Growth and Metastasis of Intraocular Tumors in Aged Mice
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Purpose: Since deterioration of the immune apparatus is closely associated with cancer, we examined the effect of aging on the growth and metastasis of intraocular melanomas in mice. Methods: Murine B16LS9 melanoma cells were transplanted into the posterior compartment of the eye (vitreous chamber) and intraocular tumor growth and development of liver metastases were evaluated in young (8–10 weeks of age) and old (>18 months of age) mice. Liver metastases were also induced by intrasplenic injection of melanoma cells. Natural killer (NK) cells from the livers of mice harboring liver metastases were evaluated in vitro for their cytolytic activity. Results: Tumors grew more rapidly in the eyes of young mice than old mice, yet old mice developed significantly more liver metastases. Increased liver metastasis in old mice was evident even when melanoma cells were injected intrasplenically as a means of bypassing the influence of the ocular immunosuppressive environment. Increased liver metastases in old mice correlated with reduced cytolytic activity of liver NK cells. Lethally irradiated young mice reconstituted with bone marrow from old donors developed significantly more liver metastases than young mice reconstituted with bone marrow from young donors, indicating that bone marrow–derived cells were the root cause of the heightened development of metastases in old mice. Conclusions: Aging affects the growth and metastasis of intraocular melanomas. Even though intraocular melanomas grow slower in old mice, the development of liver metastases is exacerbated and correlates with a reduction in liver NK cell activity in the old mouse.Keywords:
Ocular Melanoma
Early stages of melanoma can be successfully treated by surgical resection of the tumor, but there is still no effective treatment once it is progressed to metastatic phases. Although growing family of both melanoma metastasis promoting and metastasis suppressor genes have been reported be related to metastasis, the molecular mechanisms governing melanoma metastatic cascade are still not completely understood. Therefore, defining the molecules that govern melanoma metastasis may aid the development of more effective therapeutic strategies for combating melanoma. In the present study, we found that muc1 is involved in the metastasis of melanoma cells and demonstrated that muc1 disruption impairs melanoma cells migration and metastasis. The requirement of muc1 in the migration of melanoma cells was further confirmed by gene silencing in vitro. In corresponding to this result, over-expression of muc1 significantly promoted the migratory of melanoma cells. Moreover, down-regulation of muc1 expression strikingly inhibits melanoma cellular metastasis in vivo. Finally, we found that muc1 promotes melanoma migration through the protein kinase B (Akt) signaling pathway. To conclude, our findings suggest a novel mechanism underlying the metastasis of melanoma cells which might serve as a new intervention target for the treatment of melanoma.
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Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight the therapeutic potential of targeting this axis to treat metastatic melanoma.
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A77 Ocular (uveal) melanoma is the most common primary cancer of the eye and the second most common form of melanoma. Despite local therapy, about 50% of these cancers metastasize hematogenously to the liver, after which death occurs within a few months. The delay from ocular diagnosis and treatment to clinical detection of liver metastasis varies from a few months to many years, indicating that micrometastases can remain dormant for long periods of time. By the time metastatic disease becomes clinically detectable, it has grown to a large tumor burden that is highly resistant to therapy. If patients with micrometastatic disease could be identified prior to clinical presentation, prophylactic therapy may delay or prevent metastatic death. Various methods have been proposed for identifying patients with micrometastatic disease, including clinicopathologic algorithms and detection of circulating melanoma cells, but none of these methods has demonstrated adequate sensitivity and specificity for clinical decision-making in individual patients. However, we recently described a gene expression-based classification of ocular melanomas that predicts metastatic death with extremely high predictive accuracy. Primary tumors exhibiting a class 1 signature have a low risk and those with a class 2 signature a high risk of metastasis (P
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Abstract Melanoma originates from melanin-producing cells called melanocytes. Melanoma poses a great risk because of its rapid ability to spread and invade new organs. Cellular metastasis involves alteration in the gene expression profile and their transformation from epithelial to mesenchymal state. Despite of several advances, metastatic melanoma being a key cause of therapy failure and mortality remains poorly understood. p32 has been found to be involved in various physiological and pathophysiological conditions. However, the role of p32 in melanoma progression and metastasis remains underexplored. Here, we identify the role of p32 in the malignancy of both murine and human melanoma. p32 knockdown leads to reduced cell proliferation, migration, and invasion in murine and human melanoma cells. Furthermore, p32 promotes in vitro tumorigenesis, inducing oncogenes and EMT markers. Mechanistically, we show p32 regulates tumorigenic and metastatic properties through the Akt/PKB signaling pathway in both murine and human melanoma. Furthermore, p32 silencing attenuates melanoma tumor progression and lung metastasis in vivo, modulating the tumor microenvironment by inhibiting the angiogenesis, infiltration of macrophages, and leukocytes in mice. Taken together, our findings identify that p32 drives melanoma progression, metastasis, and regulates the tumor microenvironment. p32 can be a target of a novel therapeutic approach in the regulation of melanoma progression and metastasis.
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Abstract Alterations in the PI3K/AKT pathway occur in up to 70% of melanomas and are associated with disease progression. The three AKT paralogs are highly conserved but data suggest they have distinct functions. Activating mutations of AKT1 and AKT3 occur in human melanoma but their role in melanoma formation and metastasis remains unclear. Using an established melanoma mouse model, we evaluated E17K, E40K, and Q79K mutations in AKT1, AKT2, and AKT3 and show that mice harboring tumors expressing AKT1E17K had the highest incidence of brain metastasis and lowest mean survival. Tumors expressing AKT1E17K displayed elevated levels of focal adhesion factors and enhanced phosphorylation of focal adhesion kinase (FAK). AKT1E17K expression in melanoma cells increased invasion and this was reduced by pharmacologic inhibition of either AKT or FAK. These data suggest that the different AKT paralogs have distinct roles in melanoma brain metastasis and that AKT and FAK may be promising therapeutic targets. Implications: This study suggests that AKT1E17K promotes melanoma brain metastasis through activation of FAK and provides a rationale for the therapeutic targeting of AKT and/or FAK to reduce melanoma metastasis.
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Background information . MTA1 (metastasis‐associated gene 1) has been reported to be overexpressed in cancers with high potential to metastasize. Studies of the molecular mechanisms revealed that MTA1 plays an important role in the process of metastasis of many types of cancer. However, the role of MTA1 in melanoma development is unclear. Results . We have investigated the therapeutic value of MTA1 in the B16F10 melanoma cell line with the C57BL/6 mouse model. Studies in vitro showed that MTA1 promoted the metastatic ability of B16F10 cancer cells. MTA1 down‐regulation by RNA interference greatly reversed the malignant phenotypes of cancer cells. Immunohistochemical staining of MTA1 in human melanoma samples confirmed the up‐regulation of MTA1 in the process of carcinogenesis. Studies in vivo confirmed down‐regulation of MTA1 suppressed the growth and experimental metastasis of B16F10 melanoma cells. Conclusions . MTA1 plays an important role in melanoma development and metastasis. It has a promising potential as a target for in cancer gene therapy or chemotherapy.
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Melanoma is among the most aggressive tumors, and the occurrence of metastasis leads to a precipitous drop in the patients' survival. Therefore, identification of metastasis-associated biomarkers and therapeutic targets will contribute a lot to improving melanoma theranostics. Recently, microRNAs (miRNAs) have been implicated in modulating cancer invasion and metastasis, and are proved as potential non-invasive biomarkers in sera for various tumors. Here, we reported miR-23a as a novel metastasis-associated miRNA that played a remarkable role in modulating melanoma invasive and metastatic capacity and was of great value in predicting melanoma metastasis and prognosis. We found that serum miR-23a level was significantly down-regulated in metastatic melanoma patients and highly correlated with poor clinical outcomes. In addition, miR-23a level was also remarkably decreased in metastatic melanoma tissues and cell lines. Furthermore, overexpressed miR-23a suppressed the invasive and migratory property of melanoma cells by abrogating autophagy through directly targeting ATG12. Specially, miR-23a-ATG12 axis attenuated melanoma invasion and migration through autophagy-mediated AMPK-RhoA pathway. Finally, the overexpression of miR-23a prevented melanoma metastasis in vivo. Taken together, our findings demonstrate that the metastasis-associated miR-23a is not only a potential biomarker, but also a valuable therapeutic target for melanoma.
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Abstract Metastatic melanoma is a leading cause of mortality in skin cancers with few therapeutic options. However, molecular mechanisms underlying melanoma tumorigenesis and metastasis remain poorly understood. Here, for the first time, we have determined a specific role of K12/SECTM1(SECTM1) in melanoma pathogenesis. Microarray analysis of melanoma revealed that SECTM1 is higher expressed in melanoma cell lines compared to melanocytes. We confirmed that SECTM1 was upregulated in most melanoma cell lines both at the transcriptional and post-transcriptional level. In addition, SECTM1 is highly expressed in patient melanoma lesions both in primary and metastasis samples. Furthermore, overexpression of SECTM1 in melanoma cell line WM3899 dramatically increased cell invasion in vitro, and promoted tumor growth and metastasis in vivo. Consistently, reduction of SECTM1 expression in melanoma cell line WM9 inhibited tumor growth and metastasis in vivo. Mechanistically, SECTM1 upregulated expression of integrin β3 (ITGβ3), thus contributing to the progressive phenotype of SECTM1 in melanoma. Hence, this study identified SECTM1 as a novel melanoma metastasis gene. We anticipate that our findings will provide new avenues in the pathogenesis of melanoma metastasis and that targeting of SECTM1 could be a novel approach to inhibit melanoma progression. Citation Information: Cancer Res 2009;69(23 Suppl):A66.
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