Histology and histopathology Vol.14, nº 1 (1999)
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- PublicationOpen AccessClinical applications of detecting dysfunctional p53 tumor suppressor protein(Murcia : F. Hernández, 1999) Baas, I.O.; Hruban, R.H.; Offerhaus, G.J.A.The p53 gene encodes for a protein, p53, which plays a critical role in controlling the cell cycle, in DNA repair and in programed cell death (apoptosis). p53 is one of the most frequently mutated genes in human neoplasms and a variety of techniques have been developed to detect these mutations. These range from advanced molecular-genetic analyses to immunohistochemical staining for the p53 protein. This review will summarize our current understanding of the function of p53 as well as current methods to detect dysfunctional p53 and the clinical value of such analyses.
- PublicationOpen AccessMolecular and cellular basis of tissue remodeling during amphibian metamorphosis(Murcia : F. Hernández, 1999) Su, Y.; Damjanovski, S.; Shi, Y.; Shi, Y.B.Amphibian metamorphosis involves systematic transformations of various tadpole organs1 tissues. Three major types of changes take place during this process. These are remodeling, resorption, and de novo development, all of which appear to involve both cell proliferation and apoptosis (programmed cell death). All metamorphic changes are controlled by thyroid hormone (T3) and are organ-autonomous. Recent studies using primary cell cultures and a stably transformed cell line from tadpole tissues have implicated that T3 induces apoptosis cell-autonomously. This T3-induced, metamorphosis-associated apoptosis is similar to cell death in other animal species and involves similar cell death executioners. Both the activation of these executioners and the pathways leading to cell proliferation and differentiation are believed to be through transcriptional regulation by T3 receptors (TRs). TRs can activate or repress target gene transcription depending upon the presence or absence of T3, respectively. Many direct T3-response genes have been isolated and found to encode a variety of proteins that can affect both intra- and extra-cellular events. The determinations of the identities of these response genes through sequence analyses and studies on their expression profiles during development have provided strong clues toward their roles in metamorphosis. However, future studies using organ and cell culture systems andlor transient or stable transgenic technologies are required to understand how these genes transduce the T3 signal to activate the downstream cell death and proliferation/differentiation pathways.
- PublicationOpen AccessBcl-2 protein expression and gut neurohormonal polypeptidelamine production in colorectal carcinomas and tumor-neighboring mucosa, which closely correlate to the occurrence of tumor(Murcia : F. Hernández, 1999) Ohmori, Takaaki; Asahi, S.; Sato, C.; Maki, F.; Masumoto, A.; Okada, K.To clarify whether advanced colorectal carcinomas and tumor-neighboring mucosa simultaneously produce both Bcl-2 protein and gut neurohormonal polypeptides andlor amines, and the interrelationship of these phenomenon, we studied retrospective analysis of Bcl-2 protein production and neuroendocrine characteristics in 52 cases of advanced colorectal carcinoma and surrounding mucosa. All of the tumor-neighboring mucosa presented hyperplasia. The rates of enhanced immunoreactivity of the tumor-neighboring mucosa and of positive immunoreactivity of the carcinomas against human Bcl-2 protein and against human vasoactive intestinal polypeptide, pancreatic polypeptide and somatostatin were 78.8% and 94.2%, 82.7% and 59.6%, 78.8% and 67.3%, and 88.5% and 84.6% respectively. Double immunostaining for Bcl-2 protein and each peptide hormone revealed simultaneous expression. In contrast, that of tumor-neighboring mucosa and carcinomas to serotonin and chromogranin-A and to argyrophilia were 11.5% and 1.9%, 32.7% and 17.3%, and 26.9% and 21.2%, respectively. We concluded that tumor-neighboring crypt cells displayed not only hyperplasia but also neuroendocrine characteristics and that enhanced Bcl-2 protein immunoreactivity correlated with tumor occurrence in the wall of the colorectum. The production of Bcl-2 protein by tumor cells and tumorneighboring crypt cells indicates that the bcl-2 protooncogene may act not only as an inhibitor of apoptosis but also as an inducer of neuroendocrine differentiation from the latent characteristics of the endodermal stem cell.
- PublicationOpen AccessMolecular genetics of ovarian carcinomas(Murcia : F. Hernández, 1999) Diebold, J.The phenotypic variability of epithelial ovarian neoplasms correlates with a diversity of changes at the molecular level. Invasive serous and undifferentiated ovarian carcinomas are characterized by p53 mutations with p53 protein accumulation, extensive loss of genetic material of chromosome 17 and complex changes on many other chromosomes, e.g. amplification of oncogenes. These alterations are seen only in a minority of mucinous and endometrioid carcinomas, mainly in advanced stages. Overexpression of bcl-2 is seen most frequently in endometrioid carcinomas (ca. 90% of cases), which in addition show microsatellite instability in around a third of the cases, as has been described in endometrioid endometrial carcinomas. KRAS mutations are characteristic for mucinous LMP tumors and mucinous carcinomas (40-50% of cases) and are also found in a third of serous LMP tumors. In addition, serous LMP tumors show mild microsatellite instability in 30%. However, complex chromosomal aberrations are never seen in these neoplasms
- PublicationOpen AccessThrombospondin-1, PECAM-1, and regulation of angiogenesis(Murcia : F. Hernández, 1999) Sheibani, N.; Frazier, W.A.Thrombospondin-l (TSPl) is a multidomain glycoprotein expressed by many cell types. It is a multifunctional protein with important roles in regulation of vascular cell functions. Mutation or loss of tumor suppressor genes results in down regulation of TSPl expression during malignant transformation. Thus, suggesting that down regulation of TSPl may contribute to development of the tumor angiogenic phenotype and perhaps tumor metastasis. TSPl was demonstrated to be a natural inhibitor of angiogenesis. Peptides from procollagen-like domain and type 1 repeats of TSP1, like whole TSP1, inhibit the angiogenic response to a variety of angiogenic stimuli in vivo and endothelial cell (EC) migration in vitro by directly acting on ECs. The molecular mechanisms which mediate these inhibitory effects of TSPl and its peptides are not understood. TSPl expression is down regulated in the Polyoma middle T transformed mouse brain ECs (bEND.3). This may remove the TSPl inhibitory effects allowing ECs to rapidly proliferate in culture and form hemangiomas in vivo. Re-expression of TSPl in bEND.3 cells restores a normal phenotype and suppresses their ability to form hemangiomas. This is mediated by modulating expression of several genes in concert favoring a differentiated state of endothelium. TSPl transfected bEND.3 cells down regulate expression of PECAM-1, a multifunctional endothelial cell adhesion molecule with essential roles in angiogenesis. A similar phenotype to that of TSPl transfected cells was observed when endogenous PECAM-1 levels were down regulated by anti-sense transfection of bEND.3 cells. The anti-sense PECAM-1 transfected cells turn on expression of endogenous TSPl and its angioinhibitory receptor, CD36. Expression of other genes with potential roles in regulation of EC phenotype were also affected in patterns very similar to those observed in TSPl transfected bEND.3 cells. Therefore, it appears that a reciprocal relationship exists between TSPl and PECAM-1 such that they are constituents of a "switch" that regulates in concert many components of the angiogenic and differentiated phenotype of ECs.