Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental carcinomas in the glandular stomach of rats were induced by oral administration of MNNG (M-methyl-N'-nitro-N-nitrosoguanidin) for 35 weeks or ENNG (N-ethyl-N'-nitro-N-nitrosoguanidin) for 20 weeks. Rats were killed at different times after beginning of carcinogen treatment and tissue specimens were prepared for histologic investigation. Particular interest was placed on the development of tumors and on pathological findings possibly contributing to early diagnosis of stomach cancer. During the development of tumors, several dysplastic reactions were observed in the antral mucosa. They could be classified into 4 groups: One was regenerative hyperplasia (1) that meant irregular glandular proliferations without cell atypism at the margin of erosions and ulcers. This lesion was mainly found 1-9 weeks after administration of MNNG. In glandular hyperplasia (2) either crypts or glands were extended and mucosal layers were thickened. No signs of cell atypism were observed. This lesion was mainly found 12-17 weeks after administration of MNNG. Dysplasia (3) was combined with considerable structural modifications and cellular atypism. However, this lesion was limited to the mucosal layer. Neoplastic changes (4) were characterized by marked cellular atypism and extension to tunica submucosa and tunica serosa. Some tumors showed the histological patterns of benign tumors, but most of them were adenocarcinomas. In some cases metastases into pancreas, liver and lymph nodes and in one case into the 12th rib were observed. No particular enzyme patterns were found by histochemistry.
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PMID:Development of tumors in the glandular stomach of rats after oral administration of carcinogens. I. Histological findings. 13 28

In order to test the hypothesis that tumor cells with greater malignant potential should have an increased sensitivity to mutagens, four individual murine cell lines, each paired for their metastatic and nonmetastatic potentials, were compared with respect to the prevalence at which ouabain-resistant mutants could be obtained after treatment of the cells with the mutagen MNNG. No increase in the prevalence of induced mutation in metastatic cells was observed; and, in fact, in two cases (h-ras-transfected 3T3 and SP1 cells), nonmetastatic cells had a higher prevalence of mutations after MNNG treatment than did their metastatic counterparts. We suggest that the absolute level of genomic instability, measured by this means, is not critical to malignant potential and tumor progression.
Invasion Metastasis 1988
PMID:The prevalence of ouabain-resistant variants after mutagen treatment. Lack of correlation between the frequency of variant expression and the metastatic phenotype. 336 May 93

The development of a satisfactory rodent model for cancer of the large intestine began with the discovery by Laqueur and associates in 1962 that the plant product, cycasin (methylazoxymethanol glycoside), is a potent carcinogen for rodents. Soon after that, DMH, AOM, and MAM were found to be even more efficient intestinal carcinogens in rats. These three compounds, plus two direct acting carcinogens (MNNG, MNU) are used almost exclusively in current animal investigations. Although all these chemicals have some degree of activity in all rodents, they are most effective in rats. Various rat strains differ somewhat in susceptibility, Sprague-Dawley being the most sensitive to these carcinogens. Cancers of the large intestine in the animal model resemble adenocarcinomas in humans, and they spread in a similar manner except that metastases to the liver and lung are very uncommon in animals. Animal studies support epidemiological and human experimental observations of dietary factors involved in colorectal cancer formation. Most physicians believe that the majority of colorectal cancers develop from preexisting adenomas. Morson has shown that large adenomas and villous adenomas have a greater risk of developing cancer than small adenomas. Hill has theorized that there are different factors responsible for the formation of small adenomas from normal mucosa, for the growth of small to large adenomas, and for the development of cancer from large adenomas. Animal studies provide some support for this concept. Weak intestinal carcinogens tend to induce more benign adenomas than carcinomas. Very small doses of strong carcinogens also induce some adenomas and a few early polypoid intestinal cancers after a long latent period. Moderate to large amounts of DHM, for example, induce only malignant lesions even when these lesions are as small as 1 mm. These observations suggest a relationship between adenomas and carcinomas. There is also biochemical evidence to support the staged progression of carcinogenesis. An example is the graded increases in ODC activity that occur in tissues undergoing tumorigenesis.
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PMID:Animal model for colorectal cancer. 403 97

Metastatic osteosarcoma is a potential target for gene therapy, because conventional therapies are only palliative and metastatic disease is invariably fatal. Overexpression of the cyclin G1 (CYCG1) gene is frequently observed in human osteosarcoma cells, and its continued expression is found to be essential for their survival. Previously, we reported that down-regulation of cyclin G1 protein expression induced cytostatic and cytocidal effects in human MG-63 osteosarcoma cells (Skotzko et al., Cancer Research, 1995). Here, we extend these findings in a tumorigenic MNNG/HOS cell line and report on the effective inhibition of tumor growth in vivo by an antisense cyclin G1 retroviral vector when delivered as concentrated high titer vector supernatants directly into rapidly growing subcutaneous tumors in athymic nude mice. Histologic sections from the antisense cyclin G1 vector-treated tumors showed decreased mitotic indices and increased stroma formation within the residual tumors. Furthermore, in situ analysis of the cell-cycle kinetics of residual tumor cells revealed a decrease in the number of cells in S and G2/M phases of the cell cycle concomittant with an accumulation of cells in the G1 phase. Taken together, these studies demonstrate in vivo efficacy of a high-titer antisense cyclin G1 retroviral vector in an animal model of osteosarcoma.
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PMID:Retroviral vector-mediated transfer of an antisense cyclin G1 construct inhibits osteosarcoma tumor growth in nude mice. 932 69

Osteosarcoma is the most frequent malignant bone tumor in children. It is highly invasive, however, the mechanisms behind osteosarcoma cell invasion are as yet still unknown. In the present study, treatment with TNFalpha enhanced the invasiveness of two human osteosarcoma cell lines, OST and MNNG. TNFalpha treatment also induced tumor cell motility, adhesion to laminin, the expression of matrix metalloproteinase 9 (MMP9), and the nuclear translocation of nuclear factor kappaB (NFkappaB) in the osteosarcoma cells. Moreover, antioxidants inhibited TNFalpha-induced osteosarcoma cell invasion, motility and NFkappaB nuclear translocation, but not adhesion to laminin or MMP9 expression. NFkappaB decoy, another NFkappaB inhibitor, also inhibited TNFalpha-induced osteosarcoma cell invasion and motility. Therefore, motility and NFkappaB activation were possibly related to TNFalpha-induced osteosarcoma cell invasion. However, adhesion to laminin or MMP did not demonstrate any correlation with TNFalpha-induced osteosarcoma cell invasion. Although NFkappaB is known to regulate TNFalpha-induced phenotypes, it may influence only motility and invasion, but not the MMP or laminin-mediated adhesion of these osteosarcoma cells.
Clin Exp Metastasis 2000
PMID:Antioxidants inhibit TNFalpha-induced motility and invasion of human osteosarcoma cells: possible involvement of NFkappaB activation. 1123 87

Recently, stage-oriented surgery has been performed for gastric cancer, but a new strategy is necessary for stage IV gastric cancer. The first target of gene therapy for gastric cancer was for stage IV patients with-widespread lymph node metastases and/or peritoneal dissemination. We reported on suicide gene therapy in experimental gastric cancer induced by ENNG in the dog, and the results showed that in situ gene transfer of a suicide gene (Ad. CAGHSV-TK) followed by prodrug (GCV) treatment may be applicable not only to the primary gastric tumor, but also to lymph node metastasis. Next, we assessed the efficacy of in situ gene therapy with Ad. CAGHSV-TK/GCV in gastric cancer induced by MNNG in rats, and followed the histopathological changes in the gastric cancer and HSV-TK gene in peripheral blood for 30 days. The results showed that: 1) apoptosis preceded tissue degeneration; 2) histopathological efficacy requires 30 days after suicide gene therapy; and 3) the HSV-TK gene persisted for 30 days. Based on these studies, we speculated that combination treatment with endoscopy is possible for all early gastric cancer, i.e., endoscopic mucosal resection of the primary tumor plus suicide gene therapy for sentinel lymph node metastasis. New possible strategies for peritoneal dissemination are: 1) tumor dormancy therapy with adeno-associated virus (AAV); and 2) combination gene therapy with suicide genes plus gene transfer to provide immunotherapy.
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PMID:[Possibility and future problems of gene therapy for gastric cancer]. 1168 Oct 5

Aminopeptidase N (APN/CD13), a Zn2+-dependent ectopeptidase, is localized on the cell surface and functions as a transmembrane protein. Increased expression and activity of APN have been postulated to correlate with the aggressive behavior of several tumor types. In this study, the osteosarcoma cell line MNNG/HOS was stably transfected with an expression vector capable of expressing the antisense transcript of APN. Four stably transfected clones, the control clones and parental cells were characterized. Stable integration of the antisense vector was confirmed by PCR analysis of genomic DNA. Competitive RT-PCR revealed that mRNA expression of antisense-transfectants was decreased to approximately 37% of the control cell line. The activity assay showed that the enzymatic activity of APN was inhibited to approximately 51% of the control cell line. Antisense-transfection had no influence on the cellular proliferation measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, on the motility in Transwell chambers, and on the adhesive potential to collagen I. However, an in vitro invasion assay revealed a significant decrease in the number of cells that migrated through a reconstituted membrane (51% of the control cell line). The adhesive potential to Matrigel was also affected (73% of the control cell line). Furthermore, under in vivo conditions, a reduced potency to metastasize to the lung was shown in an experimental metastasis assay in nude mice. These findings demonstrate that APN plays an active role in the cellular attachment and proteolytic degradation of the extracellular matrix in the metastatic process of osteosarcomas.
Clin Exp Metastasis 2003
PMID:Inhibitory effect of antisense aminopeptidase N (APN/CD13) cDNA transfection on the invasive potential of osteosarcoma cells. 1466 89

Osteosarcoma is the most common primary malignancy of bone and patients often develop pulmonary metastases. In order to investigate the pathogenesis of human osteosarcoma, there is a great need to develop a clinically relevant animal model. Here we report the development of an osteosarcoma animal model using three related human osteosarcoma lines, the parental TE-85 and two derivative lines MNNG/HOS and 143B. In vitro characterization demonstrated that the 143B line had the greatest cell migration and the least cell adhesion activities among the three lines. The 143B line also exhibited the greatest ability for anchorage independent growth. When GFP-tagged osteosarcoma cells were injected into the proximal tibia of athymic mice, we found that 143B cells were highly tumorigenic and metastatic, and MNNG/HOS cells were tumorigenic but significantly less metastatic. TE85 cells were neither tumorigenic nor metastatic. The number of pulmonary metastases was found 50-fold higher in 143B injected animals than that in MNNG/HOS injected mice. No pulmonary metastases were detected in TE85 injected animals for up to 8 weeks. Primary tumors formed by MNNG/HOS and 143B cells could be visualized by whole body fluorescence imaging, while the pulmonary metastases were visualized on the necropsied samples. The GFP tagged 143B cells (and to a lesser extent, MNNG/HOS cells) were readily recovered from lung metastases. This clinically relevant model of human osteosarcoma provides varying degrees of tumor growth at the primary site and metastatic potential. Thus, this orthotopic model should be a valuable tool to investigate factors that promote or inhibit osteosarcoma growth and/or metastasis.
Clin Exp Metastasis 2005
PMID:An orthotopic model of human osteosarcoma growth and spontaneous pulmonary metastasis. 1617 Jun 68

The development of pulmonary metastasis is the major cause of death in osteosarcoma, and its molecular basis is poorly understood. In this study, we show that beta4 integrin is highly expressed in human osteosarcoma cell lines and tumor samples. Furthermore, highly metastatic MNNG-HOS cells have increased levels of beta4 integrin. Suppression of beta4 integrin expression by shRNA and disruption of beta4 integrin function by transfection of dominant-negative beta4 integrin was sufficient to revert this highly metastatic phenotype in the MNNG-HOS model without significantly affecting primary tumor growth. These findings suggest a role for beta4 integrin expression in the metastatic phenotype in human osteosarcoma cells. In addition, we identified a previously uncharacterized interaction between beta4 integrin and ezrin, a membrane-cytoskeletal linker protein that is implicated in the metastatic behavior of osteosarcoma. The beta4 integrin-ezrin interaction appears to be critical for maintenance of beta4 integrin expression. These data begin to integrate ezrin and beta4 integrin expression into a model of action for the mechanism of osteosarcoma metastases.
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PMID:Beta4 integrin promotes osteosarcoma metastasis and interacts with ezrin. 1959 68

We report here in vivo gene transfer between cancer cells is associated with acquisition of high metastatic behavior. The 143B-GFP cell line with high metastatic potential and the MNNG/HOS-RFP cell line with low metastatic potential, both derived from the TE85 human osteosarcoma cell line, were either co-transplanted or transplanted alone in the tibia in nude mice. Upon mixed transplantation of the two differently labeled sublines, resulting metastatic colonies are single colored either red or green, thereby demonstrating their clonality and enabling facile color-coded quantification. When MNNG/HOS-RFP and 143B-GFP were co-transplanted in the tibia, the number of lung metastases of MNNG/HOS-RFP increased eight-fold compared to MNNG/HOS-RFP transplanted alone (P < 0.01). In contrast, no enhancement of MNNG/HOS-RFP metastases occurred when MNNG/HOS-RFP and 143B-GFP were transplanted separately in the right and left tibiae, respectively. This result suggests that the presence of 143B-GFP increased the metastatic potential of MNNG/HOS-RFP within the mixed tumor. We observed transfer of the Ki-ras gene from 143B-GFP to MNNG/HOS-RFP after they were co-implanted suggesting the Ki-ras played a role in increasing the metastatic potential of MNNG/HOS-RFP in the presence of 143B-GFP. These data suggest the possible role of in vivo gene transfer in enhancing the metastatic potential of cancer cells. The data also further demonstrated the power of color-coded imaging to visualize cancer-cell/cancer-cell interactions in vivo.
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PMID:In vivo gene transfer between interacting human osteosarcoma cell lines is associated with acquisition of enhanced metastatic potential. 1962 75


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