E-cadherin-defective gastric cancer cells depend on Laminin to survive and invade

Abstract

Epithelial-cadherin (Ecad) deregulation affects cell-cell adhesion and results in increased invasiveness of distinct human carcinomas. In gastric cancer, loss of Ecad expression is a common event and is associated with disease aggressiveness and poor prognosis. However, the molecular mechanisms underlying the invasive process associated to Ecad dysfunction are far from understood. We hypothesized that deregulation of cell-matrix interactions could play an important role during this process. Thus, we focussed on LM-332, which is a major matrix component, and in Ecad/LM-332 crosstalk in the process of Ecad-dependent invasion. To verify whether matrix deregulation was triggered by Ecad loss, we used the Drosophila model. To dissect the key molecules involved and unveil their functional significance, we used gastric cancer cell lines. The relevance of this relationship was then confirmed in human primary tumours. In vivo, Ecad knockdown induced apoptosis; nonetheless, at the invasive front, cells ectopically expressed Laminin A and βPS integrin. In vitro, we demonstrated that, in two different gastric cancer cell models, Ecad-defective cells overexpressed Laminin γ2 (LM-γ2), β1 and β4 integrin, when compared with Ecad-competent ones. We showed that LM-γ2 silencing impaired invasion and enhanced cell death, most likely via pSrc and pAkt reduction, and JNK activation. In human gastric carcinomas, we found a concomitant decrease in Ecad and increase in LM-γ2. This is the first evidence that ectopic Laminin expression depends on Ecad loss and allows Ecad-dysfunctional cells to survive and invade. This opens new avenues for using LM-γ2 signalling regulators as molecular targets to impair gastric cancer progression.

The Extracellular Matrix: An Accomplice in Gastric Cancer Development and Progression

“…Moreover, our group has demonstrated that gastric cancer cells with E-cadherin dysfunction depend on laminin γ2 to survive and invade. We postulate that laminin γ2 upregulation may constitute an adaptive stimulus to allow cells to escape anoikis and invade adjacent tissues, contributing to cancer progression [62].…”

Independent apical and basal mechanical systems determine cell and tissue shape in the Drosophila wing disc

“…It has been previously reported that cells such as in gastric cancer that lose cadherins survive by upregulating the laminin/BM (Caldeira et al, 2015). When Integrins or BM are lost causing a change in cell shape, cells can still survive, remain part of the epithelium and maintain adhesion with apical mechanics.…”

Genetic and histological subtypes of gastric cancer reviewed, particularly emphasising on microsatellite instability and E-cadherin gene mutation

“…Clinical manifestations, (a family history, the presence of potential risk factors of GC, patient age, a macroscopic tumour image), and the histological type of cancer may help to determine those patients who might need future treatment because of their genetic predisposition to GC. Finally, as aforementioned in detail, the two principal subtypes of GC with MSI-H and CDH1 mutation evolve through different pathways, and those differences in molecular pathogenesis translate into a morphological distinction, which merits our attention [48,49].…”