Dormant tumour cells, their niches and the influence of immunity

Goddard, Erica T.; Božić, Ivana; Riddell, Stanley R.; Ghajar, Cyrus M.

doi:10.1038/s41556-018-0214-0

Cited by 152 publications

(134 citation statements)

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“…Upon dissemination in a secondary organ, metastatic breast cancer cells (BCCs) can undergo three fates: death, dormancy, or growth. Dormancy does not have a clear biological definition, it has been proposed a classification of dormant phenotypes into cellular dormancy (entering into reversible quiescence in G0) and tumor mass dormancy (a small cluster of cells where proliferation is counterbalanced by apoptosis due to lack of nutrients, blood supply or because of immune surveillance) (Linde et al, 2016;Goddard et al, 2018;Weidenfeld and Barkan, 2018;Lan et al, 2019). However, these states are likely to coexist within the same patients and probably the same cells can dynamically fluctuate between these different states.…”

Section: Metastatic Dormancymentioning

confidence: 99%

“…This is not entirely correct as recent data show that chemoresistance is in part actively supported by the metastatic niche and is not just a consequence of cell-cycle arrest (Carlson et al, 2019). Moreover, it has been recently shown that several patients with bone marrow-disseminated cancer cells (DCCs) that resisted treatment with FEC (fluorouracil, epirubicin, and cyclophosphamide), benefited from additional treatment with docetaxel; as this drug induces microtubule stabilization, cell-cycle arrest in the G(2)M phase and apoptosis, this suggests that a considerable fraction of dormant cells still has proliferative activity (Naume et al, 2014;Goddard et al, 2018). Notably, patients with dormant DCCs that persisted after the second therapy had worst prognosis, further supporting the idea that metastatic lesions develop from preexisting dormant DCCs (Braun et al, 2005;Naume et al, 2014).…”

Section: Metastatic Dormancymentioning

confidence: 99%

“…From these numbers the expectation might be that persistence in secondary organs is a feature restricted to few highly aggressive cells (seed) and/or to target organs with a peculiar permissive environment (soil). Yet, clinical and experimental evidence of early dissemination of breast cancers have been reported (Goddard et al, 2018), indicating that even cells from early stage disease can disseminate and persist. Moreover, several registries reported people who have developed cancers following organ transplants (Buell et al, 2005;Klein, 2011), indicating that disseminated cells survived in a quiescent state in different organs of donors with prior undiagnosed or cured cancers.…”

Section: Data From Patientsmentioning

confidence: 99%

“…Even though these in vitro models are increasing in number and complexity, their descriptive and/or predictive power is unknown, given the paucity of markers, metrics and expression data from patients. Nevertheless, there are common themes emerging from different models that led to the approval of clinical trials (Goddard et al, 2018) and to the development of tools to predict likelihood of relapse (Borgen et al, 2018). Moreover, recent publications provided explanations for epidemiological data linking inflammation with higher risk of breast cancer relapse (Cock et al, 2016;Albrengues et al, 2018).…”

Section: Challenges For the Development Of In Vitro Modelsmentioning

confidence: 99%

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In vitro Models of Breast Cancer Metastatic Dormancy

Montagner

2020

Front. Cell Dev. Biol.

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Delayed relapses at distant sites are a common clinical observation for certain types of cancers after removal of primary tumor, such as breast and prostate cancer. This evidence has been explained by postulating a long period during which disseminated cancer cells (DCCs) survive in a foreign environment without developing into overt metastasis. Because of the asymptomatic nature of this phenomenon, isolation, and analysis of disseminated dormant cancer cells from clinically disease-free patients is ethically and technically highly problematic and currently these data are largely limited to the bone marrow. That said, detecting, profiling and treating indolent metastatic lesions before the onset of relapse is the imperative. To overcome this major limitation many laboratories developed in vitro models of the metastatic niche for different organs and different types of cancers. In this review we focus specifically on in vitro models designed to study metastatic dormancy of breast cancer cells (BCCs). We provide an overview of the BCCs employed in the different organotypic systems and address the components of the metastatic microenvironment that have been shown to impact on the dormant phenotype: tissue architecture, stromal cells, biochemical environment, oxygen levels, cell density. A brief description of the organ-specific in vitro models for bone, liver, and lung is provided. Finally, we discuss the strategies employed so far for the validation of the different systems.Keywords: cancer dormancy, metastatic dormancy, in vitro models cancer, cancer metastasis, breast cancer, metastasis biology METASTATIC DORMANCYDormancy is an old concept that describes a clinical phenomenon (Klein, 2011; Uhr and Pantel, 2011), i.e., the relapse of a cancer after surgical removal of the primary tumor in a patient considered clinically disease-free for a long time. This implies that cancer cells disseminated prior to surgery and persisted as Minimal Residual Disease (MRD) for a prolonged time (arbitrarily defined, but usually longer than 5 years) before switching to aggressive growth and overt metastasis. The recurrence can be at the primary site (primary tumor dormancy) or at a secondary site (metastatic dormancy). The mechanisms underlying the two types of dormancy are likely to be partially overlapping if involving cell intrinsic genetic/epigenetic mechanisms, or distinct, if dependent on the tissue microenvironment. Clinical dormancy is common for breast, prostate, melanoma, renal, and thyroid cancers, while it is rarely observed in lung and colon cancers (Uhr and Pantel, 2011). In breast cancers, estrogen receptor (ER) status seems to profoundly influence the rate of relapse: ER− patients tend to recur within the first 5 years following primary tumor diagnosis, while ER+ patients have increased risk between 5 and 20 years (Pan et al., 2017;Pantel and Hayes, 2018). While anti-estrogen therapy significantly improved patient outcomes, a significant fraction of them still

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Section: Metastatic Dormancymentioning

confidence: 99%

Section: Metastatic Dormancymentioning

confidence: 99%

Section: Data From Patientsmentioning

confidence: 99%

Section: Challenges For the Development Of In Vitro Modelsmentioning

confidence: 99%

See 2 more Smart Citations

In vitro Models of Breast Cancer Metastatic Dormancy

Montagner

2020

Front. Cell Dev. Biol.

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“…We consider the events that lead to reactivation of these dormant tumor cells within the skeleton and discuss the translational models and preclinical studies that have helped define these mechanisms. Whereas cell‐intrinsic mechanisms and immune regulation may play a role in controlling tumor cell dormancy, for the purpose of this review we will focus on the tumor cell‐extrinsic environmental signals that may govern this process, as the former has been discussed elsewhere . We conclude with future directions to further profile dormant tumor cells and the metastatic niches in bone, and discuss the clinical implications and therapeutic opportunities of bone‐targeted agents for treating skeletal metastasis.…”

Section: Introductionmentioning

confidence: 99%

Tumor Cell Dormancy and Reactivation in Bone: Skeletal Biology and Therapeutic Opportunities

2019

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In the advanced stages of many cancers, tumor cells disseminate from the primary site and colonize distant locations such as the skeleton. These disseminated tumor cells colonizing bone can evade treatments and survive for prolonged periods in a dormant state before becoming reactivated to form overt metastases. The precise interactions between tumor cells and the bone microenvironment that promote survival, dormancy, and reactivation are currently unknown; as a result, bone metastases remain incurable. In this review we discuss the unique cellular and microenvironmental features of endosteal bone that tumor cells engage with to persist and survive, and ultimately reactivate and proliferate. Specifically, we provide a detailed summary of current perspectives on the processes of tumor cell colonization of the skeleton, and the endosteal bone cells as critical controllers of the dormant cancer cell phenotype, as well as relevant microenvironmental effects such as hypoxia. Evidence for the role of the osteoclast in controlling dormant cancer cell reactivation in bone is highlighted, preceding a discussion of therapeutics targeting the bone microenvironment, including anti‐RANK ligand and bisphosphonate therapies and their potential utility in preventing tumor cell reactivation in addition to protecting bone from tumor‐induced destruction. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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