title: Tumor cell plasticity and angiogenesis in human melanomas.
abstract: Recent molecular studies provide evidence for a significant transcriptional plasticity of tumor cell subpopulations that facilitate an active contribution to tumor vasculature. This feature is accompanied by morphological changes both in vitro and in vivo. Herein, we investigated the morphological plasticity of tumor cells with special focus on vasculogenic mimicry and neovascularisation in human melanoma and mouse xenografts of human melanoma cell lines. In melanoma xenograft experiments, different vessel markers and green fluorescent protein expression were used to show how melanoma cells contribute to neovascularization. Additionally, we analyzed neovascularization in 49 primary melanomas and 175 melanoma metastases using immunostaining for blood (CD34) and lymphatic (D2-40) vessel-specific markers. We found significantly more lymphatic vessels in primary melanomas than in melanoma metastases (p<0.0001). In contrast to the near absence of lymphatic vessels within metastases, we found extensive blood micro-neovascularization. Blood micro-neovascularization was absent in micro metastases (less than 2 mm). A significant inverse correlation between Glut-1 expression (implying local hypoxia) and the presence of microvessels indicates their functional activity as blood vessels (p<0.0001). We suggest that the hypoxic microenvironment in metastases contributes to a phenotype switch allowing melanoma cells to physically contribute to blood vessel formation.
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. daniela.mihic@usz.ch
authors.forename: Daniela
authors.initials: D
authors.lastname: Mihic-Probst
authors.forename: Kristian
authors.initials: K
authors.lastname: Ikenberg
authors.forename: Marianne
authors.initials: M
authors.lastname: Tinguely
authors.forename: Peter
authors.initials: P
authors.lastname: Schraml
authors.forename: Silvia
authors.initials: S
authors.lastname: Behnke
authors.forename: Burkhardt
authors.initials: B
authors.lastname: Seifert
authors.forename: Gianluca
authors.initials: G
authors.lastname: Civenni
authors.forename: Lukas
authors.initials: L
authors.lastname: Sommer
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D014408:Biomarkers, Tumor; D051272:Glucose Transporter Type 1; D009363:Neoplasm Proteins