The multiple uses of fluorescent proteins to visualize cancer in vivo

Key Points

  • Tumour cells can be stably transfected with fluorescent proteins.

  • Tumours and metastases that express fluorescent proteins can be visualized non-invasively in intact animals.

  • Transgenic mice can express a fluorescent protein in all cells or in specific cells, depending on the linkage of the fluorescent protein. These mice can be transplanted with tumours expressing different-coloured fluorescent proteins to create a dual-colour image of the tumour–host interaction.

  • Tumour cells can express two or more different-coloured fluorescent proteins. For example, the nucleus can be labelled with green fluorescent protein and the cytoplasm with red fluorescent protein. This enables nuclear–cytoplasmic dynamics to be visualized in vivo.

  • In vivo imaging can be at the single-cell level. For single-cell imaging on deep organs, reversible skin-flaps and chronic windows can be used. Single-cell imaging can be used to study cancer cell invasion, seeding in distant organs and dormancy.

  • Fluorescent protein imaging has significant advantages over luciferase imaging, including brighter signals, substrate independence, availability in multiple colours, and simpler and cheaper equipment requirements.

  • In vivo fluorescent imaging can be used to visualize the efficacy of candidate cancer drugs in real time in mouse models of human cancer.

  • Fluorescent proteins can be used for 'molecular imaging' to visualize the effects of single-gene changes — for example, on cancer metastasis or drug sensitivity.

  • Future uses of fluorescent proteins in human cancer diagnosis and therapy are possible — for example, in mouse models, tumours can be selectively and stably transformed in vivo by viral vectors. In the future such an approach might be used in humans to visualize tumour growth and response to therapy in real time.

Abstract

Naturally fluorescent proteins have revolutionized biology by enabling what was formerly invisible to be seen clearly. These proteins have allowed us to visualize, in real time, important aspects of cancer in living animals, including tumour cell mobility, invasion, metastasis and angiogenesis. These multicoloured proteins have allowed the colour-coding of cancer cells growing in vivo and enabled the distinction of host from tumour with single-cell resolution. Visualization of many aspects of cancer initiation and progression in vivo should be possible with fluorescent proteins.

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Figure 1: Migration of tumour cells in capillaries visualized in living animals.
Figure 2: Are metastases clonal?
Figure 3: Dual-colour tumour–host interactions.
Figure 4: A comparison of external and internal quantitative imaging.
Figure 5: Whole-body imaging to monitor tumour cell growth and treatment efficacy.
Figure 6: Whole-body fluorescence imaging of lymphoma progression in live mice.

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Robert Hoffman is the President of AntiCancer Inc.

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DATABASES

Entrez Gene

BCL2

CD105

CD31

MYC

NDPKA

nestin

p53

National Cancer Institute

breast carcinoma

neuroblastoma

FURTHER INFORMATION

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Glossary

CHRONIC-TRANSPARENT WINDOW

A tumour grown on the inner surface of the skin that can be viewed through a permanent opening in the animal, normally through a coverslip.

ORTHOTOPIC

Literally 'correct surface'. The implantation of a tumour (or other tissue) into its organ of origin.

INTRAVASATION

Passage of a cell from tissue into a blood or lymph vessel.

EXTRAVASATION

Movement of a cell out of the vasculature into interstitial spaces.

CHROMOPHORES

A molecule or part of a molecule that absorbs or emits light at specific wavelengths.

EXTINCTION COEFFICIENT

The fractional absorbance of excitation light per unit path length of absorber.

QUANTUM YIELD

The fraction of excited fluorophores that emit a fluorescence photon.

INTRAVITAL VIDEO MICROSCOPY

In vivo microscopy of a live animal with images acquired in real time.

MULTIPHOTON LASER-SCANNING MICROSCOPY

Multiphoton laser scanning microscopy (MPLSM) enables the production of long time-lapse recordings from live fluorescent specimens because it uses small beams of infrared light to illuminate only a small area of tissue at a time. So, in living tissue, damage is minimized and, because the light beam penetrates deeply, a greater volume of tissue can be examined.

TRABECULAR BONE

Non-cortical spongy-bone-containing lacunae. Trabecular bone contains the bone marrow.

TERMINAL PORTAL VENULES

Tributaries of the portal vein.

CONFOCAL LASER-SCANNING MICROSCOPE

A microscope designed to minimize out-of-focus contributions from the vertical axis to an image. A pinhole aperture eliminates out-of-focus contributions.

PRESINUSOIDAL VASCULATURE

Branches of the portal vein that leave the sinusoid.

SEVERE COMBINED IMMUNODEFICIENT (SCID) MICE

Mice that are homozygous for the SCID mutation have compromised B-cell and T-cell immunity. This lack of immunity means that they can support human tumour xenografts for preclinical studies.

ANOIKIS

Apoptosis resulting from a lack of cellular adhesion.

NUDE MICE

Strains of athymic mice bearing the recessive allele nu/nu that are mostly hairless and lack all, or most, of the T-cell population. Nude mice can accept either allografts or xenografts. nu/nu alleles on some backgrounds have near-normal numbers of T-cells.

ISOGENIC

Having the same genetic background, such as two cell lines that might differ only in a gene of interest.

FLUORESCENCE STEREOMICROSCOPY

A microscope with two oculars that is equipped with a light source and filters for excitation of a fluorescence molecule and for the visualization of the resulting emission light.

INTERNAL RIBOSOME ENTRY SITE

A region of DNA that codes for a messenger RNA sequence that can bind to ribosomes, which is often used to genetically link two proteins that would still be translated separately but be controlled by one promoter.

NEAR INFRARED

The near-infrared region of the electromagnetic spectrum (covering a wavelength range of 700 nm to 3 nm) lies just beyond the sensitivity of the human eye.

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Hoffman, R. The multiple uses of fluorescent proteins to visualize cancer in vivo. Nat Rev Cancer 5, 796–806 (2005). https://doi.org/10.1038/nrc1717

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