Integrin signal masks growth-promotion activity of HB-EGF in monolayer cell cultures

Abstract

The extracellular environment and tissue architecture contribute to proper cell function and growth control. Cells growing in monolayers on standard polystyrene tissue culture plates differ in their shape, growth rate and response to external stimuli, compared with cells growing in vivo. Here, we showed that the EGFR (epidermal growth factor receptor) ligand heparin-binding EGF-like growth factor (HB-EGF) strongly stimulated cell growth in nude mice, but not in cells cultured in vitro. We explored the effects of HB-EGF on cell growth under various cell culture conditions and found that growth promotion by HB-EGF was needed in three-dimensional (3D) or two-dimensional (2D) culture systems in which cell-matrix adhesion was reduced. Under such conditions, cell growth was extremely suppressed in the absence of HB-EGF, but markedly potentiated in the presence of HB-EGF. When the integrin signal was reduced using antibodies or knockout of either integrin β1 or focal adhesion kinase (FAK), cells showed HB-EGF-dependent growth. We also showed that EGF, transforming growth factor-α (TGFα) or ligands of other receptor tyrosine kinases (RTKs) stimulated cell growth in 3D culture, but not in tissue culture plates. These results indicate that the integrin signal was sufficient to support cell growth in 2D tissue culture plates without addition of the growth factor, whereas stimulation by growth factors was clearly demonstrated in culture systems in which integrin signals were attenuated.

MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis

“…It also hinders the proliferation of both normal and cancer cells (Henriet et al, 2000;Hotary et al, 2000;Mizushima et al, 2009), thereby acting as an endogenous antigrowth signal. However, tumor progression is governed not only by the rate of cell proliferation but also by the rate of cell attrition (Hanahan and Weinberg, 2000).…”

Evaluation of Three-Dimensional Porous Iron-Cross-Linked Alginate as a Scaffold for Cell Culture

“…Under such conditions, which allow cells to adhere to the material surface, small spheroids can grow into large ones [19]. It has been reported that integrin-mediated adhesion prompts cell growth [20] and that spheroid-forming ability is disturbed by inhibition of 1 integrin function [21]. These findings suggest that integrinmediated interactions between cells and the scaffold play a critical role in the growth of multicellular spheroids.…”

Molecular Hierarchy of Heparin-Binding EGF-like Growth Factor–Regulated Angiogenesis in Triple-Negative Breast Cancer

“…NF-kB, a member of the Rel-related proteins that includes p50, p52, v-Rel, c-Rel, RelA (p65), and RelB, is a transcription factor involved in a diversity of cellular processes, including the induction of hypoxia mediated by HB-EGF (19,20). Previous studies have shown that HB-EGF is required for anchorage-independent cell growth and subsequent angiogenesis, thus contributing to cubic structure of tumors (21,22). In addition, HB-EGF mediates reciprocal interactions between cancer cells and neighboring fibroblasts, which in association with the proangiogenic factor, PDGF, supports cancer progression (23).…”