transforming-growth-factor-beta and Adenomatous-Polyposis-Coli

Colorectal cancer is one of the leading causes of cancer-related death in the Western society, and the incidence is rising. Rare hereditary gastrointestinal polyposis syndromes that predispose to colorectal cancer have provided a model for the investigation of cancer initiation and progression in the general population. Many insights in the molecular genetic basis of cancer have emerged from the study of these syndromes. This review discusses the genetics and clinical manifestations of the three most common syndromes with gastrointestinal polyposis and an increased risk of colorectal cancer: familial adenomatous polyposis (FAP), juvenile polyposis (JP) and Peutz-Jeghers syndrome (PJS).

Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Gastrointestinal Neoplasms; Humans; Peutz-Jeghers Syndrome; Signal Transduction; Transforming Growth Factor beta

Topics: Adenomatous Polyposis Coli; Biomarkers, Tumor; Colorectal Neoplasms; Genes, APC; Genes, p53; Genes, ras; Germ-Line Mutation; Humans; Loss of Heterozygosity; Proto-Oncogene Proteins; Signal Transduction; Transforming Growth Factor beta; Wnt Proteins; Zebrafish Proteins

Hamartomatous polyposis syndromes are characterized by an overgrowth of cells or tissues native to the area in which they normally occur. Juvenile polyposis syndrome (JPS) results from germ-line mutations in the SMAD-4 gene (18q21.1) that encodes for an enzyme involved in transforming growth factor beta(TGF-beta) signal transduction. The increased neoplastic risk may result from SMAD-4 mutations in the stromal component, which stimulate epithelial dysplasia and progression to invasive malignancy. Peutz-Jeghers syndrome (PJS) is associated with germ-line mutations in the LKB1 gene (19p13.3) that encodes a multifunctional serine-threonine kinase. These mutations occur in the epithelial component, suggesting a direct tumor suppressor effect. Patients are at an increased risk of intestinal and extraintestinal malignancies, including breast, pancreatic, ovarian, testicular, and cervical cancer. Cowden's disease is associated with germ-line mutations in the PTEN gene (10q22-23) and an increased risk of breast and thyroid malignancies. Ruvalcaba-Myhre-Smith syndrome is less common; controversy suggests that it may represent a variant of Cowden's disease.. Genetic alterations underlying hamartomatous polyposis syndromes are diverse. Carcinogenesis may result from either germ-line mutations in the stroma (JPS) or as a direct result of functional deletion of tumor suppressor genes (PJS). Diagnosis depends on clinical presentation and patterns of inheritance within families. Suggested surveillance guidelines for the proband and first-degree relatives are outlined.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Age of Onset; Aged; Cell Transformation, Neoplastic; Diagnosis, Differential; Female; Genes, Tumor Suppressor; Germ-Line Mutation; Hamartoma Syndrome, Multiple; Humans; Male; Middle Aged; Neoplasm Invasiveness; Pedigree; Peutz-Jeghers Syndrome; Point Mutation; Risk Factors; Signal Transduction; Transforming Growth Factor beta

Stem cell research provides a foundation for therapeutic advancement in oncology, clinical genetics and a diverse array of degenerative disorders. For example, the elucidation of pathways governing proliferative regulation and differentiation within cellular systems will result in medical strategies aimed at the root cause of cancer. At present the characterization of reliable stem cell markers is the immediate aim in this particular field. Over the past 30 years investigators have determined many of the physical and functional properties of stem cells through careful and imaginative experimentation. Intestinal stem cells reside at the crypt base and give rise to all cell types found within the crypt. They readily undergo altruistic apoptosis in response to toxic stimuli although their progeny are hardier and will regain stem cell function to repopulate the tissue compartment, giving rise to the concept of a proliferative hierarchy. Contention exists when deciding whether the full complement of cells within a crypt is derived from either a single or multiple stems. Evidence has also arisen to challenge the long held view that colorectal tumours arise from a single mutated stem cell, as early adenomas from a human XO/XY mosaic contained distinct clones. Mechanisms governing the stem cell cycle and subsequent proliferative activity largely remain obscure. The adenomatous polyposis coli gene product has, however, been shown to promote the degradation of beta-catenin, an enhancer of cell proliferation, thereby downregulating this activity in healthy individuals.

Topics: Adenomatous Polyposis Coli; Animals; Cell Differentiation; Cell Division; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Cyclooxygenase 2; Glucagon-Like Peptides; Humans; Intestinal Mucosa; Intestines; Isoenzymes; Membrane Proteins; Neoplasms; Peptides; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Stem Cells; Transforming Growth Factor beta; Tumor Suppressor Protein p53

Topics: Adenomatous Polyposis Coli; Base Pair Mismatch; beta Catenin; Colorectal Neoplasms; Cytoskeletal Proteins; DNA Repair; DNA-Binding Proteins; Humans; Smad2 Protein; Smad4 Protein; Trans-Activators; Transforming Growth Factor beta

Topics: Adenomatous Polyposis Coli; Animals; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; DNA-Binding Proteins; Furans; Heterozygote; Isoenzymes; Loss of Heterozygosity; Mice; Mice, Knockout; Prostaglandin-Endoperoxide Synthases; Signal Transduction; Trans-Activators; Transforming Growth Factor beta

The gene for familial adenomatous polyposis coli (APC or FAP), which has previously been linked to chromosome 5q21 has been identified. The APC gene has been found to be altered by point mutations in the germ line of both adenomatous polyposis coli and Gardner's syndrome patients and somatically in tumors from sporadic colorectal cancer patients. During the hunt for the APC gene, the closely linked MCC (mutated in colorectal cancer) gene was identified and found to be altered somatically in tumors from sporadic cancer patients. These data suggest that more than one gene on chromosome 5q21 may contribute to colorectal carcinogenesis and that mutations at the APC gene can cause both adenomatous polyposis coli and Gardner's syndrome. The identification of these genes should aid in the counseling of patients with genetic predispositions to colorectal cancer. Progress has also been made in identifying specific genetic changes that occur in other gastrointestinal cancers. A mutational "hotspot" in the p53 gene in human hepatocellular carcinomas has been identified that could reflect exposure to a specific carcinogen, one candidate being aflatoxin B1.

Topics: Adenomatous Polyposis Coli; Animals; Biomarkers, Tumor; Chromosome Aberrations; Chromosome Deletion; Colorectal Neoplasms; Diet; Gardner Syndrome; Gastrointestinal Neoplasms; Genes, p53; Genes, Tumor Suppressor; Genetic Predisposition to Disease; Humans; Oncogenes; Rats; Transforming Growth Factor beta

RAC1B is a tumour-related alternative splice isoform of the small GTPase RAC1, found overexpressed in a large number of tumour types. Building evidence suggests it promotes tumour progression but compelling in vivo evidence, demonstrating a role in driving tumour invasion, is currently lacking. In the present study, we have overexpressed RAC1B in a colorectal cancer mouse model with potential invasive properties. Interestingly, RAC1B overexpression did not trigger tumour invasion, rather it led to an acceleration of tumour initiation and reduced mouse survival. By modelling early stages of adenoma initiation we observed a reduced apoptotic rate in RAC1B overexpressing tumours, suggesting protection from apoptosis as a mediator of this phenotype. RAC1B overexpressing tumours displayed attenuated TGFβ signalling and functional analysis in ex vivo organoid cultures demonstrated that RAC1B negatively modulates TGFβ signalling and confers resistance to TGFβ-driven cell death. This work defines a novel mechanism by which early adenoma cells can overcome the cytostatic and cytotoxic effects of TGFβ signalling and characterises a new oncogenic function of RAC1B in vivo.

Topics: Adenoma; Adenomatous Polyposis Coli; Animals; Apoptosis; Carcinogenesis; Disease Models, Animal; Down-Regulation; Gene Expression Regulation, Neoplastic; Intestines; Mice; Models, Biological; rac1 GTP-Binding Protein; Signal Transduction; Survival Analysis; Transforming Growth Factor beta; Tumor Suppressor Protein p53

Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from natural killer (NK) cells is a gene signature indicative of 'imprinting' by cytokines of the TGF-β family. We studied mice in which ILC1s and NK cells lacked SMAD4, a signal transducer that facilitates the canonical signaling pathway common to all cytokines of the TGF-β family. While SMAD4 deficiency did not affect ILC1 differentiation, NK cells unexpectedly acquired an ILC1-like gene signature and were unable to control tumor metastasis or viral infection. Mechanistically, SMAD4 restrained non-canonical TGF-β signaling mediated by the cytokine receptor TGFβR1 in NK cells. NK cells from a SMAD4-deficient person affected by polyposis were also hyper-responsive to TGF-β. These results identify SMAD4 as a previously unknown regulator that restricts non-canonical TGF-β signaling in NK cells.

Topics: Adenomatous Polyposis Coli; Animals; Case-Control Studies; Cell Differentiation; Gene Expression Profiling; Humans; Immunity, Innate; Immunoblotting; Immunologic Deficiency Syndromes; Killer Cells, Natural; Lymphocytes; Lymphopoiesis; Melanoma, Experimental; Mice; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Smad4 Protein; Transforming Growth Factor beta

Interactions between the epithelium and surrounding mesenchyme/stroma play an important role in normal gut morphogenesis, the epithelial response to injury, and epithelial carcinogenesis. The tumor microenvironment, composed of stromal cells including myofibroblasts and immune cells, regulates tumor growth and the cancer stem cell niche. Deletion of epimorphin (Epim), a syntaxin family member expressed in myofibroblasts and macrophages, results in partial protection from colitis and from inflammation-induced colon cancer in mice. We sought to determine whether epimorphin deletion protects from polyposis in the Apcmin/+ mouse model of intestinal carcinogenesis. Epim-/- mice were crossed to Apcmin/+ mice; Apcmin/+ and Apcmin/+/Epim-/- mice were killed at 3 mo of age. Polyp numbers and sizes were quantified in small intestine and colon, and gene expression analyses for pathways relevant to epithelial carcinogenesis were performed. Primary myofibroblast cultures were isolated, and expression and secretion of selected growth factors from Apcmin/+ and Apcmin/+/Epim-/- myofibroblasts were examined by ELISA. Small bowel polyposis was significantly inhibited in Apcmin/+/Epim-/- compared with Apcmin/+ mice. Apcmin/+/Epim-/- compared with Apcmin/+ polyps and adjacent uninvolved intestinal mucosa had increased transforming growth factor-β (TGF-β) expression and signaling with increased P-Smad2/3 expression. Myofibroblasts isolated from Apcmin/+/Epim-/- vs. Apcmin/+ mice had markedly decreased hepatocyte growth factor (HGF) expression and secretion. We concluded that Epim deletion inhibits polyposis in Apcmin/+ mice, associated with increased mucosal TGF-β signaling and decreased myofibroblast HGF expression and secretion. Our data suggest that Epim deletion reduces tumorigenicity of the stromal microenvironment.

Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Colonic Neoplasms; Disease Models, Animal; Female; Gene Expression Regulation; Hepatocyte Growth Factor; Intestinal Mucosa; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Myofibroblasts; Signal Transduction; Transforming Growth Factor beta

Colorectal cancer (CRC) is one of the common malignant tumors worldwide. Both genetic and epigenetic changes are regarded as important factors of colorectal carcinogenesis. Loss of DACH1 expression was found in breast, prostate, and endometrial cancer. To analyze the regulation and function of DACH1 in CRC, 5 colorectal cancer cell lines, 8 cases of normal mucosa, 15 cases of polyps and 100 cases of primary CRC were employed in this study. In CRC cell lines, loss of DACH1 expression was correlated with promoter region hypermethylation, and re-expression of DACH1 was induced by 5-Aza-2'-deoxyazacytidine treatment. We found that DACH1 was frequently methylated in primary CRC and this methylation was associated with reduction in DACH1 expression. These results suggest that DACH1 expression is regulated by promoter region hypermethylation in CRC. DACH1 methylation was associated with late tumor stage, poor differentiation, and lymph node metastasis. Re-expression of DACH1 reduced TCF/LEF luciferase reporter activity and inhibited the expression of Wnt signaling downstream targets (c-Myc and cyclinD1). In xenografts of HCT116 cells in which DACH1 was re-expressed, tumor size was smaller than in controls. In addition, restoration of DACH1 expression induced G2/M phase arrest and sensitized HCT116 cells to docetaxel. DACH1 suppresses CRC growth by inhibiting Wnt signaling both in vitro and in vivo. Silencing of DACH1 expression caused resistance of CRC cells to docetaxel. In conclusion, DACH1 is frequently methylated in human CRC and methylation of DACH1 may serve as detective and prognostic marker in CRC.

Topics: Adenomatous Polyposis Coli; Animals; Cell Line, Tumor; Colorectal Neoplasms; DNA Methylation; Docetaxel; Drug Resistance, Neoplasm; Epigenesis, Genetic; Eye Proteins; Female; Gene Silencing; HCT116 Cells; Heterografts; Humans; Male; Mice; Neoplasm Transplantation; Signal Transduction; Taxoids; Transcription Factors; Transforming Growth Factor beta; Wnt Proteins

The conditions Juvenile Polyposis Syndrome (JPS) and Hereditary Mixed Polyposis Syndrome (HMPS) are associated with an increased risk of colorectal carcinoma. The genetic mechanisms which explain these conditions have until recently been poorly understood. Recent interest has focused on the transforming growth factor (TGF)-beta signalling pathway and, in particular, on mutations in the SMAD4 gene. However, not all cases of JPS and HMPS have mutations in SMAD4 and focus has now shifted to other components of the TGF-beta pathway to clarify the genetic mechanisms involved in these conditions. In this report, we describe the significance of a bone morphogenetic protein receptor type 1A gene mutation in an Irish family.

Topics: Adenomatous Polyposis Coli; Adult; Bone Morphogenetic Protein Receptors, Type I; Colonic Polyps; Colorectal Neoplasms; Female; Humans; Male; Mutation; Pedigree; Signal Transduction; Smad4 Protein; Syndrome; Transforming Growth Factor beta

Bone morphogenetic proteins regulate many developmental processes during embryogenesis as well as tissue homeostasis in the adult. Signaling of bone morphogenetic proteins (BMPs) is accomplished by binding to two types of serine/threonine kinase transmembrane receptors termed type I and type II. Because a large number of ligands signal through a limited number of receptors, ligand-receptor interaction in the BMP superfamily is highly promiscuous, with a ligand binding to various receptors and a receptor binding many different BMP ligands. In this study we investigate the interaction of BMP-2 with its two high affinity type I receptors, BMP receptors IA (BMPR-IA) and BMPR-IB. Interestingly, 50% of the residues in the BMP-2 binding epitope of the BMPR-IA receptor are exchanged in BMPR-IB without a decrease in binding affinity or specificity for BMP-2. Our structural and functional analyses show that promiscuous binding of BMP-2 to both type I receptors is achieved by inherent backbone and side-chain flexibility as well as by variable hydration of the ligand-receptor interface enabling the BMP-2 surface to adapt to different receptor geometries. Despite the high degree of amino acid variability found in BMPR-IA and BMPR-IB binding equally to BMP-2, three single point missense mutations in the ectodomain of BMPR-IA cannot be tolerated. In juvenile polyposis syndrome these mutations have been shown to inactivate BMPR-IA. On the basis of our biochemical and biophysical analyses, we can show that the mutations, which are located outside the ligand binding epitope, alter the local or global fold of the receptor, thereby inactivating BMPR-IA and causing a loss of the BMP-2 tumor suppressor function in colon epithelial cells.

Topics: Adenomatous Polyposis Coli; Adult; Binding Sites; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Protein Receptors, Type II; Bone Morphogenetic Proteins; Colon; Embryonic Development; Enterocytes; Epitopes; Homeostasis; Humans; Ligands; Mutation; Protein Binding; Protein Structure, Quaternary; Protein Structure, Tertiary; Signal Transduction; Structure-Activity Relationship; Transforming Growth Factor beta; Tumor Suppressor Proteins

Germ-line mutations in bone morphogenic protein type II receptor (Bmpr2) confer susceptibility to pulmonary arterial hypertension (PAH), which is characterized by obstructive vascular lesions in small arteries. The molecular and cellular mechanisms that account for the etiology of this disorder remain elusive, as does the role of Bmpr2 in postnatal tissue homeostasis. Here we show that in adult mice, stably silencing Bmpr2 expression by RNA interference does not increase pulmonary arterial resistance but results in severe mucosal hemorrhage, incomplete mural cell coverage on vessel walls, and gastrointestinal hyperplasia. We present evidence that BMP receptor signaling regulates vascular remodeling during angiogenesis by maintaining the expression of endothelial guidance molecules that promote vessel patterning and maturation and by counteracting growth factor-induced AKT activation. Attenuation of this function may cause vascular dysmorphogenesis and predisposition to angioproliferative diseases. Our findings provide a mechanistic link between PAH and other diseases associated with the BMP/TGF-beta pathways, such as hereditary hemorrhagic telangiectasia and juvenile polyposis syndrome.

Topics: Adenomatous Polyposis Coli; Animals; Bone Morphogenetic Protein Receptors, Type II; Gene Dosage; Germ-Line Mutation; Hemorrhage; Homeostasis; Hypertension, Pulmonary; Mice; Mice, Knockout; Neovascularization, Pathologic; Proto-Oncogene Proteins c-akt; RNA Interference; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta

Colorectal cancer, one of the most common human malignancies in the Western world, is often subdivided based on tumor location in either the distal or proximal colon. Several mouse models have been developed to study human colorectal cancer, but few display this clear distinction between the two colonic locations. By crossing Apc(Min/+) and Smad3 mutant mice, we showed that combined activation of the Wnt pathway and attenuation of the transforming growth factor-beta (TGF-beta) pathway causes high multiplicity and rapid onset of invasive tumorigenesis almost exclusively in the distal colon, closely mimicking the familial adenomatous polyposis (FAP) disease and consisting with distinct colorectal cancer etiologies based on tumor location. Transcriptional profiling revealed higher expression of several TGF-beta activators in the normal distal mucosa than in proximal mucosa, suggesting a stronger reliance on TGF-beta-mediated growth control in the distal than in the proximal colon. Apc(Min/+)Smad3(-/-) mice provide an alternative model to Apc(Min/+) mice to study FAP and distal sporadic colorectal cancer. This model will be useful in dissecting mechanistic and etiologic differences between proximal and distal colonic cancer, whereas the confinement of tumorigenesis to the distal colon offers unique advantages in monitoring tumor progression by in vivo imaging.

Topics: Adenomatous Polyposis Coli; Animals; Biopsy; Colonic Neoplasms; Colorectal Neoplasms; DNA; Gene Expression Profiling; Genes, APC; Humans; Intestinal Mucosa; Mice; Mice, Knockout; Mice, Transgenic; Neoplasm Invasiveness; Polymerase Chain Reaction; Rectal Neoplasms; Smad3 Protein; Transcription, Genetic; Transforming Growth Factor beta

Topics: Adenomatous Polyposis Coli; Cell Proliferation; Gastrointestinal Neoplasms; Humans; Intestinal Mucosa; Signal Transduction; Smad4 Protein; T-Lymphocytes; Transforming Growth Factor beta

The recent findings of bone morphogenetic protein (BMP) receptor Ia mutations in juvenile polyposis and frequent Smad4 mutations in colon cancer suggest a role for BMPs in the colonic epithelium and colon cancer. We investigated the role of BMP2 in the colon.. We assessed BMP receptor expression in cell lines using the reverse-transcribed polymerase chain reaction and immunoblotting. We investigated the effect of BMP2 on cell lines using the MTT assay and by immunoblotting for markers of differentiation, proliferation, and apoptosis. We assessed the expression of BMP2, its receptors, and signal transduction elements in mouse and human colon tissue using immunohistochemistry. We also investigated the effect of the BMP antagonist noggin in vivo in mice by assessing colon tissue with immunohistochemistry and immunoblotting. Finally, we investigated the expression of BMP2 in microadenomas from familial adenomatous polyposis patients.. BMP receptors (BMPR) Ia, BMPR Ib, and BMPR II are all expressed in colonic epithelial cell lines. BMP2 inhibits colonic epithelial cell growth in vitro, promoting apoptosis and differentiation and inhibiting proliferation. BMP2, BMPRIa, BMPRIb, BMPRII, phosphorylated Smad1, and Smad4 are expressed predominantly in mature colonocytes at the epithelial surface in normal adult human and mouse colon. Noggin inhibits apoptosis and proliferation in mouse colonic epithelium in vivo. BMP2 expression is lost in the microadenomas of familial adenomatous polyposis patients.. These data suggest that BMP2 acts as a tumor suppressor promoting apoptosis in mature colonic epithelial cells.

Topics: Adenomatous Polyposis Coli; Animals; Apoptosis; beta Catenin; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein Receptors; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Protein Receptors, Type II; Bone Morphogenetic Proteins; Carrier Proteins; Cell Differentiation; Cell Division; Cell Line, Tumor; Colon; Colonic Neoplasms; Cytoskeletal Proteins; DNA-Binding Proteins; Humans; Intestinal Mucosa; Mice; Protein Serine-Threonine Kinases; Proteins; Receptors, Growth Factor; Smad Proteins; Smad1 Protein; Smad4 Protein; Trans-Activators; Transforming Growth Factor beta

Topics: Adenomatous Polyposis Coli; Alleles; Cell Transformation, Neoplastic; DNA-Binding Proteins; Humans; In Situ Hybridization, Fluorescence; Intestinal Mucosa; Smad4 Protein; Trans-Activators; Transforming Growth Factor beta

In order to characterize human desmoid tumors in vitro, the production of collagen and elastin and the expression of collagen types alpha1(I), alpha1(III) and transforming growth factor (TGF)-beta1 mRNA were investigated in six desmoid tumors; five derived from familial adenomatous polyposis patients and one from a sporadic case. The proportion of collagen production to total protein production was determined by 3H-imino acid incorporation, an indicator of collagen synthesis, using high-performance liquid chromatography (HPLC). The proportion of collagen production to total protein production was much higher in all six desmoid tumors compared with human skin fibroblasts (HSF). Quantitatively, the rate of elastin synthesis in desmoid tumor cells monitored by valine-proline peptide was also significantly higher than in HSF. Pro-alpha1(I) collagen mRNA was highly expressed in both desmoid tumors and HSF at approximately the same level, whereas pro-alpha1(III) collagen mRNA was more abundant in some of the desmoid tumors than the normal skin fibroblastic cell lines. Tumor growth factor-beta1 mRNA, which is believed to stimulate collagen synthesis, was expressed in both desmoid tumors and HSF to the same extent. These results demonstrate the increased formation of collagen and elastin in desmoid tumors in vitro and suggest that the increased synthesis of elastin rather than of collagen and TGF-beta1 may be involved in increased fibrogenesis by desmoid tumors.

Topics: Adenomatous Polyposis Coli; Adult; Blotting, Northern; Chromatography, High Pressure Liquid; Collagen; Elastin; Female; Fibromatosis, Abdominal; Humans; Imino Acids; Male; RNA, Messenger; RNA, Neoplasm; Transforming Growth Factor beta; Tumor Cells, Cultured

Topics: Adenoma; Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Biological Evolution; Colonic Neoplasms; Cytoskeletal Proteins; DNA Repair; DNA-Binding Proteins; DNA, Satellite; Fungal Proteins; Humans; Mice; Microsatellite Repeats; Models, Genetic; Mutation; MutS Homolog 2 Protein; Neoplasms; Transforming Growth Factor beta

Most colon cancers arise from polypoid adenomas, but how these benign lesions develop into malignant neoplasms is not understood. This study examined the migration of epithelial cells within human adenomatous polyps by determining the distribution of proliferating and apoptotic cells and immunoreactivity to transforming growth factor beta (TGF-beta).. Sections of surgically resected normal (n = 10) and adenomatous (n = 22) formalin-fixed tissue were examined for proliferating cells and TGF-beta isoenzymes 1-3 by immunohistochemistry and apoptotic cells by terminal deoxyuridine nick end-labeling.. The distribution of proliferating, apoptotic, and TGF-beta immunoreactive cells was strikingly reversed in adenomatous polyps compared with normal mucosa. Proliferating cells were located in the base of normal colonic crypts and TGF-beta immunoreactive and apoptotic cells near or at the luminal surface, corresponding to the normal migration of colonocytes. In adenomas, increased numbers of proliferating cells were mainly located at the luminal surface and TGF-beta immunoreactive and apoptotic cells were located principally at the crypt base.. This distribution suggests that cell migration in adenomas is not toward the lumen but instead inward toward the polyp base.

Topics: Adenomatous Polyposis Coli; Apoptosis; Cell Division; Cell Movement; Colon; Epithelium; Humans; Immunohistochemistry; Transforming Growth Factor beta