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Mechanisms of disseminated cancer cell dormancy: an awakening field

Subjects

Key Points

  • It is thought that dormant disseminated tumour cells (DTCs) are the cellular entity responsible for clinical dormancy and subsequent metastasis after surgery and adjuvant treatment.

  • Cellular dormancy is regulated by intrinsic and autocrine signals, as well as signals derived from immune and endothelial cells. Stress signalling pathways activated by exogenous stressors, intrinsic damage or microenvironmental cues can trigger dormancy.

  • The balance between ERK and p38 signalling regulates dormancy versus proliferation decisions in different cancer models.

  • Autophagy is important for the induction of dormancy and cell survival. Morphogenetic cues and intrinsic pathways that regulate cell quiescence and pluripotency or 'stemness' might also coordinate DTC dormancy.

  • Mechanisms that were thought to regulate tumour mass dormancy, such as cytotoxic CD8+ T cells or non-angiogenic endothelial cells, may in fact regulate cellular dormancy.

  • Pathways and mechanisms regulating cellular dormancy can be manipulated to induce dormancy.

  • Dormancy models have identified gene signatures that are predictive of delayed onset of metastasis in patients and have provided a first shortlist of genes that may serve as dormancy markers to test in DTCs.

Abstract

Metastases arise from residual disseminated tumour cells (DTCs). This can happen years after primary tumour treatment because residual tumour cells can enter dormancy and evade therapies. As the biology of minimal residual disease seems to diverge from that of proliferative lesions, understanding the underpinnings of this new cancer biology is key to prevent metastasis. Analysis of approximately 7 years of literature reveals a growing focus on tumour and normal stem cell quiescence, extracellular and stromal microenvironments, autophagy and epigenetics as mechanisms that dictate tumour cell dormancy. In this Review, we attempt to integrate this information and highlight both the weaknesses and the strengths in the field to provide a framework to understand and target this crucial step in cancer progression.

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Figure 1: Dormancy of heterogeneous DTC subpopulations.
Figure 2: Permissive microenvironments and cues for DTC dormancy.
Figure 3: Intracellular pathways present in dormant and proliferative DTCs.

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Acknowledgements

This work was supported by grants from the Samuel Waxman Cancer Research Foundation Tumour Dormancy Program to J.A.A-G., the US National Institutes of Health/National Cancer Institute (CA109182, CA163131) and a DoD-BCRP Grant BC112380 to M.S.S.

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Correspondence to María Soledad Sosa, Paloma Bragado or Julio A. Aguirre-Ghiso.

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J.A.A.-G. has been a consultant for Novartis and Eli Lilly and Company, and he has received grant funding from Eli Lilly and Company. He occasionally gives industry-sponsored lectures, but only if the events are free of any marketing purpose. Please note that this information may differ from information posted on corporate sites due to timing or classification differences

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Glossary

Disseminated tumour cells

(DTCs). Cells that have physically separated from the primary tumour mass and have spread to other anatomical locations through the circulation. In the context of this Review these tumour cells are not yet considered to be micrometastases as they must expand to form a small population of cells.

Dormant

A state of suspended animation or low activity of a cell or organism.

Niches

A term borrowed from ecology, it refers to a unique optimal tissue microenvironment with defined nurturing and positional cues in a given anatomical location that allows a cell or a group of cells to survive and function.

Tumour cell spheroids

Clusters of cells in a ball-like structure that can exist in suspension, for example, in the peritoneal fluid of patients with ovarian cancer. These spheroids commonly shed cells into the peritoneal cavity.

Omentum

A layer of tissue from the peritoneum that connects abdominal viscera and the stomach that is a protective and supporting cover.

Mesothelium

A mesoderm-derived epithelium that lines the body cavities.

Minimal residual disease

Remnant tumour cells that remain after treatment and that cannot be detected by conventional methods in routine clinical testing. These cells can persist in the primary site or as disseminated tumour cells and might have proliferative and/or dormant phases.

Unfolded protein response

(UPR). A cellular response to stress unique to the endoplasmic reticulum (ER) that senses the misfolding of proteins in the ER caused, for example, by overloading of the ER, oxidative damage or protein unfolding during synthesis. It activates a series of pathways that will help cells to survive by correcting the proteotoxicity caused by unfolded proteins or by activating mechanisms of cell death.

CD8+ T cells

Cytotoxic immune cells from the T cell lineage that are specialized in killing target cells (that is, virus-infected cells).

Angiogenesis

The formation of new blood vessels that create new pathways for blood flow during normal tissue development or remodelling or during pathological conditions such as tumour growth or retinopathy.

Micrometastasis

A small group of tumour cells that have grown in secondary organs but that are too small to be seen or detected by currently available detection methods. These lesions derive from a disseminated tumour cell and might not produce clinical symptoms.

Angiogenic switch

Occurs when a small tumour mass senses the lack of appropriate blood supply and activates a series of transcriptional programmes that allows the production of signals that will recruit new blood vessels.

Transformation

A process in which cells that have been immortalized acquire additional genetic and epigenetic alterations that allow them to form primary tumours.

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Sosa, M., Bragado, P. & Aguirre-Ghiso, J. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer 14, 611–622 (2014). https://doi.org/10.1038/nrc3793

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