1. Pathology Division
Research in the Pathology Division has been focused on the molecular and
cellular mechanisms of carcinogenesis and cancer progression, especially
invasion and metastasis. Studies on the clinicopathological significance of
genetic alterations in carcinogenesis in each organ were continued. Much
progress was made in the understanding of how cancer cells dissociate and
invade, through analysis of the cadherin cell adhesion system.
Pathology of Multistage Carcinogenesis and Multiple Genetic Alterations
In the liver of patients suffering from chronic active hepatitis or
cirrhosis, increased cell proliferative activity was shown to be an
important feature of early neoplastic lesions, and to be useful as a marker
for diagnosis of those lesions.(1) This abnormally induced cell
proliferation may be the mechanism underlying the accumulation of genetic
and chromosomal aberrations leading to cancer progression. In a
nodule-in-nodule lesion of hepatocellular carcinoma representing cancer
progression, involvement of p53 mutation in this process was clearly
demonstrated.(2)
In breast cancer, loss of heterozygosity (LOH) on the long arm of
chromosome 16 occurred frequently regardless of the degree of tumor spread
or phenotype.(3) Because LOH was not detected in benign proliferative
lesions, it was suggested that LOH on 16q was useful for differential
diagnosis in intracystic papillary tumors between low-grade papillary
carcinoma and papilloma.(4) Mutation of the p53 tumor-suppressor
gene was detected selectively in breast cancers with a high histologic
grade of atypia irrespective of the site and type of the mutations.(5)
However, such site and type of mutations were shown to influence the manner
of accumulation of mutant p53 protein in cancer cell nuclei; mis-sense
point mutations and in-frame deletions generally gave rise to nuclear
accumulation of p53 protein, whereas non-sense point mutations and
frameshift deletions gave rise to loss of the protein expression.(5)
In adenocarcinoma of the uterine cervix, mutation of the p53 gene
occurred preferentially in patients in advanced clinical stages and those
with poorer differentiation, whereas genomic integration of human
papillomavirus DNA type 16 or 18 was more frequent in patients in early
clinical stages and those with good differentiation.(6) Amplification of
the c-erbB-2 gene was also associated with advanced stages and
poorer prognosis of adenocarcinoma of the uterine cervix.(7) Similar
studies on gastric cancer and skin cancers were also performed.(8,9)
Alterations of Cadherin Cell Adhesion System in Cancer
The E-cadherin-mediated cell adhesion system acts as an "invasion
suppressor" system, which is widely considered to be inactivated when
the expression of E-cadherin is reduced and/or heterogeneous. The molecular
mechanisms responsible for dysfunction of this system in cancers were
further investigated. In stomach cancer cell lines lacking tight cell-cell
adhesion, mutations of the E-cadherin gene resulting in an mRNA splicing
error, and loss of the wild-type allele of the E-cadherin locus, which was
assigned to chromosome 16q22-23, were found.(10) A point mutation of the
E-cadherin gene was detected in invasive lobular carcinomas of the breast
with allele loss on chromosome 16, indicating that dysfunction of
E-cadherin could be caused by the two-hit mechanism.(11) Frequent reduced
expression of alpha-catenin was observed in scirrhous carcinomas of the
stomach and breast.(12) mRNA deletion of beta-catenin was found to disrupt
the interaction between E-cadherin and alpha-catenin in stomach cancer cell
lines.(13) Various mechanisms of inactivating the E-cadherin-mediated cell
adhesion and "invasion suppressor" system in cancers were
clarified.(14,15)
Kinases which participate in tyrosine phosphorylation of the members of
this system were examined and the c-erbB-2 product was found to be
associated with the E-cadherin-catenin complex.(16) This is the first
evidence indicating interaction between oncogene products and cell-cell
adhesion molecules. Direct association between an APC
tumor-suppressor gene product and gamma-catenin (plako-globin) was also
found.(17) These findings suggested the possibility that this system is
involved in the signaling pathway connecting cell adhesion and cell
growth.
Diagnostic Pathology
Members of the Pathology Division contributed a great deal to the
diagnostic pathology practice in the hospital.(18-20) The basic studies
described above were all performed with ideas and materials obtained
through the diagnostic pathology practice. A rare case of
adenomyoepithelial adenosis of the breast, which showed histo-pathological
features of malignant progression, was reported.(21) A cell line producing
a large amount of anti-diuretic hormone was established from a patient with
human small cell lung cancer with SIADH syndrome.(22)
List of papers
from this division
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