Cancer Res Treat.  2023 Jul;55(3):720-736. 10.4143/crt.2023.468.

Cellular Dormancy in Cancer: Mechanisms and Potential Targeting Strategies

• Min HY
• Lee HY

• KMID: 2544156
• DOI: http://doi.org/10.4143/crt.2023.468

Abstract

Cancer is a leading cause of disease-related mortality worldwide. Drug resistance is one of the primary reasons for the failure of anticancer therapy. There are a number of underlying mechanisms for anticancer drug resistance including genetic/epigenetic modifications, microenvironmental factors, and tumor heterogeneity. In the present scenario, researchers have focused on these novel mechanisms and strategies to tackle them. Recently, researchers have recognized the ability of cancer to become dormant because of anticancer drug resistance, tumor relapse, and progression. Currently, cancer dormancy is classified into “tumor mass dormancy” and “cellular dormancy.” Tumor mass dormancy represents the equilibrium between cell proliferation and cell death under the control of blood supply and immune responses. Cellular dormancy denotes the state in which cells undergo quiescence and is characterized by autophagy, stress-tolerance signaling, microenvironmental cues, and epigenetic modifications. Cancer dormancy has been regarded as the stem of primary or distal recurrent tumor formation and poor clinical outcomes in cancer patients. Despite the insufficiency of reliable models of cellular dormancy, the mechanisms underlying the regulation of cellular dormancy have been clarified in numerous studies. A better understanding of the biology of cancer dormancy is critical for the development of effective anticancer therapeutic strategies. In this review, we summarize the characteristics and regulatory mechanisms of cellular dormancy, introduce several potential strategies for targeting cellular dormancy, and discuss future perspectives.

Keyword

Neoplasms; Dormancy; Recurrence; Cancer progression; Anticancer drug resistance; Cellular dormancy

Figure

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  Fig. 1 Mechanisms underlying maintenance and awakening of dormant cancer cells. Cancer dormancy is classified as tumor mass dormancy and cellular dormancy. Tumor mass dormancy is the equilibrium between cell proliferation and cell death, which is regulated by blood supply and the immune system. Cellular dormancy is the status of reversible growth arrest and characterized by cell cycle arrest at the G0/G1 phase of the cell cycle, induction of CDK inhibitors, reduction of proliferation markers (such as Ki67 and PCNA), p38 MAPK activation, compacted chromatin structure, and reduction of cellular metabolism. Several mechanisms, such as autophagy, stress-tolerance signaling, microenvironmental cues, and epigenetic modifications, are involved in the maintenance of cellular dormancy. Dormant cancer cells escape from the dormant status via changing autocrine soluble factors autonomously and/or interacting with surrounding stromal cells in the microenvironments. CDK, cyclin-dependent kinase; MAPK, mitogen-activated protein kinase; PCNA, proliferating cell nuclear antigen.

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  Fig. 2 Intracellular modulation involved in cellular dormancy. Regulation of cell cycle machinery, such as the Rb-E2F and DREAM complexes, ECM-mediated signal transduction, p38 MAPK activation, growth factors (TGF-β family growth factors and IGFs), and ER stress-induced UPR and acquisition of senescence, autophagy, EMT, and cancer stem cell–associated phenotypes are known to be associated with cellular dormancy. DREAM, dimerization partner, Rb-like, E2F and multi-vulval class B; ECM, extracellular matrix; EMT, epithelial-mesenchymal transition; ER, endoplasmic reticulum; IGF, insulin-like growth factor; MAPK, mitogen-activated protein kinase; Rb, retinoblastoma; TGF-β, transforming growth factor-β; UPR, unfolded protein response.

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  Fig. 3 A proposed mechanism underlying the regulation of dormant cancer cells. Regulation of the UPR machinery for ER homeostasis is essential for the survival of dormant cancer cells in the presence of sustained ER stress, such as chemotherapy. RGS2 plays an important role in the survival of dormant cancer cells by maintaining protein homeostasis against chemotherapy or hostile microenvironments. ATF, activating transcription factor; ER, endoplasmic reticulum; ERAD, ER-associated protein degradation; IRE1, inositol requiring enzyme 1; PERK, protein kinase R-like endoplasmic reticulum kinase; RGS2, regulator of G protein signaling 2; Ub, ubiquitin; UPR, unfolded protein response; XBP1, X-box binding protein 1.

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  Fig. 4 Tumor relapse by awakening slow-cycling/dormant cancer cells through interaction with stromal cells in the tumor microenvironment. Increased recruitment of fibroblasts and vascular endothelial cells under proinflammatory and proliferation-promoting conditions mediated by various cytokines and growth factors stimulate the proliferation of slow-cycling/dormant cancer cells, leading to relapsed tumor formation and cancer progression. ACC, active-cycling cancer cells; CAF, cancer-associated fibroblast; CDK, cyclin-dependent kinase; COX-2, cyclooxygenase 2; EGFR, epidermal growth factor receptor; IL, interleukin; PCNA, proliferating cell nuclear antigen; PGE2, prostaglandin E2; SCC, slow-cycling cancer cells; TGF-β2, transforming growth factor-β2.

Reference

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