Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1.
Mesenchymal stem cells (MSCs) have an inhibitory effect on tumor proliferation, but the precise mechanisms are not fully understood. Here, we identified DKK-1 (dickkopf-1), secreted by MSCs and acting as a negative regulator of WNT signaling pathway, to be one of the molecules responsible for the inhibitory effect. When DKK-1 was neutralized by anti-DKK-1 antibodies, or when the expression of DKK-1 was downregulated by RNA interference (RNAi), the inhibitory effects of MSCs on K562 cell proliferation were attenuated. We also provide evidence that the expression of DKK-1 by MSCs is regulated by NANOG, a transcriptional factor ubiquitously expressed in some stem cells. Using the Cellmax artificial capillary modules that eliminate the immunosuppressive properties of MSCs, we further showed that MSCs were able to inhibit proliferation of K562 cells in a humoral microenvironment. Meanwhile, we recapture this effect of MSCs on primary leukemic hematopoietic progenitors from patients. MSCs probably have a general inhibitory effect on their neighboring cells, including malignant cells, en route to achieving tissue homeostasis.
Zhu
Y
Y
Center for Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Peoples Republic of China.
Sun
Z
Z
Han
Q
Q
Liao
L
L
Wang
J
J
Bian
C
C
Li
J
J
Yan
X
X
Liu
Y
Y
Shao
C
C
Zhao
R C
RC
D000328:Adult; D001483:Base Sequence; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008969:Molecular Sequence Data; D000071317:Nanog Homeobox Protein; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
C501126:DKK1 protein, human; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051153:Wnt Proteins