Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18-Mediated Inflammation-Independent Mechanism.

Abstract:

:Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-κB activation and reduced expression of mature IL18, but not IL1β, in gastric tumors. Genetic ablation of IL18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL1β and IL1α activity upon genetic ablation of the IL1 receptor had no effect. The specific protumorigenic role for IL18 was associated with high IL18 gene expression in the gastric tumor epithelium compared with IL1β, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL18, we found it to be highly secreted from human gastric cancer cell lines. Moreover, IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human gastric cancer cells. In clinical specimens of human gastric cancer tumors, we observed a significant positive correlation between elevated mature IL18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL18 signaling axis as a candidate therapeutic target in gastric cancer.Significance: Inflammasome activation that elevates IL18 helps drive gastric cancer by protecting cancer cells against apoptosis, with potential implications for new therapeutic strategies in this setting. Cancer Res; 78(5); 1293-307. ©2017 AACR.

journal_name

Cancer Res

journal_title

Cancer research

authors

Deswaerte V,Nguyen P,West A,Browning AF,Yu L,Ruwanpura SM,Balic J,Livis T,Girard C,Preaudet A,Oshima H,Fung KY,Tye H,Najdovska M,Ernst M,Oshima M,Gabay C,Putoczki T,Jenkins BJ

doi

10.1158/0008-5472.CAN-17-1887

subject

Has Abstract

pub_date

2018-03-01 00:00:00

pages

1293-1307

issue

5

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-17-1887

journal_volume

78

pub_type

杂志文章
  • Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes.

    abstract::Pancreatic adenocarcinomas are among the most malignant forms of cancer and, therefore, it is of especial interest to set new strategies aimed at improving the prognostic of this deadly disease. The present study was undertaken to investigate the action of cannabinoids, a new family of potential antitumoral agents, in...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-06-0169

    authors: Carracedo A,Gironella M,Lorente M,Garcia S,Guzmán M,Velasco G,Iovanna JL

    更新日期:2006-07-01 00:00:00

  • iNOS Regulates the Therapeutic Response of Pancreatic Cancer Cells to Radiotherapy.

    abstract::Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to radiotherapy, chemotherapy, or a combination of these modalities, and surgery remains the only curative intervention for localized disease. Although cancer-associated fibroblasts (CAF) are abundant in PDAC tumors, the effects of radiotherapy on CAFs and th...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-19-2991

    authors: Pereira PMR,Edwards KJ,Mandleywala K,Carter LM,Escorcia FE,Campesato LF,Cornejo M,Abma L,Mohsen AA,Iacobuzio-Donahue CA,Merghoub T,Lewis JS

    更新日期:2020-04-15 00:00:00

  • The HSP90 inhibitor ganetespib synergizes with the MET kinase inhibitor crizotinib in both crizotinib-sensitive and -resistant MET-driven tumor models.

    abstract::The proto-oncogene MET is aberrantly activated via overexpression or mutation in numerous cancers, making it a prime anticancer molecular target. However, the clinical success of MET-directed tyrosine kinase inhibitors (TKI) has been limited due, in part, to mutations in the MET kinase domain that confer therapeutic r...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-13-1156

    authors: Miyajima N,Tsutsumi S,Sourbier C,Beebe K,Mollapour M,Rivas C,Yoshida S,Trepel JB,Huang Y,Tatokoro M,Shinohara N,Nonomura K,Neckers L

    更新日期:2013-12-01 00:00:00

  • Analysis of prolactin and growth hormone production in hyperplastic and neoplastic rat pituitary tissues by the hemolytic plaque assay.

    abstract::The reverse hemolytic plaque assay (RHPA) was used to detect hormone release from cultured normal, hyperplastic, and neoplastic rat pituitary cells. Hyperplastic pituitary cells were produced by s.c. diethylstilbestrol (DES) treatment (10 mg in Silastic tubes) for 3, 6, and 9 weeks. Neoplastic pituitary cells from rat...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Lloyd RV,Coleman K,Fields K,Nath V

    更新日期:1987-02-15 00:00:00

  • Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer.

    abstract::Microsatellite instability (MSI) is a hallmark of mismatch repair (MMR) deficiency. High levels of MSI at mononucleotide and dinucleotide repeats in colorectal cancer (CRC) are attributed to inactivation of the MMR genes, hMLH1 and hMSH2. CRC with low levels of MSI (MSI-L) exists; however, its molecular basis is uncle...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-08-0002

    authors: Haugen AC,Goel A,Yamada K,Marra G,Nguyen TP,Nagasaka T,Kanazawa S,Koike J,Kikuchi Y,Zhong X,Arita M,Shibuya K,Oshimura M,Hemmi H,Boland CR,Koi M

    更新日期:2008-10-15 00:00:00

  • Phase I-II study of epirubicin in multiple myeloma.

    abstract::Forty patients with relapsed (26) or refractory (14) myeloma were treated with epirubicin of doses of 75, 90, 105, and 120 mg/m2 in groups of 6 or more patients to test for response, maximum tolerated dose, and toxicity. Thirteen patients had received prior doxorubicin and were included in the dose findings part of th...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Case DC Jr,Ervin TJ,Gams R,Sonneborn HL,Paul SD,Oldham FB

    更新日期:1988-11-01 00:00:00

  • Plant-derived human papillomavirus 16 E7 oncoprotein induces immune response and specific tumor protection.

    abstract::Vaccine strategies for treatment of human papillomavirus-induced cervical cancer are based on either the recombinant E7 fusion oncoprotein or E7 CTL peptides. The therapeutic potential of the E7-based vaccine depends on the use of different adjuvants. In this study, we describe for the first time the expression of the...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Franconi R,Di Bonito P,Dibello F,Accardi L,Muller A,Cirilli A,Simeone P,Donà MG,Venuti A,Giorgi C

    更新日期:2002-07-01 00:00:00

  • Overexpression of the tumor suppressor gene phosphatase and tensin homologue partially inhibits wnt-1-induced mammary tumorigenesis.

    abstract::The tumor suppressor phosphatase and tensin homologue (PTEN) is involved in cell proliferation, adhesion, and apoptosis. PTEN overexpression in mammary epithelium leads to reduced cell number and impaired differentiation and secretion. In contrast, overexpression of the proto-oncogene Wnt-1 in mammary epithelium leads...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-05-0181

    authors: Zhao H,Cui Y,Dupont J,Sun H,Hennighausen L,Yakar S

    更新日期:2005-08-01 00:00:00

  • Protein tyrosine phosphatase Shp2 (Ptpn11) plays an important role in maintenance of chromosome stability.

    abstract::Both activating and inactivating mutations in protein tyrosine phosphatase Ptpn11 (encoding Shp2) are associated with tumorigenesis. However, the underlying mechanisms remain unclear. Here, we show that Shp2 plays an important role in mitosis, dysregulation of which results in chromosome instability and cancer predisp...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-12-1495

    authors: Liu X,Zheng H,Qu CK

    更新日期:2012-10-15 00:00:00

  • Genetic variants on chromosome 15q25 associated with lung cancer risk in Chinese populations.

    abstract::Recent three genome-wide association studies have mapped a lung cancer susceptibility locus to chromosome 15q25 in Caucasians. However, the reported risk single nucleotide polymorphisms (SNPs) are extremely rare in Asians, arguing against any of these being causative variants. This study sought to identify other varia...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-09-0081

    authors: Wu C,Hu Z,Yu D,Huang L,Jin G,Liang J,Guo H,Tan W,Zhang M,Qian J,Lu D,Wu T,Lin D,Shen H

    更新日期:2009-06-15 00:00:00

  • Increased prevalence of K-ras oncogene mutations in lung adenocarcinoma.

    abstract::Reported estimates of ras mutation prevalence in lung adenocarcinoma of 15-24% may be underestimates because of the insensitivity of the assays used. We have devised a rapid, non-radioactive assay for ras mutations, which detects 1 mutant allele/10(3) normal alleles and have used it to study DNA isolated from 53 lung ...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Mills NE,Fishman CL,Rom WN,Dubin N,Jacobson DR

    更新日期:1995-04-01 00:00:00

  • Correlation of aromatic hydroxylation of 11 beta-substituted estrogens with morphological transformation in vitro but not with in vivo tumor induction by these hormones.

    abstract::In estrogen-induced cancer, catechol formation from administered steroids has been postulated to be a necessary event for estrogen activation and subsequent damage to cellular macromolecules. In the present study, this hypothesis has been tested using two homologous series of structurally related estrogens: estradiol,...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Liehr JG,Purdy RH,Baran JS,Nutting EF,Colton F,Randerath E,Randerath K

    更新日期:1987-05-15 00:00:00

  • Novel chemical enhancers of heat shock increase thermal radiosensitization through a mitotic catastrophe pathway.

    abstract::Radiation therapy combined with adjuvant hyperthermia has the potential to provide outstanding local-regional control for refractory disease. However, achieving therapeutic thermal dose can be problematic. In the current investigation, we used a chemistry-driven approach with the goal of designing and synthesizing nov...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-06-3212

    authors: Sekhar KR,Sonar VN,Muthusamy V,Sasi S,Laszlo A,Sawani J,Horikoshi N,Higashikubo R,Bristow RG,Borrelli MJ,Crooks PA,Lepock JR,Roti Roti JL,Freeman ML

    更新日期:2007-01-15 00:00:00

  • A Biophysical Model Uncovers the Size Distribution of Migrating Cell Clusters across Cancer Types.

    abstract::Migration from the primary tumor is a crucial step in the metastatic cascade. Cells with various degrees of adhesion and motility migrate and are launched into the bloodstream as single circulating tumor cells (CTC) or multicellular CTC clusters. The frequency and size distributions of these clusters have been recentl...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-19-1726

    authors: Bocci F,Kumar Jolly M,Onuchic JN

    更新日期:2019-11-01 00:00:00

  • Discoidin domain receptor 1 receptor tyrosine kinase induces cyclooxygenase-2 and promotes chemoresistance through nuclear factor-kappaB pathway activation.

    abstract::Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by various types of collagens and is known to play a role in cell attachment, migration, survival, and proliferation. However, little is known about the molecular mechanism(s) underlying the role of DDR1 in cancer. We report here that DDR1 indu...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-06-1215

    authors: Das S,Ongusaha PP,Yang YS,Park JM,Aaronson SA,Lee SW

    更新日期:2006-08-15 00:00:00

  • Expression of LeY and extended LeY blood group-related antigens in human malignant, premalignant, and nonmalignant colonic tissues.

    abstract::The LeY determinant, a difucosylated type 2 blood group-related antigen, is a positional isomer of the Leb blood group antigen and a fucosylated derivative of the LeX antigen. The LeX antigen behaves like an oncodevelopmental tumor-associated antigen in human colon cancer, and extended polyfucosyl LeX antigens are mor...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Kim YS,Yuan M,Itzkowitz SH,Sun QB,Kaizu T,Palekar A,Trump BF,Hakomori S

    更新日期:1986-11-01 00:00:00

  • Chromosome analysis of hepatocellular carcinoma 7777 and correlation with alpha-fetoprotein production.

    abstract::The Morris hepatocellular carcinoma 7777 is productive of extraordinarily high levels of the oncofetal protein, alpha-fetoprotein. Its chromosome composition was examined in detail since it represents the only near-diploid tumor of such productivity and has been reported to demonstrate a single unusual chromosomal alt...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Wolman SR,Cohen TI,Becker FF

    更新日期:1977-08-01 00:00:00

  • Progesterone receptor in non-small cell lung cancer--a potent prognostic factor and possible target for endocrine therapy.

    abstract::A possible involvement of gender-dependent factors has been postulated in development of human non-small-cell lung cancers (NSCLC), but its details remain unclear. In this study, we examined biological significance of progesterone receptor in NSCLCs. Progesterone receptor immunoreactivity was detected in 106 of 228 NS...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-04-3087

    authors: Ishibashi H,Suzuki T,Suzuki S,Niikawa H,Lu L,Miki Y,Moriya T,Hayashi S,Handa M,Kondo T,Sasano H

    更新日期:2005-07-15 00:00:00

  • Nerve growth factor stimulation of mouse embryonal carcinoma cell migration.

    abstract::Embryonal carcinoma cells localize to a specific array of target tissues including the male submaxillary gland following intracardiac injection. These target tissues or conditioned medium derived from them have been shown to stimulate the in vitro migration of embryonal carcinoma cells. Here we show that in vitro migr...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Kahan BW,Kramp DC

    更新日期:1987-12-01 00:00:00

  • CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer.

    abstract::Radiotherapy is used to treat many types of cancer, but many treated patients relapse with local tumor recurrence. Tumor-infiltrating myeloid cells (TIM), including CD11b (ITGAM)(+)F4/80 (EMR1)+ tumor-associated macrophages (TAM), and CD11b(+)Gr-1 (LY6G)+ myeloid-derived suppressor cells (MDSC), respond to cancer-rela...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-12-3981

    authors: Xu J,Escamilla J,Mok S,David J,Priceman S,West B,Bollag G,McBride W,Wu L

    更新日期:2013-05-01 00:00:00

  • Purification of an anemia-inducing factor from human placenta and its application to diagnosis of malignant neoplasms.

    abstract::An anemia-inducing substance was isolated from the human placenta and designated placental anemia-inducing factor (PAIF). An amount of 2.8 mg was purified from about 70 total placentas (total wet weight, 42 kg). PAIF caused hemolysis of human erythrocytes in vitro and reduced the number of erythrocytes in rabbits to 8...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Oh-Uti K,Inoue S,Minato S

    更新日期:1980-05-01 00:00:00

  • K-sam-related gene, N-sam, encodes fibroblast growth factor receptor and is expressed in T-lymphocytic tumors.

    abstract::We recently reported the isolation of the K-sam complementary DNA (cDNA), which was amplified preferentially in poorly differentiated types of stomach cancer and codes for one of the heparin-binding growth factor or fibroblast growth factor (FGF) receptor families. The K-sam-related gene, N-sam (NCC-IT-cell-derived sa...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Hattori Y,Odagiri H,Katoh O,Sakamoto H,Morita T,Shimotohno K,Tobinai K,Sugimura T,Terada M

    更新日期:1992-06-15 00:00:00

  • Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer.

    abstract::In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patie...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-11-0367

    authors: Labidi-Galy SI,Sisirak V,Meeus P,Gobert M,Treilleux I,Bajard A,Combes JD,Faget J,Mithieux F,Cassignol A,Tredan O,Durand I,Ménétrier-Caux C,Caux C,Blay JY,Ray-Coquard I,Bendriss-Vermare N

    更新日期:2011-08-15 00:00:00

  • A placental growth factor variant unable to recognize vascular endothelial growth factor (VEGF) receptor-1 inhibits VEGF-dependent tumor angiogenesis via heterodimerization.

    abstract::Angiogenesis is one of the crucial events for cancer development and growth. Two members of the vascular endothelial growth factor (VEGF) family, VEGF-A and placental growth factor (PlGF), which are able to heterodimerize if coexpressed in the same cell, are both required for pathologic angiogenesis. We have generated...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-09-2609

    authors: Tarallo V,Vesci L,Capasso O,Esposito MT,Riccioni T,Pastore L,Orlandi A,Pisano C,De Falco S

    更新日期:2010-03-01 00:00:00

  • Serum level of interleukin 6 as a prognosis factor in metastatic renal cell carcinoma.

    abstract::Interleukin (IL) 6 was measured in the serum of 138 patients with metastatic renal carcinoma before the initiation of IL-2 treatment. IL-6 was detectable in 66 patients with renal cancer (48%) and in only 8 of 70 normal adults (11%). Serum C reactive protein (CRP) and IL-6 levels are correlated, suggesting that IL-6 i...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Blay JY,Negrier S,Combaret V,Attali S,Goillot E,Merrouche Y,Mercatello A,Ravault A,Tourani JM,Moskovtchenko JF

    更新日期:1992-06-15 00:00:00

  • Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence.

    abstract::Prostate cancer biology varies from locally confined tumors with low risk for relapse to tumors with high risk for progression even after radical prostatectomy. Currently, there are no reliable biomarkers to predict tumor relapse and poor clinical outcome. In this study, we correlated expression patterns of the androg...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:10.1158/0008-5472.CAN-06-1570

    authors: Kahl P,Gullotti L,Heukamp LC,Wolf S,Friedrichs N,Vorreuther R,Solleder G,Bastian PJ,Ellinger J,Metzger E,Schüle R,Buettner R

    更新日期:2006-12-01 00:00:00

  • Effect of liposome composition and other factors on the targeting of liposomes to experimental tumors: biodistribution and imaging studies.

    abstract::We have examined the distribution of radiolabeled liposomes in tumor-bearing mice after i.v. injection. Two mouse tumors (B16 melanoma, J6456 lymphoma) and a human tumor (LS174T colon carcinoma) inoculated i.m., s.c., or in the hind footpad were used in these studies. When various liposome compositions with a mean ves...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Gabizon A,Price DC,Huberty J,Bresalier RS,Papahadjopoulos D

    更新日期:1990-10-01 00:00:00

  • Estrogen-induced potentiation of DNA damage and cytotoxicity in human breast cancer cells treated with topoisomerase II-interactive antitumor drugs.

    abstract::Hormone stimulation of responsive neoplasms is a potential strategy for improving the target selectivity of cancer chemotherapy. Using an alkaline DNA-unwinding technique to detect drug-induced DNA strand breakage, we have shown that estrogen stimulation of T-47D human breast cancer cells enhances induction of DNA cle...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Epstein RJ,Smith PJ

    更新日期:1988-01-15 00:00:00

  • A CD44 survival pathway triggers chemoresistance via lyn kinase and phosphoinositide 3-kinase/Akt in colon carcinoma cells.

    abstract::A major obstacle to successful treatment of colorectal cancer is chemotherapy resistance. Enhanced expression of variant CD44 isoforms has been associated with aggressive tumor behavior, prompting the question of whether signaling from this receptor might modulate drug sensitivity. Activation of variant CD44 in colon ...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Bates RC,Edwards NS,Burns GF,Fisher DE

    更新日期:2001-07-01 00:00:00

  • Cholesterol-induced growth stimulation, cell aggregation, and membrane properties of ascites tumor cells in culture.

    abstract::Ascites tumor cells can be cultivated at a reduced serum concentration if cholesterol (2.50 mg per 100 ml of medium) is added to the culture medium. At serum concentrations of 3%, optimal growth properties are obtained; below 3%, cell cultures usually perish after a few days. Cells grown in the presence of added chole...

    journal_title:Cancer research

    pub_type: 杂志文章

    doi:

    authors: Haeffner EW,Hoffmann CJ,Stoehr M,Scherf H

    更新日期:1984-06-01 00:00:00