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  • Review Article
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Intravital imaging of cell movement in tumours

Nature Reviews Cancer volume 3, pages 921–930 (2003)Cite this article

Key Points

  • Carcinoma cells in the primary tumour can move at up to 10 times the velocity of similar cells in vitro.

  • The highest velocities are observed for carcinoma cells in metastatic tumours that are moving along linear paths in association with extracellular-matrix (ECM) fibres.

  • Carcinoma cell motility is characterized as solitary amoeboid movement and is unrestricted by networks of ECM in mammary tumours.

  • Carcinoma cell motility is restricted at the basement membrane of blood vessels, where the cells must squeeze through small pores in the basement membrane/endothelium to gain access to the blood space.

  • Carcinoma cells in non-metastatic tumours are fragmented during intravasation as they squeeze across the basement membrane/endothelium, whereas carcinoma cells in metastatic tumours cross this restriction as intact cells.

  • Carcinoma cells in metastatic tumours are attracted to blood vessels, where they form a layer of cells that are morphologically polarized towards the vessel.

  • Chemotaxis to epidermal growth factor is shown by carcinoma cells in vitro and in vivo in primary tumours, and might be responsible for the attraction of carcinoma cells to blood vessels.

  • Cell polarity towards blood vessels is correlated with increased intravasation and metastasis.

  • The ECM and its interaction with carcinoma cells can be observed directly using the second harmonic signal from multiphoton-illuminated tumours.

  • Metastatic mammary tumours contain large numbers of rapidly moving macrophages and other leukocytes near blood vessels. These might be a source of chemotactic cytokines.

  • Intravital imaging can be productively correlated with gene-expression profiling to generate new insights into the pathways that are responsible for invasive-cell behaviour.

Abstract

Metastasis is the cause of death for patients with many types of cancer, but the process of tumour cell dissemination is poorly understood. As primary tumours are three-dimensional, departure of cells from primary tumours has been difficult to study. Multiphoton microscopy has been developed for in vivo imaging and, using this technique, we are beginning to understand how invasive tumour cells move.

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Figure 1: Definitions of types of cell movement.
Figure 2: Carcinoma cells in primary mammary tumours move along ECM fibres.
Figure 3: ECM fibres converge on blood vessels in mammary tumours.
Figure 4: Intravasation in primary mammary tumours.
Figure 5: Metastatic cells orient towards blood vessels, whereas non-metastatic cells do not.
Figure 6: Model for intravasation of metastatic tumour cells.

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Acknowledgements

We apologize to those authors whose work we could not cite directly due to space limitations. The authors acknowledge the contributions of current and former laboratory members to the work discussed in this review. The authors' research summarized here has been supported by the National Institutes of Health, and the US Department of Defense Breast Cancer Research Program.

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  1. Department of Anatomy and Structural Biology, Program in Motility and Invasion, Albert Einstein College of Medicine, Bronx, 10461, New York, USA

    John Condeelis & Jeffrey E. Segall

  2. John Condeelis & Jeffrey E. Segall

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DATABASES

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MMTV

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ERBB2

EGF

EGFR

EPS8

RAB5

CSF1

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CXCR4

FURTHER INFORMATION

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Intravital imaging

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Glossary

LASER-SCANNING MICROSCOPY

Focuses laser light on each point in the field of view to generate the image by scanning the laser beam across the field of view.

MULTIPHOTON FLUORESCENCE EXCITATION

Uses a laser beam to focus a high density of photons of twice the excitation wavelength of a fluorophore on a single point. Simultaneous absorption of two photons of half the excitation energy results in excitation of the fluorophore. The efficiency of excitation depends on the square of photon density. Higher numbers of photons can also be used: for example, simultaneous absorption of three photons at one-third the excitation energy will excite the flourophore, with a cubic dependence on photon density.

CONFOCAL MICROSCOPY

A term that is mainly applied to specific light-microscopy techniques that are designed to minimize out-of-focus contributions from the vertical axis to an image. Typical single-photon microscopy makes use of a pinhole aperture to eliminate out-of-focus contributions, whereas multiphoton (also termed two-photon) microscopy makes use of the non-linear dependence of excitation on photon density to only excite molecules in a single plane of focus.

SECOND-HARMONIC GENERATION

The scattering of light by asymmetrically arranged electron orbitals in amino acids in α-helix-containing proteins such as collagen, elastin and laminin. The scattered light is polarized along the axis of the helix and is at half the wavelength of the incident multiphoton excitation.

POLARIZATION

The orientation of the cell in a specific direction, often indicated by the alignment of the long axis of the cell with the direction of polarization.

MICRONEEDLE ASSAY

An in vivo invasion assay in which fine needles containing epidermal growth factor (EGF) in Matrigel are inserted directly into tumours of anesthetized animals. Cells that are attracted to the EGF are collected and counted.

MITOGENESIS

The initiation of the process of cell division, or mitosis.

EPITHELIAL–MESENCHYMAL TRANSITION

The transformation of cell morphology from the tightly coupled and polarized structure that is typical of a cell in an epithelium to the more irregularly shaped and isolated morphology that is typical of mesenchymal cells such as fibroblasts.

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Condeelis, J., Segall, J. Intravital imaging of cell movement in tumours. Nat Rev Cancer 3, 921–930 (2003). https://doi.org/10.1038/nrc1231

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