c-erbB-2/neu Overexpression Enhances Metastatic Potential of Human Lung Cancer Cells by Induction of Metastasis-associated Properties

Abstract

Previously, we and others have reported high levels of expression of the c-erbB-2/neu gene in non-small cell lung cancer cell lines and primary tumors. We have also found that expression of c-erbB-2/neu-encoded p185^neu was correlated with lymph node metastasis in lung squamous cell carcinomas. To investigate the potential role of the c-erbB-2/neu gene in lung cancer metastasis systematically, we introduced the human c-erbB-2/neu gene into very low p185^neu-expressing NCI-H460 human non-small cell lung cancer cells and then examined the experimental metastatic potentials among the parental NCI-H460 cells and stable transfectants with increased expression of p185^neu. Compared with the parental NCI-H460 cells, the NCI-H460 transfectants overexpressing p185^neu produced significantly more pulmonary and extrapulmonary metastatic tumors in nude mice. The changes in experimental metastatic potential in vivo were accompanied by increased invasiveness in vitro. In addition, important steps in the invasion and metastasis process, such as secretion of basement membrane-degradative enzymes and migration through reconstituted basement membrane (Matrigel), were also increased in the NCI-H460 transfectants overexpressing p185^neu. Moreover, scanning electron microscopy revealed that the p185^neu-overexpressing NCI-H460 transfectants had significantly more microvilli and membrane protrusions than the parental cells, correlating with the increased invasive properties of these cells. The results demonstrate that overexpression of p185^neu can enhance the experimental metastatic potential of NCI-H460 human lung cancer cells by promoting invasion and the other steps in the metastatic cascade.