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[Cancer Research 62, 6362-6366, November 15, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

Elimination of Colon Cancer in Germ-free Transforming Growth Factor Beta 1-deficient Mice1

Sandra J. Engle, Ilona Ormsby, Sharon Pawlowski, Gregory P. Boivin, Joanne Croft, Edward Balish and Tom Doetschman2

Departments of Molecular Genetics, Biochemistry and Microbiology [S. J. E., I. O., S. P., T. D.] and Comparative Pathology [G. P. B.], University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524; Aventis Pharmaceuticals, Bridgewater, New Jersey 08807 [S. J. E.]; Department of Surgery, University of Wisconsin Medical School, Madison, Wisconsin 53706-1087 [J. C., E. B.]; and Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425 [E. B.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
Patients with ulcerative colitis are at risk for colon cancer and frequently have microsatellite instability,which, in turn, is usually associated with inactivation of transforming growth factor (TGF) ß signaling. TGF-ß1 deficiency in mice can lead to colon cancer that is preceded by precancerous lesions having submucosal inflammation and hyperplastic crypts. Germ-free TGF-ß1-deficient mice are free of inflammation, hyperplasia, and cancer, but when reintroduced into a Helicobacter hepaticus-containing specific pathogen-free room, these lesions reappear. Because adenoma/carcinoma but not inflammation/hyperplasia is dependent on the genetic backgrounds tested, colitis is required, but not sufficient, for carcinogenesis. This animal model should provide insight into the protective role of TGF-ß1 in early stages of ulcerative colitis-associated human colon cancer.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
TGF-ß13 is at the apex of a signaling pathway that is one of the more commonly disrupted pathways in human colon cancer (1) . Human colon tumor-derived cell lines are frequently resistant to the growth-inhibitory effects of TGF-ß1 (2) , and this loss of sensitivity often results from TGFBR2 inactivating mutations. TGFBR2 mutations are found in 90% of MSI-positive tumors, and therefore account for ~13% of all human colon tumors (3) . MSI is often associated with UC-associated colon cancer (4) . Consequently, it is probable that inactivation of TGF-ß signaling also correlates with UC-associated colon cancer. The tumor suppressor effect of TGF-ß1 in humans is thought to occur at a late stage of tumorigenesis because microsatellite unstable tumors usually have TGFBR2 mutations only if the tumors are at the adenoma/carcinoma transition stage or later (5) . These studies indicate that causal relationships may exist among UC, TGF-ß signaling, genetic instability, and colon adenocarcinoma, but the basis of these relationships is unclear. Because TGF-ß1-deficient mice on an immunodeficient background develop colon cancer that is associated with inflammation (6) , they would be a useful model for determining the relationship among UC, TGF-ß, and colon cancer if it could be demonstrated that the inflammatory lesions are required for tumorigenesis. To make this determination we have eliminated inflammatory bowel lesions by making germ-free TGF-ß1-deficient mice. Here we show that in the absence of enteric flora there is no inflammation, hyperplasia, or neoplasia, and that recolonization of the mice with enteric flora can result in the reappearance of colon cancer.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
A breeding pair of Tgfb1+/- Rag2-/- mice was generously provided by Dr. Robert L. Coffman (DNX Transgenics, Princeton, NJ, presently, Dynavax Technologies, Emeryville, CA). Specific pathogen-free breeding colonies of (a) Tgfb1+/- Rag2-/- mice with a mixed genetic background of 85–94% 129S2/SvPas (formerly 129/SvPas) and the remainder CF1; and (b) Tgfb1+/- Prkdcscid/scid mice with a mixed genetic background of 85–94% C3H/HeJ, and the remainder CF1 and 129S2/SvPas were housed in a barrier facility operated by the University of Cincinnati Laboratory Animal Medicine Services. Germ-free Tgfb1+/- Rag2-/- mouse colonies were established at the University of Wisconsin Gnotobiotic Research Laboratory (Madison, WI) by caesarean derivation. The establishment, maintenance, and health surveys of the barrier-raised and germ-free mice were carried out as reported (7 , 8) . PCR for Helicobacter hepaticus was carried out by the Research Animal Diagnostic and Investigative Laboratory, Columbia, MO.

When germ-free Tgfb1+/- Rag2-/- mice were reintroduced into our barrier facility for recolonization with the resident enteric flora, they were placed in two separate specific pathogen-free rooms, SPF1 and SPF2. SPF1 is the room where the animals with colon cancer had originally been housed, and SPF2 is a similar breeding room in the same barrier facility. Maintenance and quality control for the two rooms is identical, the only known difference being that SPF2 was Helicobacter sp.-free.

Histological examination and scoring for lesion classification was done as described previously (6) . All of the analyses were performed blinded to prevent bias. A one-tailed Student t test was used for statistical analysis. Genotyping the secretory group II phospholipase A2 wild-type (Pla2g2a, C3H strain) and mutant (Pla2g2aMom1, 129 strain) alleles were identified by the PCR genotyping technique described previously (9) . DSS treatment was performed on eight each of Tgfb1+/+ Prkdcscid/scid and Tgfb1-/- Prkdcscid/scid 6–8 week-old mice as described (10) . The concentration and duration of treatment were chosen to induce a chronic inflammation similar to that seen in the original Tgfb1-/- Rag2-/- SPF1 colony without inducing acute symptoms.


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
From the outset it is necessary to make a clear distinction between the autoimmune-like multifocal inflammatory phenotype of Tgfb1-/- mice and the inflammatory lesions found in the cecums and colons of Tgfb1-/- Rag2-/- mice. Immunocompetent Tgfb1-/- mice have inflammatory lesions in multiple organs, and their median age of death is 20 days (11) . When made germ-free, these mice still die from the autoimmune-like disease (7) . However, if Tgfb1-/- mice are genetically combined with lymphocyte-deficient mice, such as Rag2 knockout (6) or Prkdcscid/scid (12) mice, they are rescued from the autoimmune phenotype, and they can live as long as 8 months. However, submucosal, primarily granulocytic inflammatory lesions with accompanying hyperplasia now occur in the cecum and colon of these mice. These lesions occur in nearly all of the immunodeficient mice regardless of the presence or absence of TGF-ß1. Consequently, the inflammatory lesions that are associated with cecum and colon in Tgfb1-/- Rag2-/- mice are unrelated to the autoimmune-like inflammatory lesions of immunocompetent Tgfb1-/- mice (6) .

Genetic Background Effects on Carcinogenesis in TGF-ß1-deficient Mice.
Immunodeficient Tgfb1-/- Prkdcscid/scid and Tgfb1-/- Rag2-/- mice were placed on predominantly C3H or 129 genetic backgrounds, respectively. In both cases the animals were devoid of the autoimmune-like inflammatory disease described above. However, in each colony immunodeficient Tgfb1+/+ and Tgfb1-/- animals developed submucosal inflammatory foci of the large intestine, and hyperplastic crypts were associated with the inflammatory lesions for Tgfb1+/+ or -/- Rag2-/- mice (6) and for Tgfb1+/+ or -/- Prkdcscid/scid mice (Fig. 1)Citation . However, only in immunocompromised TGF-ß1-deficient animals on a predominantly 129 background (Tgfb1-/- Rag2-/- mice) was progression to adenoma and adenocarcinoma observed (see Fig. 1Citation in Ref. 6 ). These results suggest that there may be modifier genes present in 129 strains that increase susceptibility for progression from hyperplasia to adenoma, and that inflammation is required but not sufficient for the development of cecum and colon cancer in immunocompromised TGF-ß1-deficient mice on a 129-strain genetic background.



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  		Fig. 1. Inflammation and hyperplasia in Tgfb1+/+ and -/- Prkdcscid/scid Mice. A, inflammation and hyperplasia in cecum of Tgfb1+/+ Prkdcscid/scid mice (x10 magnification). B, 5-fold magnification of inset depicted in A. C, inflammation and hyperplasia in cecum of Tgfb1-/- Prkdcscid/scid mice (x10 magnification). D, 5-fold magnification of inset depicted in C. h, hyperplasia; n, normal; i, inflammation.

 
Genetic Background Affects Susceptibility to Mouse Colon Cancer.
One modifier locus that has been implicated in modifying tumor development in the ApcMin mouse can be identified by the secretory group II phospholipase A2 gene allele Pla2g2aMom1. The Pla2g2aMom1 allele is a spontaneously occurring mutation propagated in specific strains of mice that results in severely deficient enzyme activity. It is linked to increased tumor numbers in ApcMin mice on the 129 background compared with ApcMin mice with a wild-type Pla2g2a allele, such as C3H mice. However, it is not completely clear whether the Pla2g2aMom1 allele is responsible for the increased susceptibility (9) . Because TGF-ß1-deficient mice are maintained on a partially mixed genetic background to circumvent embryonic lethalities, some of the predominantly C3H-background Tgfb1-/- Prkdcscid/scid mice should be homozygous for the Pla2g2aMom1 susceptibility locus. Four such mice ranging in age from 4–6 months were identified and analyzed. Two had no lesions, one had inflammation and hyperplasia, and one had an adenoma (Fig. 2)Citation . One Tgfb1+/+ wild-type Prkdcscid/scid mouse with the Pla2g2aMom1 locus also had inflammation and hyperplastic lesions but no adenomas (data not shown). Because all of the Tgfb1-/- Rag2-/- animals with H. hepaticus and the Pla2g2aMom1 locus develop adenomas and adenocarcinomas, another modifier locus (loci) must account for most of the susceptibility in that strain. Consequently, Pla2g2aMom1 could represent a weak modifier locus conferring a minor degree of susceptibility to colitis-induced colon cancer, but it does not account for the full penetrance of the colon cancer phenotype in predominantly 129 Tgfb1-/- Rag2-/- mice, because nearly all of the Tgfb1-/- Rag2-/- mice develop colon cancer (6) . Hence, there is at least one other major colon cancer susceptibility locus in strain 129 mice.



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  		Fig. 2. Pla2g2aMomI is not a major colon tumor susceptibility locus in Tgfb1-/- Rag2-/- mice. The bottom PCR-generated band represents the wild-type Pla2g2a allele (Pla2+/+), which is present in C3H mice. The top band represents the mutant Pla2g2aMom1 allele (Pla2-/-) that is present in 129 mice. Tgfb1-/- Prkdcscid/scid mice (predominantly C3H background) are represented in Lanes 3–6 and are all homozygous for the 129 strain Pla2g2aMom1 susceptibility locus, yet only one of them (Lane 4) progressed beyond hyperplasia.

 
Colitis Is Required but Not Sufficient for Carcinogenesis in Tgfb1-/- Rag2-/- Mice.
A previous study demonstrated that barrier-raised Tgfb1-/- Rag2-/- mice develop colon cancer from 3 to 6 months of age, and that inflammatory foci were always associated with the tumorigenic lesions, whereas the Tgfb1+/+ and +/- Rag2-/- mice infrequently developed lesions beyond hyperplasia (6) . Assuming that some complement of normal and/or pathogenic microbial flora resulted in an inflammatory response that, in turn, induced the tumorigenic lesions, we reasoned that making the mice germ-free would eliminate the inflammation and subsequent cancer. Barrier-raised Tgfb1+/- Rag2-/- mice were crossed, and the pregnant females were sent to the Gnotobiotic Facility in Madison, WI, where a germ-free standing colony of Tgfb1+/- Rag2-/- mice was established. Eighteen germ-free Tgfb1-/- Rag2-/- mice, 7 Tgfb1+/- Rag2-/- mice, and 6 Tgfb1+/+ Rag2-/- mice ranging from 3 to 6 months of age were analyzed for hyperplastic, adenomatous, and neoplastic lesions, as well as for submucosal inflammatory foci. Fig. 3, A and BCitation , compare histological sections of colon samples from the progenitor barrier-raised and germ-free colonies, respectively, demonstrating that the inflammatory bowel lesions had been eliminated by the germ-free conditions. None of the mice in this colony developed hyperplasia, adenoma, or adenocarcinoma, strongly suggesting that colitis is required for the development of colon cancer in TGF-ß1-deficient mice.



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  		Fig. 3. Reconstitution of natural gut flora in germ-free Tgfb1-/- Rag2-/- mice. Representative samples are from previously germ-free Tgfb1-/- Rag2-/- mice that were reintroduced into barrier rooms SPF1 in which H. hepaticus was present (A and C) or SPF2 in which H. hepaticus was not present (B and D). A, adenocarcinoma from cecum of a 3-month-old mouse (x25 magnification). B, no significant lesions from colon of a 4-month-old mouse (x25 magnification). C, adenocarcinoma from cecum of a 4-month-old mouse (x50 magnification). D, no significant lesions from cecum of a 6-month-old mouse (x20 magnification).

 
Recolonization of Germ-free Mice with Enteric Flora.
To confirm that the presence of enteric microbial content can lead to tumorigenic cecum and colon lesions associated with inflammatory bowel foci, germ-free Tgfb1+/- Rag2-/- mice from the Wisconsin germ-free colony were reintroduced into two independent SPF rooms in the University of Cincinnati barrier facility. Within 1 year the incidence of colon cancer had reappeared in the SPF1 room where mice had been housed for the original colon cancer study (6) . In contrast, no colon cancer has reappeared in 3 years in SPF2. Consistent with our previous results, colitis was always present in mice developing colon cancer in SPF1 (Fig. 3C)Citation and was never present in SPF2 where mice were free of tumorigenic lesions (Fig. 3D)Citation . These results demonstrate that gut microbial content is integral to the development of colitis in Rag2-/- mice and to the development of colon cancer in Tgfb1-/- Rag2-/- mice.

To determine whether pathogenic microflora may be involved we tested the SPF1 and SPF2 colonies for Helicobacter species. H. hepaticus was identified as the only Helicobacter species in the SPF1 colony where colitis and colon cancer had been reestablished in Tgfb1-/- Rag2-/- mice. In the Helicobacter-free SPF2 colony, no colitis, hyperplasia, adenoma, or adenocarcinoma reappeared. These results suggest that H. hepaticus may be a causative factor for colitis in the Rag2-/- colonies, and that in the absence of TGF-ß1 the resulting hyperplasia can progress to adenoma and adenocarcinoma. This is consistent with the observation that Smad3 knockout mice develop colon cancer when on a 129 genetic background (100% incidence) or a mixed 129 x C57BL/6 background (30% incidence; Ref. 13 ). However, it is not known whether the colon cancer in these mice is associated with H. hepaticus. Another 129-strain Smad3-/- colony has been maintained free of H. hepaticus, and no colitis or adenocarcinoma has been observed.4 In another study, immunodeficient C57BL/6J Rag1-/- mice were infected with H. hepaticus and bilis (14) . In approximately one-third of the Rag1-/- mice inflammatory lesions with occasional hyperplasia were found, but no progression to adenoma or carcinoma was reported. None of the Rag1+/+ mice had lesions. This study is consistent with our findings that adenoma/carcinoma but not inflammation/hyperplasia are dependent on genetic background, that H. hepaticus could be causative, and that colitis is not sufficient for progression to adenoma/carcinoma in this mouse model.

DSS-induced Inflammatory Stress in TGF-ß1-deficient Mice.
Our experiments strongly suggest that inflammatory stress, while required, is not sufficient for the development of colon cancer in TGF-ß1-deficient mice. To test this hypothesis, Tgfb1-/- Prkdcscid/scid mice, which normally have inflammatory/hyperplastic lesions but which do not progress to colon cancer, were subjected to a significant increase in large intestinal inflammatory stress. DSS treatments (1.25% DSS, 60 days) were used to determine whether increased inflammatory stress might be sufficient to induce a transition from hyperplasia to adenoma/carcinoma in 6–8-week-old Tgfb1-/- Prkdcscid/scid mice. Subsets of animals were analyzed for cecum and colon lesions at 22, 29, and 32 days of treatment and at 2, 22, and 33 days after treatment. No adenomas or adenocarcinomas developed in DSS-treated mice (Fig. 4)Citation , suggesting that increasing inflammatory stress in the large intestine does not induce progression to adenoma and adenocarcinoma. As expected, both Tgfb1+/+ and -/- Prkdcscid/scid mice develop inflammation and moderate mucosal hyperplasia during treatment. However, the Tgfb1+/+ Prkdcscid/scid mice are able to rapidly repair the mucosal damage, whereas inflammation and mucosal hyperplasia are still present in Tgfb1-/- Prkdcscid/scid mice 22 and 33 days after treatment. This supports previous evidence (6) suggesting that TGF-ß1-deficient mice may be less able to repair and maintain tissue damage than wild-type mice. These results confirm that inflammatory lesions are required for the development of colon cancer in TGF-ß1-deficient mice. However, because TGF-ß1-deficient mice on a Prkdcscid/scid (predominantly C3H) background all develop inflammatory lesions but rarely colon cancer, it is clear that inflammatory lesions are not sufficient for progression from hyperplasia to adenoma and adenocarcinoma.



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  		Fig. 4. DSS treatment of Tgfb1+/+ and -/- Prkdcscid/scid mice. Mice were treated for 60 days with DSS, and examined for type of lesion at various days during treatment and after treatment. {circ}, Tgfb1+/+ Prkdcscid/scid mice; {circ}, without type of lesion given indicates normal cecum and colon in Tgfb1+/+ Prkdcscid/scid mice; {bullet}, Tgfb1-/- Prkdcscid/scid mice; Ce, cecum; Co, colon; H, hyperplasia; I, inflammation; U, ulceration.

 
Comparison of Genetically Engineered Mouse Models of Colon Cancer.
Besides Tgfb1 Rag2 double knockout mice, there are several other mouse models for human colon cancer: Smad3, Il2, Il10, G{alpha}i2, and Muc2 knockout mice, and Cdx2 and ApcMin heterozygous mice. SMAD3 is in the TGF-ß signaling pathway, and in its absence mice can develop metastatic colon cancer with associated inflammation (13) . Similarly, Il10, Muc2, and G{alpha}i2 knockout mice, as well as Il2 and ß2 microglobulin (ß2m) double-knockout mice, all develop inflammatory bowel-associated colon cancer (Refs. 15 , 16 ; reviewed in Ref. 17 ). Cdx2 heterozygous mice develop primarily large intestinal and occasionally small intestinal tumors without loss of heterozygosity at the Cdx2 locus, and there is no associated colitis, suggesting that mild disruption of normal topographical tissue relationships could alone initiate tumorigenesis (18) . ApcMin mice have predominantly small intestinal adenomas with a few large intestinal tumors. Inhibition or elimination of inflammatory activity reduces the penetrance and multiplicity, but does not eliminate the tumor phenotype, so there may be a mild association of inflammation with the tumors, but it is not required (19) . In most of the models in which a gene was knocked out that had no previous association with colon cancer, no evidence for other mutations in any genes normally associated with colon cancer were found. Similarly, in the Tgfb1-/-, Smad3-/-, and ApcMin models, no mutations were found in colon cancer genes other than the gene of the original mutation. An exception is the Il2 ß2m double-knockout mouse in which mutations in Apc and p53 were found (16) . In summary, colitis seems to be required for tumorigenesis in most large intestinal cancer models in which Apc is not mutated. Cdx2 heterozygous mice are an exception because they develop grossly altered crypt architecture without colitis, and Apc+/min mice are an exception because they can be made germ-free without major loss of the tumor phenotype (19) . Progression to tumors could result either directly from deficiency in a tissue architecture gene, as in the Cdx2 heterozygous mice, or through an inability of the epithelium to maintain tissue integrity in the presence of inflammatory stress. Altered inflammatory response and a deficiency in maintenance of tissue architecture may combine to induce large intestinal cancer in Smad3, Tgfb1 Rag2, Il10, and G{alpha}i2 knockout mice.

Interplay between Microbial Flora and Host Response Establishes Conditions for Colon Cancer.
Together, these results demonstrate that neither enteric microbial agents nor inflammation alone cause colon cancer in Tgfb1-/- Rag2-/- mice. Because genetic background also plays an important role in the process, it is clear that the response to the microbial-induced inflammation is critical to the development of colon cancer. This is consistent with evidence that a single microbial agent can have important modulatory effects on the host expression profile, especially in areas of nutrient absorption, mucosal barrier fortification, xenobiotic metabolism, and angiogenesis (20) . Consequently, to fully understand the conditions that lead to colitis-associated colon cancer in mice, the causative microbial agent(s), and the differential responses of the host inflammatory system and colon epithelium will need to be systematically investigated. The existence of Tgfb1+/+ Rag2-/- and Tgfb1-/- Rag2-/- mice, which have different susceptibilities to colitis-associated colon cancer, will be critical to these investigations.

Relevance of Tgfb1-/- Rag2-/- Mice to Human Colon Cancer.
Having established that colitis can cause colon cancer in mice with mutations in the TGF-ß signaling pathway and that the causative factors involve an interplay between host tissue and inflammatory responses to specific component(s) of microbial flora, it is worthwhile to compare this mouse model with UC-associated colon cancer in humans. The original studies on mutations in the human TGFBR2 gene found mutations in 90% of the 15–20% of all human tumors displaying MSI, and the loss was found to occur at a late stage of tumorigenesis (5) . More recent studies have indicated that as much as 70% of microsatellite-stable colon cancer can also exhibit a blockade of TGF-ß signaling (21) , and in these cases the stage at which the tumor-suppressive activity of TGF-ß occurs is not clear. In one study of colon cancer in patients with UC, chromosomal instability preceded dysplasia (22) . Consequently, it now seems plausible that human patients with UC can develop a genetic instability-induced disruption in TGF-ß signaling before or during early stages of tumor formation. This would be consistent with our studies on TGF-ß1-deficient mice.

It is not unreasonable to suggest that in humans years of inflammatory stress could eventually lead to mutations resulting in MSI and mutations in TGFBR2 or downstream signaling genes. With a blockade in TGF-ß signaling the inflammatory stress could result in an altered inflammatory response and/or a disruption in tissue architecture, leading to an accelerated progression from hyperplasia to adenoma and adenocarcinoma. In Tgfb1-/- Rag2-/- mice the short 1–5-month period of inflammatory stress may be insufficient to generate genetic instability and subsequent mutations in TGFBR2 or downstream signaling genes, but that would not be necessary because they already have a TGF-ß signaling defect.


   ACKNOWLEDGMENTS
 
We thank Wen Yun Sun for genotyping the mutant animals and Yong-Jin Kim for assistance with the manuscript.


   FOOTNOTES
 
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.

1 Supported by NIH Grants HD26471, CA84291, ES05652, and ES06096 (to T. D.). Back

2 To whom requests for reprints should be addressed, at University of Cincinnati, 3110 Medican Sciences Building, 231 Bethesda Avenue, Cincinnati, OH 45267-0524. Back

3 The abbreviations used are: TGF, transforming growth factor; TGFBR2, transforming growth factor ß receptor type II; MSI, microsatellite instability; UC, ulcerative colitis; DSS, dextran sodium sulfate. Back

4 J. Letterio, personal communication. Back

Received 7/24/02. Accepted 9/24/02.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

  1. Kim S. J., Im Y. H., Markowitz S. D., Bang Y. J. Molecular mechanisms of inactivation of TGF-ß receptors during carcinogenesis. Cytokine Growth Factor. Rev., 11: 159-168, 2000.[Medline]
  2. Manning A. M., Williams A. C., Game S. M., Paraskeva C. Differential sensitivity of human colonic adenoma and carcinoma cells to transforming growth factor ß (TGF-ß): conversion of an adenoma cell line to a tumorigenic phenotype is accompanied by a reduced response to the inhibitory effects of TGF-ß. Oncogene, 6: 1471-1476, 1991.[Medline]
  3. Parsons R., Myeroff L. L., Liu B., Willson J. K., Markowitz S. D., Kinzler K. W., Vogelstein B. Microsatellite instability and mutations of the transforming growth factor ß type II receptor gene in colorectal cancer. Cancer Res., 55: 5548-5550, 1995.[Abstract/Free Full Text]
  4. Jass J. R., Do K. A., Simms L. A., Iino H., Wynter C., Pillay S. P., Searle J., Radford-Smith G., Young J., Leggett B. Morphology of sporadic colorectal cancer with DNA replication errors. Gut, 42: 673-679, 1998.[Abstract/Free Full Text]
  5. Markowitz S., Wang J., Myeroff L., Parsons R., Sun L., Lutterbaugh J., Fan R. S., Zborowska E., Kinzler K. W., Vogelstein B., Brattain M., Willson J. K. V. Inactivation of the type II TGF-ß receptor in colon cancer cells with microsatellite instability. Science (Wash. DC), 268: 1336-1338, 1995.[Abstract/Free Full Text]
  6. Engle S. J., Hoying J. B., Boivin G. P., Ormsby I., Gartside P. S., Doetschman T. Transforming growth factor ß1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Res., 59: 3379-3386, 1999.[Abstract/Free Full Text]
  7. Boivin G. P., Ormsby I., Jones-Carson J., O’Toole B. A., Doetschman T. Germ-free and barrier-raised TGFß1-deficient mice have similar inflammatory lesions. Transgenic Res., 6: 197-202, 1997.[Medline]
  8. Balish E., Filutowicz H. Serum antibody response of gnotobiotic athymic and euthymic mice following alimentary tract colonization and infection with Candida albicans. Can. J. Microbiol., 37: 204-210, 1991.[Medline]
  9. Kennedy B. P., Payette P., Mudgett J., Vadas P., Pruzanski W., Kwan M., Tang C., Rancourt D. E., Cromlish W. A. A natural disruption of the secretory group II phospholipase A2 gene in inbred mouse strains. J. Biol. Chem., 270: 22378-22385, 1995.[Abstract/Free Full Text]
  10. Dieleman L. A., Ridwan B. U., Tennyson G. S., Beagley K. W., Bucy R. P., Elson C. O. Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology, 107: 1643-1652, 1994.[Medline]
  11. Shull M. M., Ormsby I., Kier A. B., Pawlowski S., Diebold R. J., Yin M., Allen R., Sidman C., Proetzel G., Calvin D., Doetschman T. Targeted disruption of the mouse transforming growth factor-ß1 gene results in multifocal inflammatory disease. Nature (Lond.), 359: 693-699, 1992.[Medline]
  12. Diebold R. J., Eis M. J., Yin M., Ormsby I., Boivin G. P., Darrow B. J., Saffitz J. E., Doetschman T. Early-onset multifocal inflammation in the transforming growth factor ß1-null mouse is lymphocyte mediated. Proc. Natl. Acad. Sci. USA, 92: 12215-12219, 1995.[Abstract/Free Full Text]
  13. Zhu Y., Richardson J. A., Parada L. F., Graff J. M. Smad3 mutant mice develop metastatic colorectal cancer. Cell, 94: 703-714, 1998.[Medline]
  14. Burich A., Hershberg R., Waggie K., Zeng W., Brabb T., Westrich G., Viney J. L., Maggio-Price L. Helicobacter-induced inflammatory bowel disease in IL-10- and T cell-deficient mice. Am. J. Physiol., 281: G764-G778, 2001.[Abstract/Free Full Text]
  15. Velcich A., Yang W., Heyer J., Fragale A., Nicholas C., Viani S., Kucherlapati R., Lipkin M., Yang K., Augenlicht L. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science (Wash. DC), 295: 1726-1729, 2002.[Abstract/Free Full Text]
  16. Sohn K. J., Shah S. A., Reid S., Choi M., Carrier J., Comiskey M., Terhorst C., Kim Y. I. Molecular genetics of ulcerative colitis-associated colon cancer in the interleukin 2- and ß (2)-microglobulin-deficient mouse. Cancer Res., 61: 6912-6917, 2001.[Abstract/Free Full Text]
  17. Fedorak R. N., Madsen K. L. Naturally occurring and experimental models of inflammatory bowel disease Kirsner J. B. Shorter R. G. eds. . Inflammatory Bowel Disease, 5 Ed. 113-143, WB Saunders Company Philadelphia 1999.
  18. Chawengsaksophak K., James R., Hammond V. E., Kontgen F., Beck F. Homeosis and intestinal tumours in Cdx2 mutant mice. Nature (Lond.), 386: 84-87, 1997.[Medline]
  19. Dove W. F., Clipson L., Gould K. A., Luongo C., Marshall D. J., Moser A. R., Newton M. A., Jacoby R. F. Intestinal neoplasia in the ApcMin mouse: independence from the microbial and natural killer (beige locus) status. Cancer Res., 57: 812-814, 1997.[Abstract/Free Full Text]
  20. Hooper L. V., Wong M. H., Thelin A., Hansson L., Falk P. G., Gordon J. I. Molecular analysis of commensal host-microbial relationships in the intestine. Science (Wash. DC), 291: 881-884, 2001.[Abstract/Free Full Text]
  21. Grady W. M., Myeroff L. L., Swinler S. E., Rajput A., Thiagalingam S., Lutterbaugh J. D., Neumann A., Brattain M. G., Chang J., Kim S. J., Kinzler K. W., Vogelstein B., Willson J. K., Markowitz S. Mutational inactivation of transforming growth factor ß receptor type II in microsatellite stable colon cancers. Cancer Res., 59: 320-324, 1999.[Abstract/Free Full Text]
  22. Rabinovitch P. S., Dziadon S., Brentnall T. A., Emond M. J., Crispin D. A., Haggitt R. C., Bronner M. P. Pancolonic chromosomal instability precedes dysplasia and cancer in ulcerative colitis. Cancer Res., 59: 5148-5153, 1999.[Abstract/Free Full Text]



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T. Poutahidis, K. M. Haigis, V. P. Rao, P. R. Nambiar, C. L. Taylor, Z. Ge, K. Watanabe, A. Davidson, B. H. Horwitz, J. G. Fox, et al.
Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma
Carcinogenesis, December 1, 2007; 28(12): 2614 - 2623.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. M. Munoz, M. Upton, A. Rojas, M. K. Washington, L. Lin, A. Chytil, E. G. Sozmen, B. B. Madison, A. Pozzi, R. T. Moon, et al.
Transforming Growth Factor {beta} Receptor Type II Inactivation Induces the Malignant Transformation of Intestinal Neoplasms Initiated by Apc Mutation.
Cancer Res., October 15, 2006; 66(20): 9837 - 9844.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
J. S. Pratt, K. L. Sachen, H. D. Wood, K. A. Eaton, and V. B. Young
Modulation of Host Immune Responses by the Cytolethal Distending Toxin of Helicobacter hepaticus.
Infect. Immun., August 1, 2006; 74(8): 4496 - 4504.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Maggio-Price, P. Treuting, W. Zeng, M. Tsang, H. Bielefeldt-Ohmann, and B. M. Iritani
Helicobacter Infection Is Required for Inflammation and Colon Cancer in Smad3-Deficient Mice
Cancer Res., January 15, 2006; 66(2): 828 - 838.
[Abstract] [Full Text] [PDF]

Home page
 Vet PatholHome page
P. R. Nambiar, S. M. Kirchain, K. Courmier, S. Xu, N. S. Taylor, E. J. Theve, M. M. Patterson, and J. G. Fox
Progressive Proliferative and Dysplastic Typhlocolitis in Aging Syrian Hamsters Naturally Infected with Helicobacter spp.: A Spontaneous Model of Inflammatory Bowel Disease
Vet. Pathol., January 1, 2006; 43(1): 2 - 14.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. Tang, V. Katuri, R. Srinivasan, F. Fogt, R. Redman, G. Anand, A. Said, T. Fishbein, M. Zasloff, E. P. Reddy, et al.
Transforming Growth Factor-{beta} Suppresses Nonmetastatic Colon Cancer through Smad4 and Adaptor Protein ELF at an Early Stage of Tumorigenesis
Cancer Res., May 15, 2005; 65(10): 4228 - 4237.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Biswas, A. Chytil, K. Washington, J. Romero-Gallo, A. E. Gorska, P. S. Wirth, S. Gautam, H. L. Moses, and W. M. Grady
Transforming Growth Factor {beta} Receptor Type II Inactivation Promotes the Establishment and Progression of Colon Cancer
Cancer Res., July 15, 2004; 64(14): 4687 - 4692.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
S. H. Itzkowitz and X. Yio
Inflammation and Cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation
Am J Physiol Gastrointest Liver Physiol, July 1, 2004; 287(1): G7 - G17.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
M. M. Huycke and H. R. Gaskins
Commensal Bacteria, Redox Stress, and Colorectal Cancer: Mechanisms and Models
Experimental Biology and Medicine, July 1, 2004; 229(7): 586 - 597.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
A. B. Rogers and J. G. Fox
Inflammation and Cancer I. Rodent models of infectious gastrointestinal and liver cancer
Am J Physiol Gastrointest Liver Physiol, March 1, 2004; 286(3): G361 - G366.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
F.-F. Chu, R. S. Esworthy, P. G. Chu, J. A. Longmate, M. M. Huycke, S. Wilczynski, and J. H. Doroshow
Bacteria-Induced Intestinal Cancer in Mice with Disrupted Gpx1 and Gpx2 Genes
Cancer Res., February 1, 2004; 64(3): 962 - 968.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. E. Erdman, V. P. Rao, T. Poutahidis, M. M. Ihrig, Z. Ge, Y. Feng, M. Tomczak, A. B. Rogers, B. H. Horwitz, and J. G. Fox
CD4+CD25+ Regulatory Lymphocytes Require Interleukin 10 to Interrupt Colon Carcinogenesis in Mice
Cancer Res., September 15, 2003; 63(18): 6042 - 6050.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
R. Bommireddy, V. Saxena, I. Ormsby, M. Yin, G. P. Boivin, G. F. Babcock, R. R. Singh, and T. Doetschman
TGF-{beta}1 Regulates Lymphocyte Homeostasis by Preventing Activation and Subsequent Apoptosis of Peripheral Lymphocytes
J. Immunol., May 1, 2003; 170(9): 4612 - 4622.
[Abstract] [Full Text] [PDF]

Home page
 J. Exp. Med.Home page
D. Daniel, N. Meyer-Morse, E. K. Bergsland, K. Dehne, L. M. Coussens, and D. Hanahan
Immune Enhancement of Skin Carcinogenesis by CD4+ T Cells
J. Exp. Med., April 21, 2003; 197(8): 1017 - 1028.
[Abstract] [Full Text] [PDF]

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