Elsevier

European Journal of Cancer

Volume 38, Issue 16, November 2002, Pages 2137-2146
European Journal of Cancer

PET imaging of gene expression

https://doi.org/10.1016/S0959-8049(02)00390-8Get rights and content

Abstract

Noninvasive in vivo molecular imaging has developed over the past decade and involves nuclear (Positron emission tomography (PET), gamma camera), magnetic resonance, and in vivo optical imaging systems. Most current in vivo molecular imaging strategies are “indirect” and involve the coupling of a “reporter gene” with a complimentary “reporter probe”. Imaging the level of probe accumulation provides indirect information related to the level of reporter gene expression. Reporter gene constructs are driven by upstream promoter/enhancer elements; they can be constitutive leading to continuous transcription and used to identify the site of transduction and to monitor the level and duration of gene (vector) activity. Alternatively, they can be inducible leading to controlled gene expression, or they can function as a sensor element to monitor the level of endogenous promoters and transcription factors. Several examples of imaging endogenous biological processes in animals using reporter constructs, radiolabelled probes and PET imaging are reviewed (p53-dependent gene expression and T-cell receptor-dependent activation of T-lymphocytes). Issues related to the translation of non-invasive molecular imaging technology into the clinic are discussed.

Introduction

Positron emission tomography (PET) is an established imaging modality that has evolved over the past 30+ years and is now widely used in the clinic, particularly in oncology to define the extent of disease (for staging prior to more invasive procedures) and to identify recurrent disease. An advantage of PET imaging is the ability to obtain specific information about physiological, biochemical and molecular processes in the body. This information is quantitative (based on radiotracer principles), can be presented in three-dimensional space, and can be obtained repeatedly (sequentially) over time in the same subject. A more detailed description of PET imaging technology has been provided in previous chapters. A point that will be emphasised in this chapter is that PET is well suited to image the expression of “marker”/“reporter” transgenes. Recent studies have shown that it is possible to image endogenous molecular events using PET. This advance has been largely due to the development of a new class of reporter constructs, complimentary radiolabelled molecules (probes) and novel imaging paradigms.

“Molecular imaging” is a term that was developed in the 1990s, with roots that go back to in situ visualization of target molecules and biological processes (in situ optical imaging) 1, 2, 3, 4. Molecular imaging has evolved and become a more broadly defined term over the past decade; it includes studies that were previously described as “gene imaging” and now relates to many aspects of biology. Advances over the past 5–10 years have included non-invasive in vivo molecular imaging in animals. Although it may appear somewhat presumptuous to imply that current non-invasive imaging technologies (magnetic resonance, PET, gamma camera, etc.) can image molecular events that occur within cells, it has already been shown that it is possible to image transcriptional regulation of endogenous gene expression [5]. Needless to say, current PET, gamma camera, magnetic resonance and optical technologies that are used to image animals and patients do not visualise individual cells, much less molecules. What is so exciting about this emerging new field relates to the novel imaging paradigms that are being developed. These paradigms can be successful within the inherent spatial resolution limits of existing imaging systems, because some degree of tissue (cell) homogeneity within the resolution elements (pixels) of the resultant images can be achieved.

Section snippets

Imaging strategies

Two molecular imaging strategies—“direct” and “indirect”— will be described, and examples of each will be discussed. “Direct” imaging of endogenous genes and molecules can be defined in terms of a probe-target interaction, whereby the resultant image of probe localisation and magnitude (image intensity) is directly related to its interaction with the target molecule, epitope or enzyme. Indirect molecular-gene imaging is a little more complex in that it may involve multiple components. One

Monitoring gene therapy

A non-invasive, clinically applicable method for imaging the expression of successful gene transduction in target tissue or specific organs of the body would be of considerable value for monitoring and evaluating gene therapy in human subjects [36]. The reporter transgene(s) can be driven by any promoter/enhancer sequence of choice [37]. The promoter can be “constitutive” (leading to continuous transcription), or it can be inducible (leading to controlled expression). The promoter can also be

Issues for the future

Molecular imaging has its roots in both molecular biology and cell biology as well as in imaging technology (nuclear, magnetic resonance, optical, etc.). These disciplines have now converged to provide a well-established foundation for exciting new research opportunities and for translation into clinical applications. The development of versatile and sensitive assays that do not require tissue samples would be of considerable value for in vivo studies and the monitoring of molecular-genetic and

References (49)

  • Evaluation of a nude mouse tumor model using beta-galactosidase-expressing melanoma cells. Lab Anim Sci...
  • M. Doubrovin et al.

    Imaging transcriptional regulation of p53-dependent genes with positron emission tomography in vivo

    PNAS

    (2001)
  • T.M. Behr et al.

    Imaging tumors with peptide-based radioligands

    Q. J. Nucl. Med.

    (2001)
  • M.K. Dewanjee et al.

    Noninvasive imaging of c-myc oncogene messenger RNA with indium-111-antisense probes in a mammary tumor-bearing mouse model

    J. Nucl. Med.

    (1994)
  • S. Cammilleri et al.

    , Biodistribution of iodine-125 tyramine transforming growth factor alpha antisense oligonucleotide in athymic mice with a human mammary tumour xenograft following intratumoral injection

    Eur. J. Nucl. Med.

    (1996)
  • Phillips JA, Craig SJ, Bayley D, Christian RA, Geary R, Nicklin PL. Pharmacokinetics, metabolism, and elimination of a...
  • B. Tavitian et al.

    In vivo imaging of oligonucleotides with positron emission tomography

    Nat. Med.

    (1998)
  • M. Reivich et al.

    Measurement of local cerebral glucose metabolism in man with 18F-2-fluoro-2-deoxy-d-glucose

    Acta Neurol. Scand. Suppl

    (1977)
  • L. Sokoloff et al.

    The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat

    J. Neurochem

    (1977 May)
  • L. Sokoloff

    [1-14C]-2-deoxy-d-glucose method for measuring local cerebral glucose utilization. Mathematical analysis and determination of the “lumped” constants

    Neurosci. Res. Program Bull

    (1976)
  • L. Sokoloff

    Metabolic probes for localization of functional activity in the central nervous system

    Int. J. Neurol.

    (1984)
  • K.C. Schmidt et al.

    Fluorine-18-fluorodeoxyglucose PET to determine regional cerebral glucose utilizationa re-examination

    J. Nucl. Med.

    (1996)
  • D.E. Jones et al.

    Expression of beta-galactosidase under the control of the human c-myc promoter in transgenic mice is inhibited by mithramycin

    Oncogene

    (1995)
  • J.G. Tjuvajev et al.

    Imaging the expression of transfected genes in vivo

    Cancer Research

    (1995)
  • Cited by (0)

    View full text