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?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

Authors

Sarah J Creed

Caroline P Le

Mona Hassan

Cindy K Pon

Sabine Albold

Keefe T Chan

Matthew E Berginski

Zhendong Huang

James E Bear

ROB LANE Rob.Lane@nottingham.ac.uk
Associate Professor

Michelle L Halls

Davide Ferrari

Cameron J Nowell

Erica K Sloan



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

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