β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasionReport as inadecuate




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Breast Cancer Research

, 17:145

First Online: 25 November 2015Received: 07 July 2015Accepted: 09 November 2015DOI: 10.1186-s13058-015-0655-3

Cite this article as: Creed, S.J., Le, C.P., Hassan, M. et al. Breast Cancer Res 2015 17: 145. doi:10.1186-s13058-015-0655-3

Abstract

IntroductionFor 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.

MethodsTo 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.

Resultsβ-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.

ConclusionThese 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.

AbbreviationsβARβ-adrenoceptor

DMEMDulbecco’s modified Eagle’s medium

FBSFetal bovine serum

GFPGreen fluorescent protein

IsoIsoproterenol

MMPMatrix metalloprotease

SEMStandard error of the mean

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Author: Sarah J. Creed - Caroline P. Le - Mona Hassan - Cindy K. Pon - Sabine Albold - Keefe T. Chan - Matthew E. Berginski -

Source: https://link.springer.com/







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