The Silent Threat: Tumour Cell Dormancy and the Future of Therapy

Abstract 

Cancer, a disease characterized by uncontrollable cell proliferation, remains one of the leading causes of death worldwide, with metastasis accounting for >90% of total tumour-related deaths_[1]. Cancer recurrence, driven mostly by dormant tumour cells, remains a major hurdle in developing effective therapies. This review aims to summarize the current knowledge and findings around tumour cell dormancy and cancer recurrence, highlighting potential therapeutic paths. Understanding these processes is a fundamental part of developing new strategies, with the main aim of improving patient outcomes and ultimately lessening the burden of disease globally.

Introduction

Metastasis is the process by which cancer cells from a primary tumour spread to other organs or tissues in the body, either via the lymphatic or circulatory system, and result in the formation of secondary malignant tumours_[2]. There are three main phases of metastasis: the first is dissemination, where cells with growth-promoting mutations, also known as oncogenic driver mutations,  invade surrounding tissues and enter blood or lymphatic vessels_[3]. Endothelial cells are found in the lining of vessel walls, and cancerous cells either move through or between endothelial cells to enter a new tissue or organ. After this, a default period of dormancy follows, which is the main focus of this article_[3]. Dormancy itself plays a huge role in metastasis and the recurrence of cancer later in life.

What is Dormancy?

Dormancy is exactly what it sounds like - it is a reversible natural survival mechanism where cells cease division, and therefore reproduction, due to sudden changes in the environment or a lack of a sufficient quantity of nutrients to facilitate growth_[4]. There are two main types of dormancy: cellular dormancy and tumour mass dormancy, and either of these states can be triggered by reduced nutrients and oxygen, enabling survival in harsh, foreign environments, but also enabling the evasion of immune surveillance and therapy_[4]. 

Cellular Dormancy

To understand cellular dormancy, it is essential to first comprehend the cell cycle, which is the sequence of events that culminates in cell division, specifically mitosis. First is the G1 phase, during which a cell grows and maintains control of its internal conditions, followed by the S phase, where DNA replication occurs within the cell_[5]. Then, G2 involves preparing for mitosis by replicating organelles, followed by cell division and mitosis. This cycle continues throughout a cell’s life cycle. However, between the G1 and S phase, a cell can enter a G0 phase, which is a resting state that could last for years or even until an organism dies if unfavourable conditions are detected_[5].

Cellular dormancy could be likened to a 'time-out' for cells. When a cell goes into dormancy, it stops growing and dividing, but is still alive. This can happen when a cell's DNA is damaged or the environment is too harsh for the cell to survive in. Special proteins called cell cycle inhibitors, such as p21 and p27, help put cells in dormancy. One important protein, called p53, acts as a security guard for the cell's DNA; when it detects damaged DNA, it either triggers programmed cell death or dormancy to try to repair the damaged DNA. p21 is a 'henchman' for p53; it blocks the transition between the G1 and S phase, putting the cell into dormancy. On the other hand, p27 is regulated by growth factor signaling; an abundance of growth factors leads to the degradation of p27 and cell growth, while a low quantity of growth factors leads to an accumulation of p27 and therefore dormancy.

Eventually, when either more favourable conditions are detected, as in the case of p27-induced dormancy, or the damage has been repaired, as in the case of p21-induced dormancy, the cell resumes the proliferation and growth_[6].

Tumour Mass Dormancy

Tumour mass dormancy is defined as the ‘balance between the net increase in proliferation and net decrease in cell death, creating an equilibrium’. In simple terms, the tumour maintains a stable size because the rate of cell growth and division is balanced by the rate of cell death, and so no obvious tumour growth is observed. Tumour mass dormancy can be further classified into Angiogenic Dormancy and Immunomediated Dormancy.

Angiogenic Dormancy occurs before the angiogenic switch, which is the period when a tumour is unable to initiate growth of blood vessels towards itself_[4]. As a result, it does not receive sufficient nutrients or oxygen to sustain growth at a large scale. During this phase, anti-angiogenic factors outweigh pro-angiogenic factors, preventing a switch, leading to increased cell death and overall net tumour growth equaling zero_[4].

Immunomediated Dormancy is a state where the immune system is effective enough to keep carcinoma cells in a non-proliferative state to prevent active disease. For example, CD8+ T cells and CD4+ T cells recognise and kill cancer cells through detection of antigens on their surface, while NK cells release toxic cytokines to suppress tumour growth_[4]. As a result of constant proliferation and immune attack, the overall net tumour growth is equal to zero.

Microenvironments

Before exploring potential markers and therapies for dormant tumour cells, it is important to understand how the tumour microenvironment influences their behaviour. The incidence of dormant tumour cells in some organs, for example, is much higher than actual metastasis incidence, suggesting that the microenvironment influences whether or not recurrence takes place_[7]. 

Dormancy-Permissive Environments

Dormancy-permissive environments contain inhibitors, signals and immune surveillance which actively promote the maintenance of dormant tumour cells. All dormancy-permissive environments have low proliferative signaling, balanced immune signaling and the slowdown of metabolic processes to enable survival at a rate that is suppressive enough to prevent growth, but not harsh enough to reactivate the cells_[7].

An example that highlights this is the detection of dormant tumour cells in the bone marrow of gastric cancer patients_[7]. However, the clinical incidence of these cells becoming active is rare, as proliferative markers are often absent, indicating that they survive in a non-proliferative state for an extended period of time. Simply put, active tumour cells in bone marrow are rare, but dormant tumour cells from other organs are commonly found in patients with cancer; bone marrow is dormancy-permissive.

Dormancy-Restrictive Environments

As the name suggests, these are the exact opposite of permissive environments. Dormancy-restrictive environments are characterized by conditions that actively promote the reactivation of dormant tumour cells. These include growth-factor-rich conditions, inflammatory factors, and immunosuppressive elements_[7].

A protein that plays a key role in the dormancy-to-proliferation transition is the MLCK protein. This protein is needed for the formation of actin stress fibers, which are used for cell stiffening_[8]. Cell stiffening is important in activating specific pathways that reactivate growth signals and ultimately jumpstart cell division. Therefore, a high abundance of MLCK triggers the reactivation of many dormant cells, effectively regulating the dormancy-to-proliferation switch_[8].

Reactivation

The reactivation of dormant tumour cells is what causes recurrence, and is therefore a vital part of developing therapies. 

Epigenetic Regulators

Epigenetic regulators affect the gene expression of a cell rather than the actual genetic sequence. An example of this is Methylation, where certain proteins add methyl groups to DNA to turn genes such as p53 off_[9]. Doing this on growth proliferation genes induces dormancy, so the loss of methylation results in an increase in proliferation. Another example is Histone modification, which is where histone proteins that regulate genes and repair are chemically modified, often resulting in changes in gene accessibility_[9]. Therefore, gaining repressive histone marks reinforces quiescence, so when these marks are removed and activating marks return, proliferation increases_[9].

Transcription Factors

Regulation of protein factors, such as p21 and p27, as previously mentioned, maintains the dormant state of cells due to the inhibition of transcription_[9]. Both p21 and p27 are cell cycle inhibitors that cause cycle arrest when specific signals are detected. These signals can either come from another gene, such as the p53 gene, or from growth factors that respond to the environment. Therefore, deactivation of these genes through external factors, such as the use of tobacco or exposure to radiation, deactivates any restrictions, resulting in cell division and growth taking place without any restrictions_[9].

Possible Future Therapies

Keeping tumour cells in a dormant state, or even reactivating a dormant state, could be more targeted and efficient than other solutions such as chemotherapy. Chemotherapy itself cannot suppress dormant cells as it targets dividing cells using mitotic markers, thus rendering it useless. 

Although awakening dormant tumour cells is an option, the act of allowing them to proliferate while actively killing them means that we would be expanding the possibilities of therapy-resistant mutations occurring, and this would rapidly fuel tumor recurrence. Therefore, the utilisation of therapies that either prolong dormancy or reactivate dormancy is much more effective. 

One technique that is being actively researched is the use of demethylating agents. Demethylating agents suppress methylating genes, therefore reactivating tumour suppressor genes and growth-controlling genes that are often deactivated in tumour cells_[9]. Another possible therapy is tocreate drugs and methods that directly target dormant cells. For example, Fibronectin inhibition has been reported to hinder the survival of dormant cancer cells_[9]. However, developing technology and methods that are efficient and accurate enough to identify and kill cells is still in the early stages. Currently, the likelihood of dormant cells surviving, gaining resistance, and ultimately becoming more aggressive towards future treatment is too high to confidently test and use these methods in Vivo_[9]. 

Conclusion

Cell dormancy is a default phase in cancer metastasis. It is affected by the tumour’s environment, with some sites offering more potential for reactivation and growth than others. Fluctuations in epigenetic and transcription factors can reactivate dormant cells and lead to tumour growth. Taking advantage of these fluctuations with techniques such as demethylation paves the way for new, precise approaches that could prevent cancer before its detrimental effects take hold. More research in this area could provide insights into therapies targeting traits common to all metastatic cancers, and successful development of these therapies could improve patient outcomes in the future.

References 

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Figure 1. Sara Di Russo, Francesca Romana Liberati, Agnese Riva, Federica Di Fonzo, Alberto Macone, Giorgio Giardina, Marzia Arese, Serena Rinaldo, Francesca Cutruzzolà, and Alessio Paone. “Beyond the Barrier: The Immune-Inspired Pathways of Tumor Extravasation.” Cell Communication and Signaling 22, no. 1 (February 8, 2024). https://doi.org/10.1186/s12964-023-01429-1

Figure 2. Endo, Hiroko, and Masahiro Inoue. “Dormancy in Cancer.” Cancer Science 110, no. 2 (January 11, 2019): 474–80. https://doi.org/10.1111/cas.13917

Figure 3. Fernández-Hernández, Sofía, Miguel Ángel Hidalgo-León, Carlos Lacalle-González, Rocío Olivera-Salazar, Michael Ochieng Otieno, Jesús García-Foncillas, and Javier Martinez-Useros. “Dormancy in Colorectal Carcinoma: Detection and Therapeutic Potential.” Biomolecules 15, no. 8 (August 4, 2025): 1119. https://doi.org/10.3390/biom15081119