Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow

Johnson, Rachelle W.; Finger, Elizabeth; Olcina, Monica M.; Vilalta, Marta; Aguilera, Todd A.; Miao, Yu; Merkel, Alyssa R.; Johnson, Joshua; Sterling, Julie A.; Wu, Joy Y.; Giaccia, Amato J.

doi:10.1038/ncb3408

Cited by 217 publications

(308 citation statements)

References 71 publications

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“…Leukemia inhibitory factor (LIF), which is produced by osteoblast-lineage and bone marrow (BM) stromal cells, can induce disseminated breast cancer cell dormancy [106], a reversible growth arrest state. Accordingly LIF receptor (LIFR) functions as a metastasis inhibitor in different cancers [106,107] and, in breast cancer patients with bone metastases, low levels of LIFR are correlated with poor patient outcome.…”

Section: Routes By Which Hypoxia Affects Dtc Fatementioning

confidence: 99%

“…Accordingly LIF receptor (LIFR) functions as a metastasis inhibitor in different cancers [106,107] and, in breast cancer patients with bone metastases, low levels of LIFR are correlated with poor patient outcome. Intriguingly, hypoxia (0.5% O 2 for 24 h) and HIF signaling reduce the LIFR–STAT3–SOCS3 signaling pathway in breast cancer cells in vitro leading to downregulation of dormancy related genes.…”

Section: Routes By Which Hypoxia Affects Dtc Fatementioning

confidence: 99%

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The Different Routes to Metastasis via Hypoxia-Regulated Programs

Nobre

Entenberg

Wang

et al. 2018

Trends in Cell Biology

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Hypoxia is linked to metastasis; however, how it affects metastatic progression is not clear due to limited consensus in the literature. We posit that this lack of consensus is due to hypoxia being studied using different approaches, such as in vitro, primary tumor, or metastasis assays in an isolated manner. Here, we review the pros and cons of in vitro hypoxia assays, highlight in vivo studies that inform on physiological hypoxia, and review the evidence that primary tumor hypoxia might influence the fate of disseminated tumor cells (DTCs) in secondary organs. Our analysis suggests that consensus can be reached by using in vivo methods of study, which also allow better modeling of how hypoxia affects DTC fate and metastasis.

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Section: Routes By Which Hypoxia Affects Dtc Fatementioning

confidence: 99%

Section: Routes By Which Hypoxia Affects Dtc Fatementioning

confidence: 99%

The Different Routes to Metastasis via Hypoxia-Regulated Programs

Nobre

Entenberg

Wang

et al. 2018

Trends in Cell Biology

View full text Add to dashboard Cite

show abstract

“…Histological evidence suggests that tumor cells may come in direct contact with the bone surface at late stages of disease (Fig. 1b), but if blocking integrin signaling ablates this interaction, it may not be necessary to determine whether the mechanotransduction signals are mediated through tumor–bone or tumor–bone lining cell interactions [35, 36]. Second, how does the bone modulus influence the initial phases of bone colonization and the progression of tumor cells in the bone marrow?…”

Section: Hallmarks Of Breast Cancer Bone Metastasismentioning

confidence: 99%

“…One potential effect may be on their exit from dormancy. Leukemia inhibitor factor (LIF) receptor (LIFR) signaling in breast cancer cells has been shown to maintain a state of dormancy in the bone marrow [35]. Hypoxia down-regulates LIFR promoter activity, mRNA, and protein levels in human breast cancer cells; however, this only occurs when breast cancer cells are cultured in ~ 0.5% pO 2 .…”

Section: Hallmarks Of Breast Cancer Bone Metastasismentioning

confidence: 99%

“…The HDAC inhibitor valproic acid significantly stimulated not just LIFR mRNA levels, but 9 of 12 previously published pro-dormancy genes [35], suggesting HDAC inhibitors may be effective in promoting a chronic state of dormancy. There are currently four HDAC inhibitors that are FDA-approved, and many others that are currently in phase I–III clinical trials, for the treatment of other tumor types and diseases, including chronic treatment of epilepsy and migraines [95].…”

Section: Hallmarks Of Breast Cancer Bone Metastasismentioning

confidence: 99%

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Hallmarks of Bone Metastasis

Johnson

Suva

2017

Calcif Tissue Int

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Breast cancer bone metastasis develops as the result of a series of complex interactions between tumor cells, bone marrow cells, and resident bone cells. The net effect of these interactions are the disruption of normal bone homeostasis, often with significantly increased osteoclast and osteoblast activity, which has provided a rational target for controlling tumor progression, with little or no emphasis on tumor eradication. Indeed, the clinical course of metastatic breast cancer is relatively long, with patients likely to experience sequential skeletal-related events (SREs), often over lengthy periods of time, even up to decades. These SREs include bone pain, fractures, and spinal cord compression, all of which may profoundly impair a patient’s quality-of-life. Our understanding of the contributions of the host bone and bone marrow cells to the control of tumor progression has grown over the years, yet the focus of virtually all available treatments remains on the control of resident bone cells, primarily osteoclasts. In this perspective, our focus is to move away from the current emphasis on the control of bone cells and focus our attention on the hallmarks of bone metastatic tumor cells and how these differ from primary tumor cells and normal host cells. In our opinion, there remains a largely unmet medical need to develop and utilize therapies that impede metastatic tumor cells while sparing normal host bone and bone marrow cells. This perspective examines the impact of metastatic tumor cells on the bone microenvironment and proposes potential new directions for uncovering the important mechanisms driving metastatic progression in bone based on the hallmarks of bone metastasis.

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Circulating and disseminated tumor cells: harbingers or initiators of metastasis?

2017

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Tumor cells leave the primary tumor and enter the circulation. Once there, they are called circulating tumor cells (CTCs). A fraction of CTCs are capable of entering distant sites and persisting as disseminated tumor cells (DTCs). An even smaller fraction of DTCs are capable of progressing toward metastases. It is known that the DTC microenvironment plays an important role in sustaining their survival, regulating their growth, and conferring resistance to therapy. But we still have much to learn about the nature of these rare cell populations to predict which will progress and what exactly should cause concern for future relapse. Although recent technological advances in our ability to detect and molecularly and functionally characterize CTCs and DTCs promise to unravel this ambiguity, the timing of dissemination and the precise source of CTCs and DTCs profiled will impact the conclusions that can be made from these endeavors. In this review, we discuss the biology of CTCs and DTCs; the technologies to detect, isolate, and profile these cells; and the exceptions we must apply to our understanding of what role these cells play in the metastatic process. We conclude that a greater effort to understand the unique biology of these cells in context will positively impact our ability to use these cells to predict outcome, monitor treatment efficacy, and reveal therapeutically relevant targets to deplete these populations and ultimately prevent metastasis.

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Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow

Cited by 217 publications

References 71 publications

The Different Routes to Metastasis via Hypoxia-Regulated Programs

The Different Routes to Metastasis via Hypoxia-Regulated Programs

Hallmarks of Bone Metastasis

Circulating and disseminated tumor cells: harbingers or initiators of metastasis?

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