Research progress on therapeutic targeting of quiescent cancer cells

Figures & data

Table 1. Molecular mechanisms (gene signatures) of quiescence maintenance.

Name	Cell lines	Functionary mechanisms	References
KIf1	Fission yeast	KIf1 plays pivotal roles in G0 phase longevity through promoting the differentiation signal and inhibiting growth metabolism. In the absence of KIf1, S. pombe fails to maintain a constant cell size and normal cell morphology during quiescence	[30]
Ppk18-Mug134/Igo1 pathway	Fission yeast	The Ppk18-Mug134/Igo1 pathway is indispensable for G0 entry and establishment of robust viability during the G0 phase through regulation of PP2A^B55.	[24]
GAS6	PC3, DU145, and LNCaP cell lines (prostate cancer)	GAS6 is capable of activating Tyro3, Axl and Mer kinases and acts as a molecular switch from proliferation to dormancy.	[31]
NR2F1	HEp3 cell line (human squamous cell carcinoma)	NR2F1 controls tumor cell dormancy via SOX9 and RARβ-driven quiescence programs.	[32]
DYRK1A	SH-SY5Y cell line (neuroblastoma)	DYRK1A activates dormancy by 1) phosphorylating p27 and increasing its stability, 2) phosphorylating and degrading Cyclin D1, and 3) phosphorylating LIN52 to suppress cell cycle-dependent gene expression	[33]
DYRK1B	Various tumor types (e.g. pancreatic, ovarian, lung, colon cancer)	DYRK1B blocks transition from the G0 to G1-S phase of the cell cycle to maintain quiescence. In particular, DYRK1B controls the S phase checkpoint by stabilizing the p27^Kip1 and inducing degradation of cyclin D.	[31,34]
p21^CDKN1A	Normal LF1 human fibroblasts	Deletion of p21^CDKN1A disrupts the ability to enter quiescence and activates the DNA damage response in normal fibroblasts induced following quiescence.	[35]
p38 MAPK	HEp3 cell line (human squamous cell carcinoma)	Upon activation, p38 MAPK activates dormancy-regulating transcription factors (DEC2 and NR2F1) and CDK inhibitors (p27 and p21), leading to reversible cell cycle arrest.	[31,32]
PRDM2/RIZ	C2C12 myoblasts	The tumor suppressor PRDM2/RIZ expressed by quiescent muscle stem cells, both in vitro and in vivo, is critical for maintaining quiescence via blocking inappropriate differentiation and protecting against silencing of cell cycle and stem cell genes.	[36]
CDKs and CDK inhibitors	Human mammary epithelial cell line (MCF10A)	At the end of mitosis, cells decide to either start the next cycle by immediately stimulating CDK2 activity or enter a transient state of quiescence by inhibiting CDK2 activity. p21, a CDK inhibitor, is proposed to directly control cell fate bifurcation.	[37]
MiR-302	AG01522 normal human fibroblasts	MiR-302 levels are significantly decreased in G0 cells, which may regulate the transition between quiescence and proliferation by affecting the expression of the specific miR-302 target genes ARID4a and CCL5.	[38]
Plk1	MKN45 and MKN74 cell lines (human gastric cancer)	Plk1 activity is inhibited in quiescent cancer stem cells (CSC) and its inactivation induces quiescence of gastric CSCs via suppression of the MEK-ERK-RSK1 pathway.	[4]
MERTK	PC3, Du145, and LNCaP C4-2B cell lines (prostate cancer)	MERTK is essential for prostate cancer dormancy escape. MERTK knockdown is reported to decrease the P-Erk1/2:P-p38 ratio, enhance expression of p27, NR2F1, SOX2, and NANOG, induce higher levels of dormancy-associated histone H3 markers and cause G1/G0 arrest.	[8]

Figure 1. NET produced during inflammation awakens dormant tumor cells.

Figure 2. A regulatory network affecting the depth of quiescence.

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