To investigate the early in vivo response of hepatic stellate cells in biliary fibrosis, we examined rat livers during the first 7 days after bile duct ligation using light microscopy, immunohistochemistry, electron microscopy, and immunoelectron microscopy. At day 1 after bile duct ligation, alpha-smooth muscle actin-positive fibroblasts appeared and then increased in number around the proliferating bile ductules. With time, the destruction of the external limiting plate became accentuated because of the invasion of the proliferating bile ductules and periductural fibrosis. At day 7, stromal cells containing fat droplets appeared in the fibrous tissue adjacent to the periportal parenchyma; these are termed denuded hepatic stellate cells. In the fibrous tissue disconnected from the liver parenchyma, the denuded hepatic stellate cells were replaced by myofibroblast-like cells. Meanwhile, the expression of transforming growth factor-beta1 on biliary epithelial cells increased. These results indicate the dual origin of myofibroblasts in experimental biliary fibrosis, the periductural and periductal fibroblasts in the initial stage, and the denuded hepatic stellate cells in the subsequent stage. These two types of stromal cells may undergo myofibroblastic transformation by the transforming growth factor-beta1 secreted by the proliferating biliary epithelial cells.
Goblet cell carcinoids are rare neoplasms that predominantly occur in the appendix. In this report we present a case of goblet cell carcinoid of the appendix. A 58-year-old male patient complaining of pain in the right lower quadrant was diagnosed with acute appendicitis and underwent an appendectomy. Histological examination of the resected appendix revealed goblet cell carcinoid. Infiltration of tumor cells beyond the appendix was observed and the surgically resected margin was positive for tumor cells. Carcinoembryonic antigen (CEA) was diffusely detected by immunohistochemistry, and cytokeratin 20, neuron-specific enolase (NSE), chromogranin A and serotonin were focally observed in the tumor cells. The expression of beta-catenin and E-cadherin was investigated to compare with that of typical rectal carcinoids (n = 3) and colon adenocarcinomas (n = 3). In normal colonic and rectal mucosae, beta-catenin and E-cadherin stained positive on the plasma membrane. In the case reported here, beta-catenin showed a preserved expression on the plasma membrane of goblet cell carcinoid; a pattern similar to typical carcinoids rather than to adenocarcinomas. However, E-cadherin demonstrated a reduced expression on the plasma membrane of the tumor cells. This staining pattern was identical to those both of carcinoids and of adenocarcinomas. These findings suggest the possibility that, in some cases, the adherens junctions of goblet cell carcinoids are similar to those of typical carcinoids rather than to those of adenocarcinomas.
Malignant pleural mesothelioma is a refractory tumor with increasing incidence. In the present study, we established six mesothelioma cell lines possessing two allele deletions of the p16 INK4A gene and one allele deletion of the neurofibromatosis type 2 gene, MM16, MM21, MM26, MM35, MM46 and MM56, from pleural effusion fluids or surgically resected tumors of Japanese patients. MM21, MM26 and MM46 cells failed to develop tumors in BALB ⁄ cnude mice following subcutaneous inoculation. MM16 and MM35 cells slowly generated tumors at the site of subcutaneous inoculation in BALB ⁄ c-nude mice, but lost the expression of mesothelioma-related markers such as calretinin, D2-40 and Wilms' tumor 1 in the subcutaneous tumors. On the other hand, MM56 cells rapidly generated tumors with the expression of calretinin and D2-40 in BALB ⁄ c-nude mice following subcutaneous inoculation. In addition, orthotopic implantation of MM56 cells into BALB ⁄ c-nude mice developed diffusely growing thoracic tumors by 3 weeks after implantation. Pleural effusions were observed in these mice 4 weeks after implantation. Thoracic tumors invaded aggressively into the chest wall 5 weeks after implantation and often metastasized into the lung, rib, peritoneum and pericardial cavity. On the pleural surface, MM56 cells were growing as single or multiple cell layers with the reactive mesothelium of recipient mice. These results indicate that MM56 cells can behave in a manner characteristic of human malignant pleural mesothelioma in the thoracic cavity of BALB ⁄ c-nude mice. The in vivo model using MM56 cells may be useful for studying the biological behavior of malignant pleural mesothelioma and developing its diagnostic and therapeutic strategies. (Cancer Sci 2011; 102: 648-655) M alignant pleural mesothelioma (MPM), considered to be closely associated with asbestos exposure, is an aggressive tumor arising from mesothelial cells on the serosal surfaces of the thoracic cavity. Malignant pleural mesothelioma was once a rare disease, but its incidence is dramatically increasing worldwide. In Japan, it is expected to peak around 2025 as a result of widespread use of asbestos.(1) Malignant pleural mesothelioma is often diagnosed at an advanced stage and known to be resistant to conventional therapies. As a result it is associated with poor prognosis, with the median survival in the range of 9-17 months after the first diagnosis.(2) It is therefore important to establish a means for investigating the behaviors of MPM, leading to the development of early diagnosis and effective therapies.Cell lines and animal models of human tumors are useful for studying the characteristics of tumors. Several MPM cell lines have been established (3)(4)(5) and animal models have been produced by inoculation of MPM cells or surgically resected MPM tissues into immunodeficient mice or rats.(6-9) Orthotopic implantation models are considered to be the most useful for studying the characteristics of MPM in vivo, (10)(11)(12) but most require a long period to develop MPM aft...
The myofibroblastic transformation of hepatic stellate cells (HSC; also known as Ito cells) usually occurs following necrosis of adjacent liver cells. No report has previously found that such a transformation occurs in herpes simplex virus (HSV) hepatitis. We present an autopsy case of HSV hepatitis with myofibroblastic transformation of HSC that is different from the usual transformation of HSC. The patient was a 66-year-old woman who had received various therapies for cutaneous T-cell lymphoma. An autopsy revealed submassive hepatic necrosis with hemorrhage due to HSV hepatitis. HSV infection was confirmed by DNA in situ hybridization in liver tissue. Immunohistochemical staining for alpha-smooth muscle actin (ASMA) showed a strong positive reaction in almost all of the HSC in non-necrotic areas. However, in necrotic areas, the HSC were completely negative for ASMA. These findings indicate that not only liver cells but also HSC can become necrotic in HSV hepatitis. In contrast, in non-necrotic areas, almost all of the HSC showed active transformation to myofibroblasts.
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