TY - JOUR
T1 - Tumor cell plasticity in uveal melanoma
T2 - Microenvironment directed dampening of the invasive and metastatic genotype and phenotype accompanies the generation of vasculogenic mimicry patterns
AU - Folberg, Robert
AU - Arbieva, Zarema
AU - Moses, Jonas
AU - Hayee, Amin
AU - Sandal, Tone
AU - Kadkol, Shri Hari
AU - Lin, Amy Y.
AU - Valyi-Nagy, Klara
AU - Setty, Suman
AU - Leach, Lu
AU - Chévez-Barrios, Patricia
AU - Larsen, Peter
AU - Majumdar, Dibyen
AU - Pe'er, Jacob
AU - Maniotis, Andrew J.
N1 - Funding Information:
Supported by the National Institutes of Health (grant EY10457 ).
PY - 2006/10
Y1 - 2006/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34247105188&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34247105188&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2006.060223
DO - 10.2353/ajpath.2006.060223
M3 - Article
C2 - 17003493
AN - SCOPUS:34247105188
SN - 0002-9440
VL - 169
SP - 1376
EP - 1389
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -