FRIZZLED7 Is Required for Tumor Initiation and Metastatic Growth of Melanoma Cells.
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ABSTRACT:
SUBMITTER: Tiwary S
PROVIDER: S-EPMC4726610 | biostudies-literature | 2016
REPOSITORIES: biostudies-literature
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Project description:BackgroundPLEKHA5 has previously been identified as a novel molecule implicated in melanoma brain metastasis, a disease that continues to portend a poor prognosis. The aim of this study was to further investigate the functional role of PLEKHA5 in disseminated melanoma.MethodsThe impact of PLEKHA5 on proliferation and tumor growth was examined in vitro and in melanoma xenograft models, including brain-tropic melanomas (melanomas tending to disseminate to the brain). In vitro loss- and gain-of-function studies were used to explore the underlying mechanisms of PLEKHA5-mediated tumor growth and the crosstalk between PLEKHA5 and PI3K/AKT/mTOR or MAPK/ERK signaling. The clinical relevance of PLEKHA5 dysregulation was further investigated in a cohort of matched cranial and extracranial melanoma metastases.ResultsPLEKHA5 stable knockdown negatively regulated cell proliferation by inhibiting the G1 -to-S cell cycle transition, which coincided with upregulation of the cell cycle regulator PDCD4. Conversely, ectopic PLEKHA5 expression exhibited the inverse effect. PLEKHA5 knockdown significantly inhibited tumor growth, whereas its overexpression upregulated the growth of tumors, which was induced by cranial and subcutaneous inoculation of cells in nude mice. PLEKHA5 modulation affected PDCD4 protein stability and was coupled with changes in PI3K/AKT/mTOR pathway signaling. High PDCD4 expression in cerebral specimens was associated with better overall survival.ConclusionsThis study further supports the role of PLEKHA5 as a regulator of melanoma growth at distant sites, including the brain. Furthermore, the results highlight the significance of PDCD4 dysregulation in disseminated melanoma and implicate PDCD4 as a possible causal link between PLEKHA5 and cell proliferation and growth.
| S-EPMC7147081 | biostudies-literature
Project description:Melanoma is a lethal skin cancer prone to progression and metastasis, and resistant to therapy. Metastasis and therapy resistance of melanoma and other cancers are driven by tumor cell plasticity, largely via acquisition/loss of stem-like characteristics and transitions between epithelial and mesenchymal phenotypes (EMT/MET). NME1 is a metastasis suppressor gene that inhibits metastatic potential when its expression is enforced in melanoma and other cancers. Herein, we have unmasked a novel role for NME1 as a driver of melanoma growth distinct from its canonical function as a metastasis suppressor. NME1 promotes expansion of stem-like melanoma cells that exhibit elevated expression of stem cell markers (e.g., Sox2, Sox10, Oct-4, KLF4, and Ccnb-1), enhanced growth as melanoma spheres in culture, and enhanced tumor growth and lung colonizing activities in vivo. In contrast, NME1 expression did not affect the proliferation of melanoma cell lines in monolayer culture conditions. Silencing of NME1 expression resulted in a dramatic reduction in melanoma sphere size, and impaired tumor growth and metastatic activities of melanoma sphere cells when xenografted in immunocompromised mice. Individual cells within melanoma sphere cultures displayed a wide range of NME1 expression across multiple melanoma cell lines. Cell subpopulations with elevated NME1 expression were fast cycling and displayed enhanced expression of stem cell markers. IMPLICATIONS: Our findings suggest the current model of NME1 as a metastasis-suppressing factor requires refinement, bringing into consideration its heterogeneous expression within melanoma sphere cultures and its novel role in promoting the expansion and tumorigenicity of stem-like cells.
| S-EPMC6677611 | biostudies-literature
Project description:Melanoma growth is driven by malignant melanoma-initiating cells (MMIC) identified by expression of the ATP-binding cassette (ABC) member ABCB5. ABCB5(+) melanoma subpopulations have been shown to overexpress the vasculogenic differentiation markers CD144 (VE-cadherin) and TIE1 and are associated with CD31(-) vasculogenic mimicry (VM), an established biomarker associated with increased patient mortality. Here we identify a critical role for VEGFR-1 signaling in ABCB5(+) MMIC-dependent VM and tumor growth. Global gene expression analyses, validated by mRNA and protein determinations, revealed preferential expression of VEGFR-1 on ABCB5(+) tumor cells purified from clinical melanomas and established melanoma lines. In vitro, VEGF induced the expression of CD144 in ABCB5(+) subpopulations that constitutively expressed VEGFR-1 but not in ABCB5(-) bulk populations that were predominantly VEGFR-1(-). In vivo, melanoma-specific shRNA-mediated knockdown of VEGFR-1 blocked the development of ABCB5(+) VM morphology and inhibited ABCB5(+) VM-associated production of the secreted melanoma mitogen laminin. Moreover, melanoma-specific VEGFR-1 knockdown markedly inhibited tumor growth (by > 90%). Our results show that VEGFR-1 function in MMIC regulates VM and associated laminin production and show that this function represents one mechanism through which MMICs promote tumor growth.
| S-EPMC3083845 | biostudies-literature
Project description:Melanoma growth is driven by malignant melanoma initiating cells (MMIC) identified by expression of the ATP-binding cassette (ABC) member, ABCB5. ABCB5+ melanoma subpopulations have been shown to overexpress the vasculogenic differentiation markers CD144 (VE-cadherin) and TIE-1 and are associated with CD31-negative vasculogenic mimicry (VM), an established biomarker associated with increased patient mortality. Here we identify a critical role for VEGFR-1 signaling in ABCB5+ MMIC-dependent VM and tumor growth. Global gene expression analyses, validated by mRNA and protein determinations, revealed preferential expression of VEGFR-1 on ABCB5+ tumor cells purified from clinical melanomas and established melanoma lines. In vitro, VEGF induced in a VEGFR-1-dependent manner expression of CD144 in ABCB5+ subpopulations that constitutively expressed VEGFR-1, but not in ABCB5- bulk populations that were predominantly VEGFR-1-negative. In vivo, melanomaspecific shRNA-mediated knockdown of VEGFR-1 blocked the development of ABCB5+ VM morphology and inhibited ABCB5+ VM-associated production of the secreted melanoma mitogen, laminin. Moreover, melanoma-specific VEGFR-1 knockdown markedly inhibited tumor growth (by >90%). Our results demonstrate that VEGFR-1 function in MMIC regulates VM and associated laminin production, and show that this function represents one mechanism through which MMIC promote tumor growth. Microarray analyses were performed on purified ABCB5+ (n=5) and ABCB5- (n=5) cell subsets derived from the established human melanoma cell lines G3361 and A375 and from three distinct clinical melanoma specimen. Total RNA was extracted, processed and hybridized onto Affymetrix human HG-U133Plus2 GeneChip microarrays (Affymetrix, Santa Clara, CA).
| S-ECPF-GEOD-26569 | biostudies-other
Project description:Melanomas are highly heterogeneous tumors, but the biological significance of their different subpopulations is not clear. Using the H3K4 demethylase JARID1B (KDM5B/PLU-1/RBP2-H1) as a biomarker, we have characterized a small subpopulation of slow-cycling melanoma cells that cycle with doubling times of >4 weeks within the rapidly proliferating main population. Isolated JARID1B-positive melanoma cells give rise to a highly proliferative progeny. Knockdown of JARID1B leads to an initial acceleration of tumor growth followed by exhaustion which suggests that the JARID1B-positive subpopulation is essential for continuous tumor growth. Expression of JARID1B is dynamically regulated and does not follow a hierarchical cancer stem cell model because JARID1B-negative cells can become positive and even single melanoma cells irrespective of selection are tumorigenic. These results suggest a new understanding of melanoma heterogeneity with tumor maintenance as a dynamic process mediated by a temporarily distinct subpopulation.
| S-EPMC2882693 | biostudies-literature
Project description:Some solid tumors have reduced posttranscriptional RNA editing by adenosine deaminase acting on RNA (ADAR) enzymes, but the functional significance of this alteration has been unclear. Here, we found the primary RNA-editing enzyme ADAR1 is frequently reduced in metastatic melanomas. In situ analysis of melanoma samples using progression tissue microarrays indicated a substantial downregulation of ADAR1 during the metastatic transition. Further, ADAR1 knockdown altered cell morphology, promoted in vitro proliferation, and markedly enhanced the tumorigenicity in vivo. A comparative whole genome expression microarray analysis revealed that ADAR1 controls the expression of more than 100 microRNAs (miRNAs) that regulate many genes associated with the observed phenotypes. Importantly, we discovered that ADAR1 fundamentally regulates miRNA processing in an RNA binding–dependent, yet RNA editing–independent manner by regulating Dicer expression at the translational level via let-7. In addition, ADAR1 formed a complex with DGCR8 that was mutually exclusive with the DGCR8-Drosha complex that processes pri-miRNAs in the nucleus. We found that cancer cells silence ADAR1 by overexpressing miR-17 and miR-432, which both directly target the ADAR1 transcript. We further demonstrated that the genes encoding miR-17 and miR-432 are frequently amplified in melanoma and that aberrant hypomethylation of the imprinted DLK1-DIO3 region in chromosome 14 can also drive miR-432 overexpression.
| S-EPMC3668823 | biostudies-other
Project description:Matrix metalloproteinases (Mmps) stimulate tumor invasion and metastasis by degrading the extracellular matrix. Here we reveal an unexpected role for Mmp10 (stromelysin 2) in the maintenance and tumorigenicity of mouse lung cancer stem-like cells (CSC). Mmp10 is highly expressed in oncosphere cultures enriched in CSCs and RNAi-mediated knockdown of Mmp10 leads to a loss of stem cell marker gene expression and inhibition of oncosphere growth, clonal expansion, and transformed growth in vitro. Interestingly, clonal expansion of Mmp10 deficient oncospheres can be restored by addition of exogenous Mmp10 protein to the culture medium, demonstrating a direct role for Mmp10 in the proliferation of these cells. Oncospheres exhibit enhanced tumor-initiating and metastatic activity when injected orthotopically into syngeneic mice, whereas Mmp10-deficient cultures show a severe defect in tumor initiation. Conversely, oncospheres implanted into syngeneic non-transgenic or Mmp10(-/-) mice show no significant difference in tumor initiation, growth or metastasis, demonstrating the importance of Mmp10 produced by cancer cells rather than the tumor microenvironment in lung tumor initiation and maintenance. Analysis of gene expression data from human cancers reveals a strong positive correlation between tumor Mmp10 expression and metastatic behavior in many human tumor types. Thus, Mmp10 is required for maintenance of a highly tumorigenic, cancer-initiating, metastatic stem-like cell population in lung cancer. Our data demonstrate for the first time that Mmp10 is a critical lung cancer stem cell gene and novel therapeutic target for lung cancer stem cells.
| S-EPMC3335833 | biostudies-literature
Project description:Melanoma growth is driven by malignant melanoma initiating cells (MMIC) identified by expression of the ATP-binding cassette (ABC) member, ABCB5. ABCB5+ melanoma subpopulations have been shown to overexpress the vasculogenic differentiation markers CD144 (VE-cadherin) and TIE-1 and are associated with CD31-negative vasculogenic mimicry (VM), an established biomarker associated with increased patient mortality. Here we identify a critical role for VEGFR-1 signaling in ABCB5+ MMIC-dependent VM and tumor growth. Global gene expression analyses, validated by mRNA and protein determinations, revealed preferential expression of VEGFR-1 on ABCB5+ tumor cells purified from clinical melanomas and established melanoma lines. In vitro, VEGF induced in a VEGFR-1-dependent manner expression of CD144 in ABCB5+ subpopulations that constitutively expressed VEGFR-1, but not in ABCB5- bulk populations that were predominantly VEGFR-1-negative. In vivo, melanomaspecific shRNA-mediated knockdown of VEGFR-1 blocked the development of ABCB5+ VM morphology and inhibited ABCB5+ VM-associated production of the secreted melanoma mitogen, laminin. Moreover, melanoma-specific VEGFR-1 knockdown markedly inhibited tumor growth (by >90%). Our results demonstrate that VEGFR-1 function in MMIC regulates VM and associated laminin production, and show that this function represents one mechanism through which MMIC promote tumor growth. Microarray analyses were performed on purified ABCB5+ (n=5) and ABCB5- (n=5) cell subsets derived from the established human melanoma cell lines G3361 and A375 and from three distinct clinical melanoma specimen. Total RNA was extracted, processed and hybridized onto Affymetrix human HG-U133Plus2 GeneChip microarrays (Affymetrix, Santa Clara, CA).
2011-01-13 | E-GEOD-26569 | biostudies-arrayexpress
Project description:Metastatic melanoma is an aggressive tumor and can constitute a real therapeutic challenge despite the significant progress achieved with targeted therapies and immunotherapies, thus highlighting the need for the identification of new therapeutic targets. Adrenomedullin (AM) is a peptide with significant expression in multiple types of tumors and is multifunctional. AM impacts angiogenesis and tumor growth and binds to calcitonin receptor-like receptor/receptor activity-modifying protein 2 or 3 (CLR/RAMP2; CLR/RAMP3). In vitro and in vivo studies were performed to determine the functional role of AM in melanoma growth and tumor-associated angiogenesis and lymphangiogenesis. In this study, AM and AM receptors were immunohistochemically localized in the tumoral compartment of melanoma tissue, suggesting that the AM system plays a role in melanoma growth. We used A375, SK-MEL-28, and MeWo cells, for which we demonstrate an expression of AM and its receptors; hypoxia induces the expression of AM in melanoma cells. The proliferation of A375 and SK-MEL-28 cells is decreased by anti-AM antibody (αAM) and anti-AMR antibodies (αAMR), supporting the fact that AM may function as a potent autocrine/paracrine growth factor for melanoma cells. Furthermore, migration and invasion of melanoma cells increased after treatment with AM and decreased after treatment with αAMR, thus indicating that melanoma cells are regulated by AM. Systemic administration of αAMR reduced neovascularization of in vivo Matrigel plugs containing melanoma cells, as demonstrated by reduced numbers of vessel structures, which suggests that AM is one of the melanoma cells-derived factors responsible for endothelial cell-like and pericyte recruitment in the construction of neovascularization. In vivo, αAMR therapy blocked angiogenesis and lymphangiogenesis and decreased proliferation in MeWo xenografts, thereby resulting in tumor regression. Histological examination of αAMR-treated tumors showed evidence of the disruption of tumor vascularity, with depletion of vascular endothelial cells and a significant decrease in lymphatic endothelial cells. The expression of AM by melanoma cells promotes tumor growth and neovascularization by supplying/amplifying signals for neoangiogenesis and lymphangiogenesis.
| S-EPMC9738606 | biostudies-literature
Project description:Inflammasomes are mediators of inflammation, and constitutively activated NLRP3 inflammasomes have been linked to interleukin-1? (IL-1?)-mediated tumorigenesis in human melanoma. Whereas NLRP3 regulation of caspase-1 activation requires the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD (caspase recruitment domain)), caspase-1 activation by another danger-signaling sensor NLRP1 does not require ASC because NLRP1 contains a C-terminal CARD domain that facilitates direct caspase-1 activation via CARD-CARD interaction. We hypothesized that NLRP1 has additional biological activities besides IL-1? maturation and investigated its role in melanoma tumorigenesis. NLRP1 expression in melanoma was confirmed by analysis of 216 melanoma tumors and 13 human melanoma cell lines. Unlike monocytic THP-1 cells with prominent nuclear localization of NLRP1, melanoma cells expressed NLRP1 mainly in the cytoplasm. Knocking down NLRP1 revealed a tumor-promoting property of NLRP1 both in vitro and in vivo. Mechanistic studies showed that caspase-1 activity, IL-1? production, IL-1? secretion and nuclear factor-kB activity were reduced by knocking down of NLRP1 in human metastatic melanoma cell lines 1205Lu and HS294T, indicating that NLRP1 inflammasomes are active in metastatic melanoma. However, unlike previous reports showing that NLRP1 enhances pyroptosis in macrophages, NLRP1 in melanoma behaved differently in the context of cell death. Knocking down NLRP1 increased caspase-2, -9 and -3/7 activities and promoted apoptosis in human melanoma cells. Immunoprecipitation revealed interaction of NLRP1 with CARD-containing caspase-2 and -9, whereas NLRP3 lacking a CARD motif did not interact with the caspases. Consistent with these findings, NLRP1 activation but not NLRP3 activation reduced caspase-2, -9 and -3/7 activities and provided protection against apoptosis in human melanoma cells, suggesting a suppressive role of NLRP1 in caspase-3/7 activation and apoptosis via interaction with caspase-2 and -9. In summary, we showed that NLRP1 promotes melanoma growth by enhancing inflammasome activation and suppressing apoptotic pathways. Our study demonstrates a tumor-promoting role of NLRP1 in cancer cells.
| S-EPMC5501746 | biostudies-literature