Vasculogenic Mimicry and Tumor Angiogenesis

Abstract

Tumors require a blood supply for growth and hematogenous dissemination. Much attention has been focused on the role of angiogenesis-the recruitment of new vessels into a tumor from pre-existing vessels. However, angiogenesis may not be the only mechanism by which tumors acquire a microcirculation. Highly aggressive and metastatic melanoma cells are capable of forming highly patterned vascular channels in vitro that are composed of a basement membrane that stains positive with the periodic acid-Schiff (PAS) reagent in the absence of endothelial cells and fibroblasts. These channels formed in vitro are identical morphologically to PAS-positive channels in histological preparations from highly aggressive primary uveal melanomas, in the vertical growth phase of cutaneous melanomas, and in metastatic uveal and cutaneous melanoma. The generation of microvascular channels by genetically deregulated, aggressive tumor cells was termed "vasculogenic mimicry" to emphasize their de novo generation without participation by endothelial cells and independent of angiogenesis. Techniques designed to identify the tumor microcirculation by the staining of endothelial cells may not be applicable to tumors that express vasculogenic mimicry. Although it is not known if therapeutic strategies targeting endothelial cells will be effective in tumors whose blood supply is formed by tumor cells in the absence of angiogenesis, the biomechanical and molecular events that regulate vasculogenic mimicry provide opportunities for the development of novel forms of tumor-targeted treatments. The unique patterning characteristic of vasculogenic mimicry provides an opportunity to design noninvasive imaging techniques to detect highly aggressive neoplasms and their metastases. Tumors require a blood supply to sustain growth. The tumor microcirculation plays a central role in the hematogenous dissemination of cancers. Considerable attention has been focused on the mechanisms by which tumors acquire their blood supply. It is a well-accepted paradigm that tumors recruit new blood vessels from the existing circulation 1 -angiogenesis-either from factors secreted by the tumor cells, as Folkman 2,3 has emphasized, or from surrounding stromal cells. 4 There are two variations on the theme of tumor angiogenesis: augmentation of the angiogenic response by progenitor endothelial cells, and vessel cooption. Asahara and associates 5 described the incorporation of endothelial cell progenitors (or angioblasts) from circulating peripheral blood into sites of ischemic-driven angiogenesis. Holash and associates 6 described a process of "vessel cooption" in which tumors coopt the existing vasculature, which regresses leading to massive necrosis, and the tumor is then vascularized at the periphery by tumor angiogenesis as described above.We 7 recently described a novel process by which tumors develop a highly patterned microcirculation that is independent of angiogenesis: in aggressive primary and metastatic melanomas, the tumor cells generate acellular microcirculat...

Trophoblastic vasculogenic mimicry in gestational choriocarcinoma

“…16 Blood circulation was established in those tumors by creating vascular channels lined by tumor cells, and this process has been termed as 'vasculogenic mimicry', which underscores the de novo generation of vascular channels without involvement of non-neoplastic endothelial cells. 17,18 With vasculogenic mimicry, it is thought that tumor cells are able to sustain tumor growth and, to some extent, prevent tumor hypoxia. Thus, choriocarcinoma represents another example of human neoplastic diseases featuring vasculogenic mimicry, but unlike other tumor types, vasculogenic mimicry in choriocarcinoma occurs in all cases examined, indicating that vasculogenic mimicry is a general phenomenon associated with choriocarcinoma.…”

Putting tumours in context

“…These vessels are believed to transport blood into the depths of the tumour 82,83 . This concept has now been well-characterized [84][85][86][87] and could represent a general component of tumour development 88 . To produce more selective antiangiogenic therapies, it might be necessary to combine detailed examinations of vasculogenic mimicry with existing models of tumour angiogenesis.…”

Functional implication of BMP4 expression on angiogenesis in malignant melanoma

“…BMP4 in angiogenesis in melanoma T Rothhammer et al distribute plasma and red blood cells in vivo and in vitro, enabling the tumor to become, at least in part, independent of angiogenesis (Folberg et al, 2000;Hendrix et al, 2003;Folberg and Maniotis, 2004). Vasculogenic mimicry, however, is controversially discussed.…”

“…On the other hand, melanoma cells are able to de novo generate microcirculatory channels that are composed of extracellular matrix and lined by tumor cells. This process of formation of non-endothelial cell-lined channels has been called 'vasculogenic mimicry' (Maniotis et al, 1999;Folberg et al, 2000;Folberg and Maniotis, 2004). Several genes like VE-cadherin (vascular endothelial cadherin), laminin 5 g2 chain, TIE-1 (tyrosine kinase with immunoglobulin and EGF factor homology domains) and EphA2 (epithelial cell receptor protein-tyrosine kinase), known to be important in angiogenesis, were also identified to play a role in vasculogenic mimicry (Hendrix et al, 2003).…”