E-cadherin mutations and cell motility: a genotype-phenotype correlation.

E-cadherin has a determinant role in tumour progression, acting as an invasion and metastasis suppressor. Germline mutations of E-cadherin gene (CDH1) occur in 30% of families with Hereditary Diffuse Gastric Cancer (HDGC); of these 23% are missense mutations. The CDH1 missense mutations described to date span the entire gene and some lead to significant functional consequences. In this study, we explored the hypothesis that mutations affecting different E-cadherin protein domains have distinct effects on cell motility. To accomplish our objective we characterized the effect of eleven HDGC CDH1 germline missense mutations (T118R, L214P, G239R, A298T, T340A, P373L, R749W, E757K, E781D, P799R and V832M) on cell motility. Further, we studied their effect on the activation of signalling pathways known to be relevant for cell motility such as the EGFR, Src kinase and MAPKs. CDH1 mutations localized on the extracellular and juxtamembrane domains, both affecting the integrity of the extracellular domain, led to increased cell motility accompanied by increased EGFR activation. Moreover, we observed that cells expressing extracellular mutants exhibit increased activation of Src kinase and p38 MAPK. Our results allowed the identification of the E-cadherin domains pivotal for cell motility, further demonstrated a genotype-phenotype correlation, and defined a subset of HDGC cases which may benefit from EGFR inhibitors.

E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients.

Approximately 30% of all hereditary diffuse gastric cancer (HDGC) families carry CDH1 germline mutations. The other two thirds remain genetically unexplained and are probably caused by alterations in other genes. Using polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP)/sequencing, we screened 32 Portuguese families with a history of gastric cancer and 23 patients with early onset gastric cancer for CDH1 germline mutations. In probands negative for CDH1 mutations, we screened genes involved in hereditary cancer syndromes in which gastric cancer may be one of the component tumours, namely p53 (Li-Fraumeni Syndrome) and hMLH1 and hMSH2 (HNPCC). We also screened in these patients for mutations in Caspase-10, a gene inactivated in sporadic gastric cancer, and SMAD4, a gene whose inactivation in mice is associated with signet-ring cell carcinoma of the stomach. One of the families fulfilling the HDGC criteria harboured a CDH1 germline mutation, and one of the families with incomplete criteria harboured a p53 germline mutation. No mutations were identified in hMLH1 and hMSH2, and only sequence variants were found in SMAD4 and Caspase-10. The present work reports for the first time CDH1 germline mutations in Portuguese gastric cancer families, and highlights the need for p53 mutation screening in families lacking CDH1 germline mutations, in a country with one of the highest incidences of gastric cancer in the world. No evidence was found for a role of germline mutations in SMAD4 and Caspase-10 in families lacking CDH1 mutations.

Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers.

Epithelial-mesenchymal-transition (EMT) is a crucial process during morphogenesis of multi-cellular organisms. EMT not only is a normal developmental process but also plays a role in tumor invasion and metastasis. Indeed, molecules involved in EMT, such as the transcription factor and E-cadherin repressor Slug (SNAI2), have recently been demonstrated to be important for cancer cells to down-regulate epithelial markers and up-regulate mesenchymal markers in order to become motile and invasive. Here we summarize major studies focusing on Slug expression in human tumor samples. We review a total of 13 studies involving 1150 cases from 9 different types of tumors. It is becoming clear that this transcription factor plays a role in the progression of some tumor types, including breast and gastric cancer. Interestingly, Slug expression is not always associated with down-regulation of E-cadherin. The mode of action, the signaling pathways involved in its regulation, and the interplay with other EMT regulators need to be addressed in future studies in order to fully understand Slug's role in tumor progression.