Vimentin and Epithelial-Mesenchymal Transition in Human Breast Cancer – Observations in vitro and in vivo

Kokkinos, Maria I; Wafai, Razan; Wong, Ming Keong; Newgreen, Donald F.; Thompson, Erik W.; Waltham, Mark

doi:10.1159/000101320

Cited by 338 publications

(308 citation statements)

References 121 publications

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“…EMT is a multi-step process in which cells acquire molecular alterations that facilitate dysfunctional cell-cell adhesive interactions, loss of cell-cell junctions, and reorganization of the cytoskeleton, all of which result in the loss of apical polarity and the acquisition of a more spindle-shaped morphology [24][25][26][27][28][29]. These processes are ultimately thought to promote cancer cell progression through the basement membrane and invasion into the surrounding microenvironment.…”

Section: Epithelial-mesenchymal Transition (Emt) In Ticsmentioning

confidence: 99%

Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

Creighton

Chang‐Claude

Rosen

2010

J Mammary Gland Biol Neoplasia

232

192

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There is increasing support for the hypothesis that most tumors contain a subpopulation of cells, referred to here as tumor initiating cells (TICs), with the ability to self-renew and to regenerate all the cell types within the tumor. TICs are enriched in breast cancer patients after common treatments, indicating their intrinsic therapeutic resistance. Two independently-derived gene transcription "signatures" of TICs from different studies indicate enrichment of TICs within the recently-identified "claudin-low" intrinsic molecular subtype of breast cancer. These are characterized by high expression of markers associated with epithelial-mesenchymal transition (EMT), suggesting that claudin-low cells may arise from more immature stem or progenitor cells than other breast cancers. EMT is a process by which cells acquire molecular alterations that facilitate dysfunctional cell-cell adhesive interactions and junctions, as well as a more spindle-shaped morphology. These processes may promote cancer cell progression and invasion into the surrounding microenvironment. Induction of EMT in immortalized human mammary epithelial cells results in an increased ability to form mammospheres, and in the expression of stem cell and TIC markers, suggesting that there may be a direct link between the EMT and the gain of TIC properties. Targeting specific molecular pathways-such as Notch, Wnt, and TGFß-associated with development and EMT in the TIC subpopulation, in addition to conventional chemo-and radiation therapies that target the bulk tumor, may ultimately provide a more effective strategy in treating breast cancer. Here, we review recent evidence of the involvement of EMT in breast cancer TICs, focusing on clinical studies.

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Section: Epithelial-mesenchymal Transition (Emt) In Ticsmentioning

confidence: 99%

Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

Creighton

Chang‐Claude

Rosen

2010

J Mammary Gland Biol Neoplasia

232

192

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confidence: 99%

“…3,4 A classical EMT protein is vimentin; numerous reports show that vimentin is overexpressed in invasive human tumors but is nearly undetectable in non-invasive, stationary tumors. 3,[5][6][7] Vimentin is a Type III intermediate filament 8 and its overexpression correlates with metastatic disease, EMT induction, poor prognosis and reduced patient survival. 7,[9][10][11] Similar correlations between vimentin overexpression and invasion are observed in cancer cell lines and mouse models across most tumor types.…”

mentioning

confidence: 99%

“…7,[9][10][11] Similar correlations between vimentin overexpression and invasion are observed in cancer cell lines and mouse models across most tumor types. 6,12 In breast cancer, in particular, vimentin positive tumors were observed in younger women, usually lacked estrogen and progesterone receptors, and correlated with high-grade cancer 13 and tumor size. 14 Studies done in vitro show that vimentin is essential for cell motility and migration, loss of vimentin expression nearly eliminates cell migration 5,[15][16][17] and increased expression enhances migration.…”

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confidence: 99%

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Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Thaiparambil

Bender

Ganesh

et al. 2011

Intl Journal of Cancer

231

208

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Withaferin A (WFA) is purified from the plant Withania somnifera and inhibits the vimentin cytoskeleton. Vimentin overexpression in cancer correlates with metastatic disease, induction of epithelial to mesenchymal transition and reduced patient survival. As vimentin functions in cell motility, we wanted to test the hypothesis that WFA inhibits cancer metastasis by disrupting vimentin function. These data showed that WFA had weak cytotoxic and apoptotic activity at concentrations less than or equal to 500 nM, but retained potent anti-invasive activity at these low doses. Imaging of breast cancer cell lines revealed that WFA induces perinuclear vimentin accumulation followed by rapid vimentin depolymerization. A concomitant induction of vimentin ser56 phosphorylation was observed, which is consistent with vimentin disassembly. Structure activity relationships were established using a set of chemically modified WFA analogs and showed that the predicted vimentin-binding region of WFA is necessary to induce vimentin ser56 phosphorylation and for its anti-invasive activity. Pharmacokinetic studies in mice revealed that WFA reaches peak concentrations up to 2 lM in plasma with a half-life of 1.36 hr following a single 4 mg/kg dose. In a breast cancer metastasis mouse model, WFA showed dose-dependent inhibition of metastatic lung nodules and induced vimentin ser56 phosphorylation, with minimal toxicity to lung tissue. Based upon these studies, we conclude that WFA is a potent breast cancer anti-metastatic agent and the anti-metastatic activity of WFA is, at least in part, mediated through its effects on vimentin and vimentin ser56 phosphorylation.Metastatic disease is the major cause of death in almost all cancer types; however, most treatments are developed to target the primary tumor and not the metastases. This is due to metastatic cells being difficult to detect, highly aggressive, chemoresistant and experimentally challenging to model. 1 At present, there is no agent in clinical use that effectively prevents metastasis and most patients ultimately succumb to metastatic disease.The metastatic process can be broadly categorized into three stages-tumor cell invasion into surrounding tissue, intravasation into blood or lymphatic vessels and extravasation into a new host environment. These events are triggered by genetic and epigenetic alterations that transform stationary epithelial cells into migratory cells, a process termed epithelialmesenchymal transition (EMT). 2,3 Recent data suggests that cancer cells can re-trigger EMT to migrate into surrounding tissue. 3,4 A classical EMT protein is vimentin; numerous reports show that vimentin is overexpressed in invasive human tumors but is nearly undetectable in non-invasive, stationary tumors. 3,[5][6][7] Vimentin is a Type III intermediate filament 8 and its overexpression correlates with metastatic disease, EMT induction, poor prognosis and reduced patient survival. 7,[9][10][11] Similar correlations between vimentin overexpression and invasion are observed in cancer ce...

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“…However, Vimentin is a component of type III intermediate filaments and the archetypal mesenchymal marker most commonly used to categorize EMT. That vimentin expression is a late event in EMT points to a temporal sequence of genetic events in which loss of epithelial features directly precedes and leads to up-regulation of mesenchymal genes (Kokkinos et al, 2007;Polette et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Expression of Smad7 in Cholangiocarcinoma: Prognostic Significance and Implications for Tumor Metastasis

Huang

Liu²,

Liu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Background: There are few molecular markers known to predict cholangiocarcinoma (CCA) prognosis. Smad7 has a certain relationship with epithelial-mesenchymal transition (EMT), but its relevance to CCA in unclear. Therefore expression and clinical significance of Smad7 in CCA was the focus of this study. Methods: Expression of Smad7, E-cadherin and vimentin was assessed in 41 patients with CCA by immunohistochemistry and analyzed for associations with clinical parameters. Results: Smad7 and vimentin expression in the CCA tissue was dramatically higher than that in adjacent tissues. In addition, Smad7, vimentin and E-cadherin expression was significantly associated with CCA lymph node metastasis and perineural invasion(P≤0.05), but not other factors, such as gender, age, tumor location, tumor type and tumor differentiation degree (P>0.05). The overall survival and relapse-free survival rate was significantly higher in patients with negative Smad7 expression than those with positive Smad7 expression. Conclusion: EMT phenomena may occur in the process of CCA invasion and metastasis. Smad7, which was highly expressed in CCA, may be considered to be one feedback regulator in late stages and could have potential as a prognostic indicator for clinical assessment.

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Vimentin and Epithelial-Mesenchymal Transition in Human Breast Cancer – Observations in vitro and in vivo

Cited by 338 publications

References 121 publications

Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Expression of Smad7 in Cholangiocarcinoma: Prognostic Significance and Implications for Tumor Metastasis

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