PATHOLOGY DIVISION

1.PATHOLOGY DIVISION

　Research in the Pathology Division is based on a combination of molecular and cellular biological analyses and clinicopathological observations.
Molecular Diagnosis of Biological Aggressiveness of Human Cancers

　Numerical and structural alterations of chromosome 16 are frequent in breast cancers. A derivative chromosome, der(16)t(1;16)/der(1;16), generated by translocation between chromosome 16 and chromosome 1, is clonally detected in >30%of human breast cancers by fluorescence in situ hybridization (FISH). This translocation was correlated with a higher amount of hormone receptors in the tumor and with better prognosis.⁽¹⁾ The aneusomy was more frequent in Grade 3 carcinomas, proximal breakage was more frequent in invasive ductal carcinomas (IDCs)of the strand or solid types and in grade 2 and 3 carcinomas, and the distal breakage was more frequent in tubular/cribriform type IDCs and Grade 1 carcinomas. The der(16)t(1;16)/der(1;16)occurred in about half of all carcinomas with a 16q breakage and was correlated with the tubular/cribriform type of non- invasive and invasive ductal carcinomas and invasive lobular carcinoma.⁽²⁾ These numerical and structural chromosomal alterations appeared to occur in association with each other, and their specific combinations appeared to be involved in the establishment of morphological variety among breast carcinomas. Molecular prognostic factors of various cancers and cancer- related genes were also studied.^(3-⁶⁾
Alteration of DNA Methylation in Multistage Carcinogenesis

　The significance of changes in DNA methylation has been studied in multistage hepatocarcinogenesis. DNA hypermethylation at the D17S5 locus was frequently detected even in non- cancerous liver tissues showing chronic hepatitis or cirrhosis, which are widely considered to be precancerous conditions, but was not observed in histologically normal livers.⁽⁷⁾ The incidence of DNA hypermethylation was significantly higher in hepatocellular carcinomas (HCCs)than non- cancerous liver tissues. The HIC- 1 (hypermethylated- in- cancer) tumor suppressor gene, identified at the D17S5 locus, shoes significantly lower expression in non- cancerous liver tissues showing chronic hepatitis or cirrhosis than in histologically normal livers, and even lower expression in HCCs. These aberrations participate in hepatocarcinogenesis during both early developmental stages and malignant progression of HCCs. Newly identified enzymes regulating the DNA methylation patterns were analyzed. Levels of expression of the DNA demethylase MBD2 gene were frequently and significantly reduced in colorectal and stomach cancers when compared with the levels in the corresponding non- cancerous mucosae.⁽⁸⁾ This is the first evidence to suggest the participation of reduced expression of DNA demethylase in a specific step of multistage carcinogenesis. This reduction may be, if anything, one of the early events of carcinogenesis, but may not participate in the malignant progression of tumors.
Molecular and Cellular Mechanisms of Cancer Invasion and Metastasis

　Dysfunction of the E- cadherin- mediated cell adhesion system plays an important role in the dissociation of cancer cells from primary cancer nests.^(9,¹⁰⁾ Several mechanisms for inactivation of the E- cadherin cell adhesion system in cancer have been identified.⁽¹¹⁾ Mutations of the E- cadherin gene were analyzed in 9 gastric cancer patients under 35 years of age, and somatic, but no germline, mutations were detected in 7 of these patients. Thus, early- onset gastric cancers may be attributable to environmental factors such as Helicobacter pylori infection.⁽¹²⁾ Accumulation of b - catenin, one of the undercoat proteins of cadherin and components of the Wnt signal transduction pathway, was seen in 15 of 38 hepatocellular carcinoma (HCC) samples, and a mutation in the b - catenin gene was seen in 9 of 38 HCC samples. Aberration of b - catenin was suggested to be associated with the malignant progression of HCC.⁽¹³⁾ Bladder cancer and stomach cancer cells expressing decreased amounts of b 4 integrin were shown to have an increased potential for intraepithelial extention and peritoneal dissemination, respectively. ⁽¹⁴⁾ Motility of liver cancer cells mediated by Rho and p160ROCK was shown to play a critical role in intrahepatic metastasis. ⁽¹⁵⁾
Clinicopathological Studies

　E- cadherin was found to be expressed in certain kinds of soft tissue sarcomas, especially those with epithelioid features, suggesting that E- cadherin plays a role in the constitution of their architecture.⁽¹⁶⁾ Lymph node micrometastases of colorectal cancer were shown not to influence patient prognosis.⁽¹⁷⁾ Increased laminin- 5 g 2 chain immunoreactivity, which may reflect a high invasive potential of cancer cells, was found to be an indicator of poor prognosis for patients with squamous cell carcinoma of the tongue.⁽¹⁸⁾ Clinicopathological studies were also conducted to promote the diagnosis and treatment of various tumors.^(19-³⁶⁾




1.PATHOLOGY DIVISION



	Research in the Pathology Division is based on a combination of molecular and cellular biological analyses and clinicopathological observations. Molecular Diagnosis of Biological Aggressiveness of Human Cancers 　Numerical and structural alterations of chromosome 16 are frequent in breast cancers. A derivative chromosome, der(16)t(1;16)/der(1;16), generated by translocation between chromosome 16 and chromosome 1, is clonally detected in >30%of human breast cancers by fluorescence in situ hybridization (FISH). This translocation was correlated with a higher amount of hormone receptors in the tumor and with better prognosis.⁽¹⁾ The aneusomy was more frequent in Grade 3 carcinomas, proximal breakage was more frequent in invasive ductal carcinomas (IDCs)of the strand or solid types and in grade 2 and 3 carcinomas, and the distal breakage was more frequent in tubular/cribriform type IDCs and Grade 1 carcinomas. The der(16)t(1;16)/der(1;16)occurred in about half of all carcinomas with a 16q breakage and was correlated with the tubular/cribriform type of non- invasive and invasive ductal carcinomas and invasive lobular carcinoma.⁽²⁾ These numerical and structural chromosomal alterations appeared to occur in association with each other, and their specific combinations appeared to be involved in the establishment of morphological variety among breast carcinomas. Molecular prognostic factors of various cancers and cancer- related genes were also studied.^(3-⁶⁾ Alteration of DNA Methylation in Multistage Carcinogenesis 　The significance of changes in DNA methylation has been studied in multistage hepatocarcinogenesis. DNA hypermethylation at the D17S5 locus was frequently detected even in non- cancerous liver tissues showing chronic hepatitis or cirrhosis, which are widely considered to be precancerous conditions, but was not observed in histologically normal livers.⁽⁷⁾ The incidence of DNA hypermethylation was significantly higher in hepatocellular carcinomas (HCCs)than non- cancerous liver tissues. The HIC- 1 (hypermethylated- in- cancer) tumor suppressor gene, identified at the D17S5 locus, shoes significantly lower expression in non- cancerous liver tissues showing chronic hepatitis or cirrhosis than in histologically normal livers, and even lower expression in HCCs. These aberrations participate in hepatocarcinogenesis during both early developmental stages and malignant progression of HCCs. Newly identified enzymes regulating the DNA methylation patterns were analyzed. Levels of expression of the DNA demethylase MBD2 gene were frequently and significantly reduced in colorectal and stomach cancers when compared with the levels in the corresponding non- cancerous mucosae.⁽⁸⁾ This is the first evidence to suggest the participation of reduced expression of DNA demethylase in a specific step of multistage carcinogenesis. This reduction may be, if anything, one of the early events of carcinogenesis, but may not participate in the malignant progression of tumors. Molecular and Cellular Mechanisms of Cancer Invasion and Metastasis 　Dysfunction of the E- cadherin- mediated cell adhesion system plays an important role in the dissociation of cancer cells from primary cancer nests.^(9,¹⁰⁾ Several mechanisms for inactivation of the E- cadherin cell adhesion system in cancer have been identified.⁽¹¹⁾ Mutations of the E- cadherin gene were analyzed in 9 gastric cancer patients under 35 years of age, and somatic, but no germline, mutations were detected in 7 of these patients. Thus, early- onset gastric cancers may be attributable to environmental factors such as Helicobacter pylori infection.⁽¹²⁾ Accumulation of b - catenin, one of the undercoat proteins of cadherin and components of the Wnt signal transduction pathway, was seen in 15 of 38 hepatocellular carcinoma (HCC) samples, and a mutation in the b - catenin gene was seen in 9 of 38 HCC samples. Aberration of b - catenin was suggested to be associated with the malignant progression of HCC.⁽¹³⁾ Bladder cancer and stomach cancer cells expressing decreased amounts of b 4 integrin were shown to have an increased potential for intraepithelial extention and peritoneal dissemination, respectively. ⁽¹⁴⁾ Motility of liver cancer cells mediated by Rho and p160ROCK was shown to play a critical role in intrahepatic metastasis. ⁽¹⁵⁾ Clinicopathological Studies 　E- cadherin was found to be expressed in certain kinds of soft tissue sarcomas, especially those with epithelioid features, suggesting that E- cadherin plays a role in the constitution of their architecture.⁽¹⁶⁾ Lymph node micrometastases of colorectal cancer were shown not to influence patient prognosis.⁽¹⁷⁾ Increased laminin- 5 g 2 chain immunoreactivity, which may reflect a high invasive potential of cancer cells, was found to be an indicator of poor prognosis for patients with squamous cell carcinoma of the tongue.⁽¹⁸⁾ Clinicopathological studies were also conducted to promote the diagnosis and treatment of various tumors.^(19-³⁶⁾