Activities-Pathology Division
1. Pathology Division
The clinicopathological features of human tumors, such as multistep cancer development, grade of malignancy, multicentricity, invasion and metastasis, have been assessed in the Pathology Division on the basis of diagnostic pathology examinations of biopsy, surgical and autopsy material. Studies have also focused on the molecular mechanisms behind these features of cancer.
Diagnostic Pathology of Human Tumors
Clinicopathologically important cases have been reported in the form of case reports in order to improve diagnostic acumen.(1-4) Immunohistochemical techniques, immunocytochemical techniques, and DNA cytofluorometric analyses have been employed, in addition to morphological examination, to better define the clinicopathological characteristics of tumors(5-9) and to identify new prognostic factors.(10) As a means of preserving high quality DNA, RNA and protein in tissue sections for various polymerase chain reaction-based molecular analyses and Western blot analysis, tissues obtained surgically have been routinely fixed with cold acetone or methanol and embedded in paraffin blocks.(11)
Pathology of Multistep Cancer Development
Careful examination of the early and late stages of various human cancers has shown that cancer develops in a multi-process.(12,13) This process has been shown to be well correlated with the accumulation of multiple genetic alterations of oncogenes and tumor suppressor genes. In hepatocellular carcinoma (HCC), the concept of early HCC was established by analysis of surgical material, and the progression of HCC from the early to advanced stage was clearly shown to constitute a successive clonal expansion.(14)
Gene Alterations and Grade of Malignancy
Oncogene mutations, tumor suppressor gene mutations and chromosomal alterations frequently occur in human cancers. The clinicopathological implication of these alterations has been one of the major topics in Pathology Division. Attempts are being made to determine whether routine examination of gene alterations provides critical information for differential diagnosis between benign and malignant lesions and for making a prognosis.(15-30) Mutation of the p53 gene or abnormal accumulation of its protein in the nucleus has frequently been detected in many solid tumors, indicating a significant role of p53 in human carcinogenesis.(16,18,19,22,23,25,26) In some tumors, such as adenocarcinoma of the lung and HCC, alterations of p53 have been found to be of prognostic significance, since they were associated with stage of progression to a higher grade of malignancy.(15) Gastric cancer of the well-differentiated type and colorectal cancer have been shown to bear common genetic alterations, such as loss of heterozygosity at DCC and p53 loci.(27,28) In addition, these two tumors have similar p53 base substitution mutations, most of which are G:C-to-A:T transitions clustered at CpG dinucleotide hot spots.(30)
Differential Diagnosis between Multicentric and Metastatic Tumors
Patients sometimes present with multiple tumor nodules, and it is difficult to determine whether they are of metastatic or multicentric origin. Genetic abnormalities detected in cancers have therefore been used as fingerprints to identify the origin of tumors. For example, the pattern of chromosomal allele loss and the numerous mutations present in the 600-bp region of the p53 gene have been successfully used as markers for the genetic diagnosis of multiple tumors as second or third primary tumors or as me
tastatic tumors.(31-33)
Molecular Mechanisms of Invasion and Metastasis
Inactivation of cadherin-mediated intercellular adhesion systems may trigger the release of cancer cells and be involved in the initial step of cancer invasion.(34,35) Using surgical specimens and cultured cell lines, it has been found that undifferentiated gastric carcinoma lacks E-cadherin expression and that human lung carcinoma cell line PC9 lacks alpha-catenin expression.(36) Additional studies at the genetic level on the mechanisms of down-regulation of these cell adhesion molecules are continuing. In vitro and in vivo models of cancer invasion and metastasis have been designed using human cancer cell lines and xenografts. In these systems, anti-beta1 integrin antibody has been shown to inhibit invasion and metastasis, indicating involvement of integrin-mediated cell-to-matrix adhesion during invasion and metastasis.(37) Certain other molecules expressed in cancer cells, in addition to the cadherin- and integrin-mediated systems, have been shown to be correlated with malignant biological behavior.(38-41)
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