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Simple Summary: Tensional homeostasis describes the ability of cells and tissues to maintain their internal mechanical tension stable at a set point value. A breakdown of tensional homeostasis is the hallmark of disease progression, including cancers. In cancers of epithelial origin, this phenomenon is closely associated with dysfunction of E-cadherin. In this study, we investigated how E-cadherin mutations identified in patients with cancer affect tensional homeostasis. Our results show that mutations affecting the juxtamembrane and intracellular domains of E-cadherin are detrimental for tensional homeostasis of gastric cancer cells. In epithelia, breakdown of tensional homeostasis is closely associated with E-cadherin dysfunction and disruption of tissue function and integrity. In this study, we investigated the effect of E-cadherin mutations affecting distinct protein domains on tensional homeostasis of gastric cancer cells. We used micropattern traction microscopy to measure temporal fluctuations of cellular traction forces in AGS cells transfected with the wild-type E-cadherin or with variants affecting the extracellular, the juxtamembrane, and the intracellular domains of the protein. We focused on the dynamic aspect of tensional homeostasis, namely the ability of cells to maintain a consistent level of tension, with low temporal variability around a set point. Cells were cultured on hydrogels micropatterned with different extracellular matrix (ECM) proteins to test whether the ECM adhesion impacts cell behavior. A combination of Fibronectin and Vitronectin was used as a substrate that promotes the adhesive ability of E-cadherin dysfunctional cells, whereas Collagen VI was used to test an unfavorable ECM condition. Our results showed that mutations affecting distinct E-cadherin domains influenced differently cell tensional homeostasis, and pinpointed the juxtamembrane and intracellular regions of E-cadherin as the key players in this process. Furthermore, Fibronectin and Vitronectin might modulate cancer cell behavior towards tensional homeostasis. [ABSTRACT FROM AUTHOR]

Abstract: E-Cadherin-mediated cell–cell adhesion plays a key role in epithelial cell survival and loss of E-cadherin or β-catenin expression is associated with invasive tumor growth. Somatic E-cadherin mutations have been identified in sporadic diffuse-type gastric carcinoma. Here, we analysed the fate of E-cadherin with an in frame deletion of exon 8 compared to wild-type E-cadherin and the involved signalling events during cisplatin-induced apoptosis. We report that mutant E-cadherin was more readily cleaved during apoptosis than the wild-type form. Also β-catenin, an important binding partner of E-cadherin, was processed. E-cadherin cleavage resulted in disconnection of the actin cytoskeleton and accumulation of E-cadherin and β-catenin in the cytoplasm. Inhibitor studies demonstrated that E-cadherin cleavage was caused by a caspase-3-mediated mechanism. We identified the Akt/PKB and the ERK1/2 signalling pathways as important regulators since inhibition resulted in increased E-cadherin cleavage and apoptosis. In summary, we clearly demonstrate that somatic E-cadherin mutations affect apoptosis regulation in that way that they can facilitate the disruption of adherens junctions thereby possibly influencing the response to cisplatin-based chemotherapy. Elucidating the mechanisms that regulate the apoptotic program of tumor cells can contribute to a better understanding of tumor development and potentially be relevant for therapeutic drug design. [Copyright &y& Elsevier]

Objectives: The cell adhesion molecule E-cadherin acts as a tumor and invasion suppressor and regulates cell proliferation. The aim of the present study was to investigate the impact of wild-type (wt) E-cadherin and tumor-derived mutant E-cadherin variants on the proliferation rate of MDA-MB-435S mammary carcinoma cells and the sensitivity of the cells to the chemotherapeutic drugs cisplatin, etoposide and 5-fluorouracil (5-FU) and whether p53 is involved in the chemotherapeutic response. Methods: Proliferation rate was measured by XTT cell viability assay in the presence or absence of chemotherapeutics. Chemosensitivity was also measured by colony formation assay. Expression of p53 was investigated by immunoblot analysis. The mutational hot spot region exon 5–8 of p53 was analyzed for mutations by denaturing high-performance liquid chromatography. Results: The growth rate of MDA-MB-435S cells transfected with wt E-cadherin was reduced as compared with the parental cell line. In contrast, tumor-associated mutations of exons 8 or 9 of the E-cadherin gene interfere with the growth-suppressive function of E-cadherin. Cisplatin sensitivity of wt and mutant E-cadherin-expressing MDA-MB-435S cells was reduced as compared with E-cadherin-negative, parental MDA-MB-435S cells. In contrast, chemosensitivity of parental, wt or mutant E-cadherin-expressing MDA-MB-435S cells measured after etoposide or 5-FU exposure was found to be similar in all tested cell lines. Since p53 influences the sensitivity of cells to chemotherapeutic agents, we investigated whether the p53 expression level or mutation status were different in the nontransfected or E-cadherin-transfected MDA-MB-435S cell lines. We found that the p53 expression pattern and genomic background were similar in all cell lines and not affected by cisplatin. Conclusion: The results obtained in this study suggest that the expression and/or mutation of the E-cadherin gene influence the proliferation rate and drug sensitivity of tumor cells. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Individuals with germline E-cadherin (CDH1) mutations are at high risk of developing diffuse gastric cancer (GC) and prophylactic total gastrectomy (PTG) represents the only life-saving treatment. We reviewed all PTGs reported in literature associated with CDH1 germline mutations. A total of 224 PTGs were reported. The majority were described in the United States of America (50%), the Netherlands (17.8%), and Canada (12.5%). GC was identified in 85.4% of cases after PTG, with a high rate of "no cancer" at histopathology identified in the United States of America (19.6%). Considering the mutation type, a total of 61 different germline mutations was reported, primarily non-missense versus missense alterations (86.9% v 13.1%). Twenty-one PTGs were performed in individuals with no family history of GC, and tumor was detected in 33.3% of investigated cases; regarding individuals with a family history of GC, tumor was identified in 85% of cases. PTG remains the best treatment for individuals harboring germline CDH1 mutations and fulfilling specific clinical criteria; in other CDH1-associated conditions, PTG should be suggested, but not strongly recommended. Additional studies are required to assess the cancer risk in those conditions., (Copyright © 2022 Elsevier Inc. All rights reserved.)