Without epithelial–mesenchymal transitions, in which polarized epithelial cells are converted into motile cells, multicellular organisms would be incapable of getting past the blastula stage of embryonic development. However, this important developmental programme has a more sinister role in tumour progression. Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.

Epithelial–mesenchymal transitions in tumour progression

The Snail family of transcription factors has previously been implicated in the differentiation of epithelial cells into mesenchymal cells (epithelial-mesenchymal transitions) during embryonic development. Epithelial-mesenchymal transitions are also determinants of the progression of carcinomas, occurring concomitantly with the cellular acquisition of migratory properties following downregulation of expression of the adhesion protein E-cadherin. Here we show that mouse Snail is a strong repressor of transcription of the E-cadherin gene. Epithelial cells that ectopically express Snail adopt a fibroblastoid phenotype and acquire tumorigenic and invasive properties. Endogenous Snail protein is present in invasive mouse and human carcinoma cell lines and tumours in which E-cadherin expression has been lost. Therefore, the same molecules are used to trigger epithelial-mesenchymal transitions during embryonic development and in tumour progression. Snail may thus be considered as a marker for malignancy, opening up new avenues for the design of specific anti-invasive drugs.

The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression

https://www.cell.com/developmental-cell/pdf/S1534-5807(08)00209-8.pdf

Epithelial-Mesenchymal Transition: At the Crossroads of Development and Tumor Metastasis

Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2

The identification of genes predisposing to familial cancer is an essential step towards understanding the molecular events underlying tumorigenesis and is critical for the clinical management of affected families. Despite a declining incidence, gastric cancer remains a major cause of cancer death worldwide, and about 10% of cases show familial clustering. The relative contributions of inherited susceptibility and environmental effects to familial gastric cancer are poorly understood because little is known of the genetic events that predispose to gastric cancer. Here we describe the identification of the gene responsible for early-onset, histologically poorly differentiated, high grade, diffuse gastric cancer in a large kindred from New Zealand (Aotearoa). Genetic linkage analysis demonstrated significant linkage to markers flanking the gene for the calcium-dependent cell-adhesion protein E-cadherin. Sequencing of the E-cadherin gene revealed a G --> T nucleotide substitution in the donor splice consensus sequence of exon 7, leading to a truncated gene product. Diminished E-cadherin expression is associated with aggressive, poorly differentiated carcinomas. Underexpression of E-cadherin is a prognostic marker of poor clinical outcome in many tumour types, and restored expression of E-cadherin in tumour models can suppress the invasiveness of epithelial tumour cells. The role of E-cadherin in gastric cancer susceptibility was confirmed by identifying inactivating mutations in other gastric cancer families. In one family, a frameshift mutation was identified in exon 15, and in a second family a premature stop codon interrupted exon 13. These results describe, to our knowledge for the first time, a molecular basis for familial gastric cancer, and confirm the important role of E-cadherin mutations in cancer.

E-cadherin germline mutations in familial gastric cancer

The ability of carcinomas to invade and to metastasize largely depends on the degree of epithelial differentiation within the tumors, i.e., poorly differentiated being more invasive than well-differentiated carcinomas. Here we confirmed this correlation by examining various human cell lines derived from bladder, breast, lung, and pancreas carcinomas. We found that carcinoma cell lines with an epithelioid phenotype were noninvasive and expressed the epithelium-specific cell-cell adhesion molecule E-cadherin (also known as Arc-1, uvomorulin, and cell-CAM 120/80), as visualized by immunofluorescence microscopy and by Western and Northern blotting, whereas carcinoma cell lines with a fibroblastoid phenotype were invasive and had lost E-cadherin expression. Invasiveness of these latter cells could be prevented by transfection with E-cadherin cDNA and was again induced by treatment of the transfected cells with anti-E-cadherin mAbs. These findings indicate that the selective loss of E-cadherin expression can generate dedifferentiation and invasiveness of human carcinoma cells, and they suggest further that E-cadherin acts as an invasion suppressor.

/pdf/e-cadherin-mediated-cell-cell-adhesion-prevents-invasiveness-4b3i3zcik2.pdf

G Eberle

Papers

E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells.