Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Regulation of Spontaneous Intestinal Tumorigenesis Through the Adaptor Protein MyD88
Seth Rakoff-Nahoum, and
Ruslan Medzhitov*
Abstract:
Inflammation is increasingly recognized as an important componentof tumorigenesis, although the mechanisms and pathways involvedare not well understood. Tumor development is regulated by productsof several modifier genes, but instructions for their tumor-specificexpression are currently unknown. We show that the signalingthrough the adaptor protein MyD88 has a critical role in spontaneoustumor development in mice with heterozygous mutation in theadenomatous polyposis coli (APC) gene. We found that MyD88-dependentsignaling controls the expression of several key modifier genesof intestinal tumorigenesis and has a critical role in bothspontaneous and carcinogen-induced tumor development. This studythus reveals the important role of an innate immune signalingpathway in intestinal tumorigenesis.
Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
* To whom correspondence should be addressed. E-mail: ruslan.medzhitov{at}yale.edu
The editors suggest the following Related Resources on Science sites:
In Science Magazine
PERSPECTIVES
Toby Lawrence, Thorsten Hageman, and Frances Balkwill (6 July 2007) Science317 (5834), 51.
[DOI: 10.1126/science.1146052] |Summary »|Full Text »|PDF »
In Science Signaling
EDITORS' CHOICE
L. Bryan Ray (10 July 2007) Sci. STKE2007 (394), tw246.
[DOI: 10.1126/stke.3942007tw246] |Abstract »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
ASC-associated inflammation promotes cecal tumorigenesis in aryl hydrocarbon receptor-deficient mice.
T. Ikuta, Y. Kobayashi, M. Kitazawa, K. Shiizaki, N. Itano, T. Noda, S. Pettersson, L. Poellinger, Y. Fujii-Kuriyama, S. Taniguchi, et al. (2013)
Carcinogenesis
|Abstract »|Full Text »|PDF »
Inhibitory role of Gas6 in intestinal tumorigenesis.
R. Akitake-Kawano, H. Seno, M. Nakatsuji, Y. Kimura, Y. Nakanishi, T. Yoshioka, K. Kanda, M. Kawada, K. Kawada, Y. Sakai, et al. (2013)
Carcinogenesis
|Abstract »|Full Text »|PDF »
MyD88: A Critical Adaptor Protein in Innate Immunity Signal Transduction.
N. Warner and G. Nunez (2013)
J. Immunol.
190, 3-4
|Full Text »|PDF »
Resveratrol inhibits LPS-induced epithelial-mesenchymal transition in mouse melanoma model.
M.-C. Chen, W.-W. Chang, Y.-D. Kuan, S.-T. Lin, H.-C. Hsu, and C.-H. Lee (2012)
Innate Immunity
18, 685-693
|Abstract »|Full Text »|PDF »
MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells.
A. Ochi, A. H. Nguyen, A. S. Bedrosian, H. M. Mushlin, S. Zarbakhsh, R. Barilla, C. P. Zambirinis, N. C. Fallon, A. Rehman, Y. Pylayeva-Gupta, et al. (2012)
J. Exp. Med.
209, 1671-1687
|Abstract »|Full Text »|PDF »
Interactions Between the Microbiota and the Immune System.
L. V. Hooper, D. R. Littman, and A. J. Macpherson (2012)
Science
336, 1268-1273
|Abstract »|Full Text »|PDF »
Microbiota, Disease, and Back to Health: A Metastable Journey.
R. Blumberg and F. Powrie (2012)
Science Translational Medicine
4, 137rv7
|Full Text »|PDF »
Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCMin/+ mice.
Y. Li, P. Kundu, S. W. Seow, C. T. de Matos, L. Aronsson, K. C. Chin, K. Karre, S. Pettersson, and G. Greicius (2012)
Carcinogenesis
33, 1231-1238
|Abstract »|Full Text »|PDF »
Tpl2 ablation promotes intestinal inflammation and tumorigenesis in Apcmin mice by inhibiting IL-10 secretion and regulatory T-cell generation.
O. B. Serebrennikova, C. Tsatsanis, C. Mao, E. Gounaris, W. Ren, L. D. Siracusa, A. G. Eliopoulos, K. Khazaie, and P. N. Tsichlis (2012)
PNAS
109, E1082-E1091
|Abstract »|Full Text »|PDF »
H. Shime, M. Matsumoto, H. Oshiumi, S. Tanaka, A. Nakane, Y. Iwakura, H. Tahara, N. Inoue, and T. Seya (2012)
PNAS
109, 2066-2071
|Abstract »|Full Text »|PDF »
IRF-4 Suppresses BCR/ABL Transformation of Myeloid Cells in a DNA Binding-independent Manner.
Interleukin 21 controls tumour growth and tumour immunosurveillance in colitis-associated tumorigenesis in mice.
D. Jauch, M. Martin, G. Schiechl, R. Kesselring, H. J. Schlitt, E. K. Geissler, and S. Fichtner-Feigl (2011)
Gut
60, 1678-1686
|Abstract »|Full Text »|PDF »
Evolution of the TIR Domain-Containing Adaptors in Humans: Swinging between Constraint and Adaptation.
S. Fornarino, G. Laval, L. B. Barreiro, J. Manry, E. Vasseur, and L. Quintana-Murci (2011)
Mol. Biol. Evol.
28, 3087-3097
|Abstract »|Full Text »|PDF »
Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis.
A. C. Goodwin, C. E. D. Shields, S. Wu, D. L. Huso, X. Wu, T. R. Murray-Stewart, A. Hacker-Prietz, S. Rabizadeh, P. M. Woster, C. L. Sears, et al. (2011)
PNAS
108, 15354-15359
|Abstract »|Full Text »|PDF »
The Role of Intermediary Domain of MyD88 in Cell Activation and Therapeutic Inhibition of TLRs.
Regulation of colon cancer cell proliferation and migration by MD-2 activity.
V. Grondin, P. Seksik, S. Dumont, G. Thomas, G. Trugnan, J. F. Flejou, J. Masliah, D. Wendum, and M. Bachelet (2011)
Innate Immunity
17, 414-422
|Abstract »|PDF »
Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury.
S. Normand, A. Delanoye-Crespin, A. Bressenot, L. Huot, T. Grandjean, L. Peyrin-Biroulet, Y. Lemoine, D. Hot, and M. Chamaillard (2011)
PNAS
108, 9601-9606
|Abstract »|Full Text »|PDF »
Cancer Immunoediting: Integrating Immunity's Roles in Cancer Suppression and Promotion.
Epithelial cell proliferation in the developing zebrafish intestine is regulated by the Wnt pathway and microbial signaling via Myd88.
S. E. Cheesman, J. T. Neal, E. Mittge, B. M. Seredick, and K. Guillemin (2011)
PNAS
108, 4570-4577
|Abstract »|Full Text »|PDF »
Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4.
B. Hu, E. Elinav, S. Huber, C. J. Booth, T. Strowig, C. Jin, S. C. Eisenbarth, and R. A. Flavell (2010)
PNAS
107, 21635-21640
|Abstract »|Full Text »|PDF »
A. Mencin, J. Kluwe, and R. F. Schwabe (2010)
Gut
59, 1448-1449
|Full Text »|PDF »
An apple oligogalactan prevents against inflammation and carcinogenesis by targeting LPS/TLR4/NF-{kappa}B pathway in a mouse model of colitis-associated colon cancer.
L. Liu, Y. H. Li, Y. B. Niu, Y. Sun, Z. J. Guo, Q. Li, C. Li, J. Feng, S. S. Cao, and Q. B. Mei (2010)
Carcinogenesis
31, 1822-1832
|Abstract »|Full Text »|PDF »
Dual Roles for Immunity in Gastrointestinal Cancers.
MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18.
R. Salcedo, A. Worschech, M. Cardone, Y. Jones, Z. Gyulai, R.-M. Dai, E. Wang, W. Ma, D. Haines, C. O'hUigin, et al. (2010)
J. Exp. Med.
207, 1625-1636
|Abstract »|Full Text »|PDF »
An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer.
E. M. Michalak, C. J. Vandenberg, A. R. D. Delbridge, L. Wu, C. L. Scott, J. M. Adams, and A. Strasser (2010)
Genes & Dev.
24, 1608-1613
|Abstract »|Full Text »|PDF »
Persistent Cyclooxygenase-2 Inhibition Downregulates NF-{kappa}B, Resulting in Chronic Intestinal Inflammation in the Min/+ Mouse Model of Colon Tumorigenesis.
A. M. Carothers, J. S. Davids, B. C. Damas, and M. M. Bertagnolli (2010)
Cancer Res.
70, 4433-4442
|Abstract »|Full Text »|PDF »
The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer.
I. C. Allen, E. M. TeKippe, R.-M. T. Woodford, J. M. Uronis, E. K. Holl, A. B. Rogers, H. H. Herfarth, C. Jobin, and J. P.- Y. Ting (2010)
J. Exp. Med.
207, 1045-1056
|Abstract »|Full Text »|PDF »
Toll-like Receptor 3-Mediated Suppression of TRAMP Prostate Cancer Shows the Critical Role of Type I Interferons in Tumor Immune Surveillance.
A. I. Chin, A. K. Miyahira, A. Covarrubias, J. Teague, B. Guo, P. W. Dempsey, and G. Cheng (2010)
Cancer Res.
70, 2595-2603
|Abstract »|Full Text »|PDF »
Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis.
W.-J. Chae, T. F. Gibson, D. Zelterman, L. Hao, O. Henegariu, and A. L. M. Bothwell (2010)
PNAS
107, 5540-5544
|Abstract »|Full Text »|PDF »
Remote Control of Intestinal Tumorigenesis by Innate Immunity.
T. Secher, O. Gaillot, B. Ryffel, and M. Chamaillard (2010)
Cancer Res.
70, 1749-1752
|Abstract »|Full Text »|PDF »
The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6.
S. Vetrano, E. M. Borroni, A. Sarukhan, B. Savino, R. Bonecchi, C. Correale, V. Arena, M. Fantini, M. Roncalli, A. Malesci, et al. (2010)
Gut
59, 197-206
|Abstract »|Full Text »|PDF »
Nuclear Factor-{kappa}B and Tumor-Associated Macrophages.
Mechanism for Maintaining Homeostasis in the Immune System of the Intestine.
Y. TANIGUCHI, N. YOSHIOKA, K. NAKATA, T. NISHIZAWA, H. INAGAWA, C. KOHCHI, and G.-I. SOMA (2009)
Anticancer Res
29, 4855-4860
|Abstract »|Full Text »|PDF »
MAIL Regulates Human Monocyte IL-6 Production.
S. Seshadri, Y. Kannan, S. Mitra, J. Parker-Barnes, and M. D. Wewers (2009)
J. Immunol.
183, 5358-5368
|Abstract »|Full Text »|PDF »
Phospholipase C{varepsilon} promotes intestinal tumorigenesis of ApcMin/+ mice through augmentation of inflammation and angiogenesis.
M. Li, H. Edamatsu, R. Kitazawa, S. Kitazawa, and T. Kataoka (2009)
Carcinogenesis
30, 1424-1432
|Abstract »|Full Text »|PDF »
Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.
F. Colotta, P. Allavena, A. Sica, C. Garlanda, and A. Mantovani (2009)
Carcinogenesis
30, 1073-1081
|Abstract »|Full Text »|PDF »
Milk fat globule epidermal growth factor-8 blockade triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms.
M. Jinushi, M. Sato, A. Kanamoto, A. Itoh, S. Nagai, S. Koyasu, G. Dranoff, and H. Tahara (2009)
J. Exp. Med.
206, 1317-1326
|Abstract »|Full Text »|PDF »
Haploinsufficiency of Kruppel-Like Factor 5 Rescues the Tumor-Initiating Effect of the ApcMin Mutation in the Intestine.
B. B. McConnell, A. B. Bialkowska, M. O. Nandan, A. M. Ghaleb, F. J. Gordon, and V. W. Yang (2009)
Cancer Res.
69, 4125-4133
|Abstract »|Full Text »|PDF »
Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface.
S. Vaishnava, C. L. Behrendt, A. S. Ismail, L. Eckmann, and L. V. Hooper (2008)
PNAS
105, 20858-20863
|Abstract »|Full Text »|PDF »
The Innate Immune Receptor Nod1 Protects the Intestine from Inflammation-Induced Tumorigenesis.
G. Y. Chen, M. H. Shaw, G. Redondo, and G. Nunez (2008)
Cancer Res.
68, 10060-10067
|Abstract »|Full Text »|PDF »
Interleukin (IL) 1{beta} Induction of IL-6 Is Mediated by a Novel Phosphatidylinositol 3-Kinase-dependent AKT/I{kappa}B Kinase {alpha} Pathway Targeting Activator Protein-1.
