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Cancer Research 67, 6017, July 1, 2007. doi: 10.1158/0008-5472.CAN-07-0560
© 2007 American Association for Cancer Research
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Increased Susceptibility to Colitis-Associated Cancer of Mice Lacking TIR8, an Inhibitory Member of the Interleukin-1 Receptor Family

Cecilia Garlanda1, Federica Riva2, Tania Veliz1, Nadia Polentarutti1, Fabio Pasqualini1, Enrico Radaelli2, Marina Sironi1, Manuela Nebuloni3, Elisabetta Omodeo Zorini3, Eugenio Scanziani2 and Alberto Mantovani1,4

1 Istituto Clinico Humanitas (IRCCS), Rozzano, Italy; 2 Department of Animal Pathology, Faculty of Veterinary Medicine, 3 Pathology Unit, "L. Sacco" Department of Clinical Sciences, and 4 Institute of General Pathology, Faculty of Medicine, University of Milan, Milan, Italy

Requests for reprints: Alberto Mantovani, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Italy. Phone: 39-2-8224-2444; Fax: 39-2-8224-5101; E-mail: alberto.mantovani{at}humanitas.it.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
TIR8 (also known as SIGIRR) is a member of the interleukin-1/Toll-like receptor family with inhibitory activity on inflammatory reactions and high expression in intestinal mucosa. Here, we report that Tir8-deficient mice exhibited a dramatic intestinal inflammation in response to dextran sulfate sodium salt (DSS) administration in terms of weight loss, intestinal bleeding, and mortality and showed increased susceptibility to carcinogenesis in response to azoxymethane and DSS. Increased susceptibility to colitis-associated cancer was associated to increased permeability and local production of prostaglandin E2, proinflammatory cytokines, and chemokines. Thus, these results are consistent with the hypothesis that TIR8, by negatively regulating intestinal inflammation, plays a nonredundant role in the control of the protumor activity of chronic inflammation in the gut. [Cancer Res 2007;67(13):6017–21]


   Introduction
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 Abstract
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Materials and Methods
 Results
 Discussion
 References
 
Several lines of evidence, based on epidemiologic studies as well as animal models, are consistent with the view that chronic local inflammation plays an important role in malignant progression (1–3). The inflammatory environment of tumors is characterized by the presence of mediators and cells that act as tumor promoters (1). Soluble mediators such as cytokines, chemokines, enzymes, and growth factors are released by tumor cells and stromal cells and are responsible of leukocyte recruitment in the tumor environment, survival, and differentiation. Leukocytes infiltrating the stroma, in particular tumor-associated macrophages, promote tumor proliferation and progression, stroma deposition and remodeling, and angiogenesis and inhibit effective antitumor T-cell–dependent immunity (1, 4). A pivotal role in these pathophysiologic processes is played by the transcription factor nuclear factor {kappa}B (NF-{kappa}B), which has dual functions in promoting tumor growth. NF-{kappa}B activated in inflammatory cells in response to microbial stimuli, inflammatory cytokines, and danger signals released by necrotic cells regulates the production of cytokines, chemokines, and growth and angiogenic factors; in tumor cells, activation of NF-{kappa}B leads to the production of cell cycle genes, antiapoptotic genes, and invasive proteases (5–7).

The activation of the signaling cascade leading to NF-{kappa}B activation by interleukin-1 receptors (IL-1R) and Toll-like receptors (TLR) is tightly regulated at different levels, extracellularly and intracellularly, and more than 20 pathways of negative regulation of IL-1R/TLR signaling have been described (8, 9).

The IL-1R family member TIR8 (also known as single immunoglobulin IL-1R-related molecule, SIGIRR), an orphan receptor, inhibits signaling from the IL-1R/TLR complexes, possibly by trapping IRAK-1 and TRAF-6 (8, 10). TIR8 is characterized by the presence of a single immunoglobulin domain in its extracellular region, a conserved TIR domain, and a 95-amino-acid long tail with inhibitory properties (11, 12). TIR8 is expressed in several tissues, especially in the digestive tract, and cell-type expression is particularly high in epithelial cells (12, 13). Accordingly, there is evidence for a nonredundant regulatory role of this molecule in inflammation involving the gastrointestinal mucosa (13).

Colitis-associated cancer is a colorectal disease that arises in patients suffering from chronic inflammatory bowel disease, in particular ulcerative colitis (14). In mice, colitis-associated cancer can be induced by injection of the procarcinogen azoxymethane, followed by three cycles of exposure to dextran sodium sulfate (DSS; ref. 15), which causes chronic inflammation, mimicking inflammatory bowel disease.

Given the regulatory role of TIR8 in the intestinal tract, it was important to assess its potential involvement in colitis-associated cancer. Here, we report that Tir8 deficiency resulted in increased susceptibility to colitis-associated cancer, which was associated to higher local production of proinflammatory cytokines and chemokines. These results strongly support the hypothesis that TIR8 plays a nonredundant, tuning role in gastrointestinal inflammation–associated cancer and underline its potential as target for cancer prevention and therapy.


   Materials and Methods
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 Materials and Methods
Results
 Discussion
 References
 
Animals. Tir8-deficient (Tir8–/–) mice were generated as described (13). Mice used were 8 to 12 weeks old on a mixed (C57BL/6J x 129/Sv) or inbred (backcrossed for 11 generations with C57BL/6J) background. Littermates of Tir8–/– mice or C57BL/6J obtained from Charles River Laboratories were used as wild-type controls (Tir8+/+). Mice were housed in the specific pathogen-free animal facility of the Istituto Clinico Humanitas in individually ventilated cage systems. Procedures involving animals and their care conformed with institutional guidelines in compliance with national (4D.L. N.116, G.U., suppl. 40, 18-2-1992) and international (EEC Council Directive 86/609, OJ L 358,1,12-12-1987; NIH Guide for the Care and Use of Laboratory Animals, U.S. National Research Council 1996) laws and policies. All efforts were made to minimize the number of animals used and their suffering.

Azoxymethane/DSS–induced colon cancer. To induce colon tumors, mice were treated, as described (15), with a single dose (10 mg/kg) of the mutagenic agent azoxymethane (Sigma) followed by three cycles of 3%, 2%, or 1.5% DSS (molecular mass, 40 kDa; ICN) dissolved in sterile, distilled drinking water, resulting in a 60-day experimental period. At the end of treatment, mice were sacrificed for histologic analysis of the intestine. For cytokine production analysis, animals were sacrificed at the end of the first DSS cycle. The determination of clinical scores was done as described (13).

Histologic analysis. The large intestine was removed, rolled up, fixed in 10% neutral buffered formalin, and embedded in paraffin. H&E-stained serial tissue sections were used for pathologic evaluation in a blinded fashion by a pathologist (E.S.). Proliferative and neoplastic lesions were classified as gastrointestinal intraepithelial neoplasia, low-grade and high-grade adenoma, or adenocarcinoma. The area of each proliferative lesion was determined with an image analysis software (Win Roof, version 3.6, Mitani).

Immunohistologic analysis. Eight-micrometer-thick consecutive frozen sections were cut and mounted on Superfrost slides (Bio-Optica). Immunohistochemistry was done with the following antibodies: biotinylated anti-CD68 monoclonal antibody (mAb; clone FA-11, HyCult Biotechnology), rabbit anti-human/mouse CD3 polyclonal antibody (DakoCytomation), rat anti-mouse/rat FoxP3 mAb (clone FJK-16s, eBioscience), and rat anti-mouse CD8 mAb (BD Biosciences PharMingen). Secondary antibodies used were Envision+ System-horseradish peroxidase (HRP)–labeled polymer (antirabbit; DakoCytomation), biotinylated antirat immunoglobulin G (Vector Laboratories), and ZyMax streptavidin-HRP conjugate (Zymed). The chromogen was 3,3'-diaminobenzidine–free base. A quantitative evaluation of immunostaining was applied using WinRec Programme (Image Pro Plus) by counting immunopositive cells per field at x20 magnification.

Whole colon organ culture and colon tissue lysate. Colon segments (100–200 mg of tissue) were washed in cold PBS supplemented with penicillin and streptomycin and either homogenized in PBS containing protease inhibitors cocktail Complete (Roche Diagnostic) and stored at –80°C or cultured in 24-well flat-bottomed culture plates in RPMI 1640 with 0.1% FCS. After incubation at 37°C for 24 h, supernatants were centrifuged at 13,000 rpm at 4°C for 5 min and stored at –80°C until analyzed.

ELISA. Murine cytokines and chemokines (IL-6, tumor necrosis factor {alpha}, IL-1ß, IL-10, IFN{gamma}, KC/CXC, JE/CCL2, and MIP1{alpha}/CCL3) were measured in whole colon culture supernatants and colon tissue lysates by ELISA (R&D DuoSet ELISA Development Systems). The sandwich ELISA for PTX3 was done with the anti-murine PTX3 mAbs 2C3 and 6B11. Prostaglandin E2 (PGE2) was measured by enzyme immunoassay (Cayman Chemical Company). Levels were standardized to the content of total protein by quantification by bicinchoninic acid analysis (Pierce) and presented as nanograms or picograms of cytokine per milligram of protein.

Evaluation of colonic epithelial permeability. Colonic epithelial permeability was assessed by the penetrance of Evans blue (Sigma) from the lumen into the wall of colon on day 7 after administration of 2% DSS as described (16).

Statistical analysis. Six to 15 animals per experimental group were used throughout the study. Data are expressed as mean ± SE or SD and one-tailed or two-tailed Student's t test was used as specified. P ≤ 0.05 was considered significant. Experiments were repeated two to five times.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Deletion of Tir8 does not perturb normal gastrointestinal development, morphology, or function in nonchallenged mice. Analysis of body weight, intestinal histology in terms of morphology and number of lymphoid follicles at different time points (2, 6, 10, and 12 months of age), and cytokine and chemokine production at the intestinal level in untreated mice did not reveal differences between Tir8–/– and Tir8+/+ mice on both genetic backgrounds examined (C57BL/6 and C57BL/6x129/Sv; data not shown). These results suggest that, under homeostatic conditions in the absence of epithelial barrier erosion, Tir8 deficiency is not sufficient to result in spontaneous intestinal inflammation triggered by endogenous intestinal flora.

To assess the role of TIR8 in colitis-associated cancer, the protocol of a single azoxymethane injection followed by three cycles of DSS for 7 days and normal drinking water for 14 days was applied. Mice treated only with azoxymethane did not develop tumors during the observation period, suggesting that in the absence of induced inflammation, Tir8 deficiency per se does not increase susceptibility to cancer development.

As shown in Fig. 1 , the protocol of colitis-associated cancer resulted in dramatic susceptibility to colon inflammation in Tir8–/– mice compared with Tir8+/+ mice, with high rate of mortality associated to intestinal bleeding and weight loss, in particular in mice on C57BL/6 background, a more susceptible strain to DSS-induced colitis than 129/Sv. In C57BL/6 Tir8–/– mice fed with 3% or 2% to 1.5% DSS, mortality was 100% in 10 days or 80% at the end of the experimental period, respectively, compared with 30% or 14% in Tir8+/+ mice (Fig. 1A). In Tir8–/– mice treated with 2% to 1.5% DSS, the body weight loss was 26.5% at day 10 and 11% at day 50, compared with 7.8% and +3%, respectively, in Tir8+/+ mice (P < 0.001 and P < 0.05 at the two time points; Fig. 1B). Bleeding scores were more severe in Tir8–/– mice throughout the period analyzed (Fig. 1C). In mice on a mixed background fed with 3% DSS, mortality was 33% in Tir8–/– mice and 20% in wild-type littermates at the end of the experimental period, and the clinical scores, in terms of body weight loss and in particular of intestinal bleeding, were less severe (data not shown).


Figure 1
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  		Figure 1. Increased acute and chronic intestinal inflammation in the absence of Tir8. A, mortality of mice on C57BL/6 background fed with DSS as indicated by the bottom bars (3% for three cycles or with 2% the first cycle and 1.5% for the following two). N = 10 for the 3% DSS protocol and N = 15 for the 2% to 1.5% protocol. Percentage of weight loss (B) and bleeding score (C) in C57BL/6 mice fed with 2% to 1.5% DSS. **, P < 0.001; *, P < 0.05. D, colonic epithelial permeability to Evans blue expressed as absorbance at 620 nm per gram of colon tissue in basal conditions and on day 7 after administration of 2% DSS.

 
The permeability to Evans blue albumin was used as an index of colon epithelial permeability. Colonic epithelial permeability to Evans blue was significantly increased in Tir8–/– DSS-fed mice compared with Tir8+/+ mice (P = 0.001; Fig. 1D).

As shown in Fig. 2A , which reports results obtained in mice on a mixed background fed with 3% DSS at the end of the 60-day experimental period, the deficiency of Tir8 significantly increased the incidence of tumors (P = 0.007). When the severity of lesions was examined, a significant difference was also observed in the number of gastrointestinal intraepithelial neoplasia (P = 0.01) and of low-grade adenomas (P = 0.04), but not of high-grade adenomas (P = 0.3). Although there was no difference in incidence, high-grade adenomas tended to be bigger in Tir8–/– mice (2.67 ± 0.8 versus 1.72 ± 0.28 mm2). Given the high susceptibility of C57BL/6 mice to DSS-induced colitis, a modified protocol was used (2% in the first cycle and 1.5% in the following two cycles or 1.5% for three cycles) with increased incidence of lesions, mostly low-grade adenomas in Tir8–/– mice (P = 0.01; data not shown).


Figure 2
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  		Figure 2. Increased colon carcinogenesis in the absence of Tir8. A, number of total proliferative lesions per animal in C57BL/6x129Sv mice at the end of the treatment with azoxymethane and three cycles of 3% DSS and number of lesions divided according to severity in gastrointestinal intraepithelial neoplasia (GIN) and low-grade (Low) and high-grade (High) adenomas. N = 6 Tir8–/– and 9 Tir8+/+. B, sub-gross examination of H&E-stained sections reveals the presence of high-grade (asterisk) and low-grade (circle) adenomas projecting into the lumen concentrated along the rectal mucosa in a Tir8+/+ mouse and the presence of numerous high-grade adenomas and a single low-grade adenoma almost completely obliterating the rectal lumen in a Tir8–/– mouse. C, microscopic aspect of a low-grade adenoma in Tir8+/+ mice and of a high-grade adenoma in Tir8–/– mice (H&E, x200). D, microscopic aspect of a healing ulcer characterized by mild inflammatory changes in Tir8+/+ and an active ulcer characterized by a severe suppurative process in Tir8–/– (H&E, x100).

 
Similarly to ulcerative lesions, most of the proliferative lesions were in the distal colon and rectum, projecting into the lumen, and eventually almost completely obliterating the rectal lumen (Fig. 2B–D).

To address the mechanisms underlying increased susceptibility to inflammation and colon cancer in Tir8-deficient mice, NF-{kappa}B–regulated genes encoding proinflammatory factors involved in colon inflammation and tumor growth were measured by ELISA in lysates and supernatants of colon segments collected from mice at the end of the first DSS cycle. As shown in Table 1 , increased levels of IL-1ß, IL-6, transforming growth factor ß (TGFß), and of chemokines JE/CCL2, KC/CXC, and MIP1{alpha}/CCL3 were observed in colon homogenates from Tir8–/– mice compared with wild-type littermates. Similar results were obtained when supernatants from colon specimens were considered (22 ± 4 and 38 ± 5 ng/mg KC/CXC in Tir8+/+ and Tir8–/– mice, respectively). In addition, IL-10 and PGE2 levels were higher in Tir8–/– supernatants (P = 0.01). Interestingly, a significant decrease of IFN{gamma} in Tir8–/– supernatant was observed (4.2 ± 4.2 versus 25 ± 7 pg/mg in controls; P = 0.01).


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  		Table 1. Inflammatory mediators in colon lysates from DSS-fed mice (N = 8)

 
Finally, tumors arising in Tir8–/– mice were investigated in terms of leukocyte infiltration (Fig. 3 ). The leukocyte infiltrate of Tir8–/– tumors was characterized by a more prominent infiltration of CD68+ cells (P = 0.01) and, intriguingly, of FoxP3+ regulatory T cells (P = 0.01; Fig. 3A and B). The percentages of FoxP3+ cells over CD3+ cells were 54% and 85% in Tir8+/+ and Tir8–/– tumors, respectively, whereas the percentages of CD8+ cells over CD3+ cells were 28% and 8% in Tir8+/+ and Tir8–/– tumors.


Figure 3
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  		Figure 3. Leukocyte infiltration in Tir8+/+ and Tir8–/– tumors. A, immunostaining for CD68+ (magnification, x20), CD3+ (x20), FoxP3+ (x40), and CD8+ (x20) cells. B, number of cells per field infiltrating Tir8+/+ and Tir8–/– tumors of similar dimension and severity. Columns, mean from the whole tumor areas, corresponding to 8 to 24 fields and 18 to 30 fields at x20 magnification, from three Tir8+/+ and 2 Tir8–/– mice, respectively; bars, SE. Unpaired two-tailed Student's t test.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Colon carcinoma represents a paradigm for the connection between inflammation and cancer (6). The present study was designed to explore the regulatory role of TIR8, an inhibitory member of the IL-1/TLR family, on intestinal carcinogenesis. Results obtained confirm and extend previous observations on the increased susceptibility to intestinal inflammation of Tir8-deficient mice. Moreover, Tir8-deficient mice showed increased susceptibility to carcinogenesis in response to azoxymethane and DSS.

Activation of NF-{kappa}B has been reported in epithelial cells and macrophages from inflammatory bowel disease patients as well as in colon cancers, and anti-inflammatory therapy with inhibitors of cyclooxygenases and NF-{kappa}B signaling pathway reduces the risk of colitis-associated cancer (1, 6). TIR8 acts in vitro and in vivo as a negative regulator of NF-{kappa}B activation in response to TLR and IL-1R agonists (10, 13). In the present study, Tir8-deficient mice showed increased production of prostaglandins, inflammatory cytokines (e.g., IL-1 and IL-6), and chemokines (KC/CXC, JE/CCL2, and MIP1{alpha}/CCL3) downstream of NF-{kappa}B. These have been shown to promote inflammation-propelled neoplasia, in particular in the gastrointestinal tract (6, 15). For instance, chemokines produced by tumor cells and by recruited leukocytes influence the extent and phenotype of leukocyte infiltrate, tumor cell and endothelial cell growth and migration, and, finally, are involved in recruiting polarized T helper 2 cells and T regulatory cells (17). In particular, CXC chemokines mediate angiogenesis downstream of prostaglandins in colon cancer (18, 19).

A predominant T helper 2 inflammatory response has been implicated in colon cancer and IFN{gamma} deficiency increased the frequency of colonic neoplasms (20). The low levels of IFN{gamma} observed in Tir8–/– colons could be indicative of a T helper 2 polarized environment. Higher levels of IL-10 and TGFß, associated to higher FoxP3+ regulatory T-cell infiltrate in the tumors of Tir8-deficient mice, possibly reflect the development of an immunosuppressive response inhibiting effective antitumor T-cell–dependent immunity (17).

The results presented here show that TIR8 acts as a negative regulator of intestinal inflammation and inflammation-promoted carcinogenesis in mice. It will be important to assess whether polymorphisms at the TIR8 locus impinge on human colon cancer and whether TIR8 can be a target for pharmacologic intervention.


   Acknowledgments
 
Grant support: Sixth Research Framework Programme of the European Union (Projects NoE MUGEN LSHB-CT-2005-005203 and INNOCHEM), Ministero dell'Istruzione, Università e della Ricerca (project FIRB and "Piano Nazionale Ricerche-Biotecnologie Avanzate, tema 2"), Fondazione CARIPLO (project Nobel), and the Italian Association for Cancer Research.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank M. Necci and M. Tironi for photographic editing, S. Vetrano for technical assistance, and S. Danese for helpful discussions.


   Footnotes
 
Note: C. Garlanda, F. Riva, and T. Veliz contributed equally to this study.

Received 2/ 9/07. Revised 3/13/07. Accepted 4/ 5/07.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 2005;7:211–7.[CrossRef][Medline]
  2. Karin M, Lawrence T, Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 2006;124:823–35.[CrossRef][Medline]
  3. de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 2006;6:24–37.[CrossRef][Medline]
  4. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004;4:71–8.[CrossRef][Medline]
  5. Greten FR, Eckmann L, Greten TF, et al. IKKß links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004;118:285–96.[CrossRef][Medline]
  6. Karin M. Nuclear factor-{kappa}B in cancer development and progression. Nature 2006;441:431–6.[CrossRef][Medline]
  7. Pikarsky E, Porat RM, Stein I, et al. NF-{kappa}B functions as a tumour promoter in inflammation-associated cancer. Nature 2004;431:461–6.[CrossRef][Medline]
  8. Mantovani A, Locati M, Polentarutti N, Vecchi A, Garlanda C. Extracellular and intracellular decoys in the tuning of inflammatory cytokines and Toll-like receptors: the new entry TIR8/SIGIRR. J Leukoc Biol 2004;75:738–42.[Abstract/Free Full Text]
  9. Liew FY, Xu D, Brint EK, O'Neill LA. Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 2005;5:446–58.[CrossRef][Medline]
  10. Wald D, Qin J, Zhao Z, et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 2003;4:920–7.[CrossRef][Medline]
  11. Thomassen E, Renshaw BR, Sims JE. Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily. Cytokine 1999;11:389–99.[CrossRef][Medline]
  12. Polentarutti N, Rol GP, Muzio M, et al. Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR. Eur Cytokine Netw 2003;14:211–8.[Medline]
  13. Garlanda C, Riva F, Polentarutti N, et al. Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc Natl Acad Sci U S A 2004;101:3522–6.[Abstract/Free Full Text]
  14. Ekbom A. Risk of cancer in ulcerative colitis. J Gastrointest Surg 1998;2:312–3.[CrossRef][Medline]
  15. Becker C, Fantini MC, Schramm C, et al. TGF-ß suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 2004;21:491–501.[CrossRef][Medline]
  16. Sasaki M, Bharwani S, Jordan P, et al. The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin reduces disease activity and inflammation in dextran-sulfate induced colitis. J Pharmacol Exp Ther 2003;305:78–85.[Abstract/Free Full Text]
  17. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942–9.[CrossRef][Medline]
  18. Mizukami Y, Jo WS, Duerr EM, et al. Induction of interleukin-8 preserves the angiogenic response in HIF-1{alpha}-deficient colon cancer cells. Nat Med 2005;11:992–7.[Medline]
  19. Wang D, Wang H, Brown J, et al. CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer. J Exp Med 2006;203:941–51.[Abstract/Free Full Text]
  20. Osawa E, Nakajima A, Fujisawa T, et al. Predominant T helper type 2-inflammatory responses promote murine colon cancers. Int J Cancer 2006;118:2232–6.[CrossRef][Medline]



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