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2013 ; 73
(12
): 3649-60
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Targeting ROR1 inhibits epithelial-mesenchymal transition and metastasis
#MMPMID23771907
Cui B
; Zhang S
; Chen L
; Yu J
; Widhopf GF 2nd
; Fecteau JF
; Rassenti LZ
; Kipps TJ
Cancer Res
2013[Jun]; 73
(12
): 3649-60
PMID23771907
show ga
Metastasis is responsible for 90% of cancer-related deaths. Strategies are needed
that can inhibit the capacity of cancer cells to migrate across the anatomic
barriers and colonize distant organs. Here, we show an association between
metastasis and expression of a type I receptor tyrosine kinase-like orphan
receptor, ROR1, which is expressed during embryogenesis and by various cancers,
but not by normal postpartum tissues. We found that expression of ROR1 associates
with the epithelial-mesenchymal transition (EMT), which occurs during
embryogenesis and cancer metastasis. Breast adenocarcinomas expressing high
levels of ROR1 were more likely to have gene expression signatures associated
with EMT and had higher rates of relapse and metastasis than breast
adenocarcinomas expressing low levels of ROR1. Suppressing expression of ROR1 in
metastasis-prone breast cancer cell lines, MDA-MB-231, HS-578T, or BT549,
attenuated expression of proteins associated with EMT (e.g., vimentin, SNAIL-1/2,
and ZEB1), enhanced expression of E-cadherin, epithelial cytokeratins (e.g.,
CK-19), and tight junction proteins (e.g., ZO-1), and impaired their
migration/invasion capacity in vitro and the metastatic potential of MDA-MB-231
cells in immunodeficient mice. Conversely, transfection of MCF-7 cells to express
ROR1 reduced expression of E-cadherin and CK-19, but enhanced the expression of
SNAIL-1/2 and vimentin. Treatment of MDA-MB-231 with a monoclonal antibody
specific for ROR1 induced downmodulation of vimentin and inhibited cancer cell
migration and invasion in vitro and tumor metastasis in vivo. Collectively, this
study indicates that ROR1 may regulate EMT and metastasis and that antibodies
targeting ROR1 can inhibit cancer progression and metastasis.
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