Pathology Division

1. Pathology Division

Research in the Pathology Division is based on a combination of molecular and cellular biological analyses and clinicopathological observations.
Analysis of Genetic and Chromosomal Alterations for Human Cancer Diagnosis

The potential application of genetic and chromosomal alterations to the diagnosis in cancers of the breast^(1-5) and the stomach⁽⁶⁾ was examined. Using two-color fluorescence in situ hybridization (FISH) analysis, the presence of der(1;16), a derivative of both chromosomes 16 and 1, was examined in intraductal papillary breast tumors, in which differential diagnosis of benign or malignant type is often difficult. The der(1;16) change was detected in 77% (10 of 13) of low-grade intracystic papillary carcinomas but not in 12 benign papillomas. The incidence of alterations of other chromosomes was much lower in the papillary carcinomas. Detection of the der(1;16) alteration by FISH may be helpful in the differential diagnosis of papillary breast tumors. ⁽¹⁾ Methodological improvements in the techniques of molecular diagnosis should identify additional genetic changes that may help in the diagnosis of specific neoplasms.^(7-9)
Aberrant DNA Methylation and Carcinogenesis

Expression of DNA methyltransferase (EC2.1.1.37) was significantly increased in liver tissue showing chronic hepatitis or cirrhosis, which are considered to be precancerous conditions, compared to normal liver tissue and a slight further increase was observed in hepatocellular carcinomas (HCC).⁽¹⁰⁾ Expression of p21^WAF1/CIP1, which regulates not only cell cycle progression but also DNA methyltransferase function, was reduced in HCCs.⁽¹¹⁾ CpG methylation around the promoter region of the E-cadherin tumor/invasion suppressor gene was detected in both liver tissue showing chronic hepatitis or cirrhosis and HCCs.⁽¹²⁾ CpG methylation was significantly correlated with reduced E-cadherin expression in HCCs.⁽¹²⁾ Aberrant DNA methylation accompanied with increased expression of DNA methyltransferase may participate in hepatocarcinogenesis, even in the early developmental stages of HCCs. DNA hypermethylation at the D17S5 locus, at which a candidate tumor suppressor gene HIC-1 (hypermethylated in cancer) was identified, was found in both adjacent lung tissues and non-small cell lung cancers obtained from smokers.⁽¹³⁾ The significance of other molecular events including telomerase reactivation and protein ubiquitination in carcinogenesis was also examined.^(14-17)
Molecular and Cellular Mechanisms of Cancer Metastasis and Recurrence

The processes of invasion and metastasis consist of sequential steps involving host-tumor interactions. These interactions include homophilic cell-cell adhesion, cell-matrix adhesion, cell-endothelial cell adhesion,⁽¹⁸⁾ activation of matrix metalloproteinase⁽¹⁹⁾ and cell proliferation in target organs. The first and crucial step in cancer invasion and metastasis is the dissociation of cancer cells from primary cancer nests.⁽²⁰⁾ Dysfunction of the E-cadherin-mediated cell adhesion system plays an important role on this step. The association between decreased expression of cadherin-catenin molecules and lymph node metastasis and poor prognosis was confirmed in a large scale study of human esophageal cancers.⁽²¹⁾ This metastasis-suppressor system was found to be inactivated by various mechanisms including genetic alterations and reduced gene expression by CpG methylation of the E-cadherin gene promoter region, and tyrosine phosphorylation of b-catenin. b-catenin is found to be associated directly with receptor type tyrosine kinases, c-erbB-2 and EGF receptor, in human cancers. Growth factors specifically activated their receptors and phosphorylated b-catenin resulting in inactivation of cell adhesion function. Human cadherin-14, a novel neural-specific type II cadherin molecule was identified through protein interaction cloning.⁽²²⁾ The establishment of an in vitro model for the analysis of metastasis has been undertaken.⁽²³⁾
To improve chemotherapeutic approaches to cancer, a better understanding of the molecular mechanisms of drug resistance is essential. Cos-7 cells were transfected with the entire cDNA library of cis-diamminedichloroplatinum (II) (CDDP)-resistant ovarian cancer TYKnuR cells, and CDDP selection was used to isolate a human semaphorin E cDNA.⁽²⁴⁾ Semaphorin E was overexpressed in CDDP-resistant cell lines and was readily induced by diverse chemotherapeutic drugs, and stable transfection with semaphorin E cDNA conferred a drug-resistant phenotype to CDDP-sensitive cells. Semaphorin E was aberrantly expressed in recurrent squamous cell carcinomas after extensive radiochemotherapy.⁽²⁴⁾These results suggest the involvement of semaphorin E in drug-resistance mechanisms.
Clinicopathological Studies

A rare case of esophageal mucosal epidermization clearly detected by LugolÕs staining was reported.⁽²⁵⁾ Clinicopathological studies were also conducted to promote the diagnosis and treatment of various tumors.^(26-32)




	1. Pathology Division



		Research in the Pathology Division is based on a combination of molecular and cellular biological analyses and clinicopathological observations. Analysis of Genetic and Chromosomal Alterations for Human Cancer Diagnosis The potential application of genetic and chromosomal alterations to the diagnosis in cancers of the breast^(1-5) and the stomach⁽⁶⁾ was examined. Using two-color fluorescence in situ hybridization (FISH) analysis, the presence of der(1;16), a derivative of both chromosomes 16 and 1, was examined in intraductal papillary breast tumors, in which differential diagnosis of benign or malignant type is often difficult. The der(1;16) change was detected in 77% (10 of 13) of low-grade intracystic papillary carcinomas but not in 12 benign papillomas. The incidence of alterations of other chromosomes was much lower in the papillary carcinomas. Detection of the der(1;16) alteration by FISH may be helpful in the differential diagnosis of papillary breast tumors. ⁽¹⁾ Methodological improvements in the techniques of molecular diagnosis should identify additional genetic changes that may help in the diagnosis of specific neoplasms.^(7-9) Aberrant DNA Methylation and Carcinogenesis Expression of DNA methyltransferase (EC2.1.1.37) was significantly increased in liver tissue showing chronic hepatitis or cirrhosis, which are considered to be precancerous conditions, compared to normal liver tissue and a slight further increase was observed in hepatocellular carcinomas (HCC).⁽¹⁰⁾ Expression of p21^WAF1/CIP1, which regulates not only cell cycle progression but also DNA methyltransferase function, was reduced in HCCs.⁽¹¹⁾ CpG methylation around the promoter region of the E-cadherin tumor/invasion suppressor gene was detected in both liver tissue showing chronic hepatitis or cirrhosis and HCCs.⁽¹²⁾ CpG methylation was significantly correlated with reduced E-cadherin expression in HCCs.⁽¹²⁾ Aberrant DNA methylation accompanied with increased expression of DNA methyltransferase may participate in hepatocarcinogenesis, even in the early developmental stages of HCCs. DNA hypermethylation at the D17S5 locus, at which a candidate tumor suppressor gene HIC-1 (hypermethylated in cancer) was identified, was found in both adjacent lung tissues and non-small cell lung cancers obtained from smokers.⁽¹³⁾ The significance of other molecular events including telomerase reactivation and protein ubiquitination in carcinogenesis was also examined.^(14-17) Molecular and Cellular Mechanisms of Cancer Metastasis and Recurrence The processes of invasion and metastasis consist of sequential steps involving host-tumor interactions. These interactions include homophilic cell-cell adhesion, cell-matrix adhesion, cell-endothelial cell adhesion,⁽¹⁸⁾ activation of matrix metalloproteinase⁽¹⁹⁾ and cell proliferation in target organs. The first and crucial step in cancer invasion and metastasis is the dissociation of cancer cells from primary cancer nests.⁽²⁰⁾ Dysfunction of the E-cadherin-mediated cell adhesion system plays an important role on this step. The association between decreased expression of cadherin-catenin molecules and lymph node metastasis and poor prognosis was confirmed in a large scale study of human esophageal cancers.⁽²¹⁾ This metastasis-suppressor system was found to be inactivated by various mechanisms including genetic alterations and reduced gene expression by CpG methylation of the E-cadherin gene promoter region, and tyrosine phosphorylation of b-catenin. b-catenin is found to be associated directly with receptor type tyrosine kinases, c-erbB-2 and EGF receptor, in human cancers. Growth factors specifically activated their receptors and phosphorylated b-catenin resulting in inactivation of cell adhesion function. Human cadherin-14, a novel neural-specific type II cadherin molecule was identified through protein interaction cloning.⁽²²⁾ The establishment of an in vitro model for the analysis of metastasis has been undertaken.⁽²³⁾ To improve chemotherapeutic approaches to cancer, a better understanding of the molecular mechanisms of drug resistance is essential. Cos-7 cells were transfected with the entire cDNA library of cis-diamminedichloroplatinum (II) (CDDP)-resistant ovarian cancer TYKnuR cells, and CDDP selection was used to isolate a human semaphorin E cDNA.⁽²⁴⁾ Semaphorin E was overexpressed in CDDP-resistant cell lines and was readily induced by diverse chemotherapeutic drugs, and stable transfection with semaphorin E cDNA conferred a drug-resistant phenotype to CDDP-sensitive cells. Semaphorin E was aberrantly expressed in recurrent squamous cell carcinomas after extensive radiochemotherapy.⁽²⁴⁾These results suggest the involvement of semaphorin E in drug-resistance mechanisms. Clinicopathological Studies A rare case of esophageal mucosal epidermization clearly detected by LugolÕs staining was reported.⁽²⁵⁾ Clinicopathological studies were also conducted to promote the diagnosis and treatment of various tumors.^(26-32)