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Qualitative differences in position of sialylation and surface expression of glycolipids between murine lymphomas with low metastatic (Eb) and high metastatic (ESb) potentials and isolation of a novel disialoganglioside (GD1 alpha) from Eb cells.

Glycolipids of murine lymphoma cell lines with low metastatic (Eb) and high metastatic (ESb) potentials have been investigated. The Eb cell line was characterized by a high quantity of gangliotriaosylceramide (Gg3), gangliotetraosylceramide (Gg4), GM1b, and a new type of disialoganglioside, termed GD1 alpha. In contrast, the high metastatic ESb cell line was characterized by the absence of these glycolipids and instead by the presence of GM3, GM2, GM1a, GD1a, and GD1b gangliosides. A clear cell surface reactivity with monoclonal antibody anti-Gg3 (2D4) was observed only in Eb cells. Thus, Eb cells are distinct from ESb cells in their ability to add the GalNAc residue to LacCer, supplying Gg3 for synthesis of a series of glycolipids via an asialogangliotetraosyl pathway, while ESb cells are capable of synthesizing GM3, which initiates synthesis of ganglio-series gangliosides GM2, GM1a, GD1a, and GD1b. While disialogangliosides of ESb cells were identified as GD1a and GD1b, a disialoganglioside isolated from Eb cells was characterized as having a novel structure (referred to as GD1 alpha) as follows: (formula; see text) Thus, Eb and ESb cells are clearly different in their qualitative sialylation patterns, i.e., the position of sialic acid residues. Cell surface labeling with galactose-oxidase/NaB[3H]4 revealed a high exposure of Gg3 and Gg4 at the Eb cell surface, while both labels were absent in ESb cells. In contrast, ESb cells showed a substantial label at GM1a, which was greatly enhanced after sialidase treatment.

Animals↗

Acquisition of metastatic ability in hybridomas between two low metastatic clones of murine colon adenocarcinoma 26 defective in either platelet-aggregating activity or in vivo growth potential.

Two low metastatic clones, NL-14 and NL-44, had been isolated from the murine colon 26 adenocarcinoma after in vivo selection and subsequent in vitro cloning. NL-14 is defective in the ability to induce platelet aggregation, but it has good in vivo growth potential. NL-44 possesses low growth potential after s.c. inoculation, but it has strong platelet-aggregating ability. A ouabain-resistant variant of NL-14 and a G418-resistant variant of NL-44 were established. Each resistant cell line conserved the phenotypes of platelet-aggregating ability or in vivo growth potential as compared to the respective parental cell line. These two clones were fused to examine the metastatic potential of hybridomas. Of eight hybridomas tested, six possessed both platelet-aggregating ability and good in vivo growth potential. These six hybridomas formed a higher number of pulmonary metastases after i.v. inoculation than the parental cells. Of the two low metastatic hybridomas, one was lacking in the ability to induce platelet aggregation, and the other showed the least potential for in vivo growth. Hybridoma clones with high platelet-aggregating activity in vitro were generally arrested well in the lung following i.v. inoculation. These results suggest that platelet-aggregating ability and in vivo growth potential are two major determinants for successful experimental lung metastasis of the colon 26 adenocarcinoma.

Adenocarcinoma↗

Metastatic behavior of tumor cells isolated from primary and metastatic human colorectal carcinomas implanted into different sites in nude mice.

The purpose of these studies was to examine the growth characteristics and metastatic behavior of freshly isolated human colorectal carcinomas implanted into athymic nude mice. Four tumor lines were derived from primary colorectal carcinomas, three lines from hepatic metastases, and one line from a metastasis to a mesenteric lymph node. Subsequent to implantation into the subcutis or the muscularis, tumor lines derived from metastases grew faster in the nude mice than did cells isolated from the primary neoplasms. Regardless of the source of the cells, however, little or no visceral organ metastasis was found. Subsequent to i.v. injection, experimental lung colonies could be produced by some of the cells, but there was no correlation between lung tumor colony formation and the origin of the human colorectal cells. The intrasplenic injection of colorectal carcinoma cells provided a useful procedure to identify human colorectal carcinoma cells with metastatic potential to liver. Extensive tumor burdens in the liver were observed as early as 30 days after injection with two of the three liver metastasis-derived tumor lines. No liver metastases were found after the intrasplenic injection of cells isolated from the lymph node-derived tumor line. Ninety days after the intrasplenic injection of cells from the four primary colorectal carcinomas, limited liver metastases were observed. We conclude that metastasis of human colorectal carcinomas can be studied in nude mice, and its outcome depends upon both the intrinsic metastatic capacity of the human tumor cells and the organ environment of implantation.

Adult↗

[Chemotherapy for metastatic brain tumors with CDDP and other agents: correlation between chemotherapeutic effects and the results of in vitro chemosensitivity tests using collagen gel-embedded culture combined with computerized image analysis in metastatic brain tumors].

Chemotherapy with CDDP and/or other agents was performed in 15 patients after removal of metastatic brain tumors. A chemosensitivity test using a system of collagen gel-embedded culture and computerized image analysis was performed on the tumors from these patients. The clinical usefulness of the chemosensitivity test was evaluated by comparing chemotherapeutic effects with the results of the test. The rates of correlation of the chemosensitivity test with clinical response on brain MRI was 80%, and that of the chemosensitivity test with clinical response in tumor markers or on primary tumors was 75%. This observation suggests that the chemosensitivity test using collagen gel-embedded culture and computerized image analysis is useful in determining optimal chemotherapy for metastatic brain tumors. In ten multiple metastatic brain tumors, three complete responses, two partial responses, one minor response and four non-responses were observed on MRI. Only one case showed a false negative result on the chemosensitivity test and showed partial response. This result also indicates the effectiveness of chemotherapy based on chemosensitivity testing.

Adenocarcinoma↗

[Highly metastatic model of human hepatocellular carcinoma established in nude mice using orthotopic organ selection of metastatic variant from patient specimens].

We succeeded in establishing a highly metastatic model of human hepatocellular carcinoma (HCC) in athymic nude mice (LCI-D20). The metastatic variant was obtained by using orthotopic implantation of histologically intact tumor tissue selected from 30 fresh surgical specimens. It exhibited various features seen in clinical liver cancer patients: local growth, regional invasion, spontaneous intrahepatic, lymphnode and pulmonary metastases, and peritoneal seeding with bloody ascites. All mice with the implant-tumor died within 6 weeks due to serious metastasis. The 100% rate of transplantability and metastasis maintained for over 16 passages. The morphological characteristics of implant tumor cells were similar to those of the original specimen by histological and electronmicroscopic observation, and kept on secreting alpha-fetoprotein (AFP) in recipient animals. Those data from DNA content analysis by flow cytometry (D. I. value, 1.61) and chromosome karyotype revealed the existence of hypotriploid and hypertriploid cells. The results demonstrated that orthotopic implantation model of human HCC displayed features of human clinical HCC in animals. It should allow development of new treatment modalities and study of metastatic mechanism of human HCC.

Animals↗

PKC-dependent modulation of IkB alpha-NFkB pathway in low metastatic B16F1 murine melanoma cells and in highly metastatic BL6 cells.

Protein Kinase C (PKC) is a family of at least 11 closely related isoforms with different modality of activation, and intracellular and tissue distribution. The aim of the present work was to analyse the effect of treatment with 0.1 microM TPA as well as treatment with specific inhibitors of individual PKC isoenzymes (Gö6976 for c-PKC alpha and beta isoforms and BIM for c-PKCs and n-PKCs isoforms), on the NF-kB/IkB alpha pathway in the low and high metastatic B16F1 and BL6 murine melanoma cells. The DNA-binding activity of the transcription factors AP1, AP2, CREB and OTC was also considered. Different modality of activation for NF-kB and AP1 was demonstrated in the two cell lines with the possible specific involvement of c-PKCs isoforms. In fact, in the high metastatic BL6 cells the long-term treatment for 24 hours with TPA, with no c-PKC activation or the inhibition with Gö6976 as well as with BIM, induced an increased NF-kB and AP1 DNA-binding activity. In contrast, in the low metastatic B16F1 cells the short-term treatment with TPA, induced the activation of c-PKCs isoforms, and enhanced NF-kB and AP1 DNA-binding activity. No significant changes were demonstrated for AP2, CREB and OTC DNA-binding activity in both cell lines.

Animals↗

Carcinoma metastatic to the eye and orbit II. A clinicopathological study of 26 patients with carcinoma metastatic to the anterior segment of the eye.

In 26 of 227 patients with carcinoma metastatic to the eye or orbit, metastasis to the anterior uveal tract was the predominating feature. There was a definite propensity for the tumor to involve the horizontal meridian of the iris or ciliary body, rather than the upper or lower portions. The site of the primary tumor in the 26 patients was as follows: lung 14; breast, 9; kidney, 2; and rectum, 1. Ocular symptoms and signs produced by the metastatic tumors at onset or during the course of the disease included decreased vision (80%), a visible mass (72%), redness of the eye (56%), pain (56%), glaucoma (56%), iridocylitis (44%), and hyphema (24%). The median survival of the 26 patients with metastasis to the anterior segment of the eye was only 5.4 months from the time of ocular surgery. This is poorer than the median survival (7.2 months) of the patients with metastasis confined to the posterior segment, and much worse than the median survival (15.6 months) of the 28 patients with orbital involvement.

Adenocarcinoma↗

Metastatic melanoma of unknown primary origin shows prognostic similarities to regional metastatic melanoma: recommendations for initial staging examinations.

BACKGROUND: Metastatic melanoma of unknown primary origin accounts for approximately 2-6% of all melanoma cases. The prognostic significance of this diagnosis is still controversial. METHODS: Of 3258 patients with malignant melanoma recorded during the period 1976-1996, 2.3% had metastases of unknown primary origin. Anatomic distribution, clinical stage, and survival probabilities were evaluated. RESULTS: Thirty patients were classified as having cutaneous or subcutaneous in-transit metastases, and they showed a 5-year survival rate of 83%. Thirty-seven patients were classified as having lymph node metastasis, and their 5-year survival rate was 50%. Disseminated disease was diagnosed in only 8 patients, who had a median survival of 6 months. Comparison of survival probabilities for patients with in-transit metastases and unknown primary tumors with the probabilities for those with cutaneous primary tumors revealed a significant advantage for the former group. No significant differences were found for patients with lymph node metastasis when those with unknown primary tumors were compared with those who had cutaneous melanomas with regional lymph node metastasis. CONCLUSIONS: The clinical disease course of patients with metastatic melanoma of unknown primary origin is similar to that of patients with primary cutaneous melanoma when the same clinical stages of the disease are compared. Based on the assumption that the majority of regional metastases develop from completely regressed primary cutaneous melanoma, recommendations for initial staging examinations in patients with unknown primary tumors are given in this article.

Adolescent↗

Inhibition of highly metastatic FBJ-LL cell migration by ganglioside GD1a highly expressed in poorly metastatic FBJ-S1 cells.

For clarification of the functions of gangliosides on tumor metastasis, examination was made of the ganglioside patterns of poorly metastatic FBJ-S1 and highly metastatic FBJ-LL cells. FBJ-S1 cells expressed GM3 and GD1a, whereas FBJ-LL cells expressed GM3 and slightly expressed GD1a. The capacity for FBJ-LL cells to migrate was ten times that of FBJ-S1 cells, but decreased by a half by pretreatment with GD1a. GD1b or GT1b had the same effect as GD1a, and synthetic sialyl compounds to a lesser extent, suggesting that gangliosides contain more than two sialyl residues to inhibit the migration of FBJ-LL cells.

Animals↗

Wild-type p53 differentially affects tumorigenic and metastatic potential of murine metastatic cell variants.

The structure and the function of the p53 gene were studied in two metastatic cell variants derived from Lewis lung carcinoma. Single missense mutation at codon 334 was detected in the p53 gene of both cell variants. In spite of the identical mutation, the in vitro and in vivo growth rates of the two cell variants were differentially affected by the constitutive expression of exogenous wild-type (wt) p53 gene. In fact, only the more malignant cell line (C87) was severely affected by the wt-p53 gene introduction. However, the in vivo effects on this cell line were transient because during serial in vivo passages, cell populations lacking the wt-p53 gene were selected. Genetic mechanisms responsible for the resistance of the less metastatic cell variant (BC215) to the wt-p53 expression, were investigated. Intrinsic ability to mutate exogenous cDNA sequences was tested. We report that BC215 cells continued to express exogenous wt-p53 sequences after several in vitro passages. The expression of mdm2 gene was evaluated. The data demonstrated that BC215 cells constitutively express higher levels of mdm2 gene than C87 cells. We conclude that the overexpression of this gene might be responsible for the resistance of BC215 cells to exogenous wt-p53 gene expression.

Animals↗

Induction of the metastatic phenotype by transfection of the nuclear oncogene p53: increases in cytoplasmic diacylglycerol levels and reduction in class I major histocompatibility antigen expression are not sufficient to explain the changes in metastatic capacities.

Transfection of the oncogene encoding the nuclear protein p53 into a low-metastatic mouse carcinoma cell line resulted in enhanced metastatic capabilities in clones that showed increased p53 protein expression [Pohl J, Goldfinger N, Radler-Pohl A, Rotter V, Schirrmacher V (1988) Mol Cell Biol 8:2078-2081]. This effect seemed neither to be due to increase in cytoplasmic diacylglycerol levels nor to reduced cell-surface expression of class I major histocompatibility antigens.

Animals↗

Monoclonal antibodies against a human gastric cancer cell line with lung metastatic potential in nude mice define antigens with different expression between the primary and metastatic liver lesions.

SCK-29 is a tumor cell line derived from human gastric adenocarcinoma with the feature of producing lung metastases when xenografted in nude mice. Monoclonal antibodies were produced against SCK-29 tumor cells or their glycoproteins prepared by affinity chromatography on a lectin-agarose column. Five antigens defined by the monoclonal antibodies MG-1 to MG-5 were expressed in a large number of gastric or colonic adenocarcinomas. Among the antigens, MG-1 and MG-3 proved to be tumor-associated, since they were detected only occasionally in normal tissues. MG-5 antigen was often detected in normal gastric mucosa but not in other tissues. The degree of expression of MG-1. MG-3 and MG-5 antigens differed considerably in metastatic lesions. In metastatic liver lesions of gastric adenocarcinoma, expression of these MG antigens was less marked than in primary tumors. MG-1 and MG-3 antigens were abolished by neuraminidase digestion and periodate oxidation. MG-5 antigen was likely to be a protein antigen, since it was resistant to neuraminidase digestion and to periodate oxidation but was sensitive to protease digestion.

Adenocarcinoma↗

An immunohistochemical study of glucagonoma conducted on the metastatic lymph nodes from a patient with recurrent metastatic glucagonoma: report of a case.

In this report, we briefly present the case of a 67-year-old woman who developed recurrent glucagonoma with lymph node metastasis. An immunohistochemical study of the metastatic tumor revealed immunoreactivity of glucagon and protein kinase C (PKC)-alpha, -beta, and -gamma in the tumor cells, two types of which were seen by electron microscopy. One type had abundant secretory granules and mitochondria, while the other had few granules and mitochondria. Some granules were similar to typical A cell granules and others were atypical. An immunoelectron microscopic demonstration revealed PKC-alpha, -beta, and -gamma immunostaining in the cytoplasm of all the tumor cells, while some secretory granules had PKC immunostaining, and others had no immunostaining. Thus, it appears that metastatic glucagonoma and its associated granules are composed of two types of mature and immature cells or granules. As immunoreactivity of PKC-alpha and -gamma was found in the tumor cells, but not in the normal A cells of the islets of Langerhans, the PKC subspecies alpha and gamma, which are not present in normal pancreatic A cells, may exist in human glucagonoma cells.

Aged↗

Expression of the tumor metastatic suppressor gene in mouse melanoma model: inverse association to metastatic potential.

Data obtained in experimental cutaneous melanomas have suggested that the nm23 gene may function as a metastasis suppressor gene. The nm23 level in 8 human cutaneous melanoma cell lines and 2 murine melanoma cell lines were examined. Each melanoma cell line was transplanted subcutaneously into the flank of nude mice, and the metastatic behavior was evaluated by counting lung tumor foci and by determining host survival time. It was found that expression of nm23 mRNA in human melanomas is correlated closely with reduced metastatic behavior in experimental animals and may serve as a sensitive prognostic indicator of malignancy and survival in patients with melanomas.

Animals↗

Disseminated metastatic disease of osteosarcoma of the femur in the abdomen: unusual metastatic pattern on Tc-99m MDP bone scan.

A 25-year-old patient with osteosarcoma of the right distal femur underwent a bone scintigraphy with Tc-99m methylene diphosphonate (MDP). Whole-body bone scan revealed extensive metastatic disease in the abdominal region. Abdominal computerized tomography confirmed the presence of ascites and calcified masses on the greater omentum and peritoneal surfaces. Here we describe a case of unusual metastatic pattern of an osteosarcoma showing extensive intraabdominal metastases without prominent lung involvement after intensive chemotherapy.

Abdominal Neoplasms↗

Production of metastatic phenotype with DNA from metastatic cells but not with oncogenic DNA.

Although the tumorigenic phenotype can be transferred by transfecting DNA from a variety of human tumours into 3T3 mouse fibroblasts, the ability to transfer the metastatic phenotype in a similar manner in syngeneic animals is largely unknown. We now report that transfection of a rat mammary epithelial cell line Rama 37, which produces nonmetastasizing adenomatous tumours in syngeneic rats, with DNA from a metastasizing rat mammary cell line, Rama 800, yields some transfectants with reproducible metastatic capabilities. Nonspecific DNA or the oncogenes EJ-ras-1 or Polyoma Large T Antigen fail in this respect, although their transfectants often possess increased tumorigenic potential.

Animals↗

Phagocytosis of Candida albicans by metastatic and non metastatic human breast cancer cell lines in vitro.

Experiments were carried out to investigate the kinetic characteristics of phagocytosis of candida by metastatic (MCF-7 and ZR-75-1) and nonmetastatic (HCC70) breast cancer cell (BCC) lines. Cancer cells were mixed with candida at a ratio of 1:10 and attachment/phagocytosis were examined using cytospin preparations stained with either Giemsa or tannic acid and May-Grünwald Giemsa and by using flow cytometry. A high attachment of candida to cancer cells (29-39%) was detected as early as 10 min. Following attachment, cancer cells phagocytized yeast. The phagocytic activity of MCF-7 and ZR-75 cells was significantly higher (58-61%) than that of HCC70 cells (26%). A similar trend was observed with respect to the phagocytic index. Phagocytosis of candida by tumor cells was inhibited significantly by both cytochalasin B (50%) and by lowering temperature to 4 degrees C (66%). Phagocytosis was not associated with oxidative burst in any cell lines used. In conclusion, metastatic breast cancer cells possess phagocytic activity which may explain their invasive property.

Breast Neoplasms↗

Metastatic processes and a potential indication of treatment for metastatic lesions of renal adenocarcinoma.

Renal adenocarcinoma findings from 307 autopsied cases with metastasis to 1 and 2 organs were investigated concerning the mode of metastasis. The lung was the most frequent site of metastasis to 1 organ, although the frequency was rather low (30 per cent), followed by bones (over-all), lymph nodes (over-all) and brain, and involving frequently the thoracic spine and retroperitoneal lymph nodes. In patients with metastases to 2 organs a significant correlation was found between the pulmonary-tracheal lymph nodes and those to the lungs. Potential indications for treatment of metastatic lesions were 1) lymphadenectomy and/or radiation therapy for the retroperitoneal and para-aortic lymph nodes and 2) resection of metastatic lesions in the lungs combined with lymphadenectomy and/or radiation therapy for the pulmonary-tracheal lymph nodes. In patients without lung metastasis lymphadenectomy and/or radiation therapy for the pulmonary-tracheal lymph nodes is not always necessary.

Adenocarcinoma↗