Stem cell quiescence and its clinical relevance

Table 1 Regulation of quiescent stem cells

Stem cells	Regulatory factors
Adipose-derived stem cells	CDKI1C[14]
Airway club progenitor cells	P53[19]
Hepatic stellate cells	Laminin 521[96]
Hair follicle stem cells	MiR-22-5p[9], Acer1[43,44], Mpc1[49], OSM[83], Nlrc5[91]
Hematopoietic stem/progenitor cells	CDKI1[6], Asri[20], RB[22], Tet1[35], BMI1[36], SIN3[37], MMP[42], NRF2[45], RISP[47], SRC-3[48], Autophagy[51], NR4A1 and NR4A3[53], CD150high FOXP3+ regulatory T cells[63,71], Ebf1[64], Eosinophils[66], ICAM-1[69], lineage-committed Hdc+ myeloid cells[72], NG2+ cells[73], NPY[74], ANG[77], SHP-1[78], TGF-β[80], luteinizing hormone[89], Jak1[84], PTPN21[97]
Mammary stem cells	BCL11b[16], FOXP1
Muscle satellite (stem) cells	Rpt3[7], miR-708[27], Notch3[28,29], PTEN[30,31], ZEB1[31,55,56], miR-31[39], AMPK[46], N-cadherin and M-cadherin[68], Wnt4[75], OSM[76], Nlrc5[91], Col5a1[95]
Neural stem/progenitor cells	Notch2[8], Lfng[23], ID4[24], Notch3[25], Cpt1a[41], ASCL1[57], Huwe1[58], VCAM-1[67], MFGE8[86]

Table 2 Regulation of quiescent cancer stem cells

Type of cancer	Regulatory factor	Regulatory mechanism
Ovarian cancer	Autophagy	Knockdown of ATG5 inhibits autophagy and arrests ovarian cancer cells in G0/G1 state through upregulating production of ROS[115]
Breast cancer	SETD4	SETD4 regulates breast CSC quiescence by facilitating the formation of heterochromatin via H4K20me3 catalysis[11]
Breast cancer	LIFR	Loss of LIFR in dormant breast cancer cells reduces the expression of quiescence and cancer stem cell-associated genes, such as TGF-β2 and Notch1[131]
Breast cancer	Mitochondrial DNA	CAF-derived EVs, containing mitochondrial DNA, promote estrogen receptor-independent oxidative phosphorylation and facilitate an exit from quiescence in HT-naive breast cancer stem-like cells[133]
Breast cancer	Macrophages	Macrophages with an M1 phenotype secrete exosomes to activate NF-кB pathways, and thus reversebreast CSCs (BCSCs) quiescence; macrophages exhibiting an M2 phenotype causes quiescence and lessened proliferation via gap junctional intercellular communication[134]
Breast cancer	NOTCH4	NOTCH4 transcriptionally activates GAS1 to sustain quiescence in BCSCs[139]
Colorectal cancer	ZEB2	ZEB2 upregulates cell cycle-related factors including HDAC9, Cyclin A1, Cyclin D1, HDAC5, and TGFβ2 to keep stem cells quiescent[121]
Colorectal cancer	SPDEF	SPDEF breaks binding of β-catenin to TCF1 and TCF3, and regulates cell cycle-associated genes, such as CCND1, HDAC4, CDK6, MYC, and AXIN2, to induce a quiescent state[122]
Liver cancer	Tyrosine metabolism	Targeting tyrosine metabolism impairs quiescence by accelerating degradation of Forkhead box D3[125]
Liver cancer	CXCL1	CXCL1 induces quiescence in hepatocellular carcinoma stem cells by activation of the mTORC1 kinase[128]
Multiple myeloma	TRIM44	TRIM44 deubiquitinates HIF-1α to stabilize HIF-1α expression and HIF-1α contributes to MM stem cell quiescence[120]
Glioblastoma	Ca2+	Inhibition of store-operated channels increases capacity of mitochondria to capture Ca2+ in GSLCs, and thus impels proliferous GSLCs to turn to quiescence[9]
Glioblastoma	PSF1	Defect of PSF1 suppresses reactivation of quiescent CSCs after serum supplement or reoxygenation[135]
Melanoma	GILZ	Deficiency of GILZ expression in vivo arrests these cells in the G0 phase, and induces quiescence[127]
Pancreatic cancer	lncRNA GAS5	GAS5 restrains the cell cycle to suppress proliferation by inhibiting glucocorticoid receptors (GR) mediated cell cycle regulation[138]
Lung cancer	Fbxw7, Skp2	Knockdown of Fbxw7 upregulated c-myc and knockdown of Skp2 increased the expression of p27, and then transforms cells into quiescence[136]
AML	FOXM1	FOXM1 binds to β-catenin and decreases degradation of β-catenin protein, and thus activates the Wnt/β-catenin signaling pathways, and preserves leukemia stem cell (LSC) quiescence[123]
AML	lncRNA DANCR	Knockdown of DANCR in LSCs causes reduced stem-cell renewal and quiescence[137]
AML	EVI-1	Evi-1 depression promotes the quiescence of LSCs possibly through Notch4[141]
AML	PRC2	PRC2 regulates suppression of Cyclin D to maintain quiescence in LSCs[145]
CML	Mir-126	Endothelial cells provide miR-126 for CML LSCs to restrain cell cycle progression through targeting PI3K/AKT/mTOR signaling pathway[8,117]
CML	CXCL12	Knockout of CXCL12 in mesenchymal stromal cells promotes leukemic stem cell (LSC) expansion via downregulation of genes associated with quiescence such as TGF-β and STAT3[129]
CML	BMP4	BMP4 directly regulates quiescence of CML LSCs through regulating JAK/Stat3 pathway, dependent upon BMPR1B kinase activity[130]

AML: Acute myeloid leukemia; CML: Chronic myelogenous leukemia; LSC: Leukemia stem cell; CSC: Cancer stem cells.

Table 3 Therapeutic strategies against quiescence

Type of cancer	Therapeutic target	Potential therapy	Therapeutic mechanism
AML	HDM2	PNC-27	PNC-27 binds to mHDM2, leads to E-cadherin degradation, and causes membrane injury and cell necrobiosis[140]
AML	EVI-1	ATRA	ATRA enhances EVI-1-dependent depression of the maturation and promotes the quiescence[141,142]
AML	c-MPL	AMML2	AMML2 blocks c-MPL, stimulates entry of quiescent LSCs into the cell cycle, and increases the sensitivity of LSCs to chemotherapy[143]
AML	EZH1, EZH2	OR-S1, OR-S2	OR-S1 and OR-S2 inhibit EZH1/2, inactivate PRC2, and then eliminate quiescent LSCs, induce cell differentiation, and turn chemotherapy-resistant LSCs into a chemotherapy-sensitive population[145]
CML	Autophagy	Lys05, PIK-III	Lys05 achieves autophagy inhibition in LSCs and promotes differentiation; Lys05 and PIK-III inhibit TKI-induced autophagy and increase the sensitivity of LSCs to TKI[146]

AML: Acute myeloid leukemia; CML: Chronic myelogenous leukemia; LSC: Leukemia stem cell.