Tumor Metastasis: Molecular Insights and Evolving Paradigms

Valastyan, Scott; Weinberg, Robert A.

doi:10.1016/j.cell.2011.09.024

Cited by 3,285 publications

(2,967 citation statements)

References 110 publications

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“…43 While a role for Arf6 in tumor metastasis had been appreciated for some time, the earliest report of BRAG2 involvement in metastasis came from studies by Sabe and colleagues, who showed that knockdown of BRAG2 potently inhibited the migration of breast cancer (MDA-MB-231) cells through matrigel. 7 Moreover, upon EGF stimulation of these cells BRAG2 bound directly to the EGF receptor through association of its PH domain with phosphorylated tyrosine residues (Y1068/Y1086) in the receptor.…”

Section: Brag Proteins In Cancer Metastasismentioning

confidence: 99%

The BRAG/IQSec family of Arf GEFs

D’Souza

Casanova

2016

Small GTPases

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The IQSec/BRAG proteins are a subfamily of Arf-nucleotide exchange factors. Since their discovery almost 15 y ago, the BRAGs have been reported to be involved in diverse physiological processes from myoblast fusion, neuronal pathfinding and angiogenesis, to pathophysiological processes including X-linked intellectual disability and tumor metastasis. In this review we will address how, in each of these situations, the BRAGs are thought to regulate the surface levels of adhesive and signaling receptors. While in most cases BRAGs are thought to enhance the endocytosis of these receptors, how they achieve this remains unclear. Similarly, while all 3 BRAG proteins contain calmodulin-binding IQ motifs, little is known about how their activities might be regulated by calcium. These are some of the questions that are likely to form the basis of future research.

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Section: Brag Proteins In Cancer Metastasismentioning

confidence: 99%

The BRAG/IQSec family of Arf GEFs

D’Souza

Casanova

2016

Small GTPases

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“…3 Each of these events is classically driven by the acquisition of genetic and/or epigenetic traits in tumor cells and the cooperation of nonneoplastic stromal cells. Increased or decreased expression of several genes in tumors has been found to be correlated with metastasis.…”

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confidence: 99%

“…Increased or decreased expression of several genes in tumors has been found to be correlated with metastasis. 3 However, specific gene alterations that drive NSCLC metastasis remain largely elusive.…”

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confidence: 99%

LAMC2 enhances the metastatic potential of lung adenocarcinoma

et al. 2015

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Lung cancer is the number one cancer killer, and metastasis is the main cause of high mortality in lung cancer patients. However, mechanisms underlying the development of lung cancer metastasis remain unknown. Using genome-wide transcriptional analysis in an experimental metastasis model, we identified laminin γ2 (LAMC2), an epithelial basement membrane protein, to be significantly upregulated in lung adenocarcinoma metastatic cells. Elevated LAMC2 increased traction force, migration, and invasion of lung adenocarcinoma cells accompanied by the induction of epithelial-mesenchymal transition (EMT). LAMC2 knockdown decreased traction force, migration, and invasion accompanied by EMT reduction in vitro, and attenuated metastasis in mice. LAMC2 promoted migration and invasion via EMT that was integrin β1-and ZEB1-dependent. High LAMC2 was significantly correlated with the mesenchymal marker vimentin expression in lung adenocarcinomas, and with higher risk of recurrence or death in patients with lung adenocarcinoma. We suggest that LAMC2 promotes metastasis in lung adenocarcinoma via EMT and may be a potential therapeutic target. Cell Death and Differentiation (2015) 22, 1341-1352; doi:10.1038/cdd.2014.228; published online 16 January 2015Lung cancer is the leading cause of cancer-related death. 1 Non-small-cell lung cancer (NSCLC) accounts for~80-85% of lung cancers. 2 Only 20-30% of NSCLC are radically resectable and the majority of lung cancer patients succumb to the disease. The high mortality of NSCLC is largely attributable to late diagnosis, when metastases are present. 2 The molecular mechanisms governing metastasis of NSCLC remain poorly understood.Metastasis is a complex, multistep process, involving migration and invasion of malignant cells from the primary tumor to blood vessels, intravasation, and survival in the circulation, and ultimately extravasation, colonization, and formation of secondary tumor at distant target organs. 3 Each of these events is classically driven by the acquisition of genetic and/or epigenetic traits in tumor cells and the cooperation of nonneoplastic stromal cells. Increased or decreased expression of several genes in tumors has been found to be correlated with metastasis. 3 However, specific gene alterations that drive NSCLC metastasis remain largely elusive.Laminin γ2 (LAMC2) is a subunit of the heterotrimeric glycoprotein laminin-332 (LAM-332, formerly laminin-5), consisting of the α3, β3, and γ2 chains. Although LAMC2 is an important structural component of the epithelial basement membrane (BM) in various normal tissues, 4 there is an emerging evidence for a pathological role of LAMC2 monomer in cancer. It has been demonstrated that LAMC2 protein expression correlates with clinical outcome of stage I lung adenocarcinoma (ADC) patients. 5,6 In addition, noncontinuous expression pattern of LAMC2 predicts the prognosis of esophageal squamous cell carcinoma (SCC), 7 and secreted LAMC2 in the serum is associated with the aggressiveness of pancreatic cancer. 8 Besides, LAMC2 monom...

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“…The metastatic process comprises a complex sequence of events including invasion of the surrounding matrix, intravasation to blood or lymphatic circulation, anchorage independent survival, and extravasation into foreign tissues (1). This multistep cascade is driven by genetic and epigenetic alterations that induce motility, invasiveness, resistance to apoptosis/anoikis, and self-renewal potential in a subpopulation of tumor cells (2,3).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

Kovářová

Plachý

Kosla

et al. 2013

Molecular Cancer Research

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Comparing the gene expression profiles of metastatic and nonmetastatic cells has the power to reveal candidate metastasis-associated genes, whose involvement in metastasis can be experimentally tested. In this study, differentially expressed genes were explored in the v-src-transformed metastatic cell line PR9692 and its nonmetastatic subclone PR9692-E9. First, the contribution of homeodomain only protein X (HOPX) in metastasis formation and development was assessed. HOPX-specific knockdown decreased HOPX expression in the nonmetastatic subclone and displayed reduced cell motility in vitro. Critically, HOPX knockdown decreased the in vivo metastatic capacity in a syngeneic animal model system. Genomic analyses identified a cadre of genes affected by HOPX knockdown that intersected significantly with genes previously found to be differentially expressed in metastatic versus nonmetastatic cells. Furthermore, 232 genes were found in both screens with at least a two-fold change in gene expression, and a number of high-confidence targets were validated for differential expression. Importantly, significant changes were demonstrated in the protein expression level of three metastaticassociated genes (NCAM, FOXG1, and ITGA4), and knockdown of one of the identified HOPX-regulated metastatic genes, ITGA4, showed marked inhibition of cell motility and metastasis formation. These data demonstrate that HOPX is a metastasis-associated gene and that its knockdown decreases the metastatic activity of v-src-transformed cells through altered gene expression patterns.

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Tumor Metastasis: Molecular Insights and Evolving Paradigms

Cited by 3,285 publications

References 110 publications

The BRAG/IQSec family of Arf GEFs

The BRAG/IQSec family of Arf GEFs

LAMC2 enhances the metastatic potential of lung adenocarcinoma

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

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