Journal of Pathology and Translational Medicine

Original Articles

Expression of p53, c-myc, Transforming Growth Factor-alpha and -beta in Human Epithelial Ovarian Tumors.: Jae Hwa Lee, Young Ok Lee, Man Ha Huh; Korean J Pathol. 1996;30(1):23-31.

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Abstract PDF: The author examined expression of tumor-related antigens, such as p53 tumor supressor protein, c-myc, TGF-alpha, and TGF-beta proteins in 75 cases of surgically resected epithelial ovarian tumors. Peroxidase immunohistochemistry was used to determine the frequency of expression, the relationship among expression of these antigens and histopathological spectrums, and clinical stage, and their potential prognostic significance. The results are summarized as follows. A positive correlation was found between expression of p53(P=0.02), c-myc(P=0.03), and TGF-alpha(P=0.001) and histological degrees of malignancy(benign, borderline, or malignant) in epithelial ovarian tumors. A significant correlation was found between expression of p53 and histological degrees of malignancy in serous ovarian tumors(P=0.003) and mucinous tumors (P=0.049). A significant correlation was also found between expression of c-myc and the histological grade of serous carcinomas(P=0.02). A correlation between expression of these antigenic proteins and clinical stage of epithelial ovarian tumors was not demonstrated. Expression of p53 and c-myc was closely correlated with expression of TGF-alpha irrespective of the histological degrees of malignancy and type of epithelial ovarian tumors(0.4 < or = K < or = 0.7). The results of this study support the ideas that expression of c-myc and TGF-alpha might be a useful prognostic indicator in human ovarian carcinomas, and expression of p53 could be another indicator of prognosis, as the expression of p53 is characteristic in that the expression is mostly seen in invasive ovarian carcinomas.

Immunohistochemical Analysis of TGF-beta Expression and Angiogenesis in Infiltrating Duct Carcinoma of the Breast.: Tae Jin Lee, Nam Bok Cho, Eun Sub Park, Jae Hyung Yoo, Sung Jun Park; Korean J Pathol. 1996;30(7):557-569.

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Abstract PDF: Forty cases of infiltrating duct carcinoma of the breast were examined immunohistochemically for expression of TGF-beta and angiogenesis in order to analyze significant correlation with prognostic parameters including tumor size, axillary lymph node metastasis, clinical stage, histologic grade, estrogen receptor and progesterone receptor status. The TGF-beta expression was observed in tumors center and advancing edges of tumors. To determine microvessel density for angiogenesis, we stained endothelial cells for Factor VIII related antigen and counted microvessel within tumor. The results were as follows: 1) The strong immunohistochemical expression of TGF-beta and higher counts of microvessels were observed in advancing edges of tumors (p<0.05). 2) The TGF-beta expression in the advancing edges of tumors was closely related to clinical stage and presence of axillary lymph node metastasis (p<0.05). 3) The mean microvessel counts were significantly higher in tumors from patients with axillary lymph node metastasis and increased with increasing clinical stage (p<0.05). 4) The TGF-beta expression was not related to histologic grade, estrogen receptor and progesterone receptor status(p>0.05). Therefore, the results suggested that the TGF-beta expression and angiogenesis in infiltrating duct carcinoma of the breast may play an important part in prognostic factors, closely related to the lymph node metastasis and clinical stage.

Cellular Distribution of TGF-beta1 Peptide in Dimethylnitrosamine Induced Fibrosis of Rat Liver.: Sook Nyo Lee, Do Youn Park, Sun Kyung Lee; Korean J Pathol. 1997;31(11):1157-1165.

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Abstract: Recently attention has been focused on the biology of transforming growth factor-beta1 (TGF-beta1). TGF-beta1, a potent regulator of cell proliferation, stimulates the proliferation of many cell types of mesenchymal origin and inhibits the growth of many epithelial cells. But its cellular distribution and temporal expression remain unknown. The aim of this study was to investigate immunohistochemically the cellular distribution and temporal expression of TGF-beta1 during rat hepatic fibrosis induced by dimethylnitrosamine (DMN). At an early stage of liver fibrosis, there was evidence of multiple centrilobular hemorrhagic necrosis with parenchymal lobular collapse, and at a late stage, there was septal fibrosis with micronodule formation of the parenchyme. TGF-beta1 peptide was first expressed in centrilobular clusters of macrophage which were surrounded by many TGF-beta1 negative fat-storing cells (FSCs). Along with the progression of fibrosis, the TGF-beta1 peptide was expressed in the alpha-smooth muscle actin positive FSCs and also in some peripherally located hepatocytes of micronodules. Serum IFN-gamma was detected in the serum 2 weeks after an initial administration of DMN had reached the peak level at the 4th week and then markedly decreased at the 5th week. We think that TGF-beta1 peptide is produced by macrophages influenced by soluble IFN-gamma, and is expressed in the -smooth muscle actin positive mesenchymal cells and regenerating hepatocytes, and that this cytokine may have an important role in the synthesis of the extracellular matrix and in the regulation of hepatocytic regeneration.

The Expression of TGF-beta1 and TGF-beta Receptor I in Human Lung Cancer.: Hye Kyung Ahn, Young Hee Choi, Jung Weon Shim, Young Euy Park, Han Kyeom Kim, Jong Sang Choi, Joung Ho Han; Korean J Pathol. 1998;32(1):9-20.

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Abstract PDF: A majority of human lung cancer cell lines have developed resistance to growth inhibition via the activation of transforming growth facter-beta (TGF-beta). Previous studies have reported that growth inhibition of TGF-beta is linked to the expression of transforming growth factor-beta receptor type I (TGF-betaRI). Immunohistochemical studies of TGF-beta1 and TGF-betaRI have been carried out in 43 cases of lung neoplasm; including 25 cases of squamous cell carcinoma, 13 cases of adenocarcinoma, 2 cases of adenosquamous cell carcinoma, and 1 case each of undifferentiated carcinoma, small cell carcinoma and neuroendocrine carcinoma. Reverse transcriptase polymerase chain reaction (RT-PCR) for TGF-beta1 mRNA was also performed in 40 cases of tumors and 14 control cases of normal parenchyme. Immunohistochemically, TGF-beta1 and TGF-betaRI expression were noted in the cytoplasm of all type of tumor cells. The staining intensity and areas were examined and scored from 0 to 5. As a whole, TGF-beta1 staining scores in the neoplastic lesions were higher than that of the adjacent normal parenchyme, bronchial epithelium or alveolar epithelium. However, TGF-betaRI staining scores were generally lower than that of the adjacent normal components. The TGF-beta1 mRNA showed a higher percentage of expression in tumors than in normal control. Tumor size, lymph node metastasis, histological differentiation and histological type of tumors did not correlated with the staining score of TGF-beta1 and TGF-betaRI. These results indicate that although various types of human lung carcinoma cells produce TGF-beta1, they show a reduction in TGF-betaRI, resulting in an escape from growth inhibition by TGF-beta1.

Expression of Transforming Growth Factor-beta and Morphologic Changes of Glomerulosclerosis in FGS/NgaKist Mouse.: Hoon Kyu Oh, Yong Jin Kim, Mi Ok Park, Chul Ho Lee, Byung Hwa Hyun, In Soo Shu; Korean J Pathol. 1998;32(1):35-42.

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Abstract PDF: Focal segmental glomerulosclerosis (FSGS) is presented as not only one of the primary glomerular diseases but also as a secondary phenomenon for chronic irreversible renal diseases. The main pathological feature of FSGS is the accumulation of extracellular matrix in the glomeruli, for which overexpression of transforming growth factor-beta (TGF-beta) may be responsible for the accumulation of pathological matrix. A new animal model (FGS/NgaKist mouse) of renal failure by spontaneously generating glomerulosclerosis was developed. To elucidate the role of TGF-beta for FSGS, authors observed glomeruli of FGS/NgaKist mouse periodically. FGS/NgaKist mouse strain showed progression of proteinuria and focal glomerular sclerosis with the aging. The glomeruli showed anti IgG, IgA, IgM and complement complex deposits and extracellular matrix accumulation in the mesangium. TGF-beta mRNA and beta2antibody expressions were increased with the advance of glomerular sclerosis. The results suggest the following; FSGS of FGS/NgaKist strain is immune mediated disease and this stimuli on mesangial or endothelial cells may activate TGF-beta gene in their nuclei. This activation, in turn, can cause sclerosis by increasing TGF-beta mRNA transcription followed by secretion of TGF-beta and its action as cytokine for making collagen fibrils.

Expression of TGF-beta1 Protein in Macrophages of Tuberculous Granulomas.: Jong Im Lee, Jung Ran Kim, Tae Jung Jang, Dong Hoon Kim; Korean J Pathol. 1998;32(4):261-265.

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Abstract PDF: TGF-beta1 expression was studied in 25 patients with tuberculosis (lung, 9 cases and lymph node, 16 cases) using a polyclonal antibody in formalin-fixed paraffin embedded tissue. Nineteen cases (76.0%) out of 25 cases showed TGF-beta1 expression. TGF-beta1 was present in cytoplasm of epithelioid cells and Langhans' giant cells. Pulmonary tuberculosis and tuberculous lymphadenitis showed different patterns of staining. Five of 9 cases of pulmonary tuberculosis were positive for TGF-beta1: four of acid-fast bacilli positive cases (4/5, 80.0%) and one of acid-fast bacilli negative cases (1/4, 25.0%). However, high expression of TGF-beta1 was detected in tuberculous lymphadenitis of both acid-fast bacilli positive group (3/4, 75.0%) and acid-fast bacilli negative group (11/12, 91.7%). TGF-beta1 was also expressed in all of 6 cases of BCG-induced tuberculous lymphadenitis: 2 acid-fast bacilli positive and 4 acid-fast bacilli negative cases. TGF-beta1 expression was shown in 19 cases (86.4%) of 22 in active tuberculosis, while no TGF-beta1 expression was detected in any cases of inactive, healed tuberculosis (p<0.008). This study supports that the TGF-beta1 expression of epithelioid cells may alter their function resulting in the impaired antimycobacterial activity. Thus the increased production of TGF-beta1 may be one of the important mechanisms by which Mycobacterium tuberculosis avoids destruction by host macrophages.

Sequential Changes of Extracellular Matrix mRNA in Anti-GBM Antibody Induced Crescentic Glomerulonephritis in the Rabbit.: Moon Hyang Park, Unn Wha Lee, In Sup Han, Rho Won Chun, Jung Woo Noh; Korean J Pathol. 1998;32(9):627-637.

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Abstract: Progressive renal fibrosis is considered to be the final common pathway leading to chronic renal insufficiency, however, the mechanism regarding renal fibrosis in renal injury is not well understood. Recently, several kinds of cytokines have been known to be related to fibrosis after renal injury. The interaction between elements regulating fibrogenesis would be better understood by looking at the effect of TGF-beta1 on the synthesis and accumulation of extracellular matrix, especially collagenous proteins. Crescentic glomerulonephritis (CGN) was induced in New Zealand White rabbits by administration of guinea pig anti-GBM IgG after sensitization with guinea pig IgG; and their kidneys were analyzed for the development of crescents and fibrosis through sequential renal biopsies. Serum creatinine levels in a time course progressively increased until day 15. We semi-quantitatively assayed the levels of the expression of alpha1(I) collagen mRNA and TGF-beta1 mRNA factored for GAPDH mRNA using RT-PCR. We observed a progressive interstitial fibrosis and the expression of collagen I both in the cortex and medulla. The effect of repeated renal biopsy itself on pathology and on the expression of alpha1(I) collagen mRNA and TGF-beta1 mRNA in a time course were not significant, but a very mild increase of the expression of alpha1(I) collagen mRNA was noted at day 15. Histology showed a progressive crescent formation and interstitial fibrosis in a time course that roughly paralleled the expression of alpha1(I) collagen mRNA in both cortex and medulla. TGF-beta1 mRNA was hardly expressed at day 0 in cortex as well as in medulla. It was elevated from day 1, peaked at day 7, and then decreased. In medulla, TGF-beta1 mRNA was noticeably expressed at day 1, peaked at day 4, and then decreased. The expression of alpha1(I) collagen mRNA was seen even before inducing CGN. It was gradually and continuously increased until day 15 both in cortex and medulla. These results suggest that the expression of TGF-beta1 mRNA precedes that of alpha1(I) collagen mRNA in the early stage of CGN and has a central role for provoking the accumulation the collagen I, the most representative interstitial extracellular matrix, in the rabbit model CGN induced by anti-GBM antibody. We conclude that the measurement of the expression of TGF-beta1 mRNA and/or alpha1(I) collagen mRNA in a biopsy sample can be a useful predictor for renal outcome.

The Effects of Angiotensin Converting Enzyme Inhibitor on Progressive Glomerular Sclerosis.: Mi Ok Park, Yong Jin Kim, Hoon Kyu Oh, Chul Ho Lee, Byung Hwa Hyun, Jung Sik Kwak; Korean J Pathol. 1998;32(12):1058-1065.

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Abstract: Almost all advanced glomerular diseases have glomerular sclerotic changes to varying degrees whatever causes their primary glomerular disease are. Pathogenesis of these sclerosis has been thought of as the hyperfiltration in the primary glomerulosclerosis due to development of glomerular hypertension in each insulted glomeruli. This background gave the theoretical bases for antihypertensive therapies for supporting chronic renal insufficient patients. Angiotensin converting enzyme (ACE) inhibitor, one of the antihypertensive drugs, has received attention recently for its effectiveness. The aims of this study determined the effects and mechanism of the ACE inhibitor, enalapril, on the glomerulosclerosis in FGS/NgaKist mice, which was an animal model of chronic renal failure by generating spontaneously heavy proteinuria and progressive glomerulosclerosis. Five-week-old FGS/NgaKist mice (n=38) were assigned to four groups. Group 1a (n=6) and group 2a (n=8) fed with a vehicle, were sacrificed at the end of 10 weeks and 15 weeks, respectively. Group 1b (n=12) and 2b (n=12) received enalapril (100 mg/L) in drinking water for 5 weeks and 10 weeks from 6th week of age respectively, and were sacrified on the same day as the control groups. Doses of enanapril were maintained to 2 mg/kg/day by measuring the amount of water consumption. In enalapril groups 1b and 2b, systemic blood pressure (74.7 14.0 mm Hg, 74.3 15.9 mmHg) were significantly lower than control group 2a (116.1 4.6 mmHg, P<0.001). Similarly, degree of proteinuria lowered in enalapril group 2b versus control group 2a (0% and 50.0%, P<0.001). Glomerulosclerosis percentage significantly decreased (P<0.001) (group 1b and 2b; 1.9 6.5, 5.6 7.0 vs control 1a and 2a; 32.8 15.5, 31.4 13.8). Glomerulosclerosis score also decreased (P<0.001) (group 1b and 2b; 0.02 0.08 vs control 1a and 2a; 0.48 0.12, 0.30 0.14). The immunofluorescent staining of enalapril groups showed negative for mesangial deposition of IgG, IgA, IgM, and C3 which were positive in control groups. Immunohistochemical staining with TGF-beta1 was negative in enalapril groups and sclerotic glomeruli both enalapril groups and control groups. These results support that the ACE inhibitor has a renoprotective effect on glomerulosclerosis not only by decreasing the blood pressure but also by suppressing the immune deposits on glomeruli.

The Effects of Transforming Growth Factor beta1 on Apoptosis in Rat Hepatocellular Carcinoma.: Young Euy Park, Young Hee Choi, Won Yo Lee, Jin Ja Park, Kyung Chan Choi, Hyung Shik Shin; Korean J Pathol. 1999;33(2):71-79.

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Abstract: Based upon the concept that carcinogenesis is associated with apoptosis, specific therapies designed to enhance the susceptibility of cancer cells to undergo apoptosis could be developed. Thus, in this paper, it was designed to investigate whether, using rat animal model with chemical-induced hepatocellular carcinoma, TGF-1 in vivo could induce apoptosis in cancer. The chemical hepatocarcinogenic procedure of Solt-Farber method was used on Sprague-Dawley rats. Experimental groups were divided into group A treated with the standard Solt-Farber regimen of diethylnitrosamine (DEN) and 2-Acetaminofluorene (AAF), group B TGF-, group C TGF-1, and group D adriamycin after hepatocellular carcinoma developed. For detection of apoptotic cells, apoptotic indices were examined by the in situ end DNA labelling method. The expression of proliferating cell nuclear antigen was examined by immunohistochemical staining. Apoptosis of rat hepatocellular carcinoma cells increased significantly to 4.92+/-2.32/HPF in the group C compared with the control group (A) (2.54+/-1.13/HPF; P<0.05). Two distinctly different populations of proliferating hepatocellular carcinoma cells were identified. The cells at G1/S boundary (weak granular staining) increased to 15.75+/-6.19/HPF and 6.45+/-2.93/HPF in the groups C and D, respectively, but decreased to 2.42+/-2.06/HPF in the group B compared with the control group (A) (6.38+/-2.18/HPF; p<0.05). The cells at S phase (strong granular staining) increased to 3.37+/-2.69/HPF in the group B but decreased to 0.32+/-0.47/HPF in the group D (p<0.05). In conclusion, these results indicate that the TGF-1 may be used as an effective anticancer agent.

Expression of TGF-beta and PDGF in Monocrotaline-Induced Pulmonary Hypertension in Rats.: Min Sun Cho, Sang Ho Cho, Woo Ick Yang, Woon Sup Han; Korean J Pathol. 1999;33(8):545-554.

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Abstract PDF: Pulmonary vascular hypertension is characterized by migration and proliferation of smooth muscle cells accompanying abnormal synthesis and accumulation of extracellular proteins in vascular wall. The aim of this study is to define the role of endogneous TGF-betas and PDGF in the process of remodeling vessels through determining the temporal and spatial distribution of these growth factors in hypertensive pulmonary vessels in monocrotaline-induced pulmonary hypertension in rat. Sprague-Dawley rats were sacrificed 12 hours, 1, 2, 4, 7, 10, 14, 21, 28, and 56 days after treatment. The morphometric analysis of medial thickening and immunohistochemical study using antibodies to TGF-beta1, TGF-beta2, TGF-beta3, and PDGF were performed. Immunoreactivities for TGF-beta1 and TGF-beta3 were increased from the 14th day in the medial smooth muscle cells and PDGF showed increased expression from the 21st day in the medial smooth muscle cells. No difference in TGF-beta2 immunoreactivity was found between control and experimental groups. The expression of TGF-beta1, TGF-beta3 and PDGF increased in medial layers with the progressive thickening of pulmonary arteries which was considered to have close relation to medial hypertrophy of pulmonary arterioles. In the case of PDGF, however, the morphologic change occurred before increase in immunoreactivity was observed in the medial layer of pulmonary arterioles. Moreover, the function of isoforms of TGF-beta has yet to be completely elucidated; the different affinity to receptors and the degree of expression of these receptors that are supposed to affect the function of growth factors. Thus, further studies are needed.

Immunohistochemical Analysis of Transforming Growth Factor (TGF)-beta1 and TGF-beta Receptor II and Quantitative Analysis of TGF-beta1 mRNA during Multistep Hepatocarcinogenesis Induced by Diethylnitrosamine in Sprague-Dawley Rats.: Mee Yon Cho, Ju Han Lee, Yong Koo Kang, Nam Hee Won; Korean J Pathol. 1999;33(11):1009-1023.

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Abstract PDF: Transforming growth factor (TGF)-beta1 plays an important role in hepatocarcinogenesis and has been described as a useful tumor marker and one of the poor prognostic indicators in patients with hepatocellular carcinoma (HCC). To investigate the role and cellular localization of TGF-beta1 during multistep hepatocarcinogenesis we performed a quantitative analysis of TGF-beta1 mRNA and immunohistochemical expression of TGF-beta1 and TGF-beta receptor II (TGF-betarII) in female Sprague-Dawley rats. The experimental groups included neoplastic lesions produced by Solt-Farber's protocol, regenerating liver after partial hepatectomy, and normal control. Quantitative change of TGF-beta1 mRNA was analysed by competitive reverse-transcription polymerase chain reaction (RT-PCR). TGF-beta1 protein and TGF-betarII expression were evaluated by immunohistochemical stain. The discrete tumor nodules were detected on 14th day and then increased in number and size. Three HCCs were induced on 8th or 9th month. RT-PCR demonstrated TGF-beta1 mRNA band in all examples of the normal and regenerating liver, nodules and HCCs. Competitive RT-PCR displayed higher TGF-beta1 mRNA in nodules, HCCs and regenerating liver than in normal controls. Hepatocytes from control and regenerating livers showed weak immunoreactivity for TGF-beta1. In contrast, the cytoplasm of hepatocytes of nodules in 7th, 8th and 9th month and HCCs were intensely stained for TGF-beta1. Some sinusoidal cells showed immunoreactivity for TGF-beta1 in all experimental groups. In early phase of carcinogenesis, the cytoplasm of hepatocytes in liver of 12h, 1d and 3d showed transiently increased immunoreactivity for TGF-beta1 and The immunoreactivity decreased thereafter. TGF-beta1 mRNA was also detected in the neoplastic hepatocytes by in-situ hybridization. Although TGF-betarII expression was correlated with TGF-beta1 immunoreactivity during early phase of carcinogenesis, hepatocytes in most nodules in 7th, 8th, 9th month and carcinomas showed decreased or little immunoreactivity for TGF-betarII. Based on the above results, it is concluded that TGF-beta1 expression increases not only in precancerous nodules but also in HCCs and its increase seems to be correlated with decrease or loss of TGF-betarII expression although its mechanism remains unclear. Hepatocytes may be a major cellular source of TGF-beta1 during hepatocarcinogenesis.

Expression of Transforming Growth Factor-beta1 in Cyclosporine-Induced Nephropathy in Rats.: Yu Na Kang, Kwan Kyu Park, Mee Yul Hwang, Kun Young Kwon, Sang Sook Lee, Eun Sook Chang, Hyun Chul Kim; Korean J Pathol. 2000;34(9):642-651.

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Abstract PDF: Cyclosporine nephropathy was induced by intraperitoneal injection of cyclosporine 25 mg/kg in Sprague-Dawley rats daily for 1, 4, 8, and 12 weeks to clarify the relationship between cyclosporine nephropathy and the expression of TGF-beta1 with extracellular matrix deposition. On light microscopic examination, the kidneys in the 12 week cyclosporine-treated rats showed focal or striped fibrosis, vacuolization of tubular cells, and injury of endothelial cells. Immunohistochemically, TGF-beta1 protein was strongly expressed in the cyclosporine-treated rat kidneys, especially in the glomerular endothelial cells, interstitial endothelial cells, tubular epithelial cells, and parietal cells in the Bowman's capsule of the glomerulus as well as the periglomerular arterioles. The amount of TGF-beta1 expression was correlated with the morphological change in the cyclosporine-treated rats. Extracellular matrix, such as fibronectin and collagen IV, was also expressed in the endothelial cells of the glomerulus and the interstitium. It can be concluded, therefore that TGF-beta1 protein is probably involved in the early stage of fibrogenesis in cyclosporine nephropathy. It can be postulated that cyclosporine nephropathy results from the accumulation of extracellular matrix associated with the increase of TGF-beta1 transcription. Therefore, these results could be used in reducing fibrosis in cyclosporine nephropathy.

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