Tumor dormancy: potential therapeutic target in tumor recurrence and metastasis prevention

Abstract

In past decades, cancer patient survival has been improved with earlier detection and advancements in therapy. However, many patients who exhibit no clinical symptoms after frontline therapy subsequently suffer, often many years later, aggressive tumor recurrence. Cancer recurrence represents a critical clinical challenge in effectively treating malignancies and for patients' quality of life. Tumor cell dormancy may help to explain treatment resistance and recurrence or metastatic reactivation. Understanding the dormant stage of tumor cells may help in discovering ways to maintain the dormant state or permanently eliminate dormant residual disseminated tumor cells. Over the past decade, numerous studies indicate that various mechanisms of tumor dormancy exist, including cellular dormancy (quiescence), angiogenic dormancy, and immunologic dormancy. In this short review, we summarize recent experimental and clinical evidence for these three mechanisms and other possible tumor microenvironment mechanisms that may influence tumor dormancy.

Figure 1

Mechanisms in tumor dormancy. Tumor dormancy can lead to tumor recurrence locally or to metastasis at a distant site. Dormancy can be induced by more than one mechanism: cellular dormancy (quiescence), angiogenic dormancy (tumor mass size limit), and immunologic dormancy (immunosurveillance, balance between proliferation and apoptosis). Others mechanisms, such as epigenetic change, tumor microenvironment, CSCs, EMT, and miRNA, also may involve in tumor dormancy. A tumor microenvironment that is altered (such as by frontline treatment) can mediate tumor cell entrance into, maintenance, and exit from dormancy through interaction with cells at niches, such as endothelial cells, stroma, or immune cells.

Figure 2

Role of cell cycle regulators in the cellular dormancy (“intrinsic dormancy”) mechanism. (a) In the “typical” cell cycle pathway, upregulation of CDK inhibitors, such as p21 and p27, can inhibit cells from entering the cell cycle by downregulating cyclin/CDK activation. In this scenario, cells can enter into a quiescent state (G0). The ubiquitin ligase APC/CDH1 enhances the upregulation of p21/p27 expression by increasing the degradation of Skp2 (one of the units that constitute SCF, a p21/p27/p57 inhibitor). (b) The DREAM complex in the quiescent state (G0). MuvB recruits and interacts with p130 (RB-like), E2F4, and dimerization partner (DP), forming the DREAM complex. DYRK phosphorylates MuvB and activates the DREAM complex, which triggers cells to become quiescent. DYRK also stabilizes p27Kip1 through phosphorylation and prevents cells from moving into the G1 phase by reducing the expression of cyclin D.

Figure 3

Angiogenic dormancy (“extrinsic dormancy”) at niches. At niches, dormancy can be induced through signaling between DTCs, endothelial cells, and stroma with both upregulation and downregulation of multiple factors and signaling axes. DTCs enter dormancy with a vascular structure that is stable and non-angiogenic. In contrast, a sprouting vascular structure triggers tumor cells to exit from dormancy following an “angiogenic switch” in microenvironment, leading to tumor outgrowth and recurrence or metastasis. BMP, bone morphogenetic protein; CXCL12, Chemokine (C-X-C motif) ligand 12; EGFR, epithelial growth factor receptors; ESM-1, endothelial specific marker 1; FGF, fibroblast growth factor; HSP27, heat shock protein 27; IGFBP5, insulin-like growth factor binding protein 5; LTBPs, latent transforming growth factor β binding protein; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor β; VEGFs, vascular endothelial growth factors.

Figure 4

Immunologic dormancy (“equilibrium dormancy”) at niches. The immune system can control tumor cells through elimination, equilibrium, or escape. DTCs can enter dormancy during equilibrium states. Over years, environmental factors change or the genomic stability of DCTs changes, allowing dormant cells to escape (this state is called immunosurveillance) and reactivate to grow. At niches, immune cells, stroma, and endothelial cells can secret mitogens, immunosuppressive factors, and angiogenic factors that modify the tumor microenvironment and trigger cells to exit from dormancy and lead to recurrence or metastasis. CTL, cytotoxic T-lymphocytes; CXCL10, C-X-C motif chemokine 10; INFγ, Interferon gamma; MDSCs, myeloid-derived suppressor cells; NK, natural killer; TAMs, tumor-associated macrophages; T_REG, regulatory T-cells.