Grant Number:	4R01CA160890-05 Interpret this number
Primary Investigator:	Sloan, Erica
Organization:	University Of California Los Angeles
Project Title:	Adrenergic Regulation of Tumor Inflammation and Metastatic Dissemination
Fiscal Year:	2016

DESCRIPTION (provided by applicant): The metastatic microenvironment is receiving increasing attention as a target for new breast cancer therapies. The sympathetic nervous system (SNS) is a component of this microenvironment, and our recent studies indicated that SNS activity may support metastasis through beta-adrenergic pathways that recruit macrophages and induce a switch to pro-metastatic gene expression. Development of novel adjunctive therapeutic strategies that target neural regulation of metastasis requires characterization of the relationships between the SNS, the immune system and tumor cells. To address this need, the proposed studies utilize multimodal in vivo imaging techniques to address the following specific aims: 1. characterize SNS regulation of tumor cells in breast cancer metastasis, 2. characterize SNS regulation of tumor-associated macrophages in breast cancer metastasis, 3. characterize SNS regulation of the tumor microenvironment in breast cancer metastasis. These studies will define interactions between SNS nerve fibers, tumor cells and macrophages in the context of the tumor microenvironment and elucidate their collective effects on metastasis. Given recent clinical studies that suggest beta-blockade reduces breast cancer recurrence, the proposed studies are urgently needed to establish a mechanistic foundation for rapid translation of existing compounds (beta-blockers) and development of novel biomarkers of early cancer progression and new anti-metastatic strategies that target SNS regulation of the tumor microenvironment.




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Authors: Kim T.H. , Gill N.K. , Nyberg K.D. , Nguyen A.V. , Hohlbauch S.V. , Geisse N.A. , Nowell C.J. , Sloan E.K. , Rowat A.C. .
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ß2-Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer.
Authors: Chang A. , Le C.P. , Walker A.K. , Creed S.J. , Pon C.K. , Albold S. , Carroll D. , Halls M.L. , Lane J.R. , Riedel B. , et al. .
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Stress-driven lymphatic dissemination: An unanticipated consequence of communication between the sympathetic nervous system and lymphatic vasculature.
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The ß2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion.
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Source: Faseb Journal : Official Publication Of The Federation Of American Societies For Experimental Biology, 2016 Mar; 30(3), p. 1144-54.
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Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination.
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