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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Exp+Med
2016 ; 213
(5
): 827-40
Nephropedia Template TP
gab.com Text
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Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of
myeloid derived suppressor cells in cancer
#MMPMID27045006
D'Amico L
; Mahajan S
; Capietto AH
; Yang Z
; Zamani A
; Ricci B
; Bumpass DB
; Meyer M
; Su X
; Wang-Gillam A
; Weilbaecher K
; Stewart SA
; DeNardo DG
; Faccio R
J Exp Med
2016[May]; 213
(5
): 827-40
PMID27045006
show ga
Tumor-stroma interactions contribute to tumorigenesis. Tumor cells can educate
the stroma at primary and distant sites to facilitate the recruitment of
heterogeneous populations of immature myeloid cells, known as myeloid-derived
suppressor cells (MDSCs). MDSCs suppress T cell responses and promote tumor
proliferation. One outstanding question is how the local and distant stroma
modulate MDSCs during tumor progression. Down-regulation of ?-catenin is critical
for MDSC accumulation and immune suppressive functions in mice and humans. Here,
we demonstrate that stroma-derived Dickkopf-1 (Dkk1) targets ?-catenin in MDSCs,
thus exerting immune suppressive effects during tumor progression. Mice bearing
extraskeletal tumors show significantly elevated levels of Dkk1 in bone
microenvironment relative to tumor site. Strikingly, Dkk1 neutralization
decreases tumor growth and MDSC numbers by rescuing ?-catenin in these cells and
restores T cell recruitment at the tumor site. Recombinant Dkk1 suppresses
?-catenin target genes in MDSCs from mice and humans and anti-Dkk1 loses its
antitumor effects in mice lacking ?-catenin in myeloid cells or after depletion
of MDSCs, demonstrating that Dkk1 directly targets MDSCs. Furthermore, we find a
correlation between CD15(+) myeloid cells and Dkk1 in pancreatic cancer patients.
We establish a novel immunomodulatory role for Dkk1 in regulating tumor-induced
immune suppression via targeting ?-catenin in MDSCs.
|Animals
[MESH]
|Humans
[MESH]
|Intercellular Signaling Peptides and Proteins/immunology/*pharmacology
[MESH]
free
free
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