Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells.
The breast cancer stem cell (BCSC) hypotheses suggest that breast cancer is derived from a single tumor-initiating cell with stem-like properties, but the source of these cells is unclear. We previously observed that induction of an immune response against an epithelial breast cancer led in vivo to the T-cell-dependent outgrowth of a tumor, the cells of which had undergone epithelial to mesenchymal transition (EMT). The resulting mesenchymal tumor cells had a CD24(-/lo)CD44(+) phenotype, consistent with BCSCs. In the present study, we found that EMT was induced by CD8 T cells and the resulting tumors had characteristics of BCSCs, including potent tumorigenicity, ability to reestablish an epithelial tumor, and enhanced resistance to drugs and radiation. In contrast to the hierarchal cancer stem cell hypothesis, which suggests that breast cancer arises from the transformation of a resident tissue stem cell, our results show that EMT can produce the BCSC phenotype. These findings have several important implications related to disease progression and relapse.
Santisteban
Marta
M
Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Reiman
Jennifer M
JM
Asiedu
Michael K
MK
Behrens
Marshall D
MD
Nassar
Aziza
A
Kalli
Kimberly R
KR
Haluska
Paul
P
Ingle
James N
JN
Hartmann
Lynn C
LC
Manjili
Masoud H
MH
Radisky
Derek C
DC
Ferrone
Soldano
S
Knutson
Keith L
KL
D000818:Animals; D051927:CD24 Antigen / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045643:DNA Repair Enzymes / Q000096:biosynthesis; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D015870:Gene Expression; D018734:Genes, erbB-2; D018960:Hyaluronan Receptors / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008648:Mesoderm / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008942:Mitoxantrone / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology
D051927:CD24 Antigen; D018960:Hyaluronan Receptors; D008942:Mitoxantrone; D045643:DNA Repair Enzymes