Tissue sections from aggressive human intraocular (uveal) and metastatic cutaneous melanomas generally lack evidence of significant necrosis and contain patterned networks of interconnected loops of extracellular matrix. The matrix that forms these loops or networks may be solid or hollow. Red blood cells have been detected within the hollow channel components of this patterned matrix histologically, and these vascular channel networks have been detected in human tumors angiographically. Endothelial cells were not identified within these matrix-embedded channels by light microscopy , by transmission electron microscopy , or by using an immunohistochemical panel of endothelial cell markers (Factor VIIIrelated antigen , Ulex , CD31 , CD34 , and KDR[Flk-1]). Highly invasive primary and metastatic human melanoma cells formed patterned solid and hollow matrix channels (seen in tissue sections of aggressive primary and metastatic human melanomas) in threedimensional cultures containing Matrigel or dilute Type I collagen , without endothelial cells or fibroblasts. These tumor cell-generated patterned channels conducted dye , highlighting looping patterns visualized angiographically in human tumors. Neither normal melanocytes nor poorly invasive melanoma cells generated these patterned channels in vitro under identical culture conditions , even after the addition of conditioned medium from metastatic pattern- It is generally assumed that tumors require a blood supply for growth and metastasis. 1 The development of the tumor microcirculation compartment includes both the production of new blood vessels (angiogenesis) and their remodeling. 2 In fact, the number of vessels 3 and the patterning of the microcirculation 4 by remodeling events are used as histological markers of tumor progression. Although attention has been focused on factors that stimulate and suppress tumor angiogenesis, the molecular mechanisms underlying tumor remodeling remain enigmatic. It is therefore critical to investigate remodeling of the intratumoral microvasculature in various tumor models.Melanoma is among the better characterized tumor models with respect to prognostic staging of disease progression. The rising incidence of cutaneous melanoma makes this tumor an important public health problem. Melanoma of the interior of the eye, uveal melanoma, although much less common than cutaneous melanoma, poses a threat to vision and significant morbidity; nearly 50% of patients with uveal melanoma die from metastatic melanoma. 5 Cutaneous melanoma may disseminate through lymphatics or blood vessels. In contrast, the interior of the eye lacks lymphatics, and uveal melanoma, which develops in one of the most capillary-rich tissues of the body, is a paradigm for pure hematogeneous dissemination of cancer. 6 Therefore, the development of a tumor microcirculation in uveal melanoma is a rate-limiting step for hematological metastasis and serves as an important model for study of the cellular and molecular infrastruc-

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...

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The term vasculogenic mimicry describes the formation of fluid-conducting channels by highly invasive and genetically dysregulated tumor cells. Two distinctive types of vasculogenic mimicry have been described. Vasculogenic mimicry of the tubular type may be confused morphologically with endothelial cell-lined blood vessels. Vasculogenic mimicry of the patterned matrix type in no way resembles blood vessels morphologically or topologically. Matrix proteins such as laminin, heparan sulfate proteoglycan, and collagens IV and VI have been identified in these patterns. The patterned matrix anastomoses with blood vessels, and systemically injected tracers co-localize to these patterns. Vasculogenic mimicry of the patterned matrix type has been identified in uveal, cutaneous and mucous membrane melanomas, inflammatory and ductal breast carcinoma, ovarian and prostatic carcinoma, and soft tissue sarcomas, including synovial sarcoma rhabdomyosarcoma, osteosarcoma, and pheochromocytoma. Because the microcirculation of many tumors may be heterogeneous -including incorporated or co-opted vessels, angiogenic vessels, mosaic vessels, and vasculogenic mimicry of the tubular and patterned matrix types -therapeutic regimens that target angiogenesis alone may be ineffective against highly invasive tumors that contain patterned matrices. Vasculogenic mimicry provides an opportunity to investigate the interrelationships between the genetically dysregulated invasive tumor cell, the microenvironment, and the malignant switch.

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