TY - JOUR
T1 - Targeting sarcoma tumor-initiating cells through differentiation therapy
AU - Han, Dan
AU - Rodriguez-Bravo, Veronica
AU - Charytonowicz, Elizabeth
AU - Demicco, Elizabeth
AU - Domingo-Domenech, Josep
AU - Maki, Robert G.
AU - Cordon-Cardo, Carlos
N1 - Publisher Copyright:
© 2017 The Authors
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Human leukocyte antigen class I (HLA-I) down-regulation has been reported in many human cancers to be associated with poor clinical outcome. However, its connection to tumor-initiating cells (TICs) remains unknown. In this study, we report that HLA-I is down-regulated in a subpopulation of cells that have high tumor initiating capacity in different types of human sarcomas. Detailed characterization revealed their distinct molecular profiles regarding proliferation, apoptosis and stemness programs. Notably, these TICs can be induced to differentiate along distinct mesenchymal lineages, including the osteogenic pathway. The retinoic acid receptor signaling pathway is overexpressed in HLA-1 negative TICs. All-trans retinoic acid treatment successfully induced osteogenic differentiation of this subpopulation, in vitro and in vivo, resulting in significantly decreased tumor formation. Thus, our findings indicate down-regulated HLA-I is a shared feature of TICs in a variety of human sarcomas, and differentiation therapy strategies may specifically target undifferentiated TICs and inhibit tumor formation.
AB - Human leukocyte antigen class I (HLA-I) down-regulation has been reported in many human cancers to be associated with poor clinical outcome. However, its connection to tumor-initiating cells (TICs) remains unknown. In this study, we report that HLA-I is down-regulated in a subpopulation of cells that have high tumor initiating capacity in different types of human sarcomas. Detailed characterization revealed their distinct molecular profiles regarding proliferation, apoptosis and stemness programs. Notably, these TICs can be induced to differentiate along distinct mesenchymal lineages, including the osteogenic pathway. The retinoic acid receptor signaling pathway is overexpressed in HLA-1 negative TICs. All-trans retinoic acid treatment successfully induced osteogenic differentiation of this subpopulation, in vitro and in vivo, resulting in significantly decreased tumor formation. Thus, our findings indicate down-regulated HLA-I is a shared feature of TICs in a variety of human sarcomas, and differentiation therapy strategies may specifically target undifferentiated TICs and inhibit tumor formation.
KW - Human leukocyte antigen class I
KW - Sarcomas
KW - Tumor-initiating cells
UR - http://www.scopus.com/inward/record.url?scp=85018469402&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018469402&partnerID=8YFLogxK
U2 - 10.1016/j.scr.2017.04.004
DO - 10.1016/j.scr.2017.04.004
M3 - Article
C2 - 28433655
AN - SCOPUS:85018469402
SN - 1873-5061
VL - 21
SP - 117
EP - 123
JO - Stem Cell Research
JF - Stem Cell Research
ER -