Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment

Brabletz, Thomas; Jung, Andreas; Reu, Simone; Porzner, Marc; Hlubek, Falk; Kunz-Schughart, Leoni A.; Knuechel, Ruth; Kirchner, Thomas

doi:10.1073/pnas.171610498

Cited by 974 publications

(919 citation statements)

References 33 publications

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“…3a) and an increase in mobility when cells were cultured in FGF-1 (Figs. 3d and e) also support evidence by others that EMT can be induced in vitro in primary tumor cells [25,26]. The expression of Zeb1, Zeb2, Snail and Slug have all been implicated in EMT induction and the acquisition of an invasive cell phenotype, as reviewed in [24].…”

Section: Discussionsupporting

confidence: 76%

Separation and Characterization of Epithelial and Mesenchymal-like Murine Mammary Tumor Cells Reveals Epithelial Cell Differentiation Plasticity and Enhanced Tumorigenicity of Epithelial-enriched Tumor Cells

Palen

Jing²,

Weber³

et al. 2012

Cancer Microenvironment

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Tumors are composed of heterogeneous populations of cells including tumor-initiating cells (TICs) and metastatic precursors. While the origin of these cells is unknown, there is evidence that tumor cells can transdifferentiate from an epithelial to a mesenchymal phenotype, a property referred to as epithelial-to-mesenchymal transition (EMT). This cellular plasticity may explain the heterogeneous nature of tumors and differences in the tumorigenic and invasive properties of cells. Understanding the origin of these cells and the contribution of external factors that influence the acquisition of cellular properties is critical for the development of therapeutics to eradicate cancer. In this study, we show that primary murine tumor cells harvested from FVB/N Tg (MMTV/Neu) spontaneous mammary tumors possess differentiation plasticity and can be enriched to be epithelial or mesenchymal-like using selected culture media conditions, and we show evidence of EMT in a clonal population of primary epithelial tumor cells when cultured in fibroblast growth factor-1 (FGF-1) or transforming growth factor-β (TGF-β). We also determined that in contrast to the identification of mesenchymal-like tumor cells as TICs in orthotopic xenograph models of tumorigenicity, epithelial-enriched

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Section: Discussionsupporting

confidence: 76%

Separation and Characterization of Epithelial and Mesenchymal-like Murine Mammary Tumor Cells Reveals Epithelial Cell Differentiation Plasticity and Enhanced Tumorigenicity of Epithelial-enriched Tumor Cells

Palen

Jing²,

Weber³

et al. 2012

Cancer Microenvironment

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“…TMPRSS4 overexpression induces an EMT associated with SIP1/ZEB2 induction and E-cadherin loss in SW480 cells Because loss and/or reduction of E-cadherin expression correlates positively with tumor cell invasion and metastasis and is a key hallmark of EMT (Thiery, 2002;Thiery and Sleeman, 2006), regulation of E-cadherin in cells overexpressing TMPRSS4 was assessed. Consistent with reports from other groups (Brabletz et al, 2001;Conacci-Sorrell et al, 2003), we found that expression of E-cadherin in SW480 cells (data not shown) and the vector transfectant (Figure 5b) was induced with increasing cell confluency. However, E-cadherin expression was markedly reduced in T17 and T4 cells at both the mRNA and protein levels (Figure 5b) when compared with the vector transfectant, regardless of whether cells were seeded and grown for 2 days in sparse culture (5 Â 10 3 cells cm À2 ) or at confluency (8 Â 10 4 cells cm À2 ).…”

Section: Tmprss4 Promotes Invasion Metastasis and Emt H Jung Et Alsupporting

confidence: 92%

TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition

et al. 2007

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TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface that is highly expressed in pancreatic, colon and gastric cancer tissues. However, the biological functions of TMPRSS4 in cancer are unknown. Here we show, using reverse transcription-PCR, that TMPRSS4 is highly elevated in lung cancer tissues compared with normal tissues and is also broadly expressed in a variety of human cancer cell lines. Knockdown of TMPRSS4 by small interfering RNA treatment in lung and colon cancer cell lines was associated with reduction of cell invasion and cell-matrix adhesion as well as modulation of cell proliferation. Conversely, the invasiveness, motility and adhesiveness of SW480 colon carcinoma cells were significantly enhanced by TMPRSS4 overexpression. Furthermore, overexpression of TMPRSS4 induced loss of E-cadherin-mediated cell-cell adhesion, concomitant with the induction of SIP1/ZEB2, an Ecadherin transcriptional repressor, and led to epithelialmesenchymal transition events, including morphological changes, actin reorganization and upregulation of mesenchymal markers. TMPRSS4-overexpressing cells also displayed markedly increased metastasis to the liver in nude mice upon intrasplenic injection. Taken together, these studies suggest that TMPRSS4 controls the invasive and metastatic potential of human cancer cells by facilitating an epithelial-mesenchymal transition; TMPRSS4 may be a potential therapeutic target for cancer treatment.

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“…As for CDH1 expression, we observed in an earlier study that the quantification of CDH1 RNA in the whole biopsy is a good marker of E-cadherin expression and that non-significant intra-tumor differences were found in E-cadherin staining (Pena et al, 2005), in contrast with other authors' findings (Brabletz et al, 2001).…”

Section: Adh-gfp Adh-sn Row Column Cytokine Cytokinefull Name Medianmentioning

confidence: 62%

SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue

et al. 2009

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SNAI1, ZEB1, E-cadherin (CDH1), and vitamin D receptor (VDR) genes regulate the epithelial-mesenchymal transition (EMT) that initiates the invasion process of many tumor cells. We hypothesized that this process could also affect the behavior of normal cells adjacent to the tumor. To verify this hypothesis, the expression level of these genes was determined by quantitative RT-PCR in tumor, normal adjacent, and normal distant tissues from 32 colorectal cancer (CC) patients. In addition, we extended the study to human HaCaT normal keratinocytes and SW480-ADH colon cancer cells co-cultured with SW480-ADH cells overexpressing the mouse Snai1 gene. Of 18 CC cases with SNAI1 expression in tumor tissue, five also had SNAI1 in normal adjacent tissue (NAT). Expression of SNAI1 in tumor tissue correlated with downregulation of CDH1 and VDR genes in both tumor (P ¼ 0.047 and P ¼ 0.014, respectively) and NAT lacking SNAI1 expression (P ¼ 0.054 and P ¼ 0.003). ZEB1 expression was directly related to VDR expression in tumor tissue (r ¼ 0.39; P ¼ 0.027) and inversely to CDH1 in NAT (r ¼ À0.46; P ¼ 0.010). CDH1 and VDR were also downregulated in SW480-ADH and MaCaT cells, respectively, when they were co-cultured with Snai1-expressing cells. Furthermore, cytokine analysis showed differences in the conditioned media obtained from the two cell types. These results indicate that histologically normal tissue adjacent to tumor tissue expressing the EMT-inducing gene SNAI1 shows alterations in the expression of epithelial differentiation genes such as CDH1 and VDR.

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Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment

Cited by 974 publications

References 33 publications

Separation and Characterization of Epithelial and Mesenchymal-like Murine Mammary Tumor Cells Reveals Epithelial Cell Differentiation Plasticity and Enhanced Tumorigenicity of Epithelial-enriched Tumor Cells

Separation and Characterization of Epithelial and Mesenchymal-like Murine Mammary Tumor Cells Reveals Epithelial Cell Differentiation Plasticity and Enhanced Tumorigenicity of Epithelial-enriched Tumor Cells

TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition

SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue

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