Kelley Madden

University of Rochester | UR · Department of Biomedical Engineering (School of Engineering)

Preclinical models of breast cancer have established mechanistic links between psychological stress and cancer progression. However, epidemiological evidence linking stress and cancer is equivocal. We tested the impact of stress exposure in female mice expressing the mouse mammary tumor virus polyoma middle-T antigen (MMTV-PyMT), a spontaneous mode...

Pre-clinical evidence has linked stress exposure to tumor progression via sympathetic nervous system (SNS) activation and beta-adrenergic receptor (beta-AR) signaling. However, retrospective epidemiological studies suggest the association between stress and breast cancer is more ambiguous. To interrogate the impact of stress on the most common type...

The non-invasive, in vivo measurement of microvascular blood flow has the potential to enhance breast cancer therapy monitoring. Here, longitudinal blood flow of 4T1 murine breast cancer (N=125) under chemotherapy was quantified with diffuse correlation spectroscopy based on layer models. Six different treatment regimens involving doxorubicin, cycl...

This review will highlight recently discovered mechanisms underlying sympathetic nervous system (SNS) regulation of the immune system in hematopoiesis, thermogenesis, and inflammation. This work in mammals illuminates potential mechanisms by which the nervous and immune systems may interact in invertebrate and early vertebrate species and allow div...

Activation of the sympathetic nervous system (SNS) drives breast cancer progression in preclinical breast cancer models, but it has yet to be established if neoplastic and stromal cells residing in the tumor are directly targeted by locally released norepinephrine (NE). In murine orthotopic and spontaneous mammary tumors, tyrosine hydroxylase (TH)+...

Late-stage breast cancer remains an intractable problem, with ∼40,000 deaths annually in the United States. Pre-clinical evidence suggests psychosocial stress accelerates cancer progression. Notably, these studies feature injectable tumor models, often in immunocompromised animals exposed to prolonged stress. We have employed a model of spontaneous...

Solid tumors are composed of neoplastic cells and non-cancerous stromal cells consisting of immune cells, fibroblasts, and endothelial cells. To determine how ß2-adrenergic receptor (ß2-AR) activation of stromal cells influences cancer progression in the absence of tumor cell ß2-AR activation, we utilized the mammary adenocarcinoma 4T1, a murine mo...

A significant difference between a treated and a control group of mice with breast cancer were observed in hemodynamic parameters quantified with diffuse optics at day 3 after cyclophosphamide treatment.

Emotional stress activates the sympathetic nervous system (SNS) and release of the neurotransmitter norepinephrine to promote breast tumor pathogenesis. We demonstrate here that the metastatic mammary adenocarcinoma cell line 4T1 does not express functional adrenergic receptors (AR), the receptors activated by norepinephrine, yet stimulation of adr...

The impact of psychosocial stress on breast cancer pathogenesis has become an area of intense research in the past several years. Sympathetic nervous system (SNS) activation and release of the catecholamine norepinephrine (NE) is a major stress pathway that promotes breast cancer pathogenesis. We have evidence that SNS activation can regulate breas...

Collagen fibers can be imaged with second harmonic generation (SHG) and are associated with efficient tumor cell locomotion. Preferential locomotion along these fibers correlates with a more aggressively metastatic phenotype, and changes in SHG emission properties accompany changes in metastatic outcome. We therefore attempted to elucidate the cell...

Glioblastoma is a highly invasive and aggressive brain tumor that is very difficult to treat. The rat glioma cell line CNS-1 is a widely used, well-characterized model of infiltrative glioma. We have used CNS-1 to study tumors that initiate within the brain parenchyma. The CNS-1 cells were stably transfected with the yellow fluorescent protein (YFP...

Brain metastases from primary or secondary breast tumors are difficult to model in the mouse. When metastatic breast cancer cell lines are injected directly into the arterial circulation, only a small fraction of cells enter the brain to form metastatic foci. To study the molecular and cellular mechanisms of brain metastasis, we have transfected MB...

Unlabelled: Aging in female rats is associated with cessation of reproductive cycles, development of mammary cancer, and increased incidence of autoimmune diseases. Previously, we demonstrated an age-related decline in sympathetic noradrenergic (NA) innervation in the spleen and lymph nodes of female F344 rats accompanied by significantly reduced...

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 tri...

Tumor growth requires angiogenesis, the development of new blood vessels from existing blood vessels. Cancer cells release proangiogenic growth factors such as vascular endothelial growth factor (VEGF) to drive angiogenesis. Current cancer therapy that incorporate targeting agents that inhibit the production of new blood vessels have been only marg...

Evidence from cancer patients and animal models of cancer indicates that exposure to psychosocial stress can promote tumor growth and metastasis, but the pathways underlying stress-induced cancer pathogenesis are not fully understood. Social isolation has been shown to promote tumor progression. We examined the impact of social isolation on breast...

Activation of β-adrenergic receptors (β-AR) drives proangiogenic factor production in several types of cancers. To examine β-AR regulation of breast cancer pathogenesis, β-AR density, signaling capacity, and functional responses to β-AR stimulation were studied in four human breast adenocarcinoma cell lines. β-AR density ranged from very low in MCF...

Normal aging processes, as well as, psychological stress affect the immune system; each can act alone, or interact with each other, to cause dysregulation of immune function substantially altering physical and mental health. The sympathetic nervous system (SNS), a major mediator of stress effects on immune function, is significantly affected by nor...

In aged Fischer 344 (F334) rats, sympathetic innervation of the spleen is markedly diminished compared with young rats. To determine if this diminished noradrenergic (NA) innervation maintains a functional connection with the immune system, 3- and 17-month-old male F344 rats were treated with the NA-selective neurotoxin, 6-hydroxydopamine (6-OHDA),...

Responses of the central nervous system to stressors have modulatory effects on the immune system. Conversely, immune activation in response to antigens and pathogens alter neural activity. Progressive decline in brain and immune functions in the elderly leads to impaired cognition, re-establishment of homeostasis at age-adjusted set points, and im...

We explored the effects of aging on macrophage function in male BALB/c mice from three age groups: young (2 months), middle-aged (12 months), and old (21 months). Macrophages were collected from alveoli, peritonea, and spleens of each age group. Cells were cultured in vitro with LPS or LPS+IFN-gamma and assayed for production of IL-1, IL-12, NO, an...

An immune response can be regulated by a variety of hormones and transmitters, although it is not yet clear under what sets of circumstances such immunoregulation occurs, and in which direction immune function might be altered. That the sympathetic nervous system (SNS) plays a role in immune regulation is inferred from four lines of evidence:

When the first edition of this book published in 1994, the psychoimmunology of cancer was still emerging as a topic for serious scientific study. Now, less than ten years later, there is a huge quantity of academic literature about the relationships between psychological variables, the immune system and cancer growth, accompanied by a lively popula...

The thymus is the primary site for generation of naive T-lymphocytes in the young animal. With age, the thymus progressively involutes and fewer mature T-cells are produced and migrate to the periphery. With thymic involution, increased density of sympathetic noradrenergic (NA) innervation and concentration of norepinephrine (NE) have been observed...

In Wistar rats, reexposure to a novel conditioned stimulus (CS) previously paired with a protein antigen, hen egg lysozyme (HEL) on a single conditioning trial increased anti-HEL IgG levels relative to conditioned rats that were not reexposed to the CS, conditioned rats that were preexposed to the CS, and nonconditioned rats. These results confirm...

L-Deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, has previously been shown to improve immune responses and restore noradrenergic (NA) nerve fibers in the spleen of old rats. In tumor-bearing rats, L-deprenyl inhibited tumor incidence and enhanced tuberoinfundibular dopaminergic (TIDA) neurotransmission in the hypothalamus. The aim of the presen...

L-deprenyl, a monoamine oxidase-B inhibitor, partially reversed the age-associated decline in splenic sympathetic noradrenergic (NA) innervation and immune reactivity in old male rats. The purpose of the present study was to examine whether the effects of deprenyl on splenic sympathetic NA nerve fibers and immune functions are mediated through a me...

In aged Fischer 344 (F344) rats, sympathetic noradrenergic (NA) innervation of the spleen is markedly diminished compared with young rats. To determine if diminished NA innervation can still provide functional signals to splenic T cells, young (3 months old) and old (17 months old) F344 rats were treated with the NA-selective neurotoxin, 6-hydroxyd...

L-deprenyl, a monoamine oxidase-B inhibitor, has been shown to reverse the age-related decline in sympathetic noradrenergic innervation and immune function in old rats and enhance T cell and NK cell activity in tumor-bearing rats. The objective of the present study was to examine whether deprenyl treatment of old female rats with mammary tumors cou...

Sympathetic noradrenergic (NA) neuronal activities in the thymus, spleen and mesenteric lymph nodes (MLN) and immune responses in the spleen were examined in young male F344 rats treated daily with 0, 0.25 mg, or 2.5 mg/kg body weight of L-deprenyl, an irreversible monoamine oxidase-B (MAO-B) inhibitor. Rats were treated daily for 1, 15, or 30 days...

Previously, we have hypothesized a causal relationship between some measures of immunosenescence and the age-related decline in sympathetic noradrenergic (NA) nerve fibers in spleen and lymph nodes of F344 rats. In the present study, we investigated this interrelationship further by measuring NK cell activity, Con A-induced IL-2 production, norepin...

Previous work in our laboratories has shown a selective age-related loss of sympathetic noradrenergic (NA) nerves from the spleen and lymph nodes of rats. In contrast, NA nerve fiber density is dramatically increased in the thymus of aged mice and rats. We hypothesize that the diminished splenic NA innervation in old rats is due to cumulative oxida...

Studies of the effects of sympathectomy on immune responses invariably suggest that norepinephrine (NE) and the sympathetic nervous system have important roles in modulation of immune responses. Lymphoid organs, both primary and secondary, are innervated by NE-containing postganglionic sympathetic nerve fibers, as well as a variety of peptidergic f...

We have examined age-related alterations in sympathetic noradrenergic (NA) innervation in primary and secondary lymphoid organs from mouse and rat. As the thymus involuted with age, the density of NA innervation and norepinephrine (NE) concentration increased markedly. Total thymic NE was not altered significantly with age, suggesting that NA inner...

Age is associated with reduced immune reactivity, contributing to increased rates of infectious disease and cancer in old age. We have begun to assess the potential for sympathetic nervous system involvement in age-related immune dysfunction by characterizing sympathetic noradrenergic (NA) innervation in lymphoid organs in old animals. In the prese...

Previous reports have demonstrated that IL-1 is elevated in the Alzheimer's disease brain. We propose that beta-amyloid (A beta) in senile plaques triggers microglial interleukin-1(IL-1) release. Since microglia and monocytes have similar lineage and functions, the human monocyte cell line, THP-1, was used to determine whether A beta peptides can s...

Strain differences have been invoked to explain differing results when studying neural-immune interactions in laboratory animals. We investigated the splenic norepinephrine (NE) content and concentration in three strains of male mice (BALB/C, C57BL/6, and DBA/2), as well as possible diurnal variability in this innervation. Diurnal plasma corticoste...

Primary and secondary lymphoid organs are innervated extensively by noradrenergic sympathetic nerve fibers. Lymphocytes, macrophages, and other cells of the immune system bear functional adrenoreceptors. Norepinephrine fulfills criteria for neurotransmission with cells of the immune system as targets. In vitro, adrenergic agonists can modulate all...

We have used chemical sympathectomy with 6-hydroxydopamine (6-OHDA) in adult mice to study the role of the sympathetic nervous system (SNS) in regulating cellular proliferation and migration in lymphoid organs. Following sympathectomy, an increase in inguinal and axillary lymph node (LN) weight and cellularity was observed. This increase paralleled...

Functional changes in lymph node (LN) and spleen lymphocytes were examined following sympathetic denervation of adult mice with 6-hydroxydopamine (6-OHDA). Sympathectomy reduced in vitro proliferation to concanavalin A (ConA) by LN cells and decreased LN Thy-1+ and CD4+ T cells. At the same time, ConA-induced interferon-gamma (IFN-gamma) production...

The development of natural killer (NK) cell activity was assessed in Fischer 344 (F344) rats sympathectomized as neonates with the neurotoxin, 6-hydroxydopamine (6-OHDA). No NK cell activity was detected in sympathectomized or vehicle-injected control animals at 7 days of age. At 10 and 14 days of age, NK cell activity was reduced in spleens from s...

Noradrenergic and peptidergic nerve fibers abundantly innervate the parenchyma of both primary (bone marrow) and secondary (spleen, lymph nodes) lymphoid organs. Nerve fibers distribute within the parenchyma of these organs, as well as along smooth muscle compartments. Both noradrenaline and peptides such as substance P have been shown to fulfill t...

This chapter discusses catecholamine action and immunologic reactivity. The cells of the immune system are capable of responding to antigen in vitro, independent of most physiologic influences present in an intact organism, and the proposal of a physiologic role for catecholamines does not imply that they can replace such requirements as antigen pr...

The ontogeny of spleen cell proliferation to T and B cell mitogens and immunoglobulin secretion, measured in vitro, was examined in neonatally sympathectomized Fischer 344 (F344) rats, administered the neurotoxic drug 6-hydroxydopamine (6-OHDA) from 1 to 3 days of age. Compared to cells from age-matched controls, spleen cells from neonatally sympat...

Chemical sympathectomy of adult mice with 6-hydroxydopamine (6-OHDA) either prior to or following epicutaneous sensitization with the trinitrophenyl (TNP) hapten decreased the delayed hypersensitivity (DH) response to ear challenge. To determine if uptake of 6-OHDA into sympathetic nerve terminals, and their subsequent destruction, was required for...

We have demonstrated that the neurotransmitter norepinephrine (NE), present in the postganglionic sympathetic fibers that richly innervate lymphid organs, acts in the spleen as both a paracrine secretion, available to receptors on cells in the white pulp, and a localized neurotransmitter in nerve terminals that directly contact T lymphocytes in the...

The immune system is made up of primary and secondary lymphoid organs, containing lymphocytes and several accessory cell types, which are the key agents of immunological reactivity. Some of the basic features of immune responses are reviewed. Several pathways from the CNS to the immune system are of potential importance in physiological regulation....

INTRODUCTION Cancer patients often experience chronic emotional stress and/or other negative psychological factors, such as depression or lack of social support, with diagnosis and successive treatment 1 . Exposure to stress has been shown to influence tumor growth in a number of animal models in association with greater tumor angiogenesis and elev...