?2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion

Creed, Sarah J; Le, Caroline P; Hassan, Mona; Pon, Cindy K; Albold, Sabine; Chan, Keefe T; Berginski, Matthew E; Huang, Zhendong; Bear, James E; Lane, J Robert; Halls, Michelle L; Ferrari, Davide; Nowell, Cameron J; Sloan, Erica K

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 ?-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 ?-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 ?-adrenergic regulation of invadopodia was investigated in an orthotopic mouse model of spontaneous breast cancer metastasis. RESULTS:?-adrenoceptor activation increased the frequency of invadopodia-positive tumor cells and the number of invadopodia per cell. The effects were selectively mediated by the ?2-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. ?2-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 ?2-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 ?2-adrenoceptors as a regulator of invadopodia formation. These findings suggest novel pharmacological strategies for intervention, by using ?-blockers to target ?2-adrenoceptors to limit tumor cell dissemination and metastasis.

Citation

Creed, S. J., Le, C. P., Hassan, M., Pon, C. K., Albold, S., Chan, K. T., …Sloan, E. K. (2015). β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion. Breast Cancer Research, 17(1), Article 145. https://doi.org/10.1186/s13058-015-0655-3

• Journal Article Type: Article
• Acceptance Date: Nov 9, 2015
• Online Publication Date: Nov 25, 2015
• Publication Date: Nov 25, 2015
• Deposit Date: Apr 22, 2020
• Publicly Available Date: May 4, 2020
• Journal: Breast Cancer Research
• Print ISSN: 1465-5411
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 17
• Issue: 1
• Article Number: 145
• DOI: https://doi.org/10.1186/s13058-015-0655-3
• Public URL: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=26607426&retmode=ref&cmd=prlinks
• Publisher URL: https://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-015-0655-3