Sympathetic Nerves in Breast Cancer: Angiogenesis and Antiangiogenic Therapy
Abstract
The sympathetic nervous system (SNS) is a major pathway activated by exposure to emotional stressors. We have demonstrated SNS hard-wiring in the form of sympathetic nerve fibers in 4T1 mammary tumors, a mouse model of metastatic breast cancer. We established that 4T1 tumor cells do not express functional - or -adrenergic receptors (AR), the receptors activated by norepinephrine (NE), the neurotransmitter of the SNS. Yet, manipulation of sympathetic neurotransmission in vivo by chemical ablation of sympathetic nerves to deplete NE decreased F480+ tumor associated macrophages and reduced tumor weight. Furthermore, chronic treatment with desipramine (DMI), an antidepressant that elevates synaptic NE, increased 4T1 tumor growth, but not metastasis. DMI-induced tumor growth was not associated with increased tumor angiogenesis, and pro-tumor cytokines VEGF, IL-6, RANTES, and MIP-2 were reduced by DMI. To further dissect the tumor response to NE, mice were treated with selective AR agonists. The 2-AR agonist dexmedetomidine (DEX) increased tumor growth and metastasis in the absence of alterations in VEGF, IL-6, RANTES, and MIP-2. Treatment with the -AR agonists isoproterenol and salmeterol did not significantly alter tumor growth/metastasis. In DMI- and DEX-treated mice, tumor collagen microstructure was uniquely altered in 4T1 tumors, suggesting a novel stromal-mediated mechanism whereby elevated NE and stimulation of AR may increase tumor growth. These results suggest that NE-induced tumor growth is mediated by 2-AR activation, but other AR pathways activated by elevated synaptic NE may modulate the tumor-promoting effect of 2-AR activation. Understanding how AR pathways regulate breast tumor pathogenesis will lead to new therapies to inhibit tumor growth and metastasis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2013
- Accession Number
- ADA577686
Entities
People
- Edward B Brown
- Kelley S. Madden
- Mercedes J. Szpunar
Organizations
- University of Rochester