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, Shri Hari Kadkol, Amy Y. Lin, Klara Valyi-Nagy, Suman Setty, Lu Leach, Patricia Chévez-Barrios, Peter Larsen, Dibyen Majumdar, Jacob Pe'er, Andrew J. Maniotis

Research output: Contribution to journalArticle

54 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1376-1389
Number of pages14
JournalAmerican Journal of Pathology
Volume169
Issue number4
DOIs
StatePublished - Oct 2006

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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