151. Evidence for sympathetic nervous system modulation of mammary tumor pathogenesis via tumor collagen

Abstract

Our laboratory uses multiphoton laser scanning microscopy to study tumor collagen structure using an optical technique known as second harmonic generation (SHG). SHG is an endogenous optical signal produced when two excitation photons combine to produce one emission photon, “catalyzed” by a non-centrosymmetric structure such as ordered collagen triple helices. Manipulating collagen structure, as indicated by changes in SHG, also alters tumor growth and metastasis. We also study the role of sympathetic nervous system (SNS) activation and the neurotransmitter norepinephrine (NE) in breast cancer. To mimic SNS activation, mice were implanted with slow-release pellets containing desipramine (DMI), a NE uptake blocker. DMI elevated NE and its metabolite normetanephrine in spleen and in 4T1 tumors implanted orthotopically (in the mammary fat pad). Furthermore, DMI increased 4T1 mammary tumor growth, compared to placebo pellet controls. Tumor sections from DMI-implanted mice exhibited elevated SHG intensity. In these same images, fluorescent intensity generated by immunofluorescent staining with anti-collagen type 1 antibody was not altered by DMI treatment, indicating no alterations in total collagen (both SHG generating and non-SHG generating collagen). These results demonstrate that NE-induced tumor growth is associated with altered tumor collagen microstructure, and suggest that SNS activation may modulate tumor pathogenesis through a novel pathway, i.e., modulation of tumor extracellular matrix. The mechanisms linking SNS activation to collagen structure and tumor pathogenesis are currently under investigation.