Cell Adhesion Proteins As Tumor Suppressors

Okegawa, Takatsugu; Li, Yingming; Pong, Rey-Chen; Hsieh, Jer Tsong

doi:10.1016/s0022-5347(05)65245-7

Cited by 114 publications

(88 citation statements)

References 85 publications

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“…Similar effects were obtained on human prostatic carcinoma cells, which showed increased Ecadherin (23)(24)(25) and prostate-specific antigen (26, 27) levels, but not on fibroblasts, hepatoma, kidney cancer, or leukemic cells. It is possible that this differential response to TDF is due to the presence or absence of TDF receptors.…”

Section: Discussionsupporting

confidence: 68%

A pituitary gene encodes a protein that produces differentiation of breast and prostate cancer cells

Platica

Ivan

Holland

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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A cDNA clone of 1.1 kb encoding a 108-aa polypeptide was isolated from a human pituitary cDNA library by expression cloning. This protein was named tumor differentiation factor (TDF). The recombinant TDF protein and a 20-aa peptide, P1, selected from the ORF of the gene, induced morphological and biochemical changes consistent with differentiation of human breast and prostate cancer cells. Fibroblast, kidney, hepatoma, and leukemic lymphocytic cell lines were unaffected. Breast and prostate cancer cells aggregated in spheroidlike structures within 24 h of exposure to TDF. This effect was abrogated by a specific affinity-purified rabbit polyclonal anti-P1 Ab. E-cadherin expression was increased in a dose-dependent manner by TDF. Treatment of MCF7 cells with TDF led to production of a lactalbumin-related protein. Peptide P1 significantly decreased the growth of androgen-independent DU145 prostate cancer in severe combined immunodeficient mice. The presence of TDF protein in human sera was detected by the anti-P1 Ab, suggesting a role of TDF in endocrine metabolism. The fact that all activities of TDF can be mimicked by a peptide derived from the encoding TDF sequence opens the possibility of therapeutic applications.M alignant transformation is characterized by the uncoupling of proliferation and differentiation leading to continuing multiplication of cells and the impairment of their ability to progress to complete normal differentiation. Restoration of differentiation of malignant cells has long been considered a potential therapy of cancer (1-5).We have previously reported that an alkaline extract of rat mammosomatotropic tumor MtTW10 induced morphological and biochemical changes in rat and human breast cancer cells indicative of differentiation. Within 24 h of the exposure in vitro, the pituitary tumor extract (PTE) led to aggregation of breast cancer cells, polarization of organelles, the formation of cell junctions and basement membrane, synthesis of mRNA for casein and lactalbumin, and overexpression of E-cadherin (6). The PTE was also effective on prostate cancer cells, inducing cellular changes and overexpression of E-cadherin and prostate-specific antigen.Because this activity was not reproduced by any of the known pituitary hormones or other growth factors, studied alone or in combination, we assumed that the PTE contained a factor, which we called tumor differentiation factor (TDF). Our attempts to isolate and purify this factor by using conventional chromatographic procedures were unsuccessful. Now, using expression cloning, we report the isolation of a human cDNA clone encoding a protein responsible for this tumordifferentiating activity. We have sequenced the clone. Computer analysis indicates that it encodes a polypeptide with no significant homology to any other known sequence in the GenBank database. Our results support the proposition that TDF is a previously unrecognized pituitary factor. Materials and MethodsPituitary cDNA Library. A cDNA library prepared from a growth hormone-producing human ...

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Section: Discussionsupporting

confidence: 68%

A pituitary gene encodes a protein that produces differentiation of breast and prostate cancer cells

Platica

Ivan

Holland

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…During the last decade E-cadherin has increasingly been recognized as a potent tumour suppressor protein (Okegawa et al, 2002). Inactivation of the E-cadherin/ catenin adhesion complex usually correlates with poor prognosis and survival of cancer patients, most likely due to reinforced invasion and metastasis of tumour cells (Conacci-Sorrell et al, 2002;Cavallaro and Christofori, 2004).…”

Section: Deltaef1 and Cancer Progressionmentioning

confidence: 99%

DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells

et al. 2005

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Downregulation of E-cadherin is a crucial event for epithelial to mesenchymal transition (EMT) in embryonic development and cancer progression. Using the EpFosER mammary tumour model we show that during EMT, upregulation of the transcriptional regulator deltaEF1 coincided with transcriptional repression of E-cadherin. Ectopic expression of deltaEF1 in epithelial cells was sufficient to downregulate E-cadherin and to induce EMT. Analysis of E-cadherin promoter activity and chromatin immunoprecipitation identified deltaEF1 as direct transcriptional repressor of E-cadherin. In human cancer cells, transcript levels of deltaEF1 correlated directly with the extent of E-cadherin repression and loss of the epithelial phenotype. The protein was enriched in nuclei of human cancer cells and physically associated with the E-cadherin promoter. RNA interference-mediated downregulation of deltaEF1 in cancer cells was sufficient to derepress E-cadherin expression and restore cell to cell adhesion, suggesting that deltaEF1 is a key player in late stage carcinogenesis.

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“…The cadherin family includes N-, P-and E-cadherin (E-CAD) but only E-CAD is expressed in all epithelial tissues (1). E-CAD, a 120-kD glycoprotein located on chromosome 16 (3), is associated with intracellular proteins called catenins that mediate between extra-cellular signals and cytoskeleton microfilaments (4). The functions of E-CAD are related to tumor suppression and are generally down-regulated in epithelial tumor development and diffusion (5).…”

Section: Introductionmentioning

confidence: 99%

“…Many authors have reported that loss of E-CAD expression is associated with loss of cellular differentiation and increased cellular invasiveness (6). Moreover, E-CAD expression loss is related to high grade and advanced stage in many neoplasms, such as breast (7) and colorectal (8,9) cancers and urologic tumors (4,10). Recent studies have demonstrated that loss of normal E-CAD expression also correlates with poor prognosis in urothelial carcinoma (UC) of the upper urinary tract (11) and urinary bladder (5).…”

Section: Introductionmentioning

confidence: 99%

E-cadherin mRNA expression analysis in evaluating the natural history of urothelial bladder cell carcinoma: Results from a long-term follow-up study

Cai

Piazzini²,

Nesi³

et al. 2007

Oncol Rep

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Abstract. Many studies have indicated that the E-cadherin (E-CAD) expression loss is associated with the loss of cellular differentiation and increased cellular invasiveness and can be correlated with poor prognosis in urothelial carcinoma (UC) of the urinary bladder. The aim of this study was to define the role of E-CAD mRNA expression on recurrence, progression and survival in UC of the urinary bladder over a long follow-up period. From 30 patients with bladder UC, enrolled in our previous study, 27 were selected for this study. All patients were re-analyzed in terms of clinical and tumor characteristics, tumor pathological analysis and tumor E-CAD mRNA expression. The data were correlated to 12-year follow-up results. Significant correlations between stage (p=0.002), grade (p=0.008) and E-CAD mRNA expression were reported. E-CAD did not show any correlation in predicting recurrence or progression in bladder UC. The survival analysis demonstrated a significant relationship (p=0.019) between patients with expressed E-CAD mRNA levels and cancer-specific survival. Multivariate analysis demonstrated that expression of E-CAD mRNA levels is an independent prognostic factor in terms of cancerspecific survival in UC of the urinary bladder (p=0.002). Our study is the first to demonstrate that mRNA extraction and Northen blot analysis is to be considered a reliable method to evaluate E-CAD mRNA levels for predicting survival rate in patients affected by urothelial bladder cancers. We stress that a long follow-up period is needed to evaluate the role of molecular factors in predicting prognosis in patients affected by bladder UC.

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Cell Adhesion Proteins As Tumor Suppressors

Cited by 114 publications

References 85 publications

A pituitary gene encodes a protein that produces differentiation of breast and prostate cancer cells

A pituitary gene encodes a protein that produces differentiation of breast and prostate cancer cells

DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells

E-cadherin mRNA expression analysis in evaluating the natural history of urothelial bladder cell carcinoma: Results from a long-term follow-up study

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