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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hyaluronan-rich matrix that surrounds many tumours and facilitates tumour cell growth and invasion is thought to be predominantly synthesized by normal stromal cells stimulated by tumour cell-derived factors. This study examines the possibility that the production of tumour cell-derived factors that stimulate fibroblast glycosaminoglycan (GAG) synthesis may be blocked by exposure to differentiation-inducing agents such as retinoic acid. We have demonstrated that Hs294T, C8161 and A375 human melanoma cell lines release factors into their medium that stimulate normal fibroblast GAG synthesis. Exposure of these melanoma cells to retinoic acid failed to mediate any significant reduction in growth over a 7-day period. Retinoic acid failed to block the tumour cell production of GAG-stimulating activities and even enhanced the activities produced by the C8161 cell line, particularly at low retinoic acid concentrations (48% stimulation at 10(-9) M retinoic acid; P < 0.02). Addition of retinoic acid directly to fibroblast cultures exposed to fibroblast-conditioned medium resulted in an inhibition of GAG synthesis with a 33% inhibition observed at 10(-5) M. Addition of retinoic acid to fibroblast cultures exposed to the tumour cell-conditioned medium failed to inhibit the stimulation of GAG synthesis. Other differentiation-inducing agents, such as hexamethylene-bis-acetamide and butyrate, also failed to block the production of tumour cell-derived GAG-stimulating activities. These results demonstrate that retinoic acid and other differentiation-inducing agents fail to inhibit melanoma cell production of fibroblast GAG synthesis-stimulating factors or their action upon fibroblasts.
Melanoma Res 1997 Jun
PMID:Effect of retinoic acid on melanoma cell-derived factor stimulation of fibroblast glycosaminoglycan synthesis. 919 57

Retinoic acid (RA) and 9-cis-RA induce growth arrest and differentiation of S91 melanoma cells. RA activates retinoic acid receptors (RARs), whereas 9-cis-RA activates both RARs and retinoid X receptors (RXRs). Both classes of receptors function as ligand-dependent transcription factors. S91 melanoma cells contain mRNA for RXRalpha, RXRbeta, RARalpha, RARgamma, and RARbeta in low levels. Among these, only RARbeta gene transcription is induced by retinoids. However, at present the individual role(s) for each RXR and RAR isoform in these processes is unclear. We assessed the function of all isoforms in the S91 melanoma model by using RXR and RAR isoform-specific retinoids to study their effects on cell growth, RARbeta expression, and differentiation. Activation of each of the endogenous RXR or RAR isoforms induces RARbeta gene expression, and blocks cellular proliferation. However, only the RARgamma-ligands cause additional differentiation toward a melanocytic phenotype, which coincides with substantial apoptosis well before morphological changes are apparent. Apoptosis is completely dependent on de novo protein synthesis but cannot be induced by changes in activities of AP-1, protein kinase C, and protein kinase A, nor can it be blocked by the presence of the antioxidant glutathione. These results argue against a specific role for RARbeta, but suggest that RARgamma has a critical role in a genetic switch between melanocytes and melanoma, and induction of ligand-dependent apoptosis.
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PMID:Specific activation of retinoic acid receptors (RARs) and retinoid X receptors reveals a unique role for RARgamma in induction of differentiation and apoptosis of S91 melanoma cells. 922 81

Retinoic acid (RA) induces growth arrest and differentiation of many different tumor cells. RA activates RA receptors, which function as ligand-dependent transcriptional modulators. S91 murine melanoma cells stop proliferating and then reversibly differentiate into a melanocytic cell type after the administration of RA. The genetic changes that take place during this process serve as an excellent model for the etiology of melanoma. The use of subtractive hybridization techniques yielded several differentially expressed cDNAs that are associated with RA-induced growth arrest. One clone, cyclin D1, is repressed and is probably a differentiation marker. Two other cDNAs represent novel, RA-inducible genes. Expression of another cDNA, clone 10d, is strongly down-regulated. It is the homologue of the human gene BM28 (CDCL1) that is indispensable for entry into S phase and cell division. S91 cells that are permanently transfected with a plasmid that constitutively expresses clone 10d become significantly more resistant to RA, suggesting that repression of this gene is a critical event in RA-induced growth arrest. The use of reverse transcription-PCR for the detection of expression in human melanoma in vitro was performed to study the potential role of clone 10d/BM28 in this disease. It is expressed in 80% of melanoma cell lines but is virtually undetectable in primary melanocytes. The expression of BM28 is not regulated by RA in human, RA-resistant melanoma cells. These results suggest that clone 10d/BM28 functions as an important tumor cell growth promoter. The regulation of clone 10d may be directly mediated by RA receptors, and escape from negative regulation may, thus, contribute to the etiology of melanoma.
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PMID:Clone 10d/BM28 (CDCL1), an early S-phase protein, is an important growth regulator of melanoma. 937 13

The purpose of this study was to investigate the effects of retinoid analogues with different retinoid receptor specificity on the growth of human D10 and Cloudman S91 mouse melanoma cells. We compared the growth inhibitory effects with the ability of retinoids to downregulate cell surface expression of the melanocortin receptor (MC1-R). Retinoic acid receptor (RAR)-gamma-selective retinoids exerted the most prominent growth effects, with up to 68% and 69% inhibition in D10 and S91 cells, respectively. A retinoid X receptor (RXR)-selective compound inhibited cell growth by only 14% and 23% in D10 and S91 cells, respectively. Growth inhibition by RARalpha- and RARbeta-selective compounds was below 10% in both cells. In D10 cells, MC1-R downregulation was also induced most effectively by an RARgamma-selective retinoid (84% relative to controls). RARalpha-, RARbeta-and RXR-selective agonists induced only 16-24% MC1-R downregulation in these cells. The pattern for MC1-R downregulation was completely different in S91 cells. The RXR-selective compound was the most active (85%), followed by the RARalpha-selective agonist (58%), the RARgamma-selective compound (47%), and finally by the RARbeta-selective agonist (29%). We conclude that RARgamma-selective retinoids may have potential as therapeutic agents in melanoma. Different selectivity profiles for growth inhibition and MC1-R downregulation in S91 cells suggest that these two retinoid effects are not directly dependent on each other.
Melanoma Res 1998 Apr
PMID:Melanoma cell growth inhibition and melanocortin receptor downregulation induced by selective and non-selective retinoids. 961 Aug 63

We have established a cell line (TB) from a cerebrospinal fluid (CSF) specimen of a patient with a primary leptomeningeal melanomatosis. TB cell line was immunoreactive with the antibodies for low molecular weight neurofilament protein, vimentin, neuron-specific enolase, chromogranin, synaptophysin and HMB-45 (an antibody sensitive and specific for melanoma). When TB cells were transplanted into nude mice, the same immunohistochemical pattern present in cultured cells was found but surprisingly, a positive staining for desmin was observed. Significant amounts of serotonin and its metabolite were detectable. Retinoic acid but not nerve growth factor was able to induce differentiation towards a neuronal phenotype. In summary, TB cells represent primitive neuroectodermal cells having the potential for neuronal, myoblastic and possibly melanoblastic differentiation.
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PMID:Establishment and characterization of a human neuroectodermal cell line (TB) from a cerebrospinal fluid specimen. 1032 Jul 10

Vitamin A, its physiologic metabolites, and synthetic derivatives (retinoids) have been shown to have protective effects against the development of certain types of cancer. In addition, pharmacologic amounts of retinoids have been used with some success in the treatment of a few human tumors. The chemoprevention effect of retinoids is most likely exerted at the tumor-promotion phase of carcinogenesis. Retinoids block tumor promotion by inhibiting proliferation, inducing apoptosis, inducing differentiation, or a combination of these actions. Clinically, isotretinoin (13-cis-retinoic acid) significantly decreases the incidence of second primary tumors in patients with head-and-neck cancer and reduces appearance of non-melanoma skin cancer in patients with xeroderma pigmentosum. Retinoic acid has proved to be an effective treatment for promyelocytic leukemia. However, retinoid resistance limits its use as a single agent. Clinical trials are in progress to determine the efficacy of retinoids in treating other types of cancer such as neuroblastoma and breast carcinoma. The development of receptor-selective retinoids and selective inhibitors of retinoid metabolism may lead to further use of retinoids in both chemoprevention and treatment of cancer.
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PMID:Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. 1111 36

Retinoic acid (RA) induces growth-arrest of many tumor cell lines but it is an ineffective therapeutic against melanoma. We investigated whether the histone deacetylase (HDAC)-inhibitor sodium butyrate (BUT) can restore or potentiate the RA-response of RA-resistant human A375, and RA-responsive S91 murine melanoma cells. BUT induced expression of RARbeta and p21(waf1/cip1) mRNA in A375 cells but in S91 cells only p21(waf1/cip1) was induced. RA and BUT synergistically activated transcription of an RA-dependent reporter gene in S91, but not A375 cells. BUT increased histone H4-acetylation in both cell types. RA potentiated BUT-mediated inhibition of S91 cell proliferation, whereas A375 cells remained largely resistant to both compounds. HDAC-inhibitors may enhance the activity of RA on RA-responsive melanoma cells.
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PMID:Effects of retinoic acid and sodium butyrate on gene expression, histone acetylation and inhibition of proliferation of melanoma cells. 1116 13

Retinoic acid (RA) slows growth and induces differentiation of tumor cells through activation of RA receptors (RARs). However, melanoma cell lines display highly variable responsiveness to RA, which is a poorly understood phenomenon. By using Northern and Western blot analyses, we show that RA-resistant A375 and RA-responsive S91 melanoma cells express comparable levels of major components of RAR-signaling pathways. However, A375 cells have substantially higher intracellular reactive oxygen species (ROS) levels than S91 cells. Lowering ROS levels in A375 cells through hypoxic culture conditions restores RAR-dependent trans-activity, which could be further enhanced by addition of the antioxidant N-acetyl-cysteine. Hypoxia also enhances RAR activity in the moderately RA-responsive C32 cells, which have intermediate ROS levels. Conversely, increasing oxidative stress in highly RA-responsive S91 and B16 cells, which have low ROS levels, by treatment with H(2)O(2) impairs RAR activity. Consistent with these observations, RA more potently inhibited the proliferation of hypoxic A375 cells than that of normoxic cells. Oxidative states diminish, whereas reducing conditions enhance, DNA binding of retinoid X receptor/RAR heterodimers in vitro, providing a molecular basis for the observed inverse correlation between RAR activity and ROS levels. The redox state of melanoma cells provides a novel, epigenetic control mechanism of RAR activity and RA resistance.
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PMID:Redox control of retinoic acid receptor activity: a novel mechanism for retinoic acid resistance in melanoma cells. 1135 10

Retinoic acid (RA) induces differentiation of S91 melanoma cells through activation of RA receptor (RAR)gamma without affecting cell viability. The novel RARgamma-agonist CD437 (AHPN), however, also induces concomitant apoptosis through an unknown mechanism which was investigated here. By utilizing DNA microarray analysis, five apoptosis-associated, CD437-induced transcripts (CITs) were identified. Interestingly, all CITs are also regulated by p53 in a DNA damage response, and consistent with this interpretation, CD437 was found to cause DNA adduct-formation. However, p53 is not required for CD437-dependent regulation of CITs. Among this set of genes, induction of p21(WAF1/CIP1) is likely to be responsible for early S-phase growth-arrest of CD437-treated cells, whereas ei24 is a critical mediator of CD437-induced apoptosis in S91 cells. These data suggest an RAR-independent mechanism in which CD437 causes DNA adduct-formation, resulting in induction of a p53-independent DNA damage response, and subsequent growth-arrest and apoptosis. CD437-mediated DNA adduct-formation may also explain its apoptotic effects in other cell types.
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PMID:Retinoic acid receptor-independent mechanism of apoptosis of melanoma cells by the retinoid CD437 (AHPN). 1152 43

Retinoic acid (RA) inhibits growth and induces differentiation of B16 mouse melanoma cells. These effects are accompanied by a large increase in PKCalpha mRNA and protein levels and surprisingly an increase in activating protein-1 (AP-1) transcriptional activity. To further investigate the RA-induced AP-1 activity we established clones of B16 cells stably expressing an AP-1-luciferase reporter gene. Treatment of these clones with phorbol dibutyrate increased AP-1 activity which peaked at 2-4 h and returned to baseline level by 24 h. In contrast, RA treatment resulted in a slow increase in AP-1 activity that reached a maximum level at 48 h and was maintained for the duration of the treatment. We tested the importance of the RA-induced AP-1 activity by establishing clones which stably express a dominant negative fos gene (A-fos) and have greatly diminished AP-1 activity. Growth rates of untreated A-fos expressing cells were similar to wt B16 and clones not expressing A-fos. However, clones expressing the dominant-negative fos had a markedly decreased sensitivity to RA-induced inhibition of anchorage-dependent and -independent growth. Treatment of wt B16 cells for 48 h with RA increased melanin production by two to fourfold, but this effect was completely lost in the A-fos clones. The ability of RA to induce RARbeta and PKCalpha expression was retained in A-fos clones, suggesting that A-fos was not interfering with RAR transcription activation functions. We tested whether the RA-induced AP-1 activity might be mediated by the ERK1/2 MAPK pathway. Inhibition of ERK1/2 phosphorylation stimulated AP-1 activity, which was not additive to that induced by RA. This finding raises the possibility that this MAPK pathway may be a target of retinoid action. Our observations suggest that AP-1 transcriptional activity induced by RA likely plays an important role in the biological changes mediated by this retinoid in B16 melanoma cells.
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PMID:Retinoic acid-induced AP-1 transcriptional activity regulates B16 mouse melanoma growth inhibition and differentiation. 1249 54


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