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Jiang H, Wortsman J, Matsuoka L, Granese J, Carlson JA, Mihm M, Slominski A. Molecular spectrum of pigmented skin lesions: from nevus to melanoma. ACTA ACUST UNITED AC 2014. [DOI: 10.1586/17469872.1.5.679] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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2
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Abstract
Metastasis is a major cause of cancer mortality. Metastasis is a complex process that requires the regulation of both metastasis-promoting and metastasis suppressor genes. The discovery of metastasis suppressor genes contributes significantly to our understanding of metastasis mechanisms and provides prognostic markers and therapeutic targets in clinical cancer management. In this review, we summarize the methods that have been used to identify metastasis suppressors and the potential clinical impact of these genes.
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Affiliation(s)
- Jinchun Yan
- University of Washington Medical Center, Seattle, WA, USA.
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3
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Abstract
Metastasis is responsible for most cancer mortality. The process of metastasis is complex, requiring the coordinated expression and fine regulation of many genes in multiple pathways in both the tumor and host tissues. Identification and characterization of the genetic programs that regulate metastasis is critical to understanding the metastatic process and discovering molecular targets for the prevention and treatment of metastasis. Genomic approaches and functional genomic analyses can systemically discover metastasis genes. In this review, we summarize the genetic tools and methods that have been used to identify and characterize the genes that play critical roles in metastasis.
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Affiliation(s)
- Jinchun Yan
- University of Washington Medical Center, 1959 N. E. Pacific Street, Seattle, WA 98195, USA.
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4
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Abstract
A greater understanding of the processes of tumor invasion and metastasis, the principal cause of death in cancer patients, is essential to determine newer therapeutic targets. Metastasis suppressor genes, by definition, suppress metastasis without affecting tumorigenicity and, hence, present attractive targets as prognostic or therapeutic markers. This short review focuses on those twelve metastasis suppressor genes for which functional data exist. We also outline newly identified genes that bear promising traits of having metastasis suppressor activity, but for which functional data have not been completed. We also summarize the biochemical mechanism(s) of action (where known), and present a working model assembling potential metastasis suppression pathways.
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Affiliation(s)
- Lalita A Shevde
- Department of Pathology, 1670 University Boulevard, Volker Hall-G-038, The University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA
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5
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Abstract
Metastatic disease is the most critical impediment to cancer patient survival. However, comparatively little is known concerning the intricate pathways which govern the complex phenotypes associated with metastasis. The KISS1 metastasis suppressor gene inhibits metastasis in both in vivo melanoma and breast carcinoma models. Despite its clear physiological activity, the mechanism of KISS1 remains unclear. Recent identification of a 54 amino acid peptide of KISS1, termed metastin or kisspeptin-54, and its cognate G-protein coupled receptor (hOT7T175, AXOR12, GPR54) have provided additional clues and avenues of research. While studies have attributed KISS1 with modulation of NFkappaB regulation, experiments with metastin and its receptor implicate MAP kinase pathways and also suggest the potential of autocrine, paracrine and endocrine roles. Impacts on motility, chemotaxis, adhesion and invasion have each been documented in disparate cell lines and conflicting observations require resolution. Nevertheless, mounting clinical evidence, particularly the loss of KISS1 in metastases, correlates KISS1 and metastin receptor expression with human tumor progression. Together, the data substantiate roles for these molecules in metastasis regulation.
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Affiliation(s)
- John F Harms
- Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
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6
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Abstract
The central role of sequential accumulation of genetic alterations during the development of cancer has been firmly established since the pioneering cytogenetic studies successfully defined recurrent chromosome changes in specific types of tumor. In the course of carcinogenesis, cells experience several genetic alterations that are associated with the transition from a preneoplastic lesion to an invasive tumor and finally to the metastatic state. Tumor progression is characterized by stepwise accumulation of genetic alterations. So does the dominant metastatic clone. Modern molecular genetic analyses have clarified that genomic changes accumulate during the development and progression of cancers. In comparison with the corresponding primary tumor, additional events of chromosomal aberrations (including gains or allelic losses) are frequently found in metastases, and the incidence of combined chromosomal alterations in the primary tumor, plus the occurrence of additional aberrations in the distant metastases, correlated significantly with decreased postmetastatic survival. The deletions at 3p, 4p, 6q, 8p, 10q, 11p, 11q, 12p, 13q, 16q, 17p, 18q, 21q, and 22q, as well as the over-representations at 1q, 8q, 9q, 14q and 15q, have been found to associate preferentially with the metastatic phenotype of human cancers. Among of them, the deletions on chromosomes 8p, 17p, 11p and 13p seem to be more significant, and more detail fine regions of them, including 8p11, 8p21-12, 8p22, 8p23, 17p13.3, 11p15.5, and 13q12-13 have been suggested harboring metastasis-suppressor genes. During the past decade, several human chromosomes have been functionally tested through the use of microcell-mediated chromosome transfer (MMCT), and metastasis-suppressor activities have been reported on chromosomes 1, 6, 7, 8, 10, 11, 12, 16, and 17. However, it is not actually known at what stage of the metastatic cascade these alterations have occurred. There is still controversial with the association between the chromosomal aberrations and the metastatic phenotype of cancer. As the progression of human genome project and the establishment of more and more new techniques, it is hopeful to make clear the genetic mechanisms involved in the tumor metastasis in a not very long future, and provide new clues to predicting and controlling the metastasis.
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Affiliation(s)
- Lun-Xiu Qin
- Liver Cancer Institute Zhongshan Hospital, Fudan University, Shanghai, China.
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7
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Dong C, Slattery MJ, Rank BM, You J. In vitro characterization and micromechanics of tumor cell chemotactic protrusion, locomotion, and extravasation. Ann Biomed Eng 2002; 30:344-55. [PMID: 12051619 PMCID: PMC2788782 DOI: 10.1114/1.1468889] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The objective of this paper is to introduce some novel in vitro applications in characterizing human melanoma cell protrusion and migration in response to soluble extracellular matrix protein stimulation. Specifically, we describe two assay systems: (1) dual-micropipette manipulation and (2) flow-migration chamber. Applications of the dual-micropipet technique provided kinetic measure of cell movement, cyclic pseudopod protrusion, and subsequent cell locomotion governed by chemotactic molecular transport dynamics. Chemotactic concentration gradient was found to influence significantly pseudopod protrusion frequency and locomotion speed, but not the protrusion extension. To further characterize active tumor cell extravasation, a process that involves dynamic tumor cell adhesion to vascular endothelium under flow conditions and subsequent transendothelial migration in response to chemotactic signals from the interstitial space, we developed a flow-migration chemotaxis system. This assay enabled characterization of tumor cell transcellular migration in terms of chemotactic signal gradients, shear forces, and cell-substrate adhesion. Results suggest that shear flow plays significant roles in tumor cell extravasation that is regulated by both tumor cell motility and tumor cell adhesion to endothelial molecules in a cooperative process.
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Affiliation(s)
- Cheng Dong
- Department of Bioengineering, The Pennsylvania State University, University Park 16802, USA.
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Goodarzi G, Mashimo T, Watabe M, Cuthbert AP, Newbold RF, Pai SK, Hirota S, Hosobe S, Miura K, Bandyopadhyay S, Gross SC, Balaji KC, Watabe K. Identification of tumor metastasis suppressor region on the short arm of human chromosome 20. Genes Chromosomes Cancer 2001; 32:33-42. [PMID: 11477659 DOI: 10.1002/gcc.1164] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Acquisition of metastatic ability by prostate cancer cells is the hallmark of their lethal trait and outcome. However, the genetic alterations underlying the clinical progression and pathogenesis of prostate cancer are not well understood. Several studies involving loss of heterozygosity (LOH) and comparative genomic hybridization analysis have identified distinctively altered regions on various human chromosomes, and genomic imbalance of chromosome 20 was implicated in progression and recurrence of prostate tumors. To examine the role of chromosome 20 in prostate neoplasms, we introduced this chromosome into highly metastatic rat prostate cancer cells using the microcell-mediated chromosome transfer technique. Introduction of the chromosome resulted in significant suppression of the metastatic ability of the hybrid cells, by as much as 98%, without any interference with the in vivo growth rate or tumorigenicity of primary tumor in SCID mice. Our STS-PCR analysis on 10 hybrid clones indicates that the suppressor activity of chromosome 20 is located in the p11.23-12 region. Further examination of the hybrid clones by experimental metastasis assay and histologic analysis as well as Matrigel invasion assay suggests the involvement of the suppressor region at an early stage of invasion and extravasation. We also investigated the status of the chromosome 20 suppressor region in pathology specimens from human prostate cancer patients and detected the frequent loss of this region in high-grade tumors. These results suggest the presence of a putative suppressor gene on human chromosome 20 that is functionally involved in development of prostate cancer metastases.
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Affiliation(s)
- G Goodarzi
- Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois 62702, USA
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9
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Abstract
We have pioneered an in vitro pseudopod-generation model wherein suspended tumor cells are stimulated to form pseudopods into glass micropipettes in response to soluble collagen type IV (CIV). Pertussis toxin and removing intracellular calcium were found previously to be inhibitory to that process. We now extend those observations to dissect the roles of transmembrane calcium influx and circulating fatty acids on pseudopod extension. Removal of fatty acids from BSA in basal media resulted in abrogation of pseudopod formation, while reconstitution of free fatty acids restored cell pseudopod protrusion. We thus hypothesized that fatty acids may provide necessary pseudopod stimulatory signals. Addition of lysophosphatidic acid (LPA) to the fatty acid-free CIV solution or in an opposite pipette without CIV permitted approximately 50% pseudopod recovery in all pipette directions in a dose-dependent fashion. Thapsigargin (TG), an agent that releases internal calcium stores and causes opening of store-operated calcium channels, restored pseudopod protrusion up to 80% in CIV with fatty acid-free albumin. [Ca(2+)](i) release was non-additive when cells were stimulated by TG and LPA, suggesting overlapping [Ca(2+)](i) stores. The combination of TG and LPA in fatty acid-free albumin fully restored the pseudopod response to CIV. Addition of EGTA to chelate stimulatory media calcium blocked the pseudopod response to CIV in the presence of fatty acids. This indicates that pseudopod protrusion requires transmembrane calcium entry. Thus, extracellular lipids and calcium mobilization are required to complement CIV in pseudopod protrusion from suspended cells.
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Affiliation(s)
- Louis Hodgson
- Department of Bioengineering, Pennsylvania State University, University Park, PA, USA
| | - Elise C. Kohn
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA
| | - Cheng Dong
- Department of Bioengineering, Pennsylvania State University, University Park, PA, USA
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Goldberg SF, Harms JF, Quon K, Welch DR. Metastasis-suppressed C8161 melanoma cells arrest in lung but fail to proliferate. Clin Exp Metastasis 2000; 17:601-7. [PMID: 10845559 DOI: 10.1023/a:1006718800891] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The incidence of melanoma continues to increase at a rapid rate. As for most cancers, it is melanoma metastases, rather than the primary malignancy, that is the principal cause of death. We previously showed that the introduction of a normal copy of chromosome 6 into the metastatic human melanoma cell line C8161 suppresses metastasis at a step subsequent to tumor cells entering the bloodstream. To better define the step(s) in metastasis blocked by the addition of chromosome 6 we engineered cells that constitutively express green fluorescent protein (GFP). When these tagged, chromosome 6 hybrid cells were injected intravenously into athymic mice, grossly detectable metastases did not form. However, fluorescence microscopy revealed micro-metastases (single cells or clusters of <10 cells) in the lungs, suggesting that these cells lodged in the lungs but failed to proliferate. Cells isolated from lung up to 60 days post-injection grew in culture and/or formed tumors when injected into the skin, indicating that they were still viable, but dormant. This result implies that the gene(s) on chromosome 6 interfere specifically with growth regulatory response in the lung, but not in the skin. Thus, the gene(s) responsible for metastasis suppression represents a new class of metastasis inhibitors acting at the final stages of the metastatic cascade--that is, affecting the ability of the cells to survive and proliferate at a specific secondary site.
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MESH Headings
- Animals
- Cell Division
- Cell Survival
- Chromosomes, Human, Pair 6/genetics
- Female
- Gene Transfer Techniques
- Genes, Reporter
- Genes, Tumor Suppressor
- Green Fluorescent Proteins
- Humans
- Hybrid Cells/transplantation
- Injections, Intradermal
- Injections, Intravenous
- Luminescent Proteins/genetics
- Lung Neoplasms/genetics
- Lung Neoplasms/pathology
- Lung Neoplasms/secondary
- Melanoma/genetics
- Melanoma/pathology
- Melanoma, Experimental
- Mice
- Mice, Nude
- Microscopy, Fluorescence
- Neoplasm Metastasis/genetics
- Neoplasm Metastasis/prevention & control
- Neoplasm Transplantation
- Neoplastic Cells, Circulating
- Organ Specificity
- Recombinant Fusion Proteins/analysis
- Skin Neoplasms/secondary
- Transplantation, Heterologous
- Tumor Cells, Cultured/transplantation
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Affiliation(s)
- S F Goldberg
- Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine, Hershey 17033-2390, USA
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11
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Ronot X, Doisy A, Tracqui P. Quantitative study of dynamic behavior of cell monolayers during in vitro wound healing by optical flow analysis. ACTA ACUST UNITED AC 2000. [DOI: 10.1002/1097-0320(20000901)41:1<19::aid-cyto3>3.0.co;2-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Holland EA, Beaton SC, Kefford RF, Mann GJ. Linkage analysis of familial melanoma and chromosome 6 in 14 Australian kindreds. Genes Chromosomes Cancer 1997; 19:241-9. [PMID: 9258659 DOI: 10.1002/(sici)1098-2264(199708)19:4<241::aid-gcc6>3.0.co;2-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
CDKN2A (9p21) and CDK4 (12q13) have been identified as melanoma susceptibility genes in certain familial melanoma (FM) kindreds. There remain other FM families, however, for which there is little or no evidence for linkage of melanoma to these loci. Other loci may be involved in susceptibility to this malignancy. Chromosome 6 is deleted or rearranged in 66% of melanomas and has been targeted by several studies in an attempt to identify chromosomal regions associated with initiation or progression of melanoma. Previous studies of familial melanoma and chromosome arm 6p reported evidence suggestive of linkage for markers flanking the HLA complex. We have carried out genetic linkage analysis in 14 Australian familial melanoma kindreds using 16 short tandem repeat polymorphism (STRP) markers spanning 6p23-6q27. Analysis by maximum likelihood and non-parametric (affected pedigree member) techniques showed no evidence of linkage of melanoma in this family set to chromosome 6 (two-point Zmax = 0.5 at theta = 0.2 for D6S285). Lod scores > 1.0 were obtained for the loci D6S285, D6S105, D6S265, D6S292, and D6S311 in three individual kindreds but these were insufficiently strong for formal heterogeneity testing to confirm that a chromosome 6-linked subset of families exists. These data imply little or no role for a major chromosome 6 melanoma susceptibility locus; however the possibility of such a locus remains open and warrants further investigation.
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Affiliation(s)
- E A Holland
- Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital, N.S.W., Australia.
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13
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Miele ME, De La Rosa A, Lee JH, Hicks DJ, Dennis JU, Steeg PS, Welch DR. Suppression of human melanoma metastasis following introduction of chromosome 6 is independent of NME1 (Nm23). Clin Exp Metastasis 1997; 15:259-65. [PMID: 9174127 DOI: 10.1023/a:1018473415458] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Metastasis is suppressed more than 95% following microcell-mediated transfer of a single copy of neomycin-tagged human chromosome 6 (neo6) into the human melanoma cell lines C8161 and MelJuSo. Concomitant with metastasis suppression is upregulation of NME1 (Nm23-H1) mRNA and protein expression. The purposes of this study were to determine whether NME1 expression was responsible for metastasis suppression in neo6/melanoma hybrids, and whether genes on chromosome 6 regulate NME1. Using neo6/C8161 cells, transfection of CAT reporter constructs linked to the NME1 promoter failed to consistently induce CAT. Therefore, it does not appear that genes on chromosome 6 directly control transcription of NME1. Transfection and overexpression of NME1 in MelJuSo, under the control of the CMV promoter, resulted in 40-80% inhibition of lung metastasis following i.v. inoculation of 2 x 10(5) cells. Only one transfectant of C8161 subclone 9 (C8161cl.9) cells was suppressed for metastasis. Control transfections with pCMVneo or pSV2neo did not suppress metastasis in either cell line. Taken together, these data suggest that NME1 can reduce metastatic potential of some human melanoma cells; but, this inhibitory activity appears to be independent of the metastasis suppression following introduction of chromosome 6 into C8161 and MelJuSo human melanoma cell lines.
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Affiliation(s)
- M E Miele
- The Jake Gittlen Cancer Research Institute, Department of Experimental Pathology, The Pennsylvania State University College of Medicine, Hershey 17033-0850, USA
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14
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Liu R, Oberley TD, Oberley LW. Transfection and expression of MnSOD cDNA decreases tumor malignancy of human oral squamous carcinoma SCC-25 cells. Hum Gene Ther 1997; 8:585-95. [PMID: 9095410 DOI: 10.1089/hum.1997.8.5-585] [Citation(s) in RCA: 97] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Overexpression of human manganese-containing superoxide dismutase (MnSOD) activity has been demonstrated to suppress malignancy in human melanoma and breast carcinoma cells in vitro and in vivo. To study its effects on human oral squamous carcinoma cells, stable transfection and expression of MnSOD in SCC-25 cells have been conducted. The MnSOD-overexpressing cell clones were shown to have approximately two- to five-fold increased MnSOD activity compared to the wild-type parental- or vector control-transfected cell clones, respectively. Plating efficiency with different concentrations of serum was decreased in the high MnSOD activity cell clones. Soft agar assays demonstrated that the clonogenic fractions of high-expressing MnSOD clones were dramatically reduced. When inoculated in nude mice, tumor growth was markedly inhibited in MnSOD overexpressing cell clones compared with the wild-type or vector control transfected cell lines. Thus, gene therapy of human oral cancer by increasing the expression of MnSOD activity in target cells might be used to prevent or reduce human oral tumor malignancy.
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Affiliation(s)
- R Liu
- Radiation Research Laboratory, University of Iowa, Iowa City 52242, USA
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15
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Young MR, Lozano Y. Inhibition of tumor invasiveness by 1alpha,25-dihydroxyvitamin D3 coupled to a decline in protein kinase A activity and an increase in cytoskeletal organization. Clin Exp Metastasis 1997; 15:102-10. [PMID: 9062386 DOI: 10.1023/a:1018492525027] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The capacity of cloned metastatic Lewis lung carcinoma cells (LLC-LN7) to invade through reconstituted basement membrane-coated filters was reduced after incubation with 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]. This was observed at doses as low as 10(-10) M 1,25(OH)2D3. The 1,25(OH)2D3-treated cells also had reduced levels of protein kinase A (PKA) activity and an increase in the level of polymerized actin, properties that have previously been demonstrated for less metastatic LLC variants. In addition, levels of the intermediate filament protein vimentin increased in 1,25(OH)2D3-treated LLC-LN7 tumor cells. In contrast, the levels and distribution of tubulin were not affected by 1,25(OH)2D3. The possibility that the decline in PKA activity was involved in the 1,25(OH)2D3 modulation of the cytoskeletal components was evaluated. To accomplish this, LLC-7 transfectants whose PKA levels were blocked due to expression of a mutated PKA R(1alpha) subunit (LN7-REV) were incubated with 1,25(OH)2D3 and their levels of F-actin were measured. In the absence of 1,25(OH)2D3 treatment, the PKA-defective LN7-REV cells had an increased level of polymerized actin as compared to the wild-type LLC-LN7 cells. This level of F-actin was minimally affected by 1,25(OH)2D3, suggesting that PKA activity is required for 1,25(OH)2D3 modulation of actin polymerization. These studies show that 1,25(OH)2D3 can reduce PKA activity in tumor cells, and that this reduction in PKA may be an intermediate signal through which 1,25(OH)2D3 affects the cytoskeleton and diminishes tumor invasiveness.
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Affiliation(s)
- M R Young
- Department of Research Services, Hines V.A. Hospital, IL 60141, USA.
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16
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Meisinger J, Patel S, Vellody K, Bergstrom R, Benefield J, Lozano Y, Young MR. Protein phosphatase-2A association with microtubules and its role in restricting the invasiveness of human head and neck squamous cell carcinoma cells. Cancer Lett 1997; 111:87-95. [PMID: 9022132 DOI: 10.1016/s0304-3835(96)04517-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The role of protein phosphatase-2A (PP-2A) in regulating the motility and adhesion of human head and neck squamous cell carcinomas (HNSCC) was investigated. Immunofluorescent staining of these HNSCC cells showed PP-2A can co-localize with microtubules. That the PP-2A influences motility was shown by the increase in HNSCC cell migration through laminin and vitronectin when PP-2A was selectively inhibited with low dose okadaic acid, and by the reduction in invasion through these same matrix components by elevators of PP-2A activity. Motility of HNSCC cells through collagen I or fibronectin was not modulated by PP-2A. The reduction in HNSCC migration through vitronectin or laminin that resulted from treatment with PP-2A elevators was associated with an increase in cellular adhesiveness to these same ECM components. These studies show the association of PP-2A with the cellular cytoskeleton and its role in restricting the invasiveness of tumor cells through select extracellular matrix components.
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Affiliation(s)
- J Meisinger
- Department of Research Services, Hines V.A. Hospital, IL 60141, USA
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17
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Miele ME, Robertson G, Lee JH, Coleman A, McGary CT, Fisher PB, Lugo TG, Welch DR. Metastasis suppressed, but tumorigenicity and local invasiveness unaffected, in the human melanoma cell line MelJuSo after introduction of human chromosomes 1 or 6. Mol Carcinog 1996; 15:284-99. [PMID: 8634087 DOI: 10.1002/(sici)1098-2744(199604)15:4<284::aid-mc6>3.0.co;2-g] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Progression of human melanoma toward increasing malignant behavior is associated with several nonrandom chromosomal aberrations, most commonly involving chromosomes 1, 6, 7, 9, and 10. We previously showed that introduction of human chromosome 6 into the highly metastatic human malignant melanoma cell line C8161 completely suppressed metastasis without altering tumorigenicity (Welch DR, Chen P, Miele ME, et al., Oncogene 9:255-262, 1994). Alterations of chromosome 1 are the most frequent chromosome abnormality observed in melanomas, and they frequently arise late in tumor progression. The purpose of the study presented here was to compare the effects of chromosomes 1 and 6 on malignant melanoma metastasis. By using microcell-mediated chromosome transfer, single copies of neo-tagged human chromosomes 1 or 6 were introduced into the human melanoma cell line MelJuSo. The presence of the added chromosome was verified by G banding of karyotypes, fluorescence in situ hybridization, and screening for polymorphic markers on each chromosome. The incidence and number of metastases per lung after intravenous or intradermal injection of parental MelJuSo cells was significantly (P<0.01) greater than those of hybrids containing either chromosome 1 or chromosome 6, although chromosome 1 was a less potent inhibitor of metastasis than chromosome 6. Cultures established from primary tumors and metastases remained neomycin resistant, suggesting that portions of the added chromosomes were retained. These results strengthen the evidence for the presence of a melanoma metastasis suppressor gene on chromosome 6. neo6/MelJuSo hybrids expressed 2.4- to 3.4-fold more of the melanoma differentiation-associated gene mda-6 (previously shown to be identical to WAF1/CIP1/Sdi1/CAP20) than parental metastatic cells. mda-6/WAF1 is among the candidate genes on chromosome 6. These results also demonstrate, for the first time, the existence of metastasis suppressor genes on human chromosome 1, although these genes appear to be less potent than the one encoded on chromosome 6.
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Affiliation(s)
- M E Miele
- Department of Experimental Pathology, The Pennsylvania State University College of Medicine, Hershey, PA 17033-0850, USA
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18
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Abstract
An increase in the clinical significance of cutaneous malignant melanoma has paralleled a dramatic increase in the rate of death from this disease. The critical genetic changes associated with the genesis and progression of this disease are only beginning to be identified. This review highlights genetic changes in cutaneous melanoma and discusses the genetics of predisposition, cytogenetics, changes in proto-oncogenes and oncogenes, and evidence for the role of tumor suppressor genes in this malignancy. The viewpoint of this article is that malignant melanoma is a genetic disease.
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Affiliation(s)
- YA Su
- National Center for Human Genome Research, National Institutes of Health, Bethesda, Maryland 20892, USA
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