bromochloroacetic-acid and Adenomatous-Polyposis-Coli

We describe herein four cases of an unusual sporadic thyroid tumor that shares the morphologic features of a distinctive follicular cell neoplasm previously proposed as a feasible indicator of familial adenomatous polyposis. We also review five other similar cases reported in the literature. All of the nine patients were young women, aged 16 to 30 years. Grossly, the neoplasms measured 1.5 to 5.6 cm; they were solid and solitary, except one case, which showed two tumor nodules, one in each lobe. Histologically, the lesions were encapsulated, and they exhibited an intricate blending of cribriform, follicular, papillary, trabecular, and solid patterns of growth, with morular (squamoid) areas. Cribriform structures were prominent, being formed by anastomosing bars and arches of cells in the absence of intervening fibrovascular stroma. Follicular areas were usually devoid of colloid, and the papillae were lined by columnar cells. There were focal areas of trabecular arrangement reminiscent of hyalinizing trabecular adenoma. The tumor cells were cuboidal or tall, with frequent nuclear pseudostratification and abundant eosinophilic-to-oxyphilic cytoplasm. The nuclei were usually hyperchromatic, but nuclear grooves, pale or clear nuclei, and intranuclear cytoplasmic inclusions were variably present. Morules with peculiar nuclear clearing caused by biotin accumulation were scattered in the tumors. Vascular and/or capsular invasion were noted in all of the cases except one, and lymph node metastasis was found in two cases. Immunohistochemical stains showed reactivity for thyroglobulin, epithelial membrane antigen, cytokeratins (including 34betaE12), vimentin, estrogen and progesterone receptors, bcl-2, and Rb proteins. Follow-up in seven cases showed that all of the patients were alive with no evidence of disease at 1 to 13 years after diagnosis. Thus, the behavior of this variant seems to be similar to that of conventional papillary carcinoma Because of the distinctive histologic features, we propose naming this tumor the cribriform-morular variant of papillary carcinoma.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Carcinoma, Papillary; Female; Humans; Immunohistochemistry; Keratins; Mucin-1; Phosphopyruvate Hydratase; Thyroglobulin; Thyroid Neoplasms; Vimentin

As a key player in suppression of colon tumorigenesis, Adenomatous Polyposis Coli (APC) has been widely studied to determine its cellular functions. However, inconsistencies of commercially available APC antibodies have limited the exploration of APC function. APC is implicated in spindle formation by direct interactions with tubulin and microtubule-binding protein EB1. APC also interacts with the actin cytoskeleton to regulate cell polarity. Until now, interaction of APC with the third cytoskeletal element, intermediate filaments, has remained unexamined.. We generated an APC antibody (APC-M2 pAb) raised against the 15 amino acid repeat region, and verified its reliability in applications including immunoprecipitation, immunoblotting, and immunofluorescence in cultured cells and tissue. Utilizing this APC-M2 pAb, we immunoprecipitated endogenous APC and its binding proteins from colon epithelial cells expressing wild-type APC. Using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS), we identified 42 proteins in complex with APC, including beta-catenin and intermediate filament (IF) proteins lamin B1 and keratin 81. Association of lamin B1 with APC in cultured cells and human colonic tissue was verified by co-immunoprecipitation and colocalization. APC also colocalized with keratins and remained associated with IF proteins throughout a sequential extraction procedure.. We introduce a versatile APC antibody that is useful for cell/tissue immunostaining, immunoblotting and immunoprecipitation. We also present evidence for interactions between APC and IFs, independent of actin filaments and microtubules. Our results suggest that APC associates with all three major components of the cytoskeleton, thus expanding potential roles for APC in the regulation of cytoskeletal integrity.

Topics: Adenomatous Polyposis Coli; Antibodies; beta Catenin; Cell Line; Chromatography, High Pressure Liquid; Colon; Epithelial Cells; Fluorescent Antibody Technique; Humans; Immunoblotting; Immunoprecipitation; Intermediate Filament Proteins; Keratins; Lamin Type B; RNA Interference; Tandem Mass Spectrometry

Epidemiological evidence suggests that dietary calcium and vitamin D intake are inversely related to incidence of colon cancer. Previous studies have demonstrated that supplementation of the diet with calcium in the form of calcium tablets or low-fat dairy foods alters colonic epithelial cell proliferation from a higher- to a lower-risk pattern. The present study compared relative effects of administration of calcium carbonate at approximately 900 mg/day (calcium) with those of a low-fat dairy food diet providing about the same amount of calcium (dairy) in a cross-over "head-to-head" study of 40 subjects at risk for colonic neoplasia. Dietary intake of macronutrients was similar in the two study periods, except for a slight increase in protein intake during dairy calcium supplementation. Rectal epithelial cell proliferation was studied in flat endoscopically normal-appearing mucosa at baseline and at the end of each of the two study periods and showed a significant reduction in epithelial crypt cell labeling index from 12.5% to 9.1% (calcium) or 9.3% (dairy) as well as in proliferating cells in the upper 40% of the crypt from 0.09 to 0.03 in the calcium- and low-fat dairy-supplemented intervention groups. No significant changes in two epithelial cell differentiation markers, cytokeratin AE1 and acidic mucins, were found. Furthermore, there were no differences in epithelial cell apoptosis or expression of the proapoptotic gene product BAK. These data indicate that increased dietary calcium given as supplements or in the diet in low-fat dairy foods lowers epithelial cell proliferation indexes from a higher- to a lower-risk pattern. Because supplemental calcium has been shown to reduce the recurrence of colonic adenomatous polyps in patients at increased risk for colonic neoplasia, our data suggest that supplemental low-fat dairy foods may also be effective.

Topics: Adenomatous Polyposis Coli; Apoptosis; bcl-2 Homologous Antagonist-Killer Protein; Biopsy; Calcium Carbonate; Calcium, Dietary; Cell Differentiation; Cell Division; Colon; Colonic Neoplasms; Dairy Products; Diet; Diet, Fat-Restricted; Dietary Supplements; Epithelial Cells; Female; Humans; Keratins; Male; Membrane Proteins; Middle Aged; Mucins; Racial Groups; Rectum

Cells of the normal colonic mucosa express several types of cytokeratins, the characteristic intermediate filament proteins of epithelial cells. An immunohistochemical study was designed to examine the expression of two distinct groups of cytokeratins, recognized by monoclonal antibodies AE1 and AE3, in the colonic mucosa and to compare the findings with those obtained with a large number of polypoid lesions (adenomatous and hyperplastic) and carcinomas of the colon. AE1 and AE3 immunostaining was found in the surface epithelium and upper portions of the crypts of Lieberkühn (functional zone) of normal colonic mucosa, whereas the lower portions of the crypts (proliferative compartment) were unreactive with both AE1 and AE3. Polypoid lesions of the colonic mucosa can be placed into two categories based on their patterns of cytokeratin expression. Solitary tubular adenomas and hyperplastic polyps are composed of AE1 and AE3 nonexpressing cells with only few, patchy areas of AE1 and AE3 expressing cells present within glands and in the surface epithelium. In contrast, villous adenomas show strong AE1 and AE3 reactivity throughout the glands. Furthermore, tubular and villous adenomas, and even histologically normal mucosa in patients with familial polyposis, show AE1/AE3 expression throughout the glands and surface epithelium. Colonic carcinomas show a predominance of AE1/AE3 expressing cells. Thus, cytokeratins recognized by monoclonal antibodies AE1 and AE3 represent molecular markers of cellular maturation in the normal colonic mucosa, that are expressed in colonic carcinomas and, in addition, serve as markers that distinguish colonic mucosa and adenomas with a high risk for development of cancers from those with a lower risk.

Topics: Adenocarcinoma; Adenoma; Adenomatous Polyposis Coli; Antibodies, Monoclonal; Cell Differentiation; Cell Transformation, Neoplastic; Colon; Colonic Neoplasms; Epithelium; Humans; Hyperplasia; Intestinal Mucosa; Keratins