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(American Journal of Pathology. 2006;169:1376-1389.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060223

Tumor Cell Plasticity in Uveal Melanoma

Microenvironment Directed Dampening of the Invasive and Metastatic Genotype and Phenotype Accompanies the Generation of Vasculogenic Mimicry Patterns

Robert Folberg^*, Zarema Arbieva, Jonas Moses^*, Amin Hayee^*, Tone Sandal^*, ShriHari Kadkol^*, Amy Y. Lin^*, Klara Valyi-Nagy^*, Suman Setty^*, Lu Leach^*, Patricia Chévez-Barrios, Peter Larsen, Dibyen Majumdar^¶, Jacob Pe’er^|| and Andrew J. Maniotis^*

From the Departments of Pathology^* and Mathematics, Statistics, and Computer Science,^¶ and the Core Genomics Facility, University of Illinois at Chicago, Chicago, Illinois; the University of Illinois Cancer Center, Chicago, Illinois; the Department of Pathology, The Methodist Hospital, Houston, Texas; and the Department of Ophthalmology,|| Hadassah Hebrew University Medical Center, Jerusalem, Israel

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.

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