Lamellipodia and filopodia in metastasis and invasion

Machesky, Laura M.

doi:10.1016/j.febslet.2008.03.039

Cited by 278 publications

(259 citation statements)

References 85 publications

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“…The in vitro invasive properties of both RA FLSs and DA rat FLSs studied herein correlate with in vivo radiographic and histological joint damage (20,21), making our observations clinically relevant. Additionally, we describe a mechanism of action where calcitriol interferes with the expression of MMP-1, which is a protease implicated in cartilage and bone damage in RA (35), and with cytoskeletal rearrangement and lamellipodia formation, which are required for cell motility and invasion (36). These observations support our original hypothesis that VDR stimulation could have a central role in the regulation of synovial processes implicated in cartilage and bone erosive joint damage.…”

Section: Discussionsupporting

confidence: 76%

The Vitamin D Receptor Regulates Rheumatoid Arthritis Synovial Fibroblast Invasion and Morphology

Laragione

Shah

Gulko

2011

Mol Med

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Serum levels of vitamin D levels are commonly reduced in patients with rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. We recently identified a new vitamin D receptor transcriptional signature in synovial tissues from rats with mild and nonerosive arthritis, suggesting a vitamin D-mediated protective effect. In the present study, we address the hypothesis that part of the vitamin D protective effect is mediated via interference with fibroblast-like synoviocyte (FLS) invasive properties, an in vitro cellular phenotype that correlates with radiographic and histological damage in pristane-induced arthritis and RA. FLSs derived from DA rats with pristane-induced arthritis and RA patients were studied in an in vitro model of invasion through a collagen-rich barrier (Matrigel) over a 24-h period, in the presence or absence of calcitriol, an active form of vitamin D. Matrix metalloprotease (MMP) expression levels were analyzed with zymography and quantitative real-time polymerase chain reaction, and the cytoskeleton was studied with immunofluorescense microscopy. Calcitriol significantly inhibited DA and RA FLS invasion by 54% and 53%, respectively. Calcitriol also reduced interleukin (IL)-1β-induced expression of MMP-1 by 95% in DA FLSs and by 73.5% in RA FLS. Calcitriol treatment reduced actin cytoskeleton reorganization, reduced polarized formation of lamellipodia and reduced colocalization of phosphorylated focal adhesion kinase (p-FAK) with lamellipodia, all consistent with reduced cell ability to move and invade. In conclusion, we identified a new effect of calcitriol in FLS invasion. This discovery suggests that the reduced serum levels of vitamin D and its metabolites commonly seen in RA might increase risk for FLS-mediated cartilage and bone invasion and erosions. Treatment with vitamin D or its analogs has the potential to become a helpful adjuvant aimed at preventing or reducing joint destruction.

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Section: Discussionsupporting

confidence: 76%

The Vitamin D Receptor Regulates Rheumatoid Arthritis Synovial Fibroblast Invasion and Morphology

Laragione

Shah

Gulko

2011

Mol Med

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“…[2][3][4] Directed cell migration is typically described by the presence of chemoattractants, both in vivo and in vitro, associated to the activation or inhibition of sets of genes, and leading to the cytoskeleton reorganization and polarization. 5 This implies a functional asymmetry between the front and back sides generating preferential locations for cellular protrusion activity (lamellipodia and filopodia) to set the future direction of migration.…”

Section: Introductionmentioning

confidence: 99%

The cell ratchet: Interplay between efficient protrusions and adhesion determines cell motion

Caballero

Voituriez

Riveline

2015

Cell Adhesion & Migration

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M any physiological and pathological processes involve directed cell motion. In general, migrating cells are represented with a polarized morphology with extending and retracting protrusions at the leading edge. However, cell motion is a more complex phenomenon. Cells show heterogeneous morphologies and high protrusive dynamics is not always related to cell shape. This prevents the quantitative prediction of cell motion and the identification of cellular mechanisms setting directionality. Here we discuss the importance of protrusion fluctuations in directed cell motion. We show how their spatiotemporal distribution and dynamics determine the fluctuations and directions of cell motion for NIH3T3 fibroblasts plated on micro-patterned adhesive ratchets. 1 We introduce efficient protrusions and direction index which capture short-term cell motility over hours: these new read-outs allow the prediction of parameters characteristic for the long-term motion of cells over days. The results may have important implications for the study of biological phenomena where directed cell migration is involved, in morphogenesis and in cancer.

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“…Because central regulators of the cell front are Rho family small GTP-binding proteins (Rho GTPases), including Rac and Rho, they are pivotal regulators of actin and adhesion organization and control the formation of lamellipodia (20). Rac1 is a direct regulator of the organization of lamellipodial structure (8,16). A previous study showed that Rac1 is downstream of signaling from the complex of paxillin, FAK, and vinculin in focal adhesions and cell-cell contacts (8).…”

Section: Discussionmentioning

confidence: 99%

“…We showed that Espin was colocalized with F-actin in lamellipodia. Lamellipodia are formed when cancer cells migrate on an extracellular matrix (ECM) such as the type I collagen or fibronectin matrix (16,17). The structure is induced in many biologic processes including cell migration and drives progression of cancer invasion and metastasis via dynamic remodeling of the actin cytoskeleton (18).…”

Section: Discussionmentioning

confidence: 99%

Actin-Binding Protein, Espin: A Novel Metastatic Regulator for Melanoma

Yanagishita

Yajima

Kumasaka

et al. 2014

Molecular Cancer Research

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Espin is a multifunctional actin-bundling protein with multiple isoforms, and has special connections to hair cell stereocilia and microvillar specializations of sensory cells in the inner ear. However, there have been no reports showing the expression and function of Espin in cancers, including melanoma. Here, it is demonstrated that Espin expression is significantly increased in melanomas that spontaneously developed in RET-transgenic mice (RETmice). Importantly, the invasion capacity of Espin-depleted Mel-ret melanoma cells derived from a tumor of the RET-mouse was dramatically less than that of control melanoma cells with reductions of lamellipodia, focal adhesion kinase (FAK), and GTP-Rac1 activities. Correspondingly, the ratio of metastatic foci in Espin-depleted Mel-ret melanoma cells was significantly less than that of control melanoma cells in an in vivo melanoma metastasis model. Moreover, Espin could be a novel biomarker of melanoma in humans, because our immunohistochemical analysis data reveal that percentages of Espin-positive cells in human primary and metastatic melanomas were significantly higher than that of cells in melanocytic nevi. Together, these results indicate that Espin is not only a metastatic regulator for melanoma but also a potential biomarker of disease progression.Implications: Actin-binding protein Espin is expressed in melanoma, affects metastasis, and is a potential target for melanoma therapy. Mol Cancer Res; 12(3); 440-6. Ó2013 AACR. IntroductionThe incidence of melanoma has increased by 3.1% every year and its incidence rate has doubled over a 10-year period (1). Melanoma is the most serious skin cancer and is highly invasive and resistant to conventional therapy (2). Identification of a molecule associated with melanoma growth, progression, and metastasis will provide new insights into the design of a biomarker and a novel therapeutic strategy for melanoma. Preventing or eliminating metastasis is one of the most important challenges for therapeutic intervention. Several regulatory molecules for cancer invasion and metastasis have recently been reported as candidates for clinical applications (3). However, an effective therapy for melanoma has not yet been established (2).

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Lamellipodia and filopodia in metastasis and invasion

Cited by 278 publications

References 85 publications

The Vitamin D Receptor Regulates Rheumatoid Arthritis Synovial Fibroblast Invasion and Morphology

The Vitamin D Receptor Regulates Rheumatoid Arthritis Synovial Fibroblast Invasion and Morphology

The cell ratchet: Interplay between efficient protrusions and adhesion determines cell motion

Actin-Binding Protein, Espin: A Novel Metastatic Regulator for Melanoma

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