Increased extracellular matrix density disrupts E-cadherin/β-catenin complex in gastric cancer cells

Abstract

During gastric cancer (GC) progression, increased extracellular matrix (ECM) deposition, notably collagen type I, correlates with an overall increase in expression of the mesenchymal phenotype. In GC tissue, the intestinal epithelium exhibits impaired cell-cell adhesion and enhanced cell-ECM adhesion. The alteration of intercellular integrity is one of tumorigenesis feature including tumor invasion and metastasis. Using a density-varying ECM, we studied the effect of ECM density on both intercellular- and ECM-interactions according to alterations of ECM-mediated signaling. A dense collagen matrix increases integrin-mediated cell-ECM interactions with phosphorylated FAK and ERK signaling in human gastric adenocarcinoma cells (AGS, MKN74), which regulates GC proliferation and the chemotherapeutic response. In addition, GC cells exhibited a disrupted membranous E-cadherin/β-catenin complex and, remarkably, showed cytoplasmic or nucleic localization of β-catenin in response to collagen density. Furthermore, we found that membranous E-cadherin/β-catenin complex could be recovered by inhibiting the phosphorylation of FAK, which in turn influences the chemotherapeutic effect. These results provide insight into how matrix density differentially regulates cancer cell phenotype and may have significant implications for the design of biomaterials with appropriate physical properties for in vitro tumor models.

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

“…The expression of COL12A1 was also found upregulated in gastric cancer and positively correlated with tumor invasiveness, metastasis, and advanced clinical stage [8]. In tumor tissues of gastric cancer patients, levels of collagen type-I and -IV, fibronectin, and laminin were markedly higher than those detected in the normal tissues [60].…”

“…[59] Collagen I Higher levels in tumor tissues. [60] Collagen IV Higher levels in tumor tissues. [60] Fibronectin Higher levels in tumor tissues.…”

“…[60] Fibronectin Higher levels in tumor tissues. [60] Laminin Higher levels in tumor tissues. [60] Laminin γ2 Mediates Wnt5a-induced invasion of gastric cancer cells;…”

“…Several cancer types exhibit abnormal accumulation/deposition of particular ECM components and increased ECM stiffness, which impair drug diffusion and, consequently, decreases treatment efficacy [4,170]. Moreover, an increased ECM density perturbs cell-cell adhesion, enhances cell-ECM interaction and increases the proliferation of gastric cancer cells [60]. Therefore, modulation of ECM-related enzymes such as collagenase, MMPs or lysyl oxidases can be a promising therapeutic strategy for gastric cancer.…”

The role of collagen in cancer: from bench to bedside

“…Various experiments and clinical data have revealed collagen to be a prognostic factor correlated with cancer differentiation, cancer invasion, lymph node metastasis, and clinical stage in cancer patients ( Table 2). Lower COLI and COLIV content is a biomarker of differentiated tumors and proliferation potency of cancer cells [160,161]. The increased expression of COLIV and COLVI and the collagen structure reflect tumor angiogenesis and glioblastoma progression [162].…”