Vascular Channel Formation by Human Melanoma Cells in Vivo and in Vitro: Vasculogenic Mimicry

Abstract

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-

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.…”

Cotargeting tumor and tumor endothelium effectively inhibits the growth of human prostate cancer in adenovirus-mediated antiangiogenesis and oncolysis combination therapy

“…Experimental data from several other laboratories provided intriguing evidence that aggressive breast and prostatic carcinoma and melanoma tumors demonstrate vasculogenic mimicry, [48][49][50] by which tumor cells form de novo vasculogenic-like networks in vitro in the absence of endothelial cells or fibroblasts, concomitant with the expression of several vascular-associated markers including thrombin receptor, endothelin-B receptor, endoglin, TIE-2 or Flk1. 51 In addition to in vitro cell models, tumor cell-lined vasculature is detectable in clinical specimens, 52,53 suggesting an important role for vasculogenic mimicry in the establishment, growth and metastasis of aggressive human tumors.…”

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…For instance, some tumors can grow along pre‐existing blood vessels without evoking an angiogenic response (and indeed are refractory to VEGF blockade); this process is referred to as vascular co‐option (Carmeliet and Jain, 2011a) and is specially observed in well‐vascularized tissues such as the brain (Holash et al., 1999). Other tumors may display vasculogenic mimicry, a process by which tumor cells alter their gene expression profile toward an undifferentiated phenotype, and gain the ability to form vascular‐like structures that do not depend on VEGF for their growth (Maniotis et al., 1999; Soda et al., 2011). If such vascular subtleties are not recapitulated in transplant tumor models representing a particular organ‐specific cancer, then targeted antiangiogenic drugs may fail to accurately demonstrate their effects and limitations.…”