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Pretending to be dead to deceive opponents in fights and strike unexpectedly is a well-known cliche in books and movies. This is an analogy that loosely describes the activities of some dormant tumor cells in cancer treatment. Tumor dormancy has garnered a reasonable amount of buzz in cancer research because clinical research, especially in some breast and prostate cancers, has reported many cases of cancer relapse after years of initially successful treatment that has been attributed to the reawakening of dormant tumor cells.
Tumor dormancy is a reversible process in which cancer cells pause their cell cycle progression and go into a phase called G0 (Figure 1). In some cases, cancer cells migrate to distant organs in the early stage of the disease to become dormant, while in other more commonly reported cases, dormant cells are formed from cells that survive initial cancer treatment (Figure 2). Dormancy has been discovered to be an adaptive property that allows cancer cells to remain viable, but inactive when exposed to stressful conditions or agents such as chemotherapeutics. As a result of their inactivity and inability to proliferate rapidly (a hallmark of cancer cells), dormant tumor cells are insensitive to chemotherapeutic agents (because they target rapidly growing cells) and they can survive in their dormant state.
|The danger of dormant tumor cells lies in the fact that they can exit dormancy and become reactivated by external stimuli, genetic factors or tumor microenvironment (Fig 2). Furthermore, they have been found to acquire mutations that make them highly proliferative and resistant to chemotherapeutic agents after reactivation. As a result of this, it is safe to note that dormant cells are not asleep after all, but are lurking in anticipation for the opportunity to launch an attack, and researchers must work relentlessly to launch a counterattack in the fight for cancer therapy.|
To this effect, studies have reported three main strategies to target dormant tumor cells (Fig 3). These approaches are;
· Maintaining cells in a dormant state to prevent reawakening and metastatic relapse.
· Awakening dormant cells to make them sensitive to chemotherapeutic agents and other cancer therapy techniques.
· Targeting dormant cells to completely eradicate them.
The concept of maintaining cells in the dormant state to prevent reawakening is based on the well-known understanding that cancer cells are harmless in their dormant state and that the reactivation of dormant cells is one of the main culprits in metastatic relapse. Hence, maintaining cells in a perpetual state of dormancy is expected to be effective in preventing metastatic relapse. However, one of the drawbacks to this approach is that there is a possibility that not all dormant cancer cells will be sensitive to this treatment approach.
The second strategy that has been reported in tackling tumor dormancy is to reawaken dormant cells by ejecting them from the state of dormancy into a rapidly proliferative state to make them sensitive to cancer therapy. However, the success of this strategy depends on the ability to successfully eradicate all reawakened cells; otherwise, it could result in the formation of more aggressive tumor cells that could increase the chances of metastatic relapse.
Lastly, the presumably most efficacious method is to target and kill dormant tumor cells in their dormant state. If successful, it would completely eradicate dormant tumor cells without the fear of metastatic relapse. Still, the inability to accurately confirm the efficacy of this strategy, given the lack of appropriate diagnostic methods, is a major challenge.
To improve scientific discoveries in tumor dormancy research, we still need to tackle some important questions, including:
How can we prevent the formation of dormant tumor cells after initial treatment?
What are the factors responsible for the reactivation of dormant tumor cells?
How can we prevent the reactivation of dormant tumor cells?
How can we maintain cells in a state of dormancy if required?
Is it safer to reawaken dormant tumor cells or maintain them in a state of dormancy?
Finally, as a result of the potential dangers associated with the formation and reactivation of dormant tumor cells, it is imperative to continue to intensify efforts in identifying and understanding the mode of action of tumor dormancy promoting factors and determine the best course of action towards targeting dormant tumor cells. This is expected to go a long way in reaching a better prognosis and treatment outcome in cancer patients and could be key in reducing the incidence of cancer mortality due to cancer relapse and metastasis.
Edited by Sara Musetti
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Jahanban-Esfahlan, R., Seidi, K., Manjili, M.H., et al (2019). Tumor Cell Dormancy: Threat or Opportunity in the fight against Cancer. Cancers 11:1207
Recasens, A. and Munoz, L. (2019). Targeting Cancer Cell Dormancy. Trends in Pharmacological Sciences 40:2
Vera-Ramirez, L and Hunter, K.W (2017) Tumor cell dormancy as an adaptive cell stress response mechanisms. F100Research 6(F1000 Faculty Rev):2134