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Intravital imaging to study cancer progression and metastasis

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From Nature Reviews Cancer

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Abstract

Navigation through the bulk tumour, entry into the blood vasculature, survival in the circulation, exit at distant sites and resumption of proliferation are all steps necessary for tumour cells to successfully metastasize. The ability of tumour cells to complete these steps is highly dependent on the timing and sequence of the interactions that these cells have with the tumour microenvironment (TME), including stromal cells, the extracellular matrix and soluble factors. The TME thus plays a major role in determining the overall metastatic phenotype of tumours. The complexity and cause-and-effect dynamics of the TME cannot currently be recapitulated in vitro or inferred from studies of fixed tissue, and are best studied in vivo, in real time and at single-cell resolution. Intravital imaging (IVI) offers these capabilities, and recent years have been a time of immense growth and innovation in the field. Here we review some of the recent advances in IVI of mammalian models of cancer and describe how IVI is being used to understand cancer progression and metastasis, and to develop novel treatments and therapies. We describe new techniques that allow access to a range of tissue and cancer types, novel fluorescent reporters and biosensors that allow fate mapping and the probing of functional and phenotypic states, and the clinical applications that have arisen from applying these techniques, reporters and biosensors to study cancer. We finish by presenting some of the challenges that remain in the field, how to address them and future perspectives.

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Fig. 1: Example images obtained by intravital imaging taken from a variety of tissues.
Fig. 2: Large-volume, high-resolution intravital imaging.
Fig. 3: The contribution of high-resolution intravital imaging to our understanding of the effects of various therapies on the tumour microenvironment and cancer phenotype.

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Acknowledgements

This work was supported by the Gruss Lipper Biophotonics Center and the Integrated Imaging Program at Albert Einstein College of Medicine, the EGL Charitable Foundation and grant number CA216248.

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Authors and Affiliations

  1. Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA

    David Entenberg, Maja H. Oktay & John S. Condeelis

  2. Integrated Imaging Program, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA

    David Entenberg, Maja H. Oktay & John S. Condeelis

  3. Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA

    David Entenberg & Maja H. Oktay

  4. Department of Surgery, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA

    Maja H. Oktay & John S. Condeelis

  5. Department of Cell Biology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA

    John S. Condeelis

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  1. David Entenberg
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All authors researched data for the article, contributed substantially to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

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Glossary

Acoustic vaporization

Vascular disruption induced by vaporization of microscale or nanoscale droplets using ultrasound sonication.

Chemotactic index

A metric capable of measuring the directed movement of an organism or entity in response to a chemical stimulus.

Collective migration

The coordinated movement of a large cluster of adherent tumour cells that retain homotypic cell–cell junctions out of the tumour mass and towards the stromal blood vasculature.

Confocal microscopy

A form of high-resolution optical microscopy that captures optical sections with single-cell resolution by collecting light only from a single slice of an otherwise intact tissue.

Fluorescence ratio imaging microscopy

An optical microscopy technique that measures the ratio of two different wavelengths to quantify shifts in the fluorescence spectra of probes without the influence of system-specific parameters (for example, detector quantum efficiency, excitation intensity and optical path length).

Liver sinusoids

Highly specialized endothelial cells forming fenestrated blood vessels of the hepatic microcirculation.

Machine vision

Imaging-based automatic inspection and analysis.

Magnetic resonance imaging

A relatively low resolution but deeply penetrating imaging technique, commonly used in the clinic, which measures the effect of strong magnetic fields on the nuclei of water molecules to form an image of the structure, and sometimes function, of tissues and organs.

Mosaicked pattern

A combination or merger of multiple high-resolution, high-magnification images of a sample into a single image, producing a low-magnification, high-resolution image.

Multiphoton microscopy

A form of optical microscopy that captures optical sections with single-cell resolution by using femtosecond pulsed lasers to limit signal generation to a single slice of an otherwise intact tissue.

Optical sections

Images of a single thin plane from within a thick sample captured by removal of out-of-focus light. The name originates from the similarity these images have to those obtained from mechanically sectioned and stained tissues.

Phosphorescence quenching microscopy

In the biological sciences, an optical microscopy technique for the sensitive evaluation of oxygen consumption using optical oxygen sensors whose phosphorescence changes with oxygen concentration.

Point spread function

The 3D diffraction pattern of light formed at the focus of a lens.

Positron emission tomography

A low-resolution but deeply penetrating imaging technique, commonly used in the clinic, which forms images of the physiological function (blood flow, metabolism, neurotransmitters and drug accumulation) of organs using the emissions of an intravenously injected radioactive drug (called a ‘tracer’).

Second-harmonic generation signal

Light originating from second‐order non‐linear optical scattering by non‐centrosymmetric molecules such as collagen or microtubules.

Vessel co-option

The ability of tumour cells to incorporate pre-existing vessels from surrounding tissues, rather than using angiogenesis.

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Entenberg, D., Oktay, M.H. & Condeelis, J.S. Intravital imaging to study cancer progression and metastasis. Nat Rev Cancer 23, 25–42 (2023). https://doi.org/10.1038/s41568-022-00527-5

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