Elucidating Purinergic and Pro-inflammatory Signaling Mechanisms in Breast Cancer
type: CreativeWork
description: Integration of cancer cell-intrinsic and extrinsic signaling cues supports the emergence of tissue-specific microenvironments that stimulate neoplastic transformation and malignancy. Tumor-acquired hallmarks that maintain functional plasticity frequently result from intrinsic genomic aberrations leading to transcriptional dysregulation. Concomitantly, tumor-stromal interactions promote the accumulation of stimulatory factors that augment the wound healing response, inflammation, and metastatic dissemination. While the convergence of these signaling compartments is known to preface malignancy, the molecular mechanisms that mediate their functional effects remain enigmatic.Presented herein, Chapter One offers context to subsequent investigations into breast cancer cell-intrinsic regulation of inflammation and tumor-extrinsic communication with distant sites of metastasis. Chapter Two begins with an original characterization of breast cancer-secreted exosomes and employs a proteomic approach to identify unique protein cargo associated with malignancy. Application of an in vivo orthotopic breast tumor model and an alginate-based cell encapsulation method confirms spatiotemporal exosome signaling within the lung microenvironment. Further, mass spectrometry analysis of lungs from exosome-treated mice suggests a role for breast cancer-secreted exosomes in facilitating pre-metastatic niche formation.Chapter Three expands on the previous findings by elucidating a purinergic signaling mechanism propagated by breast cancer-secreted exosomes. Evidence presented here shows that the expression and phosphotransferase activity of a pro-angiogenic nucleoside disphosphate kinase (NDPK) are markedly elevated in exosomes secreted by metastatic breast cancer cells. Moreover, these exosomes elicit pro-angiogenic and vascular remodeling events in vitro and in vivo. Inhibition of NDPK phosphotransferase activity or blockade of the endothelium-specific P2Y1 purinoreceptor attenuates exosome…
abstract: Integration of cancer cell-intrinsic and extrinsic signaling cues supports the emergence of tissue-specific microenvironments that stimulate neoplastic transformation and malignancy. Tumor-acquired hallmarks that maintain functional plasticity frequently result from intrinsic genomic aberrations leading to transcriptional dysregulation. Concomitantly, tumor-stromal interactions promote the accumulation of stimulatory factors that augment the wound healing response, inflammation, and metastatic dissemination. While the convergence of these signaling compartments is known to preface malignancy, the molecular mechanisms that mediate their functional effects remain enigmatic.Presented herein, Chapter One offers context to subsequent investigations into breast cancer cell-intrinsic regulation of inflammation and tumor-extrinsic communication with distant sites of metastasis. Chapter Two begins with an original characterization of breast cancer-secreted exosomes and employs a proteomic approach to identify unique protein cargo associated with malignancy. Application of an in vivo orthotopic breast tumor model and an alginate-based cell encapsulation method confirms spatiotemporal exosome signaling within the lung microenvironment. Further, mass spectrometry analysis of lungs from exosome-treated mice suggests a role for breast cancer-secreted exosomes in facilitating pre-metastatic niche formation.Chapter Three expands on the previous findings by elucidating a purinergic signaling mechanism propagated by breast cancer-secreted exosomes. Evidence presented here shows that the expression and phosphotransferase activity of a pro-angiogenic nucleoside disphosphate kinase (NDPK) are markedly elevated in exosomes secreted by metastatic breast cancer cells. Moreover, these exosomes elicit pro-angiogenic and vascular remodeling events in vitro and in vivo. Inhibition of NDPK phosphotransferase activity or blockade of the endothelium-specific P2Y1 purinoreceptor attenuates exosome…
author: Duan, Suzann
keywords: Angiogenesis, Breast Cancer, Exosomes, EZH2, Inflammation, Purinergic
date published: 2019
date modified: 2026-07-27T21:45:34Z
provider: University of Nevada - Reno
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Nevada - Reno

PropertyValue
property ID: Handle
value: http://hdl.handle.net/11714/5709