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Preexisting senescent fibroblasts in the aged bladder create a tumor-permissive niche through CXCL12 secretion
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Preexisting senescent fibroblasts in the aged bladder create a tumor-permissive niche through CXCL12 secretion
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Journal Article
Preexisting senescent fibroblasts in the aged bladder create a tumor-permissive niche through CXCL12 secretion
2024
Overview
Aging is a major risk factor for cancer, but the precise mechanism by which aging promotes carcinogenesis remains largely unknown. Here, using genetically modified mouse models, we show that p16
high
senescent (p16
h
-sn) fibroblasts accumulate with age, constitute inflammatory cancer-associated fibroblasts (CAFs) and promote tumor growth in bladder cancer models. Single-cell RNA sequencing of fibroblasts from aged mice revealed higher expression of the C–X–C motif chemokine 12 gene (
Cxcl12
) in p16
h
-sn fibroblasts than in p16
low
fibroblasts. Elimination of p16
h
-sn cells or inhibition of CXCL12 signaling notebly suppressed bladder tumor growth in vivo. We identified high expression levels of
SMOC2
,
GUCY1A1
(
GUCY1A3
),
CXCL12
,
CRISPLD2
,
GAS1
and
LUM
as a signature of p16
h
-sn CAFs in humans and mice, which was associated with age and poor prognosis in patients with advanced and nonadvanced bladder cancer. Here we show that p16
h
-sn fibroblasts in the aged bladder create a cancer-permissive niche and promote tumor growth by secreting CXCL12.
Meguro et al. show an accumulation of p16
high
senescent fibroblasts in the aging bladder that serves as a cancer-permissive niche and promotes tumor growth by secreting CXCL12. Inhibition of senescence or CXCL12 signaling suppresses bladder tumor growth.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Aging
/ Animals
/ Biomedical and Life Sciences
/ Cancer-Associated Fibroblasts - metabolism
/ Cancer-Associated Fibroblasts - pathology
/ Chemokine CXCL12 - metabolism
/ Cyclin-Dependent Kinase Inhibitor p16 - genetics
/ Cyclin-Dependent Kinase Inhibitor p16 - metabolism
/ Female
/ Humans
/ Male
/ Mice
/ Urinary Bladder - metabolism
/ Urinary Bladder Neoplasms - genetics
