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)

Gangliosides may play an important role in the proliferation and spread of human malignant melanoma. Because the frequency of metastases in uveal and cutaneous melanoma differs, it is possible that they may express different gangliosides. We analyzed the ganglioside profiles of primary uveal melanoma in 14 cases and of cutaneous melanoma metastasis in 19 cases. In cutaneous melanoma, GM3 ranged from 4.2% to 74.6% and GD3 from 22.1% to 91.8% of total lipid-bound sialic acid. GM2 (found in 13 of 19 cases, ranging from 0.5% to 11.7%), GD2 (11/19, 0.5%-22.0%) and 9-O-acetyl-GD3 (13/19, 0.5%-12.6%) were also frequently observed. By contrast, in 11 cases of uveal melanoma, GM3 was > 90%, GD3 was < 10%, GM2 was < 1.1%; neither GD2 nor 9-O-acetyl-GD3 were detected. The ganglioside profiles of these uveal melanomas were virtually identical to those of normal melanocytes obtained from foreskins. Histological examination of these 11 biopsies showed a monomorphous cell composition, but neither infiltration of lymphocytes or melanophages nor cell necrosis was observed. In 3 other cases, GD3 was increased to 19.5%-46.0%. Histological examination of these 3 biopsy specimens showed at least 2 populations of tumor cells that were separable based on morphological grounds, and mononuclear inflammatory cells interspersed among the tumor cells. An increase in GD3 appears to be related to tumor polyclonality and infiltration of the tumor by lymphocytes and macrophages. These results suggest that ganglioside expression of uveal melanoma is associated with host immune responses to the tumor. Furthermore, the low metastatic capacity of uveal melanoma, in contrast to the high metastatic rate of cutaneous melanoma, may be a result of its differentiated ganglioside expression, which is strikingly similar to that of normal melanocytes.
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PMID:Variations in the ganglioside profile of uveal melanoma correlate with cytologic heterogeneity. 142 27

The ganglioside GD3 was distributed widely on melanocytes, naevi, and practically all melanomas. Not all the cells in melanoma appeared to express GD3, so that treatment with MAbs to GD3 could be expected to leave foci of tumor cells resistant to the effects of the MAbs. GM3 had a similar distribution of GD3 on melanoma, but was expressed on a lower percentage of cells in individual tumors. Expression of GM3 appeared to be suppressed on melanoma and naevus cells in the epidermis. Addition of MAbs to GM3 to those against GD3 in the treatment of melanoma may increase the lytic effect against cells coexpressing both gangliosides, but as GM3 did not appear to be expressed on GM3 -ve cells, the percentage of resistant cells may not be decreased. GD2 was expressed on only approximately 25% of primaries and less than 50% of metastases. In individual tumors there was some evidence of reciprocal expression of GD3 and GD2, so the combination of MAbs to GD3 and GD2 may decrease the percentage of melanoma cells that are resistant to either MAb alone. Both GD3 and GD2, but not GM3, was expressed on lymphocytes around melanoma metastases in LNs and around melanomas in skin. GD2 was detected on a large percentage of lymphocytes around metastases in lymph nodes, but not in the skin, suggesting that the gangliosides GD2 and GD3 may be expressed on different subsets of T-lymphocytes. These findings, together with previous studies showing that the MAbs can enhance lymphocyte responses to a variety of stimuli, provide support for the hypothesis that the clinical effects of the MAbs may reflect activation of host responses against the tumor. Further analysis of the role of gangliosides in lymphocyte function is needed.
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PMID:Ganglioside antigens in tissue sections of skin, naevi, and melanoma--implications for treatment of melanoma. 167 56

Essentially all tumors express aberrantly glycosylated glycosphingolipids and glycoproteins, more commonly known as "tumor-associated carbohydrate antigens." In this article I propose two new forms of cancer therapy, anti-adhesion therapy and ortho-signaling therapy, which exploit these tumor-associated carbohydrates in distinct ways. The aim of anti-adhesion therapy is to disrupt the requisite carbohydrate-initiated interactions that occur between tumor cells and other cell types (e.g., endothelial cells, platelets) as tumors progress and metastasize. Candidate anti-adhesion agents include purified carbohydrates or glycosphingolipids representing H, Ley, sialosyl-Lex (or -Lea) GM3, or LacCer antigens, and monoclonal antibodies directed to these structures. The aim of ortho-signaling therapy is to disrupt mitogenic signaling pathways in tumor cells that are regulated by glycosphingolipids and/or their derivatives, including pathways involving receptor protein-kinases and protein kinase C. Candidate ortho-signaling agents are the glycosphingolipid regulator PDMP (1-phenyl-2-[decanoylamino]-3-morpholino-1-propanol) and the protein kinase C inhibitor DMS (N,N-dimethylsphingosine), both of which show antitumor activity in vitro and in animal studies.
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PMID:New directions in cancer therapy based on aberrant expression of glycosphingolipids: anti-adhesion and ortho-signaling therapy. 182 92

The expression patterns of glycolipids of human renal-cell carcinoma were studied in primary tumors from 23 cases and 5 metastatic lesions from 4 cases using HPTLC (high-performance thin-layer chromatography). The expression pattern of glycolipids in primary tumors was characteristic of the histological cell type. In granular-cell carcinoma, lactosylceramide (CDH), GM3 and the longer-chain gangliosides (gangliosides migrating more slowly than GM3) increased, although in clear-cell carcinoma, CDH and other glycolipids tended to decrease. Globoside decreased in all cases but one, irrespective of cell type. In metastatic lesions of the clear-cell type, the prominent increase in longer-chain gangliosides was characteristic. Furthermore, the same expression pattern as that of metastastatic lesions was shown in 3 of 14 patients with primary clear-cell carcinoma, all of whom developed metastases soon after radical nephrectomy. These studies indicate that the increased expression of the longer-chain gangliosides in primary tumor is one of the factors associated with high metastatic potential, and also predict early post-operative development of metastasis.
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PMID:Changes in glycolipids in human renal-cell carcinoma and their clinical significance. 191 30

Several studies have shown that melanoma-associated gangliosides are immunogenic in melanoma patients and that antibodies against them have a favorable prognostic effect. Our study aims at characterizing the humoral immune response in disease-free, advanced melanoma patients vaccinated with a total ganglioside fraction extracted from pooled metastases of human melanoma, containing as major gangliosides GM3 and GD3, and as minor ones GM2 and GD2. Prior to vaccination, all patients were made disease-free by surgical removal of skin, lymph-node or other distant metastases. Repeated vaccinations were carried out intradermally with gangliosides either in the native form in buffered solution, or in the form of liposomes. Serum samples were collected at regular intervals and assayed by ELISA for the presence of specific IgG and IgM antiganglioside antibodies. Selected samples were tested by immunostaining on thin-layer plates to specify the ganglioside species involved in the reactivity. Out of 32 evaluable patients, 17 presented a significant increase in antibody titer, mostly of the IgG isotype, which was maximal between 2 and 4 months after starting injections of gangliosides, and gradually disappeared within 1 year. No significant difference could be seen between the group of 20 patients treated with native gangliosides and the group of 12 vaccinated with the gangliosides in liposomes. All gangliosides seemed to be immunogenic, but GM2 and GD2 were somewhat more reactive. The disease-free intervals for the patients who showed an antibody response to the treatment were significantly higher (p less than 0001) than those of the non-responding group, as compared by the Kaplan-Meier method.
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PMID:Humoral immune response in disease-free advanced melanoma patients after vaccination with melanoma-associated gangliosides. EORTC Cooperative Melanoma Group. 195 94

Expression of the gangliosides GM3, GD3 and GD2 was studied in tissue sections from 19 naevi, 29 primary and 83 metastatic melanoma using the ABC immunoperoxidase technique. GM3 was not detected in normal skin whereas GD2 was detected on the basal and stratum spinosum of the epidermis and on peripheral nerves in the dermis. GD3 was expressed on melanocytes but not on most other components of normal skin. However, GD3 was strongly expressed on epidermis adjacent to naevi and primary melanoma whereas GD2, in contrast to that in normal skin, was not expressed on the epidermis adjacent to 26/29 primary melanoma. All naevi were positive for GM3 and GD3 except that GM3 was not detected on junctional components of naevi. GD2 was not expressed on naevi except in areas showing neuroid differentiation. Studies on melanoma revealed that approximately 60% of primary and 75% of metastatic melanoma expressed GM3 to a varying extent. With 2 exceptions, all primary and metastatic melanomas expressed GD3 although there was variable expression within most of the individual tumours. GD2 was detected in only approximately 25% of primary and 50% of metastatic melanomas. Both GD2 and GD3 were detected on lymphocytes surrounding melanoma. The higher expression of GD2 on metastases compared to primary melanomas was consistent with the view that GD2 expression was associated with increased metastatic potential. However, the low proportion of metastases expressing GD2 and the absence of any correlation with thickness of the primary tumour suggested that GD2 expression was not a reliable marker of metastatic potential. No differences could be detected in ganglioside expression on metastases in skin or lymph nodes. These results appear to have implications for the use of MAbs against gangliosides in therapy of melanoma and in the study of melanocytic differentiation.
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PMID:Expression of the gangliosides GM3, GD3 and GD2 in tissue sections of normal skin, naevi, primary and metastatic melanoma. 334 97

The gangliosides in six colorectal and two pancreatic carcinomas were examined. Their concentration in the primary tumour and the metastases was 5-10 fold higher than in normal colon mucosa. This increase involved the simple gangliosides, GM3 and GD3, as well as complex mono- and disialogangliosides. Some complex monosialogangliosides were detected in all the colorectal and pancreatic carcinomas but neither in normal colon mucosa and pancreas nor in kidney and lung carcinomas.
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PMID:Colorectal carcinomas have a characteristic ganglioside pattern. 684 89

The correlation between levels of sialic acid and sialic acid-containing glycolipids (gangliosides) in tumors and serum with the growth characteristics of the tumors was investigated in transplantable hepatomas and squamous cell carcinomas initiated with the carcinogen N-2-fluorenylacetamide and propagated in vivo and in tissue culture. Tumor lines varied in histologic classification, growth rate, and ability to form pulmonary metastases. There was neither a correlation between growth rate and histologic classification nor between either of these two parameters and the ability to metastasize. Total and ganglioside sialic acid levels were elevated in carcinogen-treated liver and in transplantable hepatomas when contrasted with normal liver. Levels of sialic acid showed a weak correlation with the growth rate of hepatomas. Gangliosides from nonmetastatic hepatoma lines exhibited less N-acetylneuraminic acid--galactose--glucose-N--acylsphingosine (GM3) and an increased ratio of total monosialogangliosides to disialogangliosides than did metastatic lines. Ganglioside patterns of metastatic hepatoma lines more closely resembled the ganglioside patterns of normal liver than did those of the nonmetastatic lines. Concomitant elevations of total and ganglioside sialic acid levels were observed in sera of animals bearing subcutaneous implants. Serum levels of total sialic acid did correlate with total sialic acid levels found in the tumor tissues. The levels of serum sialic acid were not correlated directly with levels of serum sialyltransferase activity. Elevations of both tissue and serum ganglioside sialic acid were consistent features of liver tumorigenesis in the rat after N-2-fluorenylacetamide administration. They appeared, furthermore, to be early events not directly related to tumor cell differentiation or metastasis.
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PMID:Characteristics of transplantable tumors induced in the rat by N-2-fluorenylacetamide: elevations in tissue and serum sialic acid. 692 77

The serum concentration and composition of gangliosides were examined in 80 humans including 10 normal subjects. A significant increase was found in the total gangliosides of serum in 7 patients with cerebral astrocytomas. There was also an increased percentage of serum gangliosides with simpler structure, particularly GM3. The serum of patients with other intracranial tumors, including pituitary adenomas, ependymoma, teratoma, and metastases, did not show an increase in total ganglioside; however the pattern of simplification was found in these and in a few patients with extracranial tumors as well. The findings suggest that astrocytoma tumors shed sialoglycolipids into the circulation, and their assay may be useful in monitoring oncological therapy.
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PMID:Serum gangliosides in cerebral astrocytoma. 743 95

Spontaneously transformed Chinese hamster lung cells with high levels of resistance (approximately 100-fold to 70,000-fold) to actinomycin D, daunorubicin, or vincristine exhibit morphology and growth patterns characteristic of normal cells in vitro and reduced tumorigenicity in vivo. These reverse transformed, multidrug-resistant cells amplify and highly overexpress one or more genes encoding P-glycoprotein. Similarly, hydrocarbon-induced mouse sarcoma cells selected with actinomycin D, vincristine, or ethidium bromide developed high levels of resistance associated with reduced drug accumulation and suppression of malignancy. To determine whether human tumor cells would undergo similar changes and whether reverse transformation reflected an altered state of differentiation, nine multidrug-resistant sublines were selected with four agents from human neuroblastoma cells with well defined pathways of differentiation. Those five with resistance levels above about 125-fold showed a reduced tumor frequency as compared to control cells. All resistant sublines showed altered differentiation. The changes in transformation phenotype appear to be intrinsic and not the result of altered immunogenicity. Two additional consequences of high level multidrug resistance have been observed: change in ganglioside composition in the Chinese hamster cells, manifested as a block in higher ganglioside biosynthesis and/or a relative increase in GM3, and increase in epidermal growth factor receptor in all three cell systems. A tentative hypothesis links ganglioside and growth factor receptor changes to the change in transformation phenotype. The basis of the reverse transformation phenomenon is not known, but the major alterations in expression of P-glycoprotein, gangliosides, and the epidermal growth factor receptor implicate, in some way, the plasma membrane.
Cancer Metastasis Rev 1994 Jun
PMID:Reverse transformation of multidrug-resistant cells. 792 50


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