Distinguishing fibrovascular septa from vasculogenic mimicry patterns
ABSTRACT Molecular analyses indicate that periodic acid-Schiff (PAS)-positive (laminin-rich) patterns in melanomas are generated by invasive tumor cells by vasculogenic mimicry. Some observers, however, consider these patterns to be fibrovascular septa, generated by a stromal host response.
To delineate differences between vasculogenic mimicry patterns and fibrovascular septa in primary uveal melanomas.
Frequency distributions, associations with outcome, and thicknesses of trichrome-positive and PAS-positive looping patterns were determined in 234 primary uveal melanomas. Sequential sections of 13 additional primary uveal melanomas that contained PAS-positive/trichrome-negative looping patterns were stained for type I and type IV collagens, laminin, and fibronectin. Real-time quantitative polymerase chain reaction was performed on RNA from cultured uveal melanoma cells for the expression of COL1A1, COL4A2, and fibronectin.
Trichrome-positive loops were encountered less frequently than PAS-positive loops (10% vs 56%, respectively). Death from metastatic melanoma was strongly associated with PAS-positive (P < .001) but not with trichrome-positive (P = .57) loops. Trichrome-positive loops were significantly thicker than PAS-positive loops (P < .001). The PAS-positive patterns stained positive for laminin, type I and type IV collagens, and fibronectin. Type I collagen was detected within melanoma cells and focally within some PAS-positive patterns. Real-time quantitative polymerase chain reaction revealed 3-fold, 25-fold, and 97-fold increases, respectively, in expression of COL4A2, fibronectin, and COL1A1 by invasive pattern-forming primary melanoma cells compared with poorly invasive non-pattern-forming cells.
Fibrovascular septa are rare and prognostically insignificant in uveal melanomas, whereas vasculogenic mimicry patterns are associated with increased mortality. Type I collagen, seen focally in some vasculogenic mimicry patterns, may be synthesized by tumor cells, independent of a host stromal response.
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ABSTRACT: Pancreatic cancer is a highly aggressive malignancy with poor prognosis because of the late disease stage at diagnosis. A comprehensive analysis of DNA amplifications was undertaken to identify genes involved in pathogenesis of pancreatic carcinoma which can potentially serve as diagnostic markers and drug targets for this dismal disease. Initially, 26 fresh frozen primary pancreatic carcinomas were profiled by matrix-CGH with a spatial resolution of 2 Mb across the whole genome. Thus, 50 commonly amplified regions (CARs) were identified; they were covered by 1,113 contiguous genomic DNA clones on the newly-developed 1.1k contig chip. High-resolution profiles of 42 fresh frozen primary pancreatic tumors narrowed the 50 CARs down to 55 recurrent amplifications containing 60 minimal CARs (MCARs) and allowed the identification of target genes that might confer a selective advantage on the tumor. Furthermore, transcription profiles of six pancreatic ductal adenocarcinomas were created with the Affymetrix HG-U133 Plus 2.0 platform. The superimposition of genomic and transcription profiles revealed that 280 and 48 of 1474 overexpressed genes were enriched in recurrent amplifications and MCARs, respectively, thus emphasizing the contribution of genomic instability to disease formation. Quantitative RT-PCR verification and functional in vitro characterization led to a set of novel candidate oncogenes comprising CD14, COL1A1, COL5A1, COL6A3, CORO1A, CTSK, DOK5, ECM1, EMILIN1, FPR1, HCK, MMP9, NUSAP1, PLAUR, S100A9, SPON2, SULF2, TSPAN2, TUBA1B and TUBA1C. The results demonstrate a strong influence of tumor cells on the composition of the extracellular matrix and an enhanced reaction to those changes by overexpression of certain surface molecules and downstream associated proteins. Furthermore, also structural and regulatory components of the actin and tubulin cytoskeleton contribute significantly to the increase of migration, invasion and proliferation of tumor cells.
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ABSTRACT: Microarray gene expression profiling is a powerful tool for generating molecular cancer classifications. However, elucidating biological insights from these large data sets has been challenging. Previously, we identified a gene expression-based classification of primary uveal melanomas that accurately predicts metastatic death. Class 1 tumors have a low risk and class 2 tumors a high risk for metastatic death. Here, we used genes that discriminate these tumor classes to identify biological correlates of the aggressive class 2 signature. A search for Gene Ontology categories enriched in our class-discriminating gene list revealed a global down-regulation of neural crest and melanocyte-specific genes and an up-regulation of epithelial genes in class 2 tumors. Correspondingly, class 2 tumors exhibited epithelial features, such as polygonal cell morphology, up-regulation of the epithelial adhesion molecule E-cadherin, colocalization of E-cadherin and beta-catenin to the plasma membrane, and formation of cell-cell adhesions and acinar structures. One of our top class-discriminating genes was the helix-loop-helix inhibitor ID2, which was strongly down-regulated in class 2 tumors. The class 2 phenotype could be recapitulated by eliminating Id2 in cultured class 1 human uveal melanoma cells and in a mouse ocular melanoma model. Id2 seemed to suppress the epithelial-like class 2 phenotype by inhibiting an activator of the E-cadherin promoter. Consequently, Id2 loss triggered up-regulation of E-cadherin, which in turn promoted anchorage-independent cell growth, a likely antecedent to metastasis. These findings reveal new roles for Id2 and E-cadherin in uveal melanoma progression, and they identify potential targets for therapeutic intervention.Cancer Research 06/2006; 66(9):4602-9. DOI:10.1158/0008-5472.CAN-05-4196 · 9.33 Impact Factor
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ABSTRACT: The histological detection of laminin-rich vasculogenic mimicry patterns in human primary uveal melanomas is associated with death from metastases. We therefore hypothesized that highly invasive uveal melanoma cells forming vasculogenic mimicry patterns after exposure to a laminin-rich three-dimensional microenvironment would differentially express genes associated with invasive and metastatic behavior. However, we discovered that genes associated with differentiation (GDF15 and ATF3) and suppression of proliferation (CDKNa1/p21) were up-regulated in highly invasive uveal melanoma cells forming vasculogenic mimicry patterns, and genes associated with promotion of invasive and metastatic behavior such as CD44, CCNE2 (cyclin E2), THBS1 (thrombospondin 1), and CSPG2 (chondroitin sulfate proteoglycan; versican) were down-regulated. After forming vasculogenic mimicry patterns, uveal melanoma cells invaded only short distances, failed to replicate, and changed morphologically from the invasive epithelioid to the indolent spindle A phenotype. In human tissue samples, uveal melanoma cells within vasculogenic mimicry patterns assumed the spindle A morphology, and the expression of Ki67 was significantly reduced in adjacent melanoma cells. Thus, the generation of vasculogenic mimicry patterns is accompanied by dampening of the invasive and metastatic uveal melanoma genotype and phenotype and underscores the plasticity of these cells in response to cues from the microenvironment.American Journal Of Pathology 11/2006; 169(4):1376-89. DOI:10.2353/ajpath.2006.060223 · 4.59 Impact Factor