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)

The purpose of these studies was to investigate the relationship of the host microenvironment to the metastatic and pigmented phenotypes of the SW-1 variant of the murine K-1735 melanoma. The SW-1 subline was isolated from an amelanotic lung metastasis in a C3H/HeN mouse given an s.c. injection of the K-1735 melanoma. Cells of this line were highly metastatic and produced tumor deposits in many organs. In all sites except the brain, these lesions were predominantly amelanotic. K-1735 SW-1 cells were isolated from metastases in various organs and subsequently reinoculated into normal syngeneic recipients. Whereas the metastatic phenotype remained stable and thus was heritable, pigmentation was unstable and appeared to be modulated by the site of tumor growth. Further differences in the phenotype of K-1735 SW-1 cells growing in vivo and in culture were revealed by assays for tyrosinase activity. K-1735 SW-1 cells growing in culture did not produce melanin nor did they respond to agents that can stimulate melanin production in another mouse melanoma, the B16 line. K-1735 SW-1 cells do not, however, lack tyrosinase, since these cells are capable of producing melanin when growing in certain organs in vivo. We conclude that the host organ environment may influence a phenotype of malignant melanoma cells, i.e., pigmentation. These findings also suggest caution when extrapolating the results of in vitro biochemical assays to properties of tumor cells growing in vivo.
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PMID:Influence of organ microenvironment on pigmentation of a metastatic murine melanoma. 283 58

A histochemical study of alpha-D-mannosidase revealed that normal human melanocytes (resting state, activated, lentigo simplex) exhibit either no or just detectable activity, as do melanocytes in the initial phase of lentigo maligna. Junctional, or occasionally zone A naevocytes displayed a very low enzyme activity. On the other hand, melanocytes in the initial stage of neoplastic transformation (dysplastic naevi, advanced stage of lentigo maligna) and also melanoma cells in disorders of low malignant potential (initial naevogenic melanoma, superficial spreading melanoma) displayed a high activity uniformly throughout the cell population. In the malignant forms (nodular melanoma, recurrences, metastases), the enzyme activity was remarkably heterogeneous, suggesting a breakdown of uniformity during malignant transformation. The significance of alpha-mannosidase activity induction in the course of melanocyte neoplastic transformation is not clear at present. The results of biochemical assays suggest that the lysosomal isoenzyme is mainly responsible. Other lysosomal enzymes, and dehydrogenases studied concomitantly, did not display any comparable phenomena of induction or similar behaviour. However, the results of a comparison of alpha-mannosidase with the melanocyte reference enzyme tyrosinase suggested activity patterns in the enzyme pair which may provide a better insight into the biochemical differentiation of human melanocytes in neoplastic disorders. The possible relationship of alpha-mannosidase to melanogenesis is also discussed.
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PMID:Enzyme histochemistry of human melanomas and pigmented naevi with special reference to alpha-D-mannosidase activity. 309 14

A spontaneous, hypomelanotic variant (MI) of the highly melanotic transplantable hamster melanoma of Bomirski (Ma) is the subject of this report. Tyrosinase activity is 2-3 times higher, but melanin content significantly lower than in the parental Ma melanotic melanoma. Acid phosphatase activity is similar in both, but beta-glucuronidase and aryl-sulfatase A are 2-3 times higher in the hypomelanotic variant. Transplanted MI melanomas grow more slowly than the parental tumor, but metastasize with similar incidence and localization. Hypomelanotic variant melanoma cells, even those in grossly nonnecrotic parts of the transplants, show signs of low viability like swelling of the cytoplasm or cellular condensation, and disintegration. Autophagic vacuoles are numerous. They appear to be formed by enclosure of a portion of cytoplasm by cisternae of smooth endoplasmic reticulum or trans-Golgi network. These limiting cisternae contain tyrosinase as evidenced by deposition of electron dense reaction product on incubation with tyrosine or DOPA. Other sites of ultrastructural tyrosinase reaction are melanosomes and the smooth-surfaced cisternae and vesicles of the trans-Golgi network. We postulate the low cell viability, associated with autophagosome formation, is the cause for the growth retardation of the MI variant, and that the lower melanin content of these tyrosinase-rich cells is due to sequestration of a substantial portion of newly synthesized enzyme into autophagic vacuoles before it has the chance of being incorporated into melanosomes.
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PMID:Pathology and ultrastructural characteristics of a hypomelanotic variant of transplantable hamster melanoma with elevated tyrosinase activity. 311 4

Two melanoma cell lines, each derived from a different patient with metastatic disease, were very similar in their appearance, their growth characteristics, and their tendency to differentiate and to pigment in culture as they become confluent. These lines, UCT-Mel 1 and UCT-Mel 2, were used to study the effects of retinoic acid and other derivatives of vitamin A. When added to UCT-Mel 1 cells, retinoids had only a modest effect on plasminogen activator release and were without measurable effect on morphology, growth, or tyrosinase synthesis. In contrast, when added to UCT-Mel 2 cells, retinoids appeared to induce a more differentiated state evident as an inhibition of cell proliferation and the assumption of a dendritic morphology. Paradoxically, however, retinoids caused a striking inhibition of the density-dependent intracellular accumulation of tyrosinase and melanin that was taken to represent spontaneous in vitro differentiation. Culture of UCT-Mel 2 cells in the presence of retinoic acid resulted in initial inhibition followed by marked stimulation of cellular plasminogen activator release. The data suggest that the manner in which retinoids exert their effects on cells in vitro does not depend on the histological origin of the tumor cells being studied but on the innate responsiveness of that particular cell line to the retinoid or compound in question.
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PMID:Variable effects of retinoids on two pigmenting human melanoma cell lines. 681 52

We have recently described a new method for measurement of tyrosinase activity in small amounts of human serum (100 microliters), where the purification of tyrosinase is obtained by adsorption of the enzyme to concanavalin A sepharose. The method, which measures stereospecific dopa oxidation, was used in the winter of 1992-93 for the measurement of activity in serum obtained from 30 healthy subjects and from 10 patients with melanoma metastases. The serum tyrosinase values in the 30 subjects ranged from 0.1 to 1.0 nkatal/l, and the mean value and standard deviation was 0.4 +/- 0.2 nkatal/l. In the 10 patients with melanoma, the tyrosinase serum values ranged from 1.1 to 10.6 nkal/l, and the mean value was 3.1 nkatal/l.
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PMID:Tyrosinase activity in the serum of patients with malignant melanoma. 762 Mar 38

Malignant melanoma cells can be detected with high sensitivity in peripheral blood of patients using reverse transcription-PCR. The detection of tyrosinase mRNA that is actively expressed only in melanocytes and melanoma cells indicates the presence of melanoma cells in peripheral blood. As shown previously, tyrosinase transcripts can be found in a variety of patients with metastatic malignant melanoma. For semiquantitative analysis of these cells in peripheral blood and evaluation of possible influence of immunotherapy on the amount of circulating cells, we describe an assay combining reverse transcription-PCR and Southern blotting. In this system, the amount of circulating tumor cells was determined by interpolating the amplified tyrosinase signal strength of patient samples to an equivalent tyrosinase signal of diluted SK-mel 28 cells. We found that the amount of circulating tumor cells correlates with the tumor burden. Furthermore, in patients with regression of melanoma metastases after immunotherapy, a decrease of the amount of tumor cells in the peripheral blood was observed. Quantitative estimates of residual disease may be an accurate and sensitive predictor for the clinical course.
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PMID:A polymerase chain reaction-based semiquantitative assessment of malignant melanoma cells in peripheral blood. 766 81

The role of tumor-specific T cells in mediating the regression of metastatic melanoma has been suggested by the clinical response of patients to treatment with tumor-infiltrating lymphocytes (TIL). A number of Ags recognized by class I-restricted melanoma-specific T cells have recently been isolated, raising the hope that this will lead to the development of improved therapies. In this study, we report the cloning of a tumor Ag recognized by T cells from melanoma patient 888. Previously, we reported that TIL 888, grown from the tumor of this patient, recognized tyrosinase in an HLA-A24-restricted fashion. This line, when infused into the autologous patient, resulted in complete regression of multiple metastases. Three years later, a second TIL line, TIL 1290, was isolated from a recurrent pelvic tumor. Infusion of a mixture of TIL 888 and TIL 1290 cell lines into the patient resulted in complete regression of a residual abdominal mass and the patient remains disease-free 2 yr later. The TIL 1290 cell line, which recognized melanoma in an HLA-A24-restricted manner, failed to recognize tyrosinase. TIL 1290 was then used to screen an 888 melanoma cDNA library, and an Ag was isolated that did not correspond to any found in sequence databases. This gene, termed p15, was found to be expressed in a variety of normal tissues, and a peptide epitope recognized by TIL 1290 was found to represent the product of an nonmutated gene. Screening of additional cDNA pools resulted in the isolation of a second clone which stimulated TIL 1290. This clone also appeared to represent a transcript of the p15 gene, indicating that this gene may encode the predominant Ag recognized by TIL 1290.
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PMID:Cloning of a new gene encoding an antigen recognized by melanoma-specific HLA-A24-restricted tumor-infiltrating lymphocytes. 775 37

Previously we have demonstrated safe and effective transfer of the HSVtk cytotoxic gene to primary murine melanoma tumors by direct injection of plasmid and retroviral vectors in which the HSVtk gene is driven by the tissue-specific tyrosinase promoter. However, for general clinical application such forms of therapy should, ideally, be effective against disseminated metastases. We report here that the number of recently established lung metastases of B16 melanoma in C57BL mice treated with ganciclovir is reduced compared to controls after multiple i.v. administrations of high titer retroviral supernatant encoding the HSVtk gene, but not after administration of liposome-complexed plasmid DNA. Using polymerase chain reaction analysis, integration of the provirus was observed in metastasis-bearing lungs (4 of 6 mice) and in the spleens of some ganciclovir-treated animals (2 of 6 mice) but not in the testes, brain, heart, liver, or kidney. The reduction in the number of experimental metastases in C57BL mice exceeded the anticipated extent of transduction of tumor cells, which is indicative of a marked bystander effect. This magnitude of reduction was not observed in immunodeficient athymic mice, suggesting that the immune system plays some part in the bystander effect. In support of these data, we show that, whereas the parental tumor cells are only poorly immunogenic, an effective antitumor immune response is generated following the killing of neoplastic cells in vivo as a result of treatment with ganciclovir. These effects may be responsible for augmenting the efficacy of retroviral infection. The combination of local cell killing by the HSVtk/ganciclovir system and the induction of antitumor immunity suggests new opportunities for the design of vectors for the gene therapy of cancer.
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PMID:Systemic gene therapy of murine melanoma using tissue specific expression of the HSVtk gene involves an immune component. 795 71

B16 melanoma sublines (B16-F10-BL6 and B16-F1) exhibited elevated adenosine 3',5'-cyclic monophosphate (cAMP) levels when cultured in Dulbecco's modified Eagle's medium (DMEM) in comparison to cells in RPMI-1640 medium. In parallel, cells cultured in DMEM had increased tyrosinase activity, melanization and dendrite formation, all markers of melanoma differentiation. Also, the proliferative rates of both cell lines were decreased by 80-85% when cultured in DMEM relative to cells maintained in RPMI-1640 medium. In these studies, elevated levels of the melanin precursors tyrosine (Tyr) and phenylalanine (Phe) found in DMEM were shown not to be solely responsible for the phenotypic changes observed with DMEM. Both BL6 and B16-F1 cell lines formed more experimental pulmonary tumor metastasis in syngeneic C57BL/6 mice when maintained in DMEM vs RPMI-1640 medium. Analysis of metastasis formation in nude mice with normal and depleted natural killer (NK) cell activity revealed that the enhanced lung colonizing capacity of the BL6 cells maintained in DMEM was independent of the function of T-cell or NK-cell-mediated immunity. A close association between metastatic ability of tested lines and the expression of the membrane-associated enzyme gamma-glutamyltranspeptidase (gamma-GTPase, EC 2.3.2.2) was observed. The highly metastatic BL6 cell line had 20-fold higher levels of gamma-GTPase activity than the weakly metastatic B16-F1 cell line. Both cell lines, when grown in DMEM, had elevated gamma-GTPase activity that paralleled augmentation of metastatic ability. The dramatic changes in lung-colonizing capacity of the variant B16 melanoma cells maintained in DMEM in contrast to those grown in RPMI-1640 medium may serve as a useful model in understanding certain steps involved in triggering cell differentiation as well as metastasis development.
Clin Exp Metastasis 1993 May
PMID:Enhancement of pulmonary metastasis formation and gamma-glutamyltranspeptidase activity in B16 melanoma induced by differentiation in vitro. 809 41

Expression of an extended panel of cytokine genes was investigated by reverse polymerase chain reaction (PCR) in 10 freshly excised melanoma metastases infiltrated by lymphocytes (TIL). cDNA encoding for CD3-delta and tyrosinase could be amplified in all samples, confirming the presence of T lymphocytes and melanoma cells. Cytokine genes possibly transcribed by both cell types, such as GM-CSF, IL-6 and IL-10 could be amplified from 5, 2 and 2 samples respectively. In contrast, IL-1 beta and TNF-alpha mRNA were never detectable, IL-1 alpha, IL-3 and IL-7 mRNA could be observed only in one case each. Transcripts encoding for TGF-beta 1 were observed in 8 samples, while TGF-beta 2 and 3 mRNA were detectable in only 2 specimens. mRNA encoding for cytokine genes typically transcribed by antigen-stimulated T lymphocytes, such as IL-2, IL-4 and IFN-gamma were rarely or never detectable (none, none and 1 of the samples respectively). In one case, where no cytokine gene transcription was detectable at the time of surgery, we addressed the question of the antigenicity of the tumor and of the functional competence of TIL. A primary tumor cell line was generated and cultured TIL were induced to transcribe IL-2 and IFN-gamma genes by incubation with the autologous irradiated tumor cell line, but not with autologous EBV-transformed cells. In these conditions, tumor-specific cytotoxic T lymphocytes (CTL) could be generated only after 3 weekly re-stimulations. In contrast, if autologous irradiated EBV-transformed cells were added to the cultures, specific CTL could be detected after one single tumor stimulation. Thus, signs of active responsiveness in terms of lymphokine gene mRNA are seldom detectable in melanoma metastases. Tumor-specific responses, however, including IL-2 and IFN-gamma gene expression and generation of CTL can be produced in vitro from specimens in which no cytokine gene mRNA is detectable ex vivo.
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PMID:The pattern of cytokine gene expression in freshly excised human metastatic melanoma suggests a state of reversible anergy of tumor-infiltrating lymphocytes. 818 65


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