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

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

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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.
Original languageEnglish
Article number145
Number of pages12
JournalBreast Cancer Research
Volume17
Issue number1
DOIs
Publication statusPublished - 2015

Cite this

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. / β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion. In: Breast Cancer Research. 2015 ; Vol. 17, No. 1.
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title = "β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion",
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.",
author = "Creed, {Sarah J} and Le, {Caroline P} and Mona Hassan and Pon, {Cindy K} and Sabine Albold and Chan, {Keefe T} and Berginski, {Matthew E} and Zhendong Huang and Bear, {James E} and Lane, {J Robert} and Halls, {Michelle L} and Davide Ferrari and Nowell, {Cameron J} and Sloan, {Erica K}",
year = "2015",
doi = "10.1186/s13058-015-0655-3",
language = "English",
volume = "17",
journal = "Breast Cancer Research",
issn = "1465-5411",
publisher = "Springer-Verlag London Ltd.",
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Creed, SJ, Le, CP, Hassan, M, Pon, CK, Albold, S, Chan, KT, Berginski, ME, Huang, Z, Bear, JE, Lane, JR, Halls, ML, Ferrari, D, Nowell, CJ & Sloan, EK 2015, 'β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion', Breast Cancer Research, vol. 17, no. 1, 145. https://doi.org/10.1186/s13058-015-0655-3

β2-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.

In: Breast Cancer Research, Vol. 17, No. 1, 145, 2015.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion

AU - Creed, Sarah J

AU - Le, Caroline P

AU - Hassan, Mona

AU - Pon, Cindy K

AU - Albold, Sabine

AU - Chan, Keefe T

AU - Berginski, Matthew E

AU - Huang, Zhendong

AU - Bear, James E

AU - Lane, J Robert

AU - Halls, Michelle L

AU - Ferrari, Davide

AU - Nowell, Cameron J

AU - Sloan, Erica K

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

UR - http://breast-cancer-research.biomedcentral.com/track/pdf/10.1186/s13058-015-0655-3?site=breast-cancer-research.biomedcentral.com

U2 - 10.1186/s13058-015-0655-3

DO - 10.1186/s13058-015-0655-3

M3 - Article

VL - 17

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 1

M1 - 145

ER -