|Grant Number:||1R01CA160890-01A1 Interpret this number|
|Primary Investigator:||Sloan, Erica|
|Organization:||University Of California Los Angeles|
|Project Title:||Adrenergic Regulation of Tumor Inflammation and Metastatic Dissemination|
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. PUBLIC HEALTH RELEVANCE: Metastasis is the major cause of morbidity and mortality in breast cancer. The studies described here evaluate the translational opportunity of targeting the sympathetic nervous system as a key regulator of pro-metastatic tumor-associated macrophages and tumor cell dissemination. These studies provide mechanistic foundation for development of novel anti-metastatic therapies that target neural regulation of the tumor microenvironment.
?2-Adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression.
Authors: Lamkin DM, Sung HY, Yang GS, David JM, Ma JC, Cole SW, Sloan EK
Source: Psychoneuroendocrinology, 2015 Jan;51, p. 262-70.
EPub date: 2014 Oct 12.
Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment.
Authors: Kim-Fuchs C, Le CP, Pimentel MA, Shackleford D, Ferrari D, Angst E, Hollande F, Sloan EK
Source: Brain Behav Immun, 2014 Aug;40, p. 40-7.
EPub date: 2014 Mar 17.
Lymphovascular and neural regulation of metastasis: shared tumour signalling pathways and novel therapeutic approaches.
Authors: Le CP, Karnezis T, Achen MG, Stacker SA, Sloan EK
Source: Best Pract Res Clin Anaesthesiol, 2013 Dec;27(4), p. 409-25.
EPub date: 2013 Oct 15.
Bioluminescent orthotopic model of pancreatic cancer progression.
Authors: Chai MG, Kim-Fuchs C, Angst E, Sloan EK
Source: J Vis Exp, 2013 Jun 28;null(76), p. null.
EPub date: 2013 Jun 28.
PEGylation of interferon ?2 improves lymphatic exposure after subcutaneous and intravenous administration and improves antitumour efficacy against lymphatic breast cancer metastases.
Authors: Kaminskas LM, Ascher DB, McLeod VM, Herold MJ, Le CP, Sloan EK, Porter CJ
Source: J Control Release, 2013 Jun 10;168(2), p. 200-8.
EPub date: 2013 Mar 15.
Chronic stress enhances progression of acute lymphoblastic leukemia via ?-adrenergic signaling.
Authors: Lamkin DM, Sloan EK, Patel AJ, Chiang BS, Pimentel MA, Ma JC, Arevalo JM, Morizono K, Cole SW
Source: Brain Behav Immun, 2012 May;26(4), p. 635-41.
EPub date: 2012 Jan 25.
The sympathetic nervous system induces a metastatic switch in primary breast cancer.
Authors: Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, Arevalo JM, Morizono K, Karanikolas BD, Wu L, Sood AK, Cole SW
Source: Cancer Res, 2010 Sep 15;70(18), p. 7042-52.
EPub date: 2010 Sep 7.