β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion.
|Title||β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Creed 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|
|Journal||Breast Cancer Res|
|Keywords||Adrenergic 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|
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.
|Alternate Journal||Breast Cancer Res.|
|PubMed Central ID||PMC4660629|
|Grant List||CA160890 / CA / NCI NIH HHS / United States |
R01 CA160890 / CA / NCI NIH HHS / United States