The Different Routes to Metastasis via Hypoxia-Regulated Programs

doi:10.1016/j.tcb.2018.06.008

Trends in Cell Biology

Volume 28, Issue 11, November 2018, Pages 941-956

https://doi.org/10.1016/j.tcb.2018.06.008 Get rights and content

Highlights

Hypoxia is associated with resistance to therapy and metastasis onset but mechanistically this link is still unclear.

In vitro assays to study hypoxia in metastasis have limitations that lead to limited consensus on how it drives metastasis.

New intravital imaging technologies enable studies of hypoxia and metastasis in physiological contexts, revealing unanticipated roles of hypoxia not observed in vitro.

In vivo studies revealed that hypoxia could decrease motility speed while increasing invasiveness and priming tumor cells for dormancy after dissemination.

In vivo analysis of hypoxia and DTC fate may reveal its link to metastasis and poor prognosis and how to prevent recurrence.

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.

Section snippets

Hypoxia in Cell Fate and Cancer

Evolution and organism development have revealed how natural hypoxic environments influence cell survival and reprogramming. During evolution, organisms capable of efficiently handling oxidative stress and using oxygen for energy production exhibited survival and evolutionary advantages [1]. Normal mammalian development occurs in a moderate-to-severe hypoxic environment that is responsible for aspects of developmental morphogenesis. Oxygen concentrations in the uterine environment range from 1

Hypoxia, Motility, and Directionality in the Primary Tumor

Hypoxia is one microenvironmental parameter historically implicated in both metastasis initiation [13] and therapy resistance [14]. Early on, two studies performed in mouse models showed that tail vein injection of tumor cells previously exposed to hypoxic conditions (<0.1% O₂), followed by reoxygenation, led to a dramatic increase in resulting metastases 13, 15. These experiments, along with the advent of a small polarographic needle sensor for measurement of tissue oxygen levels, enabled a

Routes by Which Hypoxia Affects DTC Fate

A large body of literature that has been expertly reviewed recently links in vitro hypoxia to the epithelial-to-mesenchymal transition or EMT, which allows epithelial cells to reduce their interaction with other epithelial cells and become motile 5, 90, 91. Given that these mechanisms and papers were reviewed in the past we focus here primarily on in vivo studies. Also, because we attempt to understand how naturally occurring hypoxia in target organs affects DTC behavior, we do not focus on how

Concluding Remarks and Future Perspectives

Our analysis of recent literature reveals that understanding how hypoxia affects metastasis will require high resolution intravital imaging at single cell resolution and/or other methods that complement intravital imaging in vivo. These are key to help define the actual phenotypes of cells in primary tumors and secondary organs both in hypoxic and normoxic microenvironments. It is expected that in vivo studies will then inform more physiologic in vitro assays. Finally, the notion that hypoxia

Acknowledgments

ARN and JAA-G were supported by the Samuel Waxman Cancer Research Foundation Tumor Dormancy Program, NIH/NCI CA163131 CA109182 CA218024 and CA196521. JC, YW, and DE acknowledge the support of Einstein’s Integrated Imaging Program, and the National Institutes of Health grants CA100324, and CA216248.

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View full text

Trends in Cell Biology

ReviewThe Different Routes to Metastasis via Hypoxia-Regulated Programs

Highlights

Section snippets

Hypoxia in Cell Fate and Cancer

Hypoxia, Motility, and Directionality in the Primary Tumor

Routes by Which Hypoxia Affects DTC Fate

Concluding Remarks and Future Perspectives

Acknowledgments

Dev. Cell

Cell

Methods Enzymol.

Cancer Cell

Curr. Biol.

Methods

Cell Rep.

J. Biol. Chem.

Am. J. Pathol.

Neoplasia

Structure

Drug Resist. Updates

Cancer Cell

Role of hypoxia in the evolution and development of the cardiovascular system

Antioxid. Redox Signal.

Oxygen, epigenetics and stem cell fate

Regen. Med.

Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects

J. Natl. Cancer Inst.

The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy

Hypoxia (Auckl)

Direct visualization of the phenotype of hypoxic tumor cells at single cell resolution in vivo using a new hypoxia probe

Intravital

Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments

Nat. Cell Biol.

Hypoxia-driven selection of the metastatic phenotype

Cancer Metastasis Rev.

Hypoxia-mediated metastasis

Adv. Exp. Med. Biol.

Hypoxia, gene expression, and metastasis

Cancer Metastasis Rev.

Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells

Proc. Natl. Acad. Sci. U. S. A.

A factor of importance in the radio sensitivity of tumours

Br. J. Radiol.

Effects of reoxygenation on cells from hypoxic regions of solid tumors: anticancer drug sensitivity and metastatic potential

J. Natl. Cancer Inst.

Detection and characterization of tumor hypoxia using pO2 histography

Antioxid. Redox Signal.

Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response

Br. J. Radiol.

Molecular imaging of hypoxia

J. Nucl. Med.

Matrigel: a complex protein mixture required for optimal growth of cell culture

Proteomics

Targeting aurora kinase A inhibits hypoxia-mediated neuroblastoma cell tumorigenesis

Anticancer Res.

Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells

Proc. Natl. Acad. Sci. U. S. A.

Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis

Proc. Natl. Acad. Sci. U. S. A.

2D protrusion but not motility predicts growth factor-induced cancer cell migration in 3D collagen

J. Cell Biol.

Rate of death of hypoxic cells in multicell spheroids

Radiat. Res.

Intratumoral oxygen gradients mediate sarcoma cell invasion

Proc. Natl. Acad. Sci. U. S. A.

Hypoxia down-regulates MCP-1 expression: implications for macrophage distribution in tumors

J. Leukoc. Biol.

Hypoxia inhibits macrophage migration

Eur. J. Immunol.

Inhibition of monocyte and macrophage chemotaxis by hypoxia and inflammation – a potential mechanism

Eur. J. Immunol.

Hypoxia inhibits the migratory capacity of human monocyte-derived dendritic cells

Immunol. Cell Biol.

Both macrophages and hypoxia play critical role in regulating invasion of gastric cancer in vitro

Acta Oncol.

Observing the cell in its native state: imaging subcellular dynamics in multicellular organisms

Science

Multiparametric classification links tumor microenvironments with tumor cell phenotype

PLoS Biol.

Review
The Different Routes to Metastasis via Hypoxia-Regulated Programs

Detection and characterization of tumor hypoxia using pO₂ histography