Epidermal Growth Factor Receptor Overexpression Results in Increased Tumor Cell Motility In vivo Coordinately with Enhanced Intravasation and Metastasis

Abstract

Although overexpression of the epidermal growth factor receptor (EGFR; ErbB1) has been correlated with poor prognosis in breast and other cancers, clinical trials of ErbB1 inhibitors have shown limited efficacy in inhibiting tumor proliferation. To evaluate other possible roles of ErbB1 in tumor malignancy besides proliferation, we have developed a series of tools for analysis of intravasation. Overexpression of ErbB1 in MTLn3 mammary adenocarcinoma cells results in increased intravasation and lung metastasis from tumors formed by injection of cells in the mammary fat pad. However, increased ErbB1 expression has no effect on primary tumor growth and lung seeding efficiency of cells injected i.v. Chemotactic responses to low concentrations of EGF in vitro and cell motility in vivo in the primary tumor measured using intravital imaging are significantly increased by ErbB1 overexpression. The increased cell motility is restricted to ErbB1-overexpressing cells in tumors containing mixtures of cells expressing different ErbB1 levels, arguing for a cell-autonomous effect of increased ErbB1 expression rather than alteration of the tumor microenvironment. In summary, we propose that ErbB1 overexpression makes more significant contributions to intravasation than growth in some tumors and present a novel model for studying ErbB1 contributions to tumor metastasis via chemotaxis and intravasation. (Cancer Res 2006; 66(1): 192-7)

Monomeric red fluorescent proteins with a large Stokes shift

“…Preclonal mixtures of human mammary adenocarcinoma MDA-MB-231, rat mammary adenocarcinoma MTLn3 and MTLn3 cells overexpressing ErbB1 (20) stably expressing LSSmKates either in cytosol or targeted to the nucleus had high brightness and normal in vitro proliferation rates indicating low cytotoxicity. The stable cell lines exhibited good photostability during time-lapse imaging ( Fig.…”

“…We next examined the use of LSS-mKates under 2PE using a xenograft mouse model by orthotopically transplanting the metastatic mammary adenocarcinoma MTLn3 or MTLn3 cells overexpressing ErbB1 (20). We stably coexpressed LSS-mKates targeted to the nucleus.…”

β1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells

“…Similar results were also obtained while treating wild-type A549 cells with the anti-b1 inhibitory antibody AIIB2 (29). As EGF is a known inducer of tumor cell invasion (Xue et al, 2006), to evaluate the In all, 5 Â 10 4 A549 b1 ctrl and b1 sh cells were seeded on the upper side of the filters and incubated in 0.1% bovine serum albumin RPMI and let migrate for 6 h. To test the ability of cells to migrate in basal conditions, no additional stimuli were added in the lower chamber. Cells migrating to the lower side were fixed, stained with Diff-Quick kit and counted under a phase-contrast microscope.…”

Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation

“…Epidermal growth factor receptor (EGFR or ErbB1) and human epidermal growth factor receptor-2 (HER2 or ErbB2) are members of the receptor tyrosine kinase family and play a key role in normal development. They are always overexpressed in malignant tumors and are thought to contribute to tumor progression (34,35). Yates and colleagues (36,37) found that in vitro inhibition of autocrine EGFR signaling increased E-cadherin expression and cell-cell heterotypic adhesion and that E-cadherin upregulation was prevented by expressing a downregulation-resistant EGFR variant.…”