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Endothelial protein C receptor function in murine and human breast cancer development

Academic Article
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Overview

authors

  • Schaffner, F.
  • Yokota, N.
  • Carneiro-Lobo, T.
  • Kitano, M.
  • Schaffer, M.
  • Anderson, G. M.
  • Mueller, B. M.
  • Esmon, C. T.
  • Ruf, Wolfram

publication date

  • April 2013

journal

  • PLoS One  Journal

abstract

  • Several markers identify cancer stem cell-like populations, but little is known about the functional roles of stem cell surface receptors in tumor progression. Here, we show that the endothelial protein C receptor (EPCR), a stem cell marker in hematopoietic, neuronal and epithelial cells, is crucial for breast cancer growth in the orthotopic microenvironment of the mammary gland. Mice with a hypomorphic allele of EPCR show reduced tumor growth in the PyMT-model of spontaneous breast cancer development and deletion of EPCR in established PyMT tumor cells significantly attenuates transplanted tumor take and growth. We find expansion of EPCR(+) cancer stem cell-like populations in aggressive, mammary fat pad-enhanced human triple negative breast cancer cells. In this model, EPCR-expressing cells have markedly increased mammosphere- and tumor-cell initiating activity compared to another stable progenitor-like subpopulation present at comparable frequency. We show that receptor blocking antibodies to EPCR specifically attenuate in vivo tumor growth initiated by either EPCR(+) cells or the heterogenous mixture of EPCR(+) and EPCR(-) cells. Furthermore, we have identified tumor associated macrophages as a major source for recognized ligands of EPCR, suggesting a novel mechanism by which cancer stem cell-like populations are regulated by innate immune cells in the tumor microenvironment.

subject areas

  • Adipose Tissue
  • Animals
  • Antigens, CD
  • Breast Neoplasms
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cluster Analysis
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Glycoproteins
  • Humans
  • Macrophages
  • Mammary Glands, Animal
  • Mice
  • Neoplastic Stem Cells
  • Receptors, Cell Surface
  • Transplantation, Heterologous
  • Tumor Burden
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Identity

PubMed Central ID

  • PMC3621887

International Standard Serial Number (ISSN)

  • 1932-6203 (Electronic) 1932-6203 (Linking)

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0061071

PubMed ID

  • 23593394
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Additional Document Info

start page

  • e61071

volume

  • 8

issue

  • 4

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