Dormant cancer cells: programmed quiescence, senescence, or both?

Abstract

Metastasis is the overwhelming driver of cancer mortality, accounting for the majority of cancer deaths. Many patients present with metastatic relapse years after eradication of the primary lesion. Disseminated cancer cells can undergo a durable proliferative arrest and lie dormant in secondary tissues before reentering the cell cycle to seed these lethal relapses. This process of cancer cell dormancy remains poorly understood, largely due to difficulties in studying these dormant cells. In the face of these challenges, the application of knowledge from the cellular senescence and quiescence fields may help to guide future thinking on the study of dormant cancer cells. Both senescence and quiescence are common programs of proliferative arrest that are integral to tissue development and homeostasis. Despite phenotypic differences, these two states also share common characteristics, and both likely play a role in cancer dormancy and delayed metastatic relapse. Understanding the cell biology behind these states, their overlaps and unique characteristics is critical to our future understanding of dormant cancer cells, as these cells likely employ some of the same molecular programs to promote survival and dissemination. In this review, we highlight the biology underlying these non-proliferative states, relate this knowledge to what we currently know about dormant cancer cells, and discuss implications for future work toward targeting these elusive metastatic seeds.

Escape from senescence: molecular basis and therapeutic ramifications

“…Moreover, based on these facts, senescence has been proposed as a driver of cancer dormancy. The latter is characterised by cells that remain alive in an arrested state and can be reactivated to give rise to tumour relapse and metastatic disease [67,74,144,145]. Interestingly, a cellular state termed quiescence, which is distinct from cellular senescence but shares some common features, has been proposed to play a role in cancer dormancy [3,145].…”

“…The latter is characterised by cells that remain alive in an arrested state and can be reactivated to give rise to tumour relapse and metastatic disease [67,74,144,145]. Interestingly, a cellular state termed quiescence, which is distinct from cellular senescence but shares some common features, has been proposed to play a role in cancer dormancy [3,145]. Quiescent cells are, like senescent cells, cell‐cycle arrested; however, this arrest is reversible and involves another set of molecular pathways (p27 Kip1 activation), while secretory properties and macromolecular damage are absent [3].…”

Cellular Dormancy in Cancer: Mechanisms and Potential Targeting Strategies

“…In addition, senescent cells display persistent DNA damage responses, altered chromatin structure (senescence-associated heterochromatin foci), elevated β-galactosidase (β-gal) activity, and a hypersecretory ability known as the "senescence-associated secretory phenotype" (SASP) [24,47,48]. Senescence is induced in response to various stressful stimuli such as oncogene expression and chemotherapy [47].…”

“…Despite the presence of senescence-associated characteristics in dormant cancer cells [24,47] and the similarities between senescence and dormancy (such as induction by stressful stimuli, growth arrest accompanied by p21 upregulation, and p38 MAPK activation) [24,49], several…”

Unveiling the role of cellular dormancy in cancer progression and recurrence

“…Despite remarkable advances in the field of oncology, cancer continues to be a leading cause of mortality worldwide [1]. Growing evidence points to the emergence of dormant cells as a contributor to the disease's aptitude to evade therapeutic interventions [2,3 ]. Beyond proliferation, the phenotypic switch of cellular dormancy is characterized by a substantial decrease in biosynthetic activity, such as RNA transcription and protein translation [10,11].…”