Cancer cell dormancy: mechanisms and implications of cancer recurrence and metastasis

Figures & data

Figure 1 Schematic view of dormancy-related tumor cells and molecules in tumor development.

Notes: PT contains various cancer cells, including proliferative cells, dormant cells, and cancer stem cells. PT microenvironment is also heterogeneous in oxygen concentration and the ECM. When PT cancer cells invade into peripheral blood (named circulating tumor cells [CTCs]), some of them can undergo an epithelial-to-mesenchymal transition (EMT) and obtain a stem-like phenotype. In addition, these PT cancer cells can sequentially disseminate to distant organs such as the BM (named DTCs). These cancer cells experience a genetic, epigenetic, and phenotypic conversion. PT hypoxic microenvironment could induce the expression of dormancy markers in cancer cells and decrease the chemosensitivity. When DTCs arrive at the BM, the permissive niche (TGFβ2, p21/p27, BMP7-BMPR2, GAS6/AXL, NR2F1-RARβ-SOX9, FOXO3, HIGD1A, SOX2, Oct4, etc.) can contribute to maintaining a dormant state of DTCs. Conversely, the lung is a restrictive microenvironment to DTC dormancy. A high concentration of oxygen and the special ECM (TGFβ1/3, Coco, Zeb1, HIF-1α, POSTN, VCAM-1, AKT, SFK, etc.) can awaken the dormant cancer cells to form micrometastases in the lung. Especially, the ratio of ERK MAPK/p38 MAPK plays a crucial role in this dormancy and reactivation. A high ratio of p38 MAPK/ERK MAPK can induce DTCs entering into dormancy, and in turn a high ratio of ERK MAPK/p38 MAPK can reactivate dormant cancer cells to proliferate. In addition, dormancy DTCs in the BM also can disseminate to other distant sites and then hide and/or wake up to form secondary tumor at a particular point in time.
Abbreviations: BM, bone marrow; DTC, disseminated tumor cells; ECM, extracellular matrix; PT, primary tumor.

Table 1 Molecular mechanism of cancer cell dormancy and reactivation

Molecular mechanism	Dormancy	Reactivation	Uncertain
Intracellular signals	p38MAPK,^Citation50 p16,^Citation50 p21,^Citation62 p27,^Citation19 p53,^Citation50 MKK4,^Citation58,Citation59 NR2F1/RARβ/SOX9^Citation67	ERKMAPK,^Citation50 PI3K/AKT,^Citation60 GILZ,^Citation62 FOXO3A^Citation62	JNK^Citation56,Citation57
Extracellular signals	TGFβ2/TGFβ-RIII,^Citation68 BMP7/BMPR2,^Citation73 BMP4,^Citation76 AXL/GAS6,^Citation82^–^Citation84 TBK1,^Citation88 miR122(3)/miR23b,^Citation91,Citation92 LIFR/STAT3/SOCS3,^Citation108 DEC2^Citation19	TGF-β3,^Citation66 MERTK,^Citation85 POSTN,^Citation89 SFK,^Citation125 Fra-1,^Citation87 Coco^Citation69	LTBP-2,^Citation64 Tyro3,^Citation87 TGF-β1^Citation65
Bone marrow niche	atRA,^Citation67 HIGD1A,^Citation110,Citation111 PP2A^Citation112	VCAM-1,^Citation79 Zeb1,^Citation120 HIF-1α,^Citation21 LOXL2^Citation102

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