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 |
Volume | 17 |
Issue | 1 |
Pagination | 145 |
Date Published | 2015 |
ISSN | 1465-542X |
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 |
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. |
DOI | 10.1186/s13058-015-0655-3 |
Alternate Journal | Breast Cancer Res. |
PubMed ID | 26607426 |
PubMed Central ID | PMC4660629 |
Grant List | CA160890 / CA / NCI NIH HHS / United States R01 CA160890 / CA / NCI NIH HHS / United States |