1. Pathology Division
Research in the Pathology Division is based on a combination of molecular and cellular biological methods and access to a large and comprehensive store of clinicopathological data obtained through routine diagnostic work at the National Cancer Center Hospital. The division is devoted mainly to studies of high-risk conditions for the development of malignancies, the mechanisms of multistage carcino-genesis, especially tumor progression from early to late-stage cancer, and the mechanisms of cancer invasion and metastasis.
Pathology of Multistage Carcinogenesis and Alterations of Cancer-related Genes
The frequency of p53 nuclear staining in the nondysplastic squamous epithelia surrounding multicentric squamous cell carcinoma of the aerodigestive tract was found to be higher than in the nondysplastic epithelia surrounding unicentric carcinoma, indicating that nuclear accumulation of p53 in the squamous epithelia surrounding multicentric carcinoma probably reflects heavier exposure and/or increased susceptibility to carcinogenes of the affected individuals.(1)
Small adenocarcinomas of the lung were examined histopathologically in order to study multistep progression from in situ neoplasia to advanced carcinoma.(2) In situ neoplasia, which develops by replacement of alveolar lining cells without destructive growth, progresses to advanced carcinoma containing areas of active fibroblastic and angiogenic proliferation, or partially progresses to poorly differentiated adenocarcinoma showing largely solid growth. A process of multistage carcinogenesis similar to that which had previously been shown in hepato-ellular carcinoma was found to occur in the case of pulmonary adeno-carcinoma.
Studies were performed to compare individual gene and chromosome alterations and histopathological characteristics in various human cancers.(3-7) In breast cancer, amplification of the c-erbB-2 oncogene, loss of heterozygosity on chromosome 17p, and point mutation of the p53 gene were shown to be associated with aggressive morphological phenotypes, e.g., the comedo type, which shows a high histological grade of atypia, even at the pre-invasive stage.(3) It was suggested that these gene alterations occur in breast cancers with a high proliferation rate, regardless of the presence of invasion, and that other molecular mechanisms are involved in the process of invasion.
Molecular and Cellular Mechanisms of Cancer Invasion and Metastasis
The first and crucial step in cancer invasion and metastasis is the dissociation of cancer cells from primary cancer nests. The molecular mechanisms of inactivation of the E-cadherin-mediated cell adhesion and invasion suppressor system have been analyzed. The system was found to be inactivated by various mechanisms including genetic alterations and reduced expression and tyrosine phosphorylation of E-cadherin and/or alpha- and beta-catenins.(8) CpG methylation of the promoter region of the E-cadherin gene reduced the expression of E-cadherin in loosely adhesive cancer cells.(9) It was clarified that beta-catenin directly associates with the c-erbB-2 oncogene product and is phosphorylated at tyrosine residues.(10) cDNA clones for a cadherin molecule were isolated from a cDNA library of human hepatocellular carcinoma cells which lacked E- and P-cadherin expression but exhibited cell aggregation activity, and were found to encode cadherin-6, the human counterpart of rat K-cadherin.(11)
An in vitro peritoneal dissemination model using cultured mesothelial cells was established. By using this model, it was demonstrated that beta1-integrin-dependent and -independent adhesion between ovarian cancer cells and mesothelial cells was involved in the process of peritoneal dissemination.(12)
Application of Molecular and Genetic Analyses to Cancer Diagnosis
Several molecules were identified as being potentially useful for making difficult decisions in routine pathological practice. A mesothelial cell-specific molecule that is useful for differential diagnosis of mesothelioma and carcinoma was identified.(13)
Based on patterns of specific gene abnormalities, objective evaluation of the origin of multiple cancers was shown to be possible.(14) In multiple breast cancer, comparison of the pattern of LOH on chromosome 16q was shown to yield results compatible with the morphological classification and was suggested to be of diagnostic value to determine whether the origin of tumors is single or multicentric. Amplification of oncogenes and expression of tumor suppressor gene products were found to correlate well with the degree of cancer cell aggressiveness.(15,16)
Clinicopathological Studies
Studies were conducted to compare diagnostic imaging features of tumors, the clinical course of patients, and the histopathological features of the tumors.(17-22)
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