Tumor Cell Dormancy: Threat or Opportunity in the Fight against Cancer

Abstract

Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including angiogenic switch, immune escape, cancer stem cells, extracellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer and discuss the implications of such approaches in cancer treatment.

Tumor microenvironment complexity and therapeutic implications at a glance

“…ECM may act as a barrier for drug delivery through increased tissue stiffness and desmoplasia or a gate for breaching the basement membrane to promote metastasis [2,122]. Furthermore, the ECM of distant organs can be remotely shaped into permissive/restrictive soils by soluble factors/CTCs/exosomes from primary tumors to facilitate the seeding of metastasizing cancer cells (See for review [9]).…”

“…Thus, they can serve as valuable prognostic, diagnostic, and biosensing tools to detect cancer cells that are clinically undetectable, and to make plans for timely and precise therapeutic interventions (Fig. 2e) [9].…”

“…Recent advances in tumor biology have shown that a comprehensive analysis of the multiple exchanges between tumor cells and their neighboring microenvironment is essential to understand the different underlying mechanisms of tumor growth and metastasis [8]. The loss of tissue integrity, carcinogenesis and further progress occurs as a consequence of reciprocal interactions between tumor cells with non-cellular (ECM) and cellular components of the TME [9,10]. Therefore, on the other side of the argument, interactions in reactive non-neoplastic cells, genetically-altered tumor cells, and ECM control the majority of the stages of tumorigenesis effectively including clonal evolution, cancer heterogeneity, epithelial-mesenchymaltransition (EMT), migration, invasion, development of metastasis, neovascularization, apoptosis and chemotherapeutic drug resistance [11][12][13][14].…”

TIE2 Induces Breast Cancer Cell Dormancy and Inhibits the Development of Osteolytic Bone Metastases

“…As a consequence, dormant cells can persist as residual disease in treated patients and cause a recurrence in the form of bone metastases sometimes after decades of life apparently free of cancer [3]. DTCs and HSCs share similarities in the way they are retained within the bone marrow and are rendered dormant, which allowed the identification of some dormancy-inducing factors, such as BMP7 or GAS6 [44]. However, it has not been possible to implement them in clinical trials so far.…”

Mesoporous Silica Nanoparticles for the Treatment of Complex Bone Diseases: Bone Cancer, Bone Infection and Osteoporosis

“…Dormant cells are cells that stop dividing but still survive in a quiescent state, waiting for the appropriate environmental conditions to re-enter the cell cycle again [99]. These cells are clinically undetectable and, consequently, constitute a major issue for future tumor recurrence and metastases [100]. Current pharmacological approximations are aimed at maintaining cancer cells in the dormant state; reactivating dormant cells to increase their susceptibility to drugs; and eliminating cancer cells.…”