry, and prognosis. Right: provides a diagram of factors involved in formation of vascular mimicry in breast cancer.
Glioblastoma