β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion.

Titleβ2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion.
Publication TypeJournal Article
Year of Publication2015
AuthorsCreed SJ, Le CP, Hassan M, Pon CK, Albold S, Chan KT, Berginski ME, Huang Z, Bear JE, J Lane R, Halls ML, Ferrari D, Nowell CJ, Sloan EK
JournalBreast Cancer Res
Volume17
Issue1
Pagination145
Date Published2015
ISSN1465-542X
KeywordsAdrenergic beta-2 Receptor Agonists, Breast Neoplasms, Cell Line, Tumor, Cell Surface Extensions, Female, Focal Adhesions, Humans, Neoplasm Invasiveness, Neoplasm Transplantation, Receptors, Adrenergic, beta-2, Signal Transduction
Abstract

INTRODUCTION: For efficient metastatic dissemination, tumor cells form invadopodia to degrade and move through three-dimensional extracellular matrix. However, little is known about the conditions that favor invadopodia formation. Here, we investigated the effect of β-adrenoceptor signaling - which allows cells to respond to stress neurotransmitters - on the formation of invadopodia and examined the effect on tumor cell invasion.

METHODS: To characterize the molecular and cellular mechanisms of β-adrenergic signaling on the invasive properties of breast cancer cells, we used functional cellular assays to quantify invadopodia formation and to evaluate cell invasion in two-dimensional and three-dimensional environments. The functional significance of β-adrenergic regulation of invadopodia was investigated in an orthotopic mouse model of spontaneous breast cancer metastasis.

RESULTS: β-adrenoceptor activation increased the frequency of invadopodia-positive tumor cells and the number of invadopodia per cell. The effects were selectively mediated by the β2-adrenoceptor subtype, which signaled through the canonical Src pathway to regulate invadopodia formation. Increased invadopodia occurred at the expense of focal adhesion formation, resulting in a switch to increased tumor cell invasion through three-dimensional extracellular matrix. β2-adrenoceptor signaling increased invasion of tumor cells from explanted primary tumors through surrounding extracellular matrix, suggesting a possible mechanism for the observed increased spontaneous tumor cell dissemination in vivo. Selective antagonism of β2-adrenoceptors blocked invadopodia formation, suggesting a pharmacological strategy to prevent tumor cell dissemination.

CONCLUSION: These findings provide insight into conditions that control tumor cell invasion by identifying signaling through β2-adrenoceptors as a regulator of invadopodia formation. These findings suggest novel pharmacological strategies for intervention, by using β-blockers to target β2-adrenoceptors to limit tumor cell dissemination and metastasis.

DOI10.1186/s13058-015-0655-3
Alternate JournalBreast Cancer Res.
PubMed ID26607426
PubMed Central IDPMC4660629
Grant ListCA160890 / CA / NCI NIH HHS / United States
R01 CA160890 / CA / NCI NIH HHS / United States