Mechanisms of Hereditary Diffuse Gastric Cancer Initiation: The role of E-cadherin in the Epithelial-Mesenchymal Transition

Hereditary;gastric;cancer;HDGC;EMT;Epithelial-mesencymal;E-cadherin

Beetham, Henry Guy Scott ; Guilford, Parry

University of Otago

关键词: Hereditary;    gastric;    cancer;    HDGC;    EMT;    Epithelial-mesencymal;    E-cadherin;   

Others  :  https://ourarchive.otago.ac.nz/bitstream/10523/2617/1/BeethamHenryGS2012BBiomedScHons.pdf

美国|英语

来源: Otago University Research Archive

【 摘 要 】

Hereditary diffuse gastric cancer (HDGC) is a dominantly inherited cancer syndrome caused by germline mutations in the CDH1 gene which encodes the calcium-dependent, cell-cell adhesion protein E-cadherin [1,2]. Early stage HDGC is characterized by multiple foci of stage T1a signet ring cell carcinomas (SRCC). These foci are relatively indolent [3], however some eventually undergo an epithelial-mesenchymal transition (EMT) changing them into aggressive mesenchymal cells. At present it is not known definitively how the loss of E-cadherin and CDH1 germline mutations contribute to tumour initiation primarily in HDGC. The aim of this research was to determine whether the abrogation of E-cadherin expression alone is sufficient to induce an EMT, or if other mechanisms are also required. In order to analyse the early events of HDGC in vitro, an isogenic breast cell line model system with CDH1 knockout (-/-) cells was chosen. E-cadherin loss was found to affect cell morphology, proliferation rate, nucleoli number and cell adherence of the mammary epithelial cells. Transcriptome profiling performed on the isogenic cell lines showed E-cadherin loss resulted in an upregulation of genes involved in the tight junction complex such as claudin and occludin. The majority of EMT markers expected to be involved in cells undergoing an EMT were not upregulated. CDH1 loss also affected migration rates and growth in 3D culture. Overall, this study showed that E-cadherin loss alone was insufficient to cause a complete EMT in our model system. However, some genes associated with gastric and breast cancer progression were differentially expressed: S100-calcium binding proteins, matrix metallopeptidases (MMPs), and mucins. Hence, these CDH1 -/- cells show an increased ;;cancer-like’ phenotype but still remain relatively indolent, at least in the observed time frame.