The lymphovascular embolus of inflammatory breast cancer expresses a stem cell-like phenotype

Am J Pathol. 2008 Aug;173(2):561-74. doi: 10.2353/ajpath.2008.071214. Epub 2008 Jul 3.

Abstract

Inflammatory breast carcinoma (IBC) is a particularly lethal form of breast cancer characterized by exaggerated lymphovascular invasion, which is a phenotype recapitulated in our human xenograft MARY-X. MARY-X generated spheroids in vitro that resemble the embryonal blastocyst. Because of the resemblance of the spheroids to the embryonal blastocyst and their resistance to traditional chemotherapy/radiotherapy, we hypothesized that the spheroids expressed a stem cell-like phenotype. MARY-X spheroids expressed embryonal stem cell markers including stellar, rex-1, nestin, H19, and potent transcriptional factors, oct-4, nanog, and sox-2, which are associated with stem cell self-renewal and developmental potential. Most importantly, MARY-X spheroids expressed a cancer stem cell profile characterized by CD44(+)/CD24(-/low), ALDH1, and most uniquely, CD133. A significant percentage of single cells of MARY-X exhibited distinct proliferative and morphogenic potencies in vitro. As few as 100 cells derived from single-cell clonogenic expansion were tumorigenic with recapitulation of the IBC phenotype. Prototype stem cell signaling pathways such as notch3 were active in MARY-X. The stem cell phenotype exhibited by MARY-X also was exhibited by the lymphovascular emboli of human IBC cases independent of their molecular subtype. This stem cell-like phenotype may contribute to the aggressive nature of IBC but also may lend itself to selective targeting.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biomarkers, Tumor / metabolism*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Polarity
  • Cell Transformation, Neoplastic*
  • Female
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Lymphatic Vessels / metabolism
  • Lymphatic Vessels / pathology*
  • Mice
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / metabolism*
  • Signal Transduction
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Transplantation, Heterologous

Substances

  • Biomarkers, Tumor