Tumor cell plasticity in uveal melanoma: microenvironment directed dampening of the invasive and metastatic genotype and phenotype accompanies the generation of vasculogenic mimicry patterns.
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.
Folberg
Robert
R
Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., 110 CSN (MC 847), Chicago, IL 60612, USA. rfolberg@uic.edu
Arbieva
Zarema
Z
Moses
Jonas
J
Hayee
Amin
A
Sandal
Tone
T
Kadkol
Shrihari
S
Lin
Amy Y
AY
Valyi-Nagy
Klara
K
Setty
Suman
S
Leach
Lu
L
Chévez-Barrios
Patricia
P
Larsen
Peter
P
Majumdar
Dibyen
D
Pe'er
Jacob
J
Maniotis
Andrew J
AJ
D014408:Biomarkers, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis / Q000235:genetics; D008545:Melanoma / Q000098:blood supply / Q000235:genetics* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D014407:Tumor Cells, Cultured; D014604:Uveal Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology*
D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen