1. Pathology Division

Research in the Pathology Division is based on a combination of molecular and cellular biological analyses and clinicopathological observations.

Genetic and Chromosomal Alterations in Human Cancers

Alterations at the DNA level were examined in resected human gastrointestinal, liver, and breast tumors and clinical implications of these alterations were investigated.^(1-7)
LOH on chromosome 16q was shown to occur frequently in breast carcinomas regardless of histological type and the degree of tumor extension. Examination of LOH on 16q by microsatellite polymorphism analyses using fine-needle aspiration specimens was suggested to be a supportive tool for preoperative diagnosis of breast tumors.⁽⁷⁾ Using FISH analysis of interphase nuclei of tumor cells, loss of chromosome 16q was frequently detected in a clonal fashion in low-grade intracystic papillary carcinomas. In this cancer type, the aberrant chromosome 16 showing loss of 16q24 was frequently found to be fused to chromosome 1q, and the formation of the derivative chromosome appeared to occur at early developmental stages. The detection of loss of 16q and (1;16) fusion were suggested to be helpful in the differential diagnosis of intraductal papillary breast tumors.

DNA Methylation and Other Epigenetic Alterations in Human Cancers

In order to clarify the significance of DNA methylation in both early and late stages of hepatocarcinogenesis, the DNA methylation state of chromosome 16, on which LOH has frequently been detected in human hepatocellular carcinomas (HCCs), was examined.⁽⁸⁾ DNA hypermethylation was observed at several loci on both 16p and 16q; the chromosome locus at which HCCs showed the highest incidence of DNA hypermethylation was the TAT locus (16q22.2). Frequent DNA hypomethylation was detected at a locus on 16q. Aberrant DNA methylation occurred more frequently in advanced HCCs than in early HCCs. Furthermore, DNA hypermethylation was frequently observed even in chronic hepatitis and liver cirrhosis. The incidence of DNA hypermethylation was higher than that of LOH. These data suggest that DNA hypermethylation might predispose the locus to allelic loss. Aberrant DNA methylation is a significant change which may contribute to the early developmental stages of HCCs. Other epigenetic events,⁽⁹⁾ e.g. post-transcriptional inactivation of the p16^INK4 tumor suppressor gene⁽¹⁰⁾ and ubiquitin-conjugation with cytokeratin 8,⁽¹¹⁾ in carcinogenesis have also been investigated.

Molecular and Cellular Mechanisms of Cancer Invasion and Metastasis

The first, crucial, step in cancer invasion and metastasis is the dissociation of cancer cells from primary cancer nests. Dysfunction of the E-cadherin-mediated cell adhesion system plays an important role in this step. This system, as an invasion suppressor, was found to be inactivated by various mechanisms including genetic alterations⁽¹²⁾ and reduced expression via CpG methylation of the promoter region of the E-cadherin gene, and tyrosine phosphorylation of beta-catenin.
beta-catenin is found to be associated directly with receptor type tyrosine kinases, c-erbB-2 and the EGF receptor in human cancers. Growth factor specifically activated its receptors and phosphorylated b-catenin resulting in inactivation of the cell adhesion function. N-terminally deleted beta-catenin which binds to c-erbB-2, but not to cadherin, inhibited the association between endogenous beta-catenin and c-erbB-2 protein and suppressed the tyrosine phosphorylation of beta-catenin. Cells expressing truncated beta-catenin exhibited markedly reduced invasiveness and peritoneal metastasis in vitro and in vivo, respectively, in the nude mouse model.⁽¹³⁾ The phorbol ester-induced signal transduction regulating cell to matrix adhesion and cell to cell adhesion in a coordinate manner was investigated in colon cancer cells.⁽¹⁴⁾ It was reported that beta-catenin was associated with the APC tumor suppressor and that the expression of beta-catenin was regulated by APC in vitro. The altered regulation of beta-catenin expression was also observed in colonic epithelial cells of familial polyposis patients in vivo.⁽¹⁵⁾ Other cell-cell and cell-matrix adhesion molecules were investigated in human cancers^(16-19) and the establishment of an in vitro model for analyzing cancer is underway.^(20,21)

Clinicopathologic Studies

Four cases of papillary thymic carcinoma, a new clinicopathologic entity, were described. An intimate anatomic relationship with the coexisting spindle cell thymoma component seen in three of these cases strongly implies a histogenetic association. In addition, clinicopathologic studies were conducted to promote the diagnosis and treatment of tumors of the lung⁽²²⁾ and liver.^(23-27)

List of papers from this division

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