![]() Eventually, in response to microenvironmental cues, DCCs gain the ability to re-enter the cell cycle and adapt to their new microenvironment, thereby progressing to metastatic outgrowth. This period is termed “metastatic cancer dormancy” and occurs between initial therapy and metastatic relapse. At some point, DCCs reach distant organs and infiltrate into the stroma, although they cannot grow into macroscopic lesions until they escape dormancy. More recently, these circulating DCCs have been shown to evade immune surveillance by expressing programmed death ligand 1 (PDL-1) thus, they can persist for an extended period 4, 5. These dormant cancer cells (DCCs) are more susceptible to antiproliferative drugs. In circulation, cancer cells are likely to exhibit mitotic arrest through reversible G0-G1 arrest, termed quiescence, in which they remain viable but do not increase. Once cancer cells successfully penetrate into the blood or lymphatic circulatory system, they can disseminate throughout the body. During this process, cancer cells usually promote vascularization in tumor tissues to sculpt a permissive microenvironment for cancer cell proliferation and gain access to the bloodstream 3. The initiation step of metastasis begins when cancer cells at the primary tumor growth site foster basement membrane degradation and enter the underlying interstitial matrix 2. Metastasis is considered a series of linear events, termed the invasion–metastasis cascade 1. Although the clinical importance of metastasis is therefore apparent, its underlying mechanisms remain unclear. Such metastatic outgrowth rapidly becomes uncontrollable with chemoradiation and manages to seed additional metastatic colonies, resulting in the disruption of vital organ function. However, even patients who are considered clinically free of cancer cells after initial treatment frequently relapse with distant metastasis. The primary treatment for cancer is the surgical removal of cancer cells, which is often combined with chemoradiotherapy to kill surgically inaccessible cancer cells throughout the body. In the present review, we attempt to consolidate the existing literature to provide a framework for the understanding of this crucial step in cancer progression. Upon the binding of circulating DCCs to extracellular molecules, various signaling cascades are activated and reinitiate cell proliferation. The cytotoxic activity of immune cells can cause cancer cells to enter a dormant state, and chronic inflammation can reactivate cancer proliferation at distant sites. Over the last decade, a growing body of literature has revealed the mechanisms involved in cancer dormancy and reawakening. Therefore, understanding the biology of DCC reawakening is key to preventing metastasis. Eventually, DCCs can reawaken in response to signals, which are not yet fully understood, resulting in recurrence and metastasis. Moreover, they can interpret homoeostatic signals from the microenvironment, thereby evading immune surveillance and chemotherapy. These dormant cancer cells (DCCs) are rarely detectable with current diagnostic systems. Cancer cells are likely to disseminate during cancer progression, and some may enter dormancy, remaining viable but not increasing. ![]() ![]() Recurrent cancer that spreads to distant sites is the leading cause of disease-related death among cancer patients.
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