transforming-growth-factor-beta and Polyps

to evaluate the effects of tamoxifen on the expression of TGF-beta and p27 proteins in polyps and adjacent endometrium of women after menopause.. prospective study with 30 post-menopausal women with diagnosis of breast cancer, taking tamoxifen (20 mg/day), presenting diagnosis of suspect endometrial polyps through transvaginal ultrasonography, and submitted to diagnostic and surgical hysterectomy to withdraw the polyps and adjacent endometrium. A immunohistochemical study has been done to verify the expression of the TGF-beta and p27 proteins in the polyps and adjacent endometrium. These proteins' quantification has been done by morphometry.. the patients' average age was 61.7 years old; their average age at the menopause onset was 49.5; and the average of using tamoxifen was 25.3 months. The average concentration of positive cells for TGF-beta protein in the glandular and stroma polyp epithelium was 62.6+/-4.5 cells/mm(2). For the p27, in the glandular polyp epithelium, it was 24.2+/-18.6 cells/mm(2) and for the stroma, 19.2+/-15.2 cells/mm(2). There was no significant difference between the expression of TGF-beta and p27 in the glandular epithelial form the polyps and the adjacent endometrium. The expression of proteins in the polyp and adjacent endometrium with its respective glandular and stroma epithelium showed a significant difference for the p27 protein (r=0.9, p<0.05).. we have concluded that the TGF-beta expression is not related to the effect of tamoxifen on the growing of endometrial polyps, but the absence of polyps' malignization by tamoxifen may be explained by the high expression of p27 protein in its glandular epithelium.

Topics: Cyclin-Dependent Kinase Inhibitor p27; Endometrial Neoplasms; Female; Humans; Middle Aged; Polyps; Postmenopause; Tamoxifen; Transforming Growth Factor beta

The tumor suppressor Smad4 mediates signaling by the transforming growth factor beta (TGF-beta) superfamily of ligands. Previous studies showed that several TGF-beta family members exert important functions in hematopoiesis. Here, we studied the role of Smad4 in adult murine hematopoiesis using the inducible Mx-Cre/loxP system. Mice with homozygous Smad4 deletion (Smad4(Delta/Delta)) developed severe anemia 6 to 8 weeks after induction (mean hemoglobin level 70 g/L). The anemia was not transplantable, as wild-type mice reconstituted with Smad4(Delta/Delta) bone marrow cells had normal peripheral blood counts. These mice did not develop an inflammatory disease typical for mice deficient in TGF-beta receptors I and II, suggesting that the suppression of inflammation by TGF-beta is Smad4 independent. The same results were obtained when Smad4 alleles were deleted selectively in hematopoietic cells using the VavCre transgenic mice. In contrast, lethally irradiated Smad4(Delta/Delta) mice that received wild-type bone marrow cells developed anemia similar to Smad4(Delta/Delta) mice that did not receive a transplant. Liver iron stores were decreased and blood was present in stool, indicating that the anemia was due to blood loss. Multiple polyps in stomach and colon represent a likely source of the bleeding. We conclude that Smad4 is not required for adult erythropoiesis and that anemia is solely the consequence of blood loss.

Topics: Anemia; Animals; Bone Marrow Transplantation; Erythropoiesis; Flow Cytometry; Gastrointestinal Hemorrhage; Intestinal Polyposis; Iron Deficiencies; Liver; Mice; Mice, Transgenic; Polyps; Reverse Transcriptase Polymerase Chain Reaction; Smad4 Protein; Stomach Diseases; Transforming Growth Factor beta

To determine whether leiomyoma, adenomyosis and endometrial polyps are associated with changes in uterine cavity matrix metalloproteinases (MMP-2 and MMP-9) and cytokines.. Uterine cavity irrigation was performed in women with leiomyoma, adenomyosis and endometrial polyps, and in women with a normal uterus. MMP-2 and MMP-9 were assayed in the uterine washings by gelatin zymography. For individual subjects, the total MMP level was obtained by adding the semi-quantitative scores of band densities related to gelatinases in the zymograms. Interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and transforming growth factor-beta1 (TGF-beta1) were measured using enzyme-linked immunosorbant assay (ELISA) kits.. The uterine cavity of patients with leiomyoma, adenomyosis and endometrial polyps had significantly higher MMP scores than controls. Although the mean IL-1beta levels were elevated in uteri harboring a pathology compared with the normal uteri, the cytokine was significantly elevated only in the adenomyotic group. Significantly elevated levels of IFN-gamma were found in uteri with leiomyoma and endometrial polyps. Uterine washings from leiomyoma and adenomyosis contained significantly elevated mean levels of TGF-beta1 compared with controls, while TNF-alpha was significantly higher only in leiomyoma. When uterine cytokine levels were compared in relation to individual MMP levels a significant relationship was found between TGF-beta1 and elevated levels of MMP-9 and total MMPs in leiomyoma. A significant relationship was also found between IL-1beta and elevated levels of MMP-2, MMP-9 and total MMPs in the endometrial polyp group.. The uterine cavity in leiomyoma, adenomyosis and endometrial polyps contains elevated levels of MMPs and cytokines compared with the normal uterus. In some pathologies elevated cytokines are associated with elevated MMPs.

Topics: Cytokines; Endometrial Neoplasms; Endometriosis; Female; Humans; Interferon-gamma; Interleukin-1; Leiomyoma; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Polyps; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Uterine Diseases; Uterine Neoplasms; Uterus

The tumor suppressor SMAD4, also known as DPC4, deleted in pancreatic cancer, is a central mediator of TGF-beta signaling. It was previously shown that mice homozygous for a null mutation of Smad4 (Smad4-/-) died prior to gastrulation displaying impaired extraembryonic membrane formation and endoderm differentiation. Here we show that Smad4+/- mice began to develop polyposis in the fundus and antrum when they were over 6 - 12 months old, and in the duodenum and cecum in older animals at a lower frequency. With increasing age, polyps in the antrum show sequential changes from hyperplasia, to dysplasia, in-situ carcinoma, and finally invasion. These alterations are initiated by a dramatic expansion of the gastric epithelium where Smad4 is expressed. However, loss of the remaining Smad4 wild-type allele was detected only in later stages of tumor progression, suggesting that haploinsufficiency of Smad4 is sufficient for tumor initiation. Our data also showed that overexpression of TGF-beta1 and Cyclin D1 was associated with increased proliferation of gastric polyps and tumors. These studies demonstrate that Smad4 functions as a tumor suppressor in the gastrointestinal tract and also provide a valuable model for screening factors that promote or prevent gastric tumorigenesis.

Topics: Age Factors; Animals; Cyclin D1; DNA-Binding Proteins; Genes, Tumor Suppressor; Haploidy; Loss of Heterozygosity; Mice; Polyps; Smad4 Protein; Stomach Neoplasms; Trans-Activators; Transforming Growth Factor beta