Snail, Slug, and Smad‐interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma

Elloul, Sivan; Elstrand, Mari Bukholt; Nesland, Jahn M.; Tropé, Claes G.; Kvalheim, Gunnar; Goldberg, Iris; Reich, Reuven; Davidson, Ben

doi:10.1002/cncr.20946

Cited by 392 publications

(348 citation statements)

References 61 publications

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“…These results are also in line with the recent observation that SNAI1 expression is a requisite for lymph node metastasis of human breast carcinoma cells (Olmeda et al, 2007b). On the other hand, the strong influence of Snai2 silencing in reduction of liver and lung metastasis could be related to the cell survival properties (Inoue et al, 2002;Perez-Losada et al, 2003;Kajita et al, 2004) or the specific migration properties conferred by Snai2 (Barrallo-Gimeno and Nieto, 2005;Elloul et al, 2005;Come et al, 2006) that could restrain effective lung and liver colonization in its absence.…”

Section: Discussionsupporting

confidence: 88%

“…Nevertheless, a significant decrease of MMP9 and mesenchymal markers was detected in CarB-shSnai2 xenografts (Figure 5), suggesting that Snai2 can control certain aspects of tumor invasion/differentiation in determined tumor contexts. These observations are also compatible with the differential roles proposed for Snai1 and Snai2 factors in individual vs collective tumor invasion, or distinct anatomic dissemination of breast and ovarian tumors (Elloul et al, 2005(Elloul et al, , 2006Come et al, 2006), and for Snai2 in wound healing migration (Savagner et al, 2005).…”

Section: Discussionsupporting

confidence: 87%

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Snai1 and Snai2 collaborate on tumor growth and metastasis properties of mouse skin carcinoma cell lines

et al. 2008

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Snai1 (Snail) and Snai2 (Slug), the two main members of Snail family factors, are important mediators of epithelial-mesenchymal transitions and involved in tumor progression. We recently reported that Snai1 plays a major role in tumor growth, invasion and metastasis, but the contribution of Snai2 to tumorigenesis is not yet well understood. To approach this question we have silenced Snai2 and/or Snai1 by stable RNA interference in two independent mouse skin carcinoma (HaCa4 and CarB) cell lines. We demonstrate that Snai2 knockdown has a milder effect, but collaborates with Snai1 silencing in reduction of tumor growth potential of either carcinoma cell line when injected into nude mice. Importantly, Snai1 or Snai2 silencing dramatically influences the metastatic ability of squamous carcinoma HaCa4 cells, inducing a strong reduction in liver and lung distant metastasis. However, only Snai1 knockdown has an effective action on invasiveness and fully abolishes tumor cell dissemination into the spleen. These results demonstrate that Snai1 and Snai2 collaborate on primary tumor growth and specifically contribute to site-specific metastasis of HaCa4 cells. These data also indicate that Snai1 is the major regulator of local invasion, supporting a hierarchical participation of both factors in the metastatic process.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 87%

Snai1 and Snai2 collaborate on tumor growth and metastasis properties of mouse skin carcinoma cell lines

et al. 2008

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“…The analysis of the Snai2-expressing mice identified that 'uncontrolled' Snai2 expression induces cancer in mice. These findings further indicated that overexpression of SNAI2 by human tumours could be of importance to both cell fate selection by genotoxic anticancer agents (Perez-Mancera et al, 2005) and clinical management of human cancer patients (Elloul et al, 2005;Shih et al, 2005;Bermejo-Rodriguez et al, 2006;Come et al, 2006). These results suggested that Snai2 expression was protecting cells from death by genetic alterations as a consequence of an inherent, basal level of genetic instability (Sanchez-Garcia, 1997;Pérez-Caro et al, 2005;Perez-Mancera et al, 2005).…”

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confidence: 79%

“…The implication of SNAI2 in human cancer seems to be wider than initially expected (Elloul et al, 2005;Gupta et al, 2005;Shih et al, 2005;Bermejo-Rodriguez et al, 2006;Come et al, 2006). Nevertheless, the molecular mechanisms by which SNAI2 participates in these biological processes are not yet clear.…”

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confidence: 90%

Transcriptomal profiling of the cellular response to DNA damage mediated by Slug (Snai2)

et al. 2008

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Snai2-deficient cells are radiosensitive to DNA damage. The function of Snai2 in response to DNA damage seems to be critical for its function in normal development and cancer. Here, we applied a functional genomics approach that combined gene-expression profiling and computational molecular network analysis to obtain global dissection of the Snai2-dependent transcriptional response to DNA damage in primary mouse embryonic fibroblasts (MEFs), which undergo p53-dependent growth arrest in response to DNA damage. Although examination of the response showed that overall expression of p53 target gene expression patterns was similarly altered in both control and Snai2-deficient cells, we have identified and validated candidate Snai2 target genes linked to Snai2 gene function in response to DNA damage. This work defines for the first time the effect of Snai2 on p53 target genes in cells undergoing growth arrest, elucidates the Snai2-dependent molecular network induced by DNA damage, points to novel putative Snai2 targets, and suggest a mechanistic model, which has implications for cancer management.

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“…A number of transcription factors that are important regulators of EMT in development act as repressors of E-cadherin expression. Elevated expression of several of these factors including Snail, Slug, SIP1 and Twist have been identified in EOC and associated with less favorable patient outcomes [72][73][74][75][76]. Ectopic expression of Snail, Slug or Twist in ovarian cancer cell lines results in repression of E-cadherin with accompanying EMT, enhanced motility, and invasiveness suggesting that transcriptional regulation of E-cadherin may be operational in EOC [72,75].…”

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confidence: 99%

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Hudson

Zeineldin

Stack

2008

Clin Exp Metastasis

165

172

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The mesodermally derived normal ovarian surface epithelium (OSE) displays both epithelial and mesenchymal characteristics and exhibits remarkable phenotypic plasticity during post-ovulatory repair. The majority of epithelial ovarian carcinomas (EOC) are derived from the OSE and represent the most lethal of all gynecological malignancies, as most patients (~70%) present at diagnosis with disseminated intra-abdominal metastasis. The predominant pattern of EOC metastasis involves pelvic dissemination rather than lymphatic or hematologic spread, distinguishing EOC from other solid tumors. Acquisition of the metastatic phenotype involves a complex series of interrelated cellular events leading to dissociation (shedding) and dispersal of malignant cells. A key event in this process is disruption of cell-cell contacts via modulation of intercellular junctional components. In contrast to most carcinomas that downregulate E-cadherin expression during tumor progression, an unique feature of primary well-differentiated ovarian cancers is a gain of epithelial features, characterized by an increase in expression of E-cadherin. Subsequent reacquisition of mesenchymal features is observed in more advanced tumors with concomitant loss of E-cadherin expression and/ or function during progression to metastasis. The functional consequences of this remarkable phenotypic plasticity are not fully understood, but may play a role in modulation of cell survival in suspension (ascites), chemoresistance, and intraperitoneal anchoring of metastatic lesions. Keywords ovarian cancer; epithelium; cadherin; keratin; vimentin; epithelial-mesenchymal transition; plasticity Ovarian Cancer-OverviewTumors arising from the ovarian epithelium account for ~90% of ovarian malignancies and epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecologic malignancy, resulting in approximately 15,280 deaths in the United States alone in 2006 [1]. These distressing statistics are largely due to the low detection rate of disease confined to the ovary (stage 1) when 5-year survival is >90%. Approximately 75% of women are initially diagnosed with disseminated intra-abdominal disease (stage III-IV) and have a 5-year survival of <20%.Ovarian tumors are pathologically heterogeneous with four major histotypes: serous, endometroid, clear cell and mucinous. These classifications are histogenetically based on The early steps of EOC metastasis involve shedding of the cells from the primary tumor to form free floating cells or multi-cellular aggregates (MCAs) in ascites [ Fig. 1]. Cell-cell and cell-matrix adhesion molecules mediate interaction of metastasizing tumor cells with mesothelial cells lining the inner surface of the peritoneal cavity and the sub-mesothelial extracellular matrix (ECM). Localized proteolytic degradation of sub-mesothelial ECM components facilitates migration of tumor cells and anchoring of secondary lesions on adjacent pelvic organs, and at later stages, metastasis to distant organs [9,10]. However, the majority of wo...

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Snail, Slug, and Smad‐interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma

Cited by 392 publications

References 61 publications

Snai1 and Snai2 collaborate on tumor growth and metastasis properties of mouse skin carcinoma cell lines

Snai1 and Snai2 collaborate on tumor growth and metastasis properties of mouse skin carcinoma cell lines

Transcriptomal profiling of the cellular response to DNA damage mediated by Slug (Snai2)

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

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