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Journal ArticleDOI

Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE2-Mediated Suppression of Antitumor Immunity.

TL;DR: It is shown that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes HCC development by creating a tumor-promoting microenvironment, and the importance of the gut-liver axis in obesity-associated HCC is shown.
Abstract: Obesity increases the risk of cancers, including hepatocellular carcinomas (HCC). However, the precise molecular mechanisms through which obesity promotes HCC development are still unclear. Recent studies have shown that gut microbiota may influence liver diseases by transferring its metabolites and components. Here, we show that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes HCC development by creating a tumor-promoting microenvironment. LTA enhances the senescence-associated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesity-induced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E2 (PGE2) production suppresses the antitumor immunity through a PTGER4 receptor, thereby contributing to HCC progression. Moreover, COX2 overexpression and excess PGE2 production were detected in HSCs in human HCCs with noncirrhotic, nonalcoholic steatohepatitis (NASH), indicating that a similar mechanism could function in humans.Significance: We showed the importance of the gut-liver axis in obesity-associated HCC. The gut microbiota-driven COX2 pathway produced the lipid mediator PGE2 in senescent HSCs in the tumor microenvironment, which plays a pivotal role in suppressing antitumor immunity, suggesting that PGE2 and its receptor may be novel therapeutic targets for noncirrhotic NASH-associated HCC. Cancer Discov; 7(5); 522-38. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 443.

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522
 | 
CANCER DISCOVERYMay 2017 www.aacrjournals.org
RESEARCH ARTICLE
Gut Microbiota Promotes Obesity-Associated
Liver Cancer through PGE
2
-Mediated
Suppression of Antitumor Immunity
Tze Mun Loo
1
, Fumitaka Kamachi
1
, Yoshihiro Watanabe
1
, Shin Yoshimoto
2,3
, Hiroaki Kanda
4
,
Yuriko Arai
1,2
, Yaeko Nakajima-Takagi
5
, Atsushi Iwama
5
, Tomoaki Koga
6
, Yukihiko Sugimoto
6
,
Takayuki Ozawa
1
, Masaru Nakamura
1
, Miho Kumagai
1
, Koichi Watashi
7,8
, Makoto M. Taketo
9
,
Tomohiro Aoki
10
, Shuh Narumiya
10,11,12
, Masanobu Oshima
12,13
, Makoto Arita
14,15,16,17
,
Eiji Hara
2,12,18
, and Naoko Ohtani
1,16
ABSTRACT
Obesity increases the risk of cancers, including hepatocellular carcinomas (HCC).
However, the precise molecular mechanisms through which obesity promotes HCC
development are still unclear. Recent studies have shown that gut microbiota may influence liver
diseases by transferring its metabolites and components. Here, we show that the hepatic transloca-
tion of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes
HCC development by creating a tumor-promoting microenvironment. LTA enhances the senescence-
associated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesity-
induced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and
COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E
2
(PGE
2
) production
suppresses the antitumor immunity through a PTGER4 receptor, thereby contributing to HCC progres-
sion. Moreover, COX2 overexpression and excess PGE
2
production were detected in HSCs in human
HCCs with noncirrhotic, nonalcoholic steatohepatitis (NASH), indicating that a similar mechanism could
function in humans.
SIGNIFICANCE: We showed the importance of the gut–liver axis in obesity-associated HCC. The gut
microbiota–driven COX2 pathway produced the lipid mediator PGE
2
in senescent HSCs in the tumor
microenvironment, which plays a pivotal role in suppressing antitumor immunity, suggesting that
PGE
2
and its receptor may be novel therapeutic targets for noncirrhotic NASH-associated HCC.
Cancer Discov; 7(5); 522–38. ©2017 AACR.
1
Department of Applied Biological Science, Faculty of Science and Tech-
nology, Tokyo University of Science, Chiba, Japan.
2
Division of Cancer Biol-
ogy, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo,
Japan.
3
LSI Medience Corporation, Tokyo, Japan.
4
Division of Pathology,
Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
5
Department of Cellular and Molecular Medicine, Graduate School of
Medicine, Chiba University, Chiba, Japan.
6
Department of Pharmaceutical
Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto
University, Kumamoto, Japan.
7
Department of Virology II, National Insti-
tute of Infectious Diseases, Tokyo, Japan.
8
CREST, Japan Science and
Technology Agency (JST), Saitama, Japan.
9
Department of Pharmacol-
ogy, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho,
Kyoto, Japan.
10
Center for Innovation in Immunoregulation Technology
and Therapeutics, Kyoto University Graduate School of Medicine, Konoe-
cho Yoshida, Kyoto, Japan.
11
Medical Innovation Center, Kyoto University
Graduate School of Medicine, Kyoto, Japan.
12
AMED-CREST, AMED, Japan
Agency for Medical Research and Development, Tokyo, Japan.
13
Division
of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa,
Japan.
14
Laboratory for Metabolomics, RIKEN Center for Integrative
Medical Sciences, Kanagawa, Japan.
15
Graduate School of Medical Life
Science, Yokohama City University, Kanagawa, Japan.
16
PRESTO, Japan
Science and Technology Agency, Kawaguchi, Saitama, Japan.
17
Division of
Physiological Chemistry and Metabolism, Graduate School of Pharmaceu-
tical Sciences, Keio University, Tokyo, Japan.
18
Department of Molecular
Microbiology, Research Institute for Microbial Diseases, Osaka Univer-
sity, Osaka, Japan.
Note: Supplementary data for this article are available at Cancer Discovery
Online (http://cancerdiscovery.aacrjournals.org/).
Current address for N. Ohtani: Department of Pathophysiology, Osaka City
University, Graduate School of Medicine, Osaka, Japan.
Corresponding Author: Naoko Ohtani, Department of Pathophysiology,
Osaka City University, Graduate School of Medicine, Asahimachi 1-4-3,
Abeno-ku, Osaka, 545-8585, Japan. Phone: 81-6-6645-3710; Fax: 81-6-
6645-3712; E-mail: ohtani.naoko@med.osaka-cu.ac.jp
doi: 10.1158/2159-8290.CD-16-0932
©2017 American Association for Cancer Research.
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May 2017 
CANCER DISCOVERY | 523
INTRODUCTION
Obesity has become a worldwide health problem and is
known to increase the risk of diabetes, cardiovascular disease,
and several types of cancer (1). Although hypernutrition-
related systemic alterations are thought to be involved in
cancer development (2–4), the molecular mechanisms that
integrate these events still remain largely unclear. Among
obesity-associated cancers, liver cancer has been shown to
have a strong relationship with obesity, based on epidemio-
logical studies (1). The most common risk factor for hepato-
cellular carcinoma (HCC) is long-term infection by hepatitis
B virus (HBV) or hepatitis C virus (HCV; ref. 5). However,
obesity-associated nonalcoholic fatty liver disease (NAFLD)
and nonalcoholic steatohepatitis (NASH) have recently
emerged as important risk factors for liver cancer (6). There-
fore, elucidation of the precise molecular mechanisms medi-
ating the development of obesity-induced NASH- associated
HCC is urgently needed.
We previously reported that increased enterohepatic cir-
culation of the obesity-induced Gram-positive gut microbial
metabolite deoxycholic acid (DCA) facilitates HCC develop-
ment by inducing cellular senescence and the senescence-
associated secretory phenotype (SASP) in hepatic stellate cells
(HSC) in the tumor microenvironment. This recently identi-
fied phenotype of senescent cells involves secretion of a series
of inflammatory cytokines, chemokines, matrix-remodeling
factors, and growth factors (7), suggesting that the gut–liver
axis plays a pivotal role in inducing cellular senescence of
HSCs and liver tumorigenesis (4). The importance of the
SASP phenotype has also been recognized in vivo in a variety
of pathophysiologic contexts, giving rise to not only deleteri-
ous effects such as chronic inflammation and tumorigenesis
(4, 8, 9), but also beneficial effects such as embryonal develop-
ment (10, 11), immunosurveillance (12–14), and tissue repair
(15, 16), depending on the biological context. Indeed, the
paracrine effects of SASP have been reported to be dependent
on the surrounding cells (17), particularly on the p53 status
of these cells (18). Accumulating evidence has indicated that
SASP is regulated by a combination of several transcription
factors, epigenetic regulators, and metabolic pathways, in
response to DNA damage (19–23). DCA can create DNA
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Loo et al.
RESEARCH ARTICLE
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CANCER DISCOVERYMay 2017 www.aacrjournals.org
damage by elevating the levels of reactive oxygen species
(ROS), thereby inducing cellular senescence and the SASP
to promote obesity-associated HCC (4). However, the trigger
that initiates the SASP signals may vary depending on physi-
ologic status, and thus the precise mechanisms regulating
the expression of SASP factors need to be elucidated in each
pathophysiologic setting (24).
One of the mechanisms that may trigger the SASP could be
Toll-like receptor (TLR) signaling. High mobility group box
1 (HMGB1) activates TLR4-mediated cytokine signals in an
autocrine manner in senescent cells (25). In addition, previous
in vivo studies have demonstrated that TLR4-mediated inflam-
matory signals induced by the Gram-negative bacterial com-
ponent lipopolysaccharide (LPS) are important for promoting
liver fibrosis and fibrosis-associated liver tumorigenesis (26).
However, in our obesity-associated HCC model, Gram-posi-
tive bacteria, but not Gram-negative bacteria, were found to
be dramatically increased in obese mice fed a high-fat diet
(HFD; ref. 4), consistent with previous reports (27). Moreover,
we did not observe the reduction of obesity-associated liver
tumor formation in TLR4-deficient mice as compared with
those in wild-type mice when we performed the same protocol
of neonatal 7,12-dimethylbenz(a)anthracene (DMBA) treat-
ment with HFD (4), suggesting that TLR4-mediated signals
are unlikely to be involved in the acceleration of obesity-
associated HCC in our experimental setting.
In this study, we investigated the effects of the signals by
lipoteichoic acid (LTA), a cell wall component from Gram-
positive bacteria, on the induction of the SASP factors in
DCA-induced senescent HSCs and on obesity-associated liver
tumor development. We newly identified that a gut micro-
biota–driven COX2 pathway generated the lipid mediator
prostaglandin E
2
(PGE
2
), which functioned as a key SASP
factor in the tumor microenvironment. Our current study
provides important mechanistic insights into the relevance
of the gut–liver axis in obesity-associated liver carcinogenesis.
RESULTS
A Normal Diet Delays Liver
Carcinogenesis Compared with an HFD
We previously reported that neonatal DMBA treatment
in HFD-fed mice resulted in development of HCC within
30 weeks, and demonstrated that DCA, an obesity-associated
gut microbial metabolite, is a critical factor promoting obesity-
associated HCC development (4). To further define the role of
DCA itself, DMBA-treated mice were fed DCA with a normal
diet (ND; Fig. 1A). DCA administration in ND-fed mice did
not induce HCC development at 30 weeks, at which point
HFD-fed mice exhibited HCC with sufficient body-weight gain
(Fig. 1B–D). Senescence markers, such as upregulation of p21
and the DNA damage response marker 53BP1, were detected
in HSCs in the livers of mice fed DCA and an ND, reaching
levels similar to those in the livers of HFD-fed mice at 30 weeks
(Fig. 1E). However, at this time point, the frequency of SASP
induction in HSCs was much lower in livers from mice fed DCA
and an ND as compared with that in mice fed an HFD (Fig. 1E,
IL1
β, Groα, and IL6). We found that mice fed DCA and an ND
required approximately six more months for complete SASP
induction and HCC development at the 55-week time point
(Fig. 1B–E). Therefore, we speculated that other factors underly-
ing the HFD-fed obese liver could be necessary to accelerate the
effects of DCA in aggressively promoting HCC development.
Accordingly, we searched for factors that promote obesity-
associated HCC progression, based on (i) the obesity-induced
gut microbial component(s) and (ii) the increased lipid storage
in the liver tumor areas of HFD-fed obese mice.
LTA- and TLR2-Mediated Signaling Promotes
Obesity-Associated HCC Development
When we reanalyzed the gut microbial profiles of DMBA-
treated mice, we again noted that HFD-fed mice exhibited a
dramatic increase in Gram-positive gut microbiota in their
feces (Supplementary Fig. S1; refs. 4, 27). The gut microbial
overgrowth and increased hepatic translocation of the gut
microbial components and metabolites from the intestine,
the so-called gut–liver axis, are known to play a role in the
pathogenesis of liver disorders (26, 28). We therefore exam-
ined whether LTA, a major cell wall component in Gram-
positive bacteria, accumulated in the livers of DMBA-treated
and HFD-fed mice. We found relatively high amounts of
LTA accumulation in the areas of the liver tumors (Fig.
2A). Because LTA is a major ligand of the innate immu-
nity receptor TLR2, we next investigated the involvement
of TLR2-mediated signaling in liver tumor development.
Interestingly, both the numbers and sizes of HFD-induced
liver tumors were strikingly reduced in TLR2-deficient mice,
although body weights were not different between the two
groups (Fig. 2B–E). Accordingly, in livers from TLR2-defi-
cient mice, the expression of SASP factors, such as IL1
β,
Gro
α, and IL6, was significantly reduced in HSCs, suggest-
ing that TLR2-mediated signaling induced the expression of
SASP factors (Fig. 2F). Notably, however, the presence of p21
and 53BP1 foci was still observed in activated HSCs from
TLR2-deficient mice (Fig. 2F). The majority of senescent
signals are detected in the HSCs but not in HCC cells in the
tumor region (Supplementary Fig. S2). Taken together, these
results suggest that TLR2-mediated signaling is important
for the upregulation of SASP factors in senescent HSCs but
not for the induction of senescent cell-cycle arrest.
Figure 1.  DCA administration with ND induced a long delay in liver carcinogenesis as compared with HFD. A, Timeline of the experimental procedure
(ND, n = 3; ND + DCA 30 weeks, n = 3; ND + DCA 55 weeks, n = 5; HFD, n = 15). Eut, euthanasia. B, The average body weight of each group at the indicated
age. Data, means ± SD. **, P < 0.01. D, DMBA-treated. C, The average liver tumor numbers and the relative size distribution (classified as >6 mm, 2 mm–6
mm, 2 mm). **, P < 0.01. D, Macroscopic photograph of livers of male wild-type mice kept with ND (left), with ND and DCA 30 weeks (the second from
left), with ND and DCA 55 weeks (the second from right), with HFD (right) for 30 weeks after the administration of DMBA. The arrowheads indicate HCCs.
E, Immunofluorescence analysis of liver section. HSCs were visualized by α-smooth muscle actin staining (α-SMA; green) and the cell nuclei were stained
by 4,6-diamidino-2-phenylindole (DAPI; blue). Arrowheads indicate α-SMA expressing cells that were positive for indicated markers (red). The histograms
indicate the percentages of α-SMA expressing cells that were positive for indicated markers. Data of three to four individual mice in each group are
represented as means ± SD. More than 100 cells in total were counted for statistical analysis. Data, means ± SD. *, P < 0.05; **, P < 0.01.
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Gut Microbiota Promotes Obesity-Linked HCC via Immune Escape
RESEARCH ARTICLE
May 2017 
CANCER DISCOVERY | 525
α
0
35
70
0
40
80
0
30
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0
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0
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0
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0
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2–6 mm
ӌ
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Eut
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1 cm
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ND HFD
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+
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(30 w)
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(30 w)
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DCA+ (55 w)
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Loo et al.
RESEARCH ARTICLE
526
 | 
CANCER DISCOVERYMay 2017 www.aacrjournals.org
Figure 2.  LTA and TLR2-mediated signaling promote obesity-associated HCC development. A, Immunohistochemical staining of LTA (red), α-SMA
(green), and DAPI (blue) in 30-week-old male mouse liver sections. Scale bars, 50 µm. Data, means ± SD. **, P < 0.01. B, Timeline of the experimental pro-
cedure [wild-type (WT) ND, n = 23; WT HFD, n = 15; Tlr2
−/−
, n = 12]. Eut, euthanasia; D, DMBA-treated. C, The average body weight of each group at the age
of 30 weeks. Data, means ± SD. **, P < 0.01. D, DMBA-treated. D, The average liver tumor numbers and the relative size distribution (classified as >6 mm,
2 mm–6 mm, 2 mm). **, P < 0.01. E, Representative macroscopic photographs of liver. Arrowheads indicate HCCs. F, Immunofluorescence analysis of liver
section. HSCs were visualized by α-smooth muscle actin staining (α-SMA; green) and the cell nuclei were stained by DAPI. Arrowheads indicate α-SMA
expressing cells that were positive for indicated markers (red). The histograms indicate the percentages of α-SMA expressing cells that were positive
for indicated markers. Scale bars, 25 µm. Data of three to four individual mice in each group are represented as means ± SD. More than 100 cells in total
were counted for statistical analysis. Data, means ± SD. NS, not significant; **, P < 0.01.
C
F
D
WT
WT
Tlr 2
/
D-HFDD-ND
Body weight (g)
**
NS
A
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030
Weeks
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-
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Nontumor
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TL;DR: It is shown that the relative proportion of Bacteroidetes is decreased in obese people by comparison with lean people, and that this proportion increases with weight loss on two types of low-calorie diet.
Abstract: Two groups of beneficial bacteria are dominant in the human gut, the Bacteroidetes and the Firmicutes. Here we show that the relative proportion of Bacteroidetes is decreased in obese people by comparison with lean people, and that this proportion increases with weight loss on two types of low-calorie diet. Our findings indicate that obesity has a microbial component, which might have potential therapeutic implications.

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Additional excerpts

  • ...4), consistent with previous reports (27)....

    [...]

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"Gut Microbiota Promotes Obesity-Ass..." refers background in this paper

  • ...Obesity has become a worldwide health problem and is known to increase the risk of diabetes, cardiovascular disease, and several types of cancer (1)....

    [...]

  • ...Among obesity-associated cancers, liver cancer has been shown to have a strong relationship with obesity, based on epidemiological studies (1)....

    [...]

Journal ArticleDOI
TL;DR: The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks.
Abstract: Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and fuel inflammation associated with aging and cancer progression. Thus, cellular senescence might participate in four complex biological processes (tumor suppression, tumor promotion, aging, and tissue repair), some of which have apparently opposing effects. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks.

1,723 citations


"Gut Microbiota Promotes Obesity-Ass..." refers background in this paper

  • ...This recently identified phenotype of senescent cells involves secretion of a series of inflammatory cytokines, chemokines, matrix-remodeling factors, and growth factors (7), suggesting that the gut–liver axis plays a pivotal role in inducing cellular senescence of HSCs and liver tumorigenesis (4)....

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Journal ArticleDOI
04 Jul 2013-Nature
TL;DR: It is shown that senescence-associated secretory phenotype (SASP) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice, and a similar pathway may contribute to at least certain aspects of obesity- associated HCC development in humans as well.
Abstract: Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer. As the worldwide obesity epidemic has shown no signs of abating, better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer, the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs), which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer or depleted of senescent HSCs, indicating that the DCA-SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis, indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.

1,593 citations


"Gut Microbiota Promotes Obesity-Ass..." refers background in this paper

  • ...This recently identified phenotype of senescent cells involves secretion of a series of inflammatory cytokines, chemokines, matrix-remodeling factors, and growth factors (7), suggesting that the gut–liver axis plays a pivotal role in inducing cellular senescence of HSCs and liver tumorigenesis (4)....

    [...]

  • ...We previously demonstrated that our mouse model developed histologically less fibrotic and lipid-accumulated HCCs, representing a potent novel animal model for human noncirrhotic NASH-associated HCCs (4)....

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  • ...We previously found that the histology of HFD-induced HCC in our mouse model is less fibrotic and that this mouse model could be used as an animal model for noncirrhotic NASH-associated HCC in humans (4)....

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  • ...Moreover, we did not observe the reduction of obesity-associated liver tumor formation in TLR4-deficient mice as compared with those in wild-type mice when we performed the same protocol of neonatal 7,12-dimethylbenz(a)anthracene (DMBA) treatment with HFD (4), suggesting that TLR4-mediated signals are unlikely to be involved in the acceleration of obesityassociated HCC in our experimental setting....

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  • ...org damage by elevating the levels of reactive oxygen species (ROS), thereby inducing cellular senescence and the SASP to promote obesity-associated HCC (4)....

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Journal ArticleDOI
03 Apr 2015-Science
TL;DR: Evidence is reviewed that stromal cells of the tumor microenvironment mediate this restriction by excluding T cells from the vicinity of cancer cells, and overcoming this T cell checkpoint may enable optimal immunotherapy.
Abstract: Effective immunotherapy promotes the killing of cancer cells by cytotoxic T cells. This requires not only that cancer-specific T cells be generated, but also that these T cells physically contact cancer cells. The coexistence in some patients of cancer cells and T cells that recognize them indicates that tumors may exhibit the phenomenon of immune privilege, in which immunogenic tissue is protected from immune attack. Here, we review the evidence that stromal cells of the tumor microenvironment mediate this restriction by excluding T cells from the vicinity of cancer cells. Overcoming this T cell checkpoint may thus enable optimal immunotherapy.

1,583 citations


"Gut Microbiota Promotes Obesity-Ass..." refers background in this paper

  • ...The PD-1 blockade can recover the functions of effector T cells, and an anti–PD-1 antibody is now being clinically used for the treatment of various cancers (48, 49)....

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