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

Abstract

More recently, disease metastasis and relapse in many cancer patients several years (even some decades) after surgical remission are regarded as tumor dormancy. However, the knowledge of this phenomenon is cripplingly limited. Substantial quantities of reviews have summarized three main potential models that can be put forth to explain such process, including angiogenic dormancy, immunologic dormancy, and cellular dormancy. In this review, newly uncovered mechanisms governing cancer cell dormancy are discussed, with an emphasis on the cross talk between dormant cancer cells and their microenvironments. In addition, potential mechanisms of reactivation of these dormant cells in certain anatomic sites including lymph nodes and bone marrow are discussed. Molecular mechanism of cellular dormancy in head and neck cancer is also involved.

Keywords: cancer cell dormancy; disseminated tumor cells; head and neck cancer; hypoxia; lymph node metastasis.

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.