transforming-growth-factor-beta and Intestinal-Polyps

Juvenile polyps are hamartomatous polyps found primarily in infants and children, and in association with juvenile polyposis (JP; OMIM #174900), Cowden syndrome (CS; OMIM #158350), and Bannayan-Riley-Ruvalcaba syndrome (BRRS; OMIM# 153480). Although solitary juvenile polyps are benign lesions, when present in JP patients they may lead to gastrointestinal cancers. Germline mutations in MADH4 and BMPR1A predispose to JP, and both genes are involved in TGF-beta superfamily signaling pathways. In CS and BRRS, juvenile polyps are a less consistent feature, and CS patients are at risk for breast and thyroid cancers. Mutations of the tumor suppressor gene PTEN have been found in the germline of both CS and BRRS patients. Despite different underlying genetic mechanisms, these and other syndromes share the same phenotypic feature of juvenile polyps.

Topics: Animals; Child; Child, Preschool; DNA-Binding Proteins; Genetic Predisposition to Disease; Germ-Line Mutation; Hamartoma Syndrome, Multiple; Humans; Infant; Intestinal Polyposis; Intestinal Polyps; Mice; Phosphoric Monoester Hydrolases; PTEN Phosphohydrolase; Smad4 Protein; Syndrome; Trans-Activators; Transforming Growth Factor beta; Tumor Suppressor Proteins

Topics: Adenoma; Animals; Cell Division; Cell Transformation, Neoplastic; Colorectal Neoplasms; DNA-Binding Proteins; Gene Expression Regulation; Humans; Intestinal Polyps; Mice; Mutation; Signal Transduction; Smad3 Protein; Smad4 Protein; Trans-Activators; Transforming Growth Factor beta

Epidemiological and experimental evidence suggests that estrogen replacement therapy reduces the risk of colon cancer in postmenopausal women. Estrogen receptor beta (ERβ) is thought to be the principal mediator of the estrogen effect in the colon. Recent studies by our team suggested positive regulation of the transforming growth factor (TGF)β pathway by estrogen in mice colonocytes. We therefore wanted to investigate the effects of ERβ agonist treatment on intestinal tumorigenesis in Apc(Min/+) mice. Weaned Apc(Min/+) mice were injected subcutaneously three times a week for 12 wk with vehicle or ERβ-selective agonist, diarylpropionitrile (DPN, 5 mg/kg). DPN administration resulted in a significant reduction in small intestinal polyp multiplicity in both Apc(Min/+) male and female mice. Furthermore, the mean diameter of small intestinal polyps was lower in DPN-treated than vehicle-treated males, along with lower BrdU incorporation indices in jejunal and colon epithelial cells of both sexes. DPN treatment also increased apoptosis in colon epithelium as measured by TUNEL assay and cleaved caspase 3 quantification. The effect of DPN on various components of the TGFβ pathway was also studied in colonocytes. DPN treatment increased expression of TGFβ1 and TGFβ3 transcripts, levels of nuclear and phosphorylated Smad2 as well as p27 cell-cycle inhibitor, a TGFβ pathway target gene. Our results demonstrate that DPN treatment reduces intestinal tumorigenesis in Apc(Min/+) mice. Furthermore, we suggest that positive regulation of the TGFβ pathway by ERβ activation could contribute to the protective role of estrogen in intestinal tumor development.

Topics: Adenomatous Polyposis Coli Protein; Animals; Apoptosis; Blotting, Western; Caspase 3; Cell Nucleus; Cell Proliferation; Colon; Epithelium; Estrogen Receptor beta; Female; Gene Expression; In Situ Nick-End Labeling; Injections, Subcutaneous; Intestinal Neoplasms; Intestinal Polyps; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nitriles; Phosphorylation; Propionates; Reverse Transcriptase Polymerase Chain Reaction; Smad2 Protein; Transforming Growth Factor beta

While there is evidence that specific T cell populations can promote the growth of established tumors, instances where T cell activity causes neoplasms to arise de novo are infrequent. Here, we employed two conditional mutagenesis systems to delete the TGF-β signaling pathway component Smad4 in T cells and observed the spontaneous development of massive polyps within the gastroduodenal regions of mice. The epithelial lesions contained increased levels of transcripts encoding IL-11, IL-6, TGF-β, IL-1β, and TNF-α, and lamina propria cells isolated from lesions contained abundant IL-17A+CD4+ T cells. Furthermore, we found that Smad4 deficiency attenuated TGF-β-mediated in vitro polarization of FoxP3+CD4+ T cells, but not IL-17A+CD4+ T cells, suggesting that the epithelial lesions may have arisen as a consequence of unchecked Th17 cell activity. Proinflammatory cytokine production likely accounted for the raised levels of IL-11, a cytokine known to promote gastric epithelial cell survival and hyperplasia. Consistent with IL-11 having a pathogenic role in this model, we found evidence of Stat3 activation in the gastric polyps. Thus, our data indicate that a chronic increase in gut Th17 cell activity can be associated with the development of premalignant lesions of the gastroduodenal region.

Topics: Animals; Disease Models, Animal; Gastrointestinal Neoplasms; Gene Expression; Interleukin-11; Interleukin-1beta; Interleukin-6; Intestinal Polyps; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Transgenic; Precancerous Conditions; Smad4 Protein; T-Lymphocyte Subsets; Th17 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Germline mutations in STK11 (also known as LKB1) are found in individuals with Peutz-Jeghers syndrome (PJS) manifesting with gastrointestinal polyps that contain a prominent stromal component. Epithelia in polyps of Stk11(+/-) mice can retain a functional copy of Stk11 (refs. 2,3), and loss of heterozygosity is not an obligate feature of human polyps, raising the possibility of non-epithelial origins in tumorigenesis. Here we show that either monoallelic or biallelic loss of murine Stk11 limited to Tagln-expressing mesenchymal cells results in premature postnatal death as a result of gastrointestinal polyps indistinguishable from those in PJS. Stk11-deficient mesenchymal cells produced less TGFbeta, and defective TGFbeta signaling to epithelial cells coincided with epithelial proliferation. We also noted TGFbeta signaling defects in polyps of individuals with PJS, suggesting that the identified stromal-derived mechanism of tumor suppression is also relevant in PJS.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Blotting, Western; Cell Proliferation; Cells, Cultured; Epithelial Cells; Female; Fibroblasts; Gastrointestinal Tract; Humans; Injections, Intraperitoneal; Integrases; Intestinal Polyps; Longevity; Male; Mesoderm; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Muscle Proteins; Muscle, Smooth; Peutz-Jeghers Syndrome; Polymerase Chain Reaction; Protein Kinases; Protein Serine-Threonine Kinases; RNA, Messenger; Selective Estrogen Receptor Modulators; Smad2 Protein; Stromal Cells; Tamoxifen; TOR Serine-Threonine Kinases; Transforming Growth Factor beta

The epithelial-mesenchymal transition (EMT) occurs commonly during carcinoma invasion and metastasis, but not during early tumorigenesis. Microarray data demonstrated elevation of vimentin, a mesenchymal marker, in intestinal adenomas from Apc Min/+ (Min) mice. We have tested the involvement of EMT in early tumorigenesis in mammalian intestines by following EMT-associated markers. Elevated vimentin RNA expression and protein production were detected within neoplastic cells in murine intestinal adenomas. Similarly, vimentin protein was detected in both adenomas and invasive adenocarcinomas of the human colon, but not in the normal colonic epithelium or in hyperplastic polyps. Expression of E-cadherin varied inversely with vimentin. In addition, the expression of fibronectin was elevated while that of E-cadherin decreased. Canonical E-cadherin suppressors, such as Snail, were not elevated in the same tumor. Elevated vimentin expression in the adenoma was not correlated with persistent Ras signaling, but was strongly correlated with reduced proliferation indices, active Wnt signaling, and TGF-beta signaling, as demonstrated by its dependence on Smad3. We designate our observations of expression of only some of the canonical features of EMT as "truncated EMT". These unexpected observations are interpreted as reflecting the involvement of a core of the EMT system during the tissue remodeling of early tumorigenesis.

Topics: Adenoma; Adenomatous Polyposis Coli Protein; Animals; Azoxymethane; Cadherins; Cell Proliferation; Epithelium; Fibronectins; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Intestinal Neoplasms; Intestinal Polyps; Mesoderm; Mice; Mutation; Neoplasm Invasiveness; Phenotype; ras Proteins; Signal Transduction; Snail Family Transcription Factors; Transcription Factors; Transforming Growth Factor beta; Vimentin; Wnt Proteins

Familial juvenile polyposis is an autosomal dominant disease characterized by a predisposition to hamartomatous polyps and gastrointestinal cancer. Here it is shown that a subset of juvenile polyposis families carry germ line mutations in the gene SMAD4 (also known as DPC4), located on chromosome 18q21.1, that encodes a critical cytoplasmic mediator in the transforming growth factor-beta signaling pathway. The mutant SMAD4 proteins are predicted to be truncated at the carboxyl-terminus and lack sequences required for normal function. These results confirm an important role for SMAD4 in the development of gastrointestinal tumors.

Topics: Cell Membrane; Cell Nucleus; Chromosome Mapping; Chromosomes, Human, Pair 18; Colorectal Neoplasms; DNA-Binding Proteins; Female; Frameshift Mutation; Gastrointestinal Neoplasms; Genes, DCC; Genes, Tumor Suppressor; Genetic Predisposition to Disease; Germ-Line Mutation; Hamartoma Syndrome, Multiple; Humans; Intestinal Polyps; Male; Pedigree; Polymerase Chain Reaction; Sequence Deletion; Signal Transduction; Smad4 Protein; Trans-Activators; Transforming Growth Factor beta