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HGF converts ErbB2/Neu epithelial morphogenesis to cell invasion
Hanane Khoury1, Monica A Naujokas, Dongmei Zuo
1Molecular Oncology Group, McGill University Health Center, McGill University, Montreal, Quebec, H3A 1A1, Canada.
Molecular Biology of the Cell
|November 19, 2004
Summary
Hepatocyte growth factor (HGF) signaling disrupts ErbB2/Neu-driven epithelial cell invasion by impacting cell junctions. This interaction highlights a pathway crucial for cancers with ErbB2/Neu overexpression and stromal HGF.
Area of Science:
- Cell Biology
- Molecular Oncology
- Epithelial Morphogenesis
Background:
- The hepatocyte growth factor (HGF) receptor, Met, and the ErbB2/Neu receptor are implicated in epithelial cell morphogenesis and cancer progression.
- Both Met and ErbB2/Neu are expressed in breast epithelia, and their signaling pathways are associated with poor prognosis.
- HGF is often found in the tumor stroma, suggesting potential interactions with epithelial receptors like ErbB2/Neu.
Purpose of the Study:
- To investigate the consequences of cooperation between HGF/Met signaling and ErbB2/Neu signaling in epithelial cells.
- To determine how HGF influences ErbB2/Neu-induced epithelial morphogenesis and invasion.
- To elucidate the molecular mechanisms underlying the interaction between these two signaling pathways.
Main Methods:
- Utilizing Madin-Darby canine kidney (MDCK) epithelial cells in three-dimensional cultures.
- Employing a constitutively activated ErbB2/Neu receptor (NeuNT) to induce an invasive morphogenic program.
- Treating cells with HGF and a pharmacological inhibitor of the mitogen-activated protein kinase kinase (MEK) pathway.
- Assessing changes in cell-cell junction proteins (claudin-1, E-cadherin, ZO-1) and cell invasion.
Main Results:
- HGF disrupts NeuNT-induced epithelial morphogenesis, leading to cell-cell junction breakdown, dispersal, and single-cell invasion.
- A decrease in claudin-1 and E-cadherin, along with ZO-1 internalization, was observed.
- HGF-induced invasion was abrogated by MEK pathway inhibition, which restored E-cadherin and ZO-1 at cell-cell junctions.
- MEK-dependent pathways are involved in HGF-mediated disruption of cell junctions and invasion.
Conclusions:
- Physiological signals downstream from the HGF/Met receptor synergize with ErbB2/Neu to enhance the malignant phenotype.
- This synergy promotes the breakdown of cell-cell junctions and increases cell invasion.
- These findings are particularly relevant for cancers overexpressing ErbB2/Neu in the presence of stromal HGF.