TABLE 1.

The effect of MSCs on tumor dormancy.

MSCs types	The effect on tumor dormancy	Factor/signal	Mechanism	Brief introduction	References
BMSCs	Dual role	TGF-β1	(1). Promoting breast cancer cell proliferation by inhibiting the angiogenic dormancy (2). Inducing squamous cell carcinoma latency by regulating cell-cycle gene transcription to control a reversible G1 cell-cycle arrest.	In terms of different tumors, TGF-β1 can play distinct roles on tumor dormancy.	Ghajar et al., 2013; Brown et al., 2017; Jahanban-Esfahlan et al., 2019
	Promoting	TGF-β2 GAS6	(1). Driving CSCs and DTCs into quiescence by inducing low ERK/P38 signal ratio (2). Induced tumor dormancy by crosstalking with AXL and GAS6 (3). GAS6 can regulate tumor dormancy by being combined with TAM receptors such as AXL and Tyro3	The dormant tumor cells can express abundant TGF-β2 to maintain the dormant state. GAS6 can be derived from BMSCs or osteoblasts	Taichman et al., 2013; Yumoto et al., 2016; Goddard et al., 2018; Axelrod et al., 2019; Hen and Barkan, 2020
	Regulating	TGF-β3	Promoting the proliferation and metastasis of head and neck cancer by inducing matrix-specific protein periostin	TGF-β family members are involved in tumor cells proliferation, differentiation, and tumor dormancy.	Qin et al., 2016
	Promoting	atRA	Increasing the expression of TGF-β2 via activating p38 and p27 MAPK-dependent pathways	TGF-β2 mainly provokes dormancy during tumor progression	Linde et al., 2016
	Promoting	BMP4	Inducing breast cancer dormancy via activating SMAD1/5 signaling	BMP is one subgroup of the TGF-β family, which can influence the induction of tumor dormancy	Gao et al., 2012
	Promoting	BMP7	Inhibit tumor cell growth and drive CSCs into dormancy by mediating the expression of N-myc downstream-regulated gene 1 (NDRG1) and activating p38 MAPK and p21	BMP7 could induce dormancy of prostate cancer	Kobayashi et al., 2011; Widner et al., 2018
	Promoting	CXCL12	(1). Inducing BMSCs to migrate to cancer site (2). Triggering DTC dormancy by promoting the exchange of cell-cell information and cellular adhesion between MSCs and DTCs (3). Regulating tumor dormancy by mediating the tumor inflammatory responses	CXCL12 is a classic chemokine that can promote tumor cells in the bone marrow to enter dormancy.	Balkwill, 2004; Widner et al., 2018; Susek et al., 2018
	Inhibiting	IL-10	Inhibit the growth of lymphoma and leukemia cells by reducing the secretion of interleukin IL-10	MSCs can regulate the expression of IL-10 to induce tumor dormancy	Lee et al., 2019
	Regulating	NE	(1). Binding with β2-adrenergic receptors (2). Modulating the expression levels of GAS6	The neurons can regulate tumor dormancy through releasing NE	Widner et al., 2018
	Promoting	MiR-127 MiR-197 MiR-222 MiR-223 MiR-23b	(1). Driving breast cancer cells into quiescence through reducing the expression of CXCL12 (2). The DTCs can promote BMSCs to express abundant distinct miRNAs such as miR222/223 and miR23b, all of which can result in the dormancy of certain DTCs by suppressing the TGF-b pathway	Dormant breast cancers could promote MSC to release exosomes including distinct miRNA such as miR-127, -197, -222, and -223 The quiescent phenotype of tumor cells can be reversed by antagomiR-222/223	Guasch and Blanpain, 2004; Ono et al., 2014; Bliss et al., 2016
	Prompting	Cell cannibalism	The cannibalism of MSCs could also drive MDA-MB-231 BCCs to enter dormancy under demanding conditions	The cannibalized MDA-MB-231 BCCs obtain a similar cell phenotype with dormant tumor cells	Bartosh et al., 2016
	Promoting	TWIST1	Inducing tumor micrometastatic dormancy by activating tumor growth-inhibitory signals pathway	The expression of TWIST1 is upregulating after being co-cultured with BMSCs in 3D non-adherent culture platforms	Tran et al., 2011
	Promoting	LOX JNK p38	Driving MDA-MB-231 BCCs into dormancy through cooperating with TWIST1	TWIST1 can regulate micrometastatic dormancy by interacting with LOX, JNK, and p38	El-Haibi et al., 2012
	Promoting	SASP	(1). Activating cytokine and chemokine signaling (2). Inhibiting cell proliferation and vascular development (3). Initiating inflammatory/immune response	There is an obviously upregulating of the expression of CXCL1, CXCL2, GCSF IL-1α, IL-1β, IL-8, and PAI-1, all of which are integral to the expression of the senescence-associated secretory phenotype (SASP)	Özcan et al., 2015; Bartosh et al., 2017
	Promoting	Cellular morphology	Inducing tumor cell dormancy by regulating the changes of extracellular matrix such as hypoxia and ECM detachment	Cellular morphology changes show many analogous features with cell cannibalism	Sosa et al., 2013
	Promoting	JNK SAPK FTIs	(1). The breast tumor cell morphology change makes these cells enter into dormancy through activating the JNK/SAPK signaling pathway (2). FTIs can induce breast cancer cells into reversible dormancy by undergoing morphology	There are direct and indirect links between morphology changes and tumor dormancy.	Chatterjee and van Golen, 2011
hUCMSCs	Promoting	β-catenin c-Myc Wnt	(1). Driving lung cancer cells to be arrested in the G0/G1 phase (2). Driving hepatocellular cancer cells are arrested in the S phase (3). Downregulating the expression of β-catenin and c-Myc	The detailed mechanisms of hUCMSCs on tumor dormancy may include inducing cell cycle arrest, promoting tumor cell apoptosis, as well as inhibiting the migration of cancer cell	Yuan et al., 2018
TA-MSCs	Promoting	TRAIL CXCL12 TGF-β MMPs microRNAs	(1). Drive epithelial tumor cells to enter dormancy during the tissue remodeling stage (2). Inhibit angiogenesis by expressing inhibitory factors (3). Initiating a cell cannibalism behavior	TA-MSCs often play an important role in the progression of tumor growth and metastasis.	Lee et al., 2012; Li et al., 2019
AMSCs	Promoting	miRNAs Wnt TGF-β	(1). Regulating the tumor dormancy of breast cancer by secreting multiple circulating miRNAs (2). Arrested dormant BCCs in G0/G1 phase and S phase	The AMSCs are capable of transporting the exosomes carrying miRNAs to BCCs, which can target the Wnt and TGF-β signaling pathways, thus regulating tumor dormancy.	Mohd Ali et al., 2020

MSCs, mesenchymal stem cells; BMSCs, bone marrow-derived mesenchymal stem cells; hUCMSCs, Human umbilical cord mesenchymal stem cells; TA-MSCs, tumor-associated mesenchymal stem cells; AMSCs, adipose tissue-derived mesenchymal stem cells; CSCs, cancer stem cells; DTC, disseminated tumor cells.