β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion Public Deposited

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  • [Beta]2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion
Creator
  • Bear, James
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Chan, Keefe T
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
    • Other Affiliation: Current address: Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia
Abstract
  • 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.
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DOI
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Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Creed et al.
Language
  • English
Bibliographic citation
  • Breast Cancer Research. 2015 Nov 25;17(1):145
Publisher
  • BioMed Central
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