Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of growth factors have been implicated as stimuli of thyroid cell proliferation; overexpression of these growth factors and/or their receptors may play a role in the growth of thyroid tumors. To determine if immunohistochemical detection of growth factors and/or their receptors correlates with morphological alterations in proliferative lesions of thyroid, we examined the localization of epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha) and their common receptor, EGF-receptor (EGF-R), insulin-like growth factor-1 (IGF-1), IGF-1-receptor (IGF-R) and IGF binding proteins (IGFBP)-1, -2, -3, and -4, nerve growth factor (NGF), and its receptor NGF-receptor (NGF-R), transforming growth factor-beta (TGF-beta), and basic fibroblast growth factor (bFGF), in normal thyroid tissue and various thyroid tumors. We applied the streptavidin-biotin technique to formalin-fixed, paraffin-embedded tissues. We studied 8-16 different cases of each of the following: normal human thyroid, multinodular hyperplasia, follicular adenoma, papillary carcinoma, follicular carcinoma, medullary carcinoma, and anaplastic carcinoma. EGF, TGF-alpha, and their receptor EGF-R were widely expressed in normal thyroid and in all the thyroid lesions examined. IGF-1 and IGFBP-1 were diffusely present in all different thyroid tissues as well. There was no difference in staining intensity or distribution that correlated with the pathological process. IGFBP-4 seemed to have a variable expression. IGFBP-2 and -3 were detected only in medullary carcinomas.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Expression of growth factors and growth factor receptors in normal and tumorous human thyroid tissues. 778 37

Frame-shift mutations in a run of 10 adenines (A10) of the transforming growth factor-beta receptor type 2 gene (TGF-beta RII) are commonly seen in inherited and sporadic colonic cancers that exhibit microsatellite instability. A10 mutations and instability also are commonly seen in hereditary nonpolyposis colon cancer-associated adenomas. However, instability is quite rare in sporadic adenomas, and the timing of acquisition of A10 mutations with respect to the sporadic adenoma-carcinoma sequence has not been reported. We evaluated 100 sporadic colorectal cancers and 164 sporadic adenomas for microsatellite instability with a set of 10 tetranucleotide polymerase chain reaction primer sets and for A10 frame-shift mutations. A10 mutations were significantly associated with microsatellite instability in colorectal cancers, being seen in 9 of 11 cancers with 50% or greater instability and in 0 of 89 tumors with less than 50% instability (P < 0.0001). A10 mutations were not detected in any adenomas, only three of which (1.8%) exhibited significant (30% or greater) instability. We conclude that both TGF-beta RII frame-shift mutations and microsatellite instability occur at a relatively late stage of sporadic colorectal tumorigenesis. A10 frame-shift mutations appear to be restricted to sporadic colorectal cancers with extensive microsatellite instability.
 ...
PMID:Transforming growth factor-beta receptor type 2 mutations and microsatellite instability in sporadic colorectal adenomas and carcinomas. 921 28

The transforming growth factor-beta (TGF-beta) type II receptor (RII) is a colon cancer suppressor gene that is inactivated by mutation in 90% of human colon cancers arising via the microsatellite instability (MSI) pathway of carcinogenesis. To determine the pathophysiological consequence of RII mutations, we have determined the timing of their onset among 22 MSI human colon adenomas of varying stages. No RII mutations were detected in any early MSI adenoma, including all those with simple tubular or villous histology. The earliest RII mutation detected was in a region of high-grade dysplasia but was absent from the surrounding simple adenoma. Six additional RII mutations were all found in highly progressed adenomas that contained regions of frankly invasive adenocarcinoma. These RII mutations were detected in both the advanced adenomas and their adjacent regions of carcinoma. RII mutation is a late event in MSI adenomas and correlates tightly with progression of these adenomas to cancer.
 ...
PMID:Mutation of the type II transforming growth factor-beta receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. 967 77

Many colorectal cancer cells are resistant to the anti-proliferative effects of transforming growth factor-beta (TGF-beta). TGF-beta also acts as paracrine factor from cancer cells on their mesenchymal cells. The aim of this study was to examine the expression of TGF-beta and its receptors in human colorectal cancer tissue and determine any relationship with cancer growth. In situ hybridization and Northern blot hybridization detection of TGF-beta1, type I and type II receptor mRNA and immunohistochemical staining of TGF-beta1 were performed using 11 human colorectal adenomas, 22 colorectal cancers and ten normal colorectal mucosas as control. TGF-beta receptor mRNAs were expressed mainly by normal colorectal epithelial cells and adenoma. However, mRNAs for TGF-beta receptors were only faintly, if at all, expressed in eight of 22 human colorectal cancers. In addition, intense signals of TGF-beta1 mRNA and the protein were detected in all colorectal cancers. TGF-beta receptor mRNAs and TGF-beta1 protein were also distributed in fibroblasts and endothelial cells in the interstitium. Moreover, Smad 4 protein was translocated to nucleus in primarily cultured adenoma cells, but not in cancer cells after TGF-beta stimulation. The escape of human colon cancer from TGF-beta-mediated growth inhibition by down-regulation of TGF-beta receptors as well as the effects of TGF-beta on stroma formation and angiogenesis indicate a possible role for TGF-beta in the progression of colon cancer in an intact host.
 ...
PMID:Down-regulation of TGF-beta receptors in human colorectal cancer: implications for cancer development. 1038 96

Activin A belongs to the transforming growth factor-beta superfamily that exerts a wide range of biologic activities on cellular proliferation and differentiation. Although it was suggested that gonadal tissue is the primary site of activin production, several extragonadal sources have subsequently been identified, including human thyrocytes. The goal of the present study was to evaluate serum activin A levels in a series of patients with different thyroid disorders during the active state of the diseases and after recovery. Serum activin A levels were evaluated in 60 healthy subjects (controls), 8 with multinodular nontoxic goiter (MNG), 30 hyperthyroid (15 with Graves' disease (GD), 12 with autonomous hyperfunctioning adenoma (ATA), and 3 with thyrotropin (TSH)-secreting pituitary adenoma, 16 hypothyroid (11 with Hashimoto's thyroiditis and 5 after total thyroidectomy), and 9 patients with resistance to thyroid hormone (RTH) by commercial enzyme-linked immunosorbent assay (ELISA) kit. Patients with GD and ATA showed activin A levels higher than those found in controls and similar to those observed in MNG (GD, 0.74 +/- 0.3 ng/mL; ATA, 0.86 +/- 0.4; and MNG; 1.0 +/- 0.2 vs. controls: 0.39 +/- 0.5, p < 0.001), while in patients with Hashimoto's thyroiditis, total thyroidectomy or RTH activin A levels were similar to those of controls. In conclusion, this study demonstrates that thyroid hyperplasia and hyperfunction result in increased levels of activin A, although the normal levels observed in thyroidectomized patients clearly demonstrate that the thyroid gland is not the predominant source of activin A in normal conditions. Because activin A may exert negative action on thyrocyte proliferation, it is conceivable that activin A hypersecretion in thyroid disorders might represent a counteracting mechanism.
 ...
PMID:Serum activin A levels in different thyroid disorders. 1259 25

Conversion of normal epithelial cells to tumors is associated with a shift in transforming growth factor-beta (TGF-beta) function: reduction of tumor suppressor activity and increase of oncogenic activity. However, specific mechanisms of this functional alteration during human colorectal carcinogenesis remain to be elucidated. TGF-beta signaling involves Smad2/3 phosphorylated at linker regions (pSmad2/3L) and COOH-terminal regions (pSmad2/3C). Using antibodies specific to each phosphorylation site, we herein showed that Smad2 and Smad3 were phosphorylated at COOH-terminal regions but not at linker regions in normal colorectal epithelial cells and that pSmad2/3C were located predominantly in their nuclei. However, the linker regions of Smad2 and Smad3 were phosphorylated in 31 sporadic colorectal adenocarcinomas. In particular, late-stage invasive and metastatic cancers typically showed a high degree of phosphorylation of Smad2/3L. Their extent of phosphorylation in 11 adenomas was intermediate between those in normal epithelial cells and adenocarcinomas. Whereas pSmad2L remained in the cytoplasm, pSmad3L was located exclusively in the nuclei of Ki-67-immunoreactive adenocarcinomas. In contrast, pSmad3C gradually decreased as the tumor stage progressed. Activated c-Jun NH(2)-terminal kinase in cancers could directly phosphorylate Smad2/3L. Although Mad homology 2 region sequencing in the Smad4 gene revealed a G/A substitution at codon 361 in one adenocarcinoma, the mutation did not correlate with phosphorylation. No mutations in the type II TGF-beta receptor and Smad2 genes were observed in the tumors. In conclusion, pSmad3C, which favors tumor suppressor activity of TGF-beta, was found to decrease, whereas c-Jun NH(2)-terminal kinase tended to induce the phosphorylation of Smad2/3L in human colorectal adenoma-carcinoma sequence.
 ...
PMID:Acceleration of Smad2 and Smad3 phosphorylation via c-Jun NH(2)-terminal kinase during human colorectal carcinogenesis. 1566 91

Although transforming growth factor-beta (TGF-beta) is both a suppressor and promoter of tumorigenesis, its contribution to early tumor suppression and staging remains largely unknown. In search of the mechanism of early tumor suppression, we identified the adaptor protein ELF, a beta-spectrin from stem/progenitor cells committed to foregut lineage. ELF activates and modulates Smad4 activation of TGF-beta to confer cell polarity, to maintain cell architecture, and to inhibit epithelial-to-mesenchymal transition. Analysis of development of colon cancer in (adult) elf+/-/Smad4+/-, elf+/-, Smad4+/-, and gut epithelial cells from elf-/- mutant mouse embryos pinpoints the defect to hyperplasia/adenoma transition. Further analysis of the role of ELF in human colorectal cancer confirms reduced expression of ELF in Dukes' B1 stage tissues (P < 0.05) and of Smad4 in advanced colon cancers (P < 0.05). This study indicates that by modulating Smad 4, ELF has a key role in TGF-beta signaling in the suppression of early colon cancer.
 ...
PMID:Transforming growth factor-beta suppresses nonmetastatic colon cancer through Smad4 and adaptor protein ELF at an early stage of tumorigenesis. 1589 14

Some markers of angiogenic endothelial cells are emerging as targets of cancer therapy. The present study compares the expression of CD105 with that of other endothelial markers in all tissue layers during the development of colon cancer. We immunohistochemically analyzed the expression of the colon adenoma-carcinoma sequence by endothelial cells using a panel of eight endothelial markers. We examined sections from endoscopic mucosal resection and surgical resection of tubular adenoma (n=31), carcinoma in adenoma (n=11), and adenocarcinoma (n=34). Cylindrical cores were punched out from donor paraffin blocks of normal mucosa adjacent to tumors, from tumor lesions of mucosa, submucosa, muscularis propria, subserosa, and serosa, and from lymph node metastases. CD31 (PECAM-1) was universally expressed in the blood vessels of adenoma-carcinoma lesions as well as in normal mucosal vessels (80-95%), with no significant differences. In contrast, cancer-associated blood vessels (up to 80%) and cancer cells themselves expressed high levels of CD105. In normal mucosa, CD105 was weakly expressed in endothelial cells of capillaries (< or =21%), and significant differences in its expression in endothelial cells between the normal mucosa and adenoma, carcinoma in adenoma, and adenocarcinoma were found. Flt-1, Flk-1, transforming growth factor-beta1, transforming growth factor-beta receptor II, and CD44 were strongly expressed in the cancer cells but were not expressed in the blood vessels. Vascular endothelial growth factor was expressed at <30% in the blood vessels of adenoma, carcinoma in adenoma, and carcinoma. Moreover, this study provided evidence that CD105 was expressed exclusively in endothelial blood vessels by double immunostaining of CD105 and D2-40. The present study shows that de novo blood vessels of colon cancer specifically express CD105. These findings provide the basis for novel antiangiogenic cancer therapies.
 ...
PMID:Endoglin (CD105) expression in angiogenesis of colon cancer: analysis using tissue microarrays and comparison with other endothelial markers. 1617 81

It has been well documented that there are two major pathways in colorectal carcinogenesis. One is the chromosomal instability pathway (adenoma-carcinoma sequence), which is characterized by allelic losses on chromosome 5q (APC), 17p (p53), and 18q (DCC/SMAD4), and the other is a pathway that involves microsatellite instability. Recent progress in molecular biology, however, has shown that colorectal carcinogenesis is not necessarily clearly divided into these two pathways, but is in fact more complicated. Other routes, including the transforming growth factor-beta/SMAD pathway, the serrated pathway, and the epigenetic pathway, have been reported. Cross talk among these pathways has also been reported. In the invasion and metastasis steps of colorectal cancers, many more genes have now been identified as being involved in proteolysis, adhesion, angiogenesis, and cell growth. Recently accumulated evidence indicates that colorectal cancer is a genetically heterogeneous and complicated disease.
 ...
PMID:Colorectal cancer: genetics of development and metastasis. 1669 51