Expression of L1-CAM and ADAM10 in Human Colon Cancer Cells Induces Metastasis

Gavert, Nancy; Sheffer, Michal; Raveh, Shani; Spaderna, Simone; Shtutman, Michael; Brabletz, Thomas; Barany, Francis; Paty, Phillip; Notterman, Daniel A.; Domany, Eytan; Ben-Ze’ev, Avri

doi:10.1158/0008-5472.can-07-0991

Cited by 186 publications

(209 citation statements)

References 39 publications

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“…For example ADAM10 confers metastatic capacity in colorectal cancer 45 . Loss of SFRP1 and SFRP2 expression due to promoter hypermethylation has been frequently observed in proliferating and invasive tumors of different nature 8 .…”

Section: Discussionmentioning

confidence: 99%

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

et al. 2011

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It is well established that embryonic mouse retinal neurogenesis requiresNotch and Wnt signaling are also required for the development of vertebrate neural retina.This structure develops from a neuroepithelium composed of multipotent progenitors, which undergo a series of competence states to give rise to six neuronal and one glial cell types 2 . As progenitor cells produce the various cell types, Notch through lateral inhibition, maintains neighboring cells in a multipotent, proliferative state, ensuring that sufficient numbers of progenitors are retained for consecutive waves of neurogenesis. Thus, downregulation of Notch is a prerequisite for retinal neuronal differentiation 2 .Wnt/βcatenin signaling has also been implicated in the proliferation of vertebrate retinal precursors. However, in the mouse embryonic neural retina this function is limited to progenitor cells located in the periphery 3, 4 . In contrast, Wnt/βcatenin signaling is not active in the central retina and cell proliferation and differentiation proceed normally in mice with conditional deletion of βcatenin in the neural retina, although retinal lamination is altered 5 .Similarly, retinal specific inactivation of Fzd5, a non-canonical Wnt receptor mostly impacts on retinal vasculature formation but has no effect on neurogenesis 6 By analyzing the functional consequences of Sfrp1 and Sfrp2 compound inactivation during mouse retinal neurogenesis, we demonstrate here a novel and Wnt-independent role of Sfrps in the regulation of Notch signaling. We explain this finding by demonstrating that Sfrps can bind and downregulate the activity of ADAM10, a metalloprotease with multiple substrates including Notch, N-cadherin and APP. 4 RESULTS Sfrp1 and Sfrp2 are essential for proper eye developmentSfrp1 and Sfrp2 are expressed during murine eye development with a complementary pattern that includes all eye structures 7 . Sfrp1 transcripts are localized to the optic cup periphery and the retina pigmented epithelium from E10.5, while Sfrp2 is predominant in the neural retina (Fig. S1). Despite restricted mRNA expression, Sfrp proteins efficiently diffuse in the extracellular space 17 and Sfrp1 was immunodetected, albeit at low levels, also in the neural retina (Fig. S1), supporting the proposed Sfrp functional redundancy 9, 11, 12 .Accordingly, the eye of Sfrp1 and Sfrp2 single null embryos appeared histologically normal.In contrast at E16.5, the latest viable stage, the eyes of Sfrp1 -/-;Sfrp2 -/-compound mutants (n=20) were smaller than those of control littermates (n=30) with morphological visible alterations, including dorsal peripheral defects, reduction of the lens size, abnormal cornea and eye lid formation, increased thickness of the neural retina and abnormal vitreal accumulation of mesenchyme-derived angioblasts that normally form the hyaloid artery, the major vascular structure of the embryonic eye (Fig. S2). Inactivation of Sfrp1/2 alters retinal neurogenesisMultipotent progenitors in the neural retina generates neuronal and one glial cells wi...

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Section: Discussionmentioning

confidence: 99%

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

et al. 2011

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“…This is the not the first example of an axon guidance molecule being implicated in carcinoma. For example, L1-CAM, which plays critical roles in axon guidance and cell migration during the development of the nervous system, also promotes invasion and motility in colon cancer cells as well as tumor formation and the metastasis in nude mice (13,47). This functional role of L1-CAM is modulated by a family of sheddase called ADAM (a disintegrin and metalloprotease).…”

Section: Discussionmentioning

confidence: 99%

Novel Roles of the Chemorepellent Axon Guidance Molecule RGMa in Cell Migration and Adhesion

Lah

Key

2012

Molecular and Cellular Biology

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The repulsive guidance molecule A (RGMa) is a contact-mediated axon guidance molecule that has significant roles in central nervous system (CNS) development. Here we have examined whether RGMa has novel roles in cell migration and cell adhesion outside the nervous system. RGMa was found to stimulate cell migration from Xenopus animal cap explants in a neogenindependent and BMP-independent manner. RGMa also stimulated the adhesion of Xenopus animal cap cells, and this adhesion was dependent on neogenin and independent of calcium. To begin to functionally characterize the role of specific domains in RGMa, we assessed the migratory and adhesive activities of deletion mutants. RGMa lacking the partial von Willebrand factor type D (vWF) domain preferentially perturbed cell adhesion, while mutants lacking the RGD motif affected cell migration. We also revealed that manipulating the levels of RGMa in vivo caused major migration defects during Xenopus gastrulation. We have revealed here novel roles of RGMa in cell migration and adhesion and demonstrated that perturbations to the homeostasis of RGMa expression can severely disrupt major morphogenetic events. These results have implications for understanding the role of RGMa in both health and disease. Repulsive guidance molecule (RGM) was first identified in the embryonic chick retinotectal system as a chemorepulsive molecule for retinal axons (35). Subsequently, three different RGMs (RGMa, RGMb, and RGMc) were identified in mouse, and each was found to have a unique spatiotemporal expression pattern (41,48). RGMa is a membrane-bound protein with ϳ430 amino acid (aa) residues that has a glycosylphosphatidylinositol (GPI)-anchored C-terminal domain and a conventional N-terminal signal peptide (35,48). It is cysteine rich and contains a putative autoproteolytic cleavage site, a single tri-amino acid motif, ArgGly-Asp (RGD), a partial von Willebrand factor type D (vWF) domain, and two hydrophobic domains at the N and C termini. These key molecular structures, except for the RGD domain (which is absent in RGMb in most animal models), are shared by all members of the RGM family (5, 35). A conserved RSDSPEI sequence, 5= to the partial von Willebrand type D domain, is present within RGMa from mammals, frogs, and birds. To date, the roles of these different RGM domains remain unknown.The first RGM receptor was identified by cell surface binding of chick RGM to cells expressing neogenin, a member of the immunoglobulin superfamily of transmembrane receptors (31,35,43,(54)(55)(56)(57). RGMa-neogenin interactions are involved in axon guidance in the developing visual system and in axon tract formation in the embryonic brain in vivo (31,35,54,55,57,58). RGMa also has chemorepulsive activity during laminar patterning of the developing mouse dentate gyrus in vitro (4). Interestingly, RGMa knockout mice did not show an abnormality in retinal topography but displayed an exencephalic phenotype in ϳ50% of embryos, suggesting that RGMa plays a role in neural tube closure (37). We and others...

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“…In the present study, to investigate coordination between energy metabolism and cell-cycle progression of cancer cells in vivo, we have used a human colorectal cancer cell line HCT116 to provide a liver metastasis model in superimmunodeficient NOD/SCID/IL-2Rg c null (NOG) mice (14)(15)(16)(17)(18). To examine energy metabolism of individual cancer cells in metastatic tumors, we used HCT116 cells labeled with a cell-cycle phase-dependent fluorescent marker system Fucci (19).…”

Section: Introductionmentioning

confidence: 99%

Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

Bao

Mukai

Hishiki

et al. 2013

Molecular Cancer Research

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Activation of aerobic glycolysis in cancer cells is well known as the Warburg effect, although its relation to cellcycle progression remains unknown. In this study, human colon cancer cells were labeled with a cell-cycle phasedependent fluorescent marker Fucci to distinguish cells in G 1 -phase and those in S þ G 2 /M phases. Fucci-labeled cells served as splenic xenograft transplants in super-immunodeficient NOG mice and exhibited multiple metastases in the livers, frozen sections of which were analyzed by semiquantitative microscopic imaging mass spectrometry. Results showed that cells in G 1 -phase exhibited higher concentrations of ATP, NADH, and UDP-N-acetylglucosamine than those in S and G 2 -M phases, suggesting accelerated glycolysis in G 1 -phase cells in vivo. Quantitative determination of metabolites in cells synchronized in S, G 2 -M, and G 1 phases suggested that efflux of lactate was elevated significantly in G 1 -phase. By contrast, ATP production in G 2 -M was highly dependent on mitochondrial respiration, whereas cells in S-phase mostly exhibited an intermediary energy metabolism between G 1 and G 2 -M phases. Isogenic cells carrying a p53-null mutation appeared more active in glycolysis throughout the cell cycle than wild-type cells. Thus, as the cell cycle progressed from G 2 -M to G 1 phases, the dependency of energy production on glycolysis was increased while the mitochondrial energy production was reciprocally decreased.Implications: These results shed light on distinct features of the phase-specific phenotypes of metabolic systems in cancer cells. Mol Cancer Res; 11(9); 973-85. Ó2013 AACR.

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Expression of L1-CAM and ADAM10 in Human Colon Cancer Cells Induces Metastasis

Cited by 186 publications

References 39 publications

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

Novel Roles of the Chemorepellent Axon Guidance Molecule RGMa in Cell Migration and Adhesion

Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

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