Cancer Gene Therapy (2017) 24, 1–5

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved 0929-1903/17
[Link]/cgt

REVIEW
Imaging techniques: new avenues in cancer gene and cell
therapy
Z Saadatpour1, A Rezaei2, H Ebrahimnejad3, B Baghaei4, G Bjorklund5, M Chartrand6, A Sahebkar7, H Morovati8, HR Mirzaei9 and
H Mirzaei10

Cancer is one of the world’s most concerning health problems and poses many challenges in the range of approaches associated
with the treatment of cancer. Current understanding of this disease brings to the fore a number of novel therapies that can be
useful in the treatment of cancer. Among them, gene and cell therapies have emerged as novel and effective approaches. One of
the most important challenges for cancer gene and cell therapies is correct monitoring of the modified genes and cells. In fact,
visual tracking of therapeutic cells, immune cells, stem cells and genetic vectors that contain therapeutic genes and the various
drugs is important in cancer therapy. Similarly, molecular imaging, such as nanosystems, fluorescence, bioluminescence, positron
emission tomography, single photon-emission computed tomography and magnetic resonance imaging, have also been found to
be powerful tools in monitoring cancer patients who have received therapeutic cell and gene therapies or drug therapies. In this
review, we focus on these therapies and their molecular imaging techniques in treating and monitoring the progress of the
therapies on various types of cancer.

Cancer Gene Therapy (2017) 24, 1–5; doi:10.1038/cgt.2016.61; published online 11 November 2016

INTRODUCTION vectors that could carry various therapeutic genes.9,15 The

Cancer is one of important diseases in various populations detection of these therapeutic genes is one of the important
throughout the world.1,2 Various cellular and molecular targets aspects in this technology. There are also various classes of marker
are involved in the initial stages and during progression of genes that can encode enzymes, proteins or cell-surface receptors.
cancer.3–6 Complexity in the networks of various cellular and Imaging modalities enable clinicians to detect these gene markers
molecular pathways lead to difficulties in treating this disease.7 For at various levels of progression or remission. Additionally, cell
this reason, research findings in new treatment therapies have therapy, including stem cell and immune cell therapies, have
opened new horizons in the treatment of cancer.5,16 Several
opened significant new windows of opportunity in the treatment
studies have suggested that the injection of stem cells and
of cancer.8–10 Gene and cell therapies particularly represent a new
immune cell-containing therapeutic agents (genes or drugs) can
horizon in cancer therapy, because of their effectiveness in also control the progression of cancer. Imaging modalities can
treating cancer. However, there are some associated limitations of effectively track these cells and monitor corresponding responses
note.11,12 One limitation is in tracking and monitoring therapeutic to treatment in these therapies.11–13 In this review, we will
genes or cells during the course of therapy, as well as the summarize various imaging techniques that can be applied in
responses to treatment. Molecular imaging is a new field, which gene and cell therapy to treatment of cancer.
can go far in solving many of these concerns by more effectively
tracking and monitoring therapeutic genes and cells.11–13 These
techniques enable one to monitor biological processes at both the IMAGING TECHNIQUES AND CANCER THERAPY
cellular and subcellular levels in a living organism.13 Today, many cancer researchers are working hard to find better
For instance, molecular imaging could be used for monitoring ways to treat these diseases. As a result, researchers have explored
gene expression, multiple simultaneous molecular events in and used various therapies such as gene and cell therapy, targeted
response to treatment.11–13 Hence, various studies have indicated therapy and nanodrugs in their treatment plans.11–13 One of the
that the utilization of molecular imaging is an essential tool for main limitations in applying biological therapies is monitoring or
monitoring tumor response to various therapies/drugs, gene tracking these drugs. With emerging molecular imaging, we have
expression and tracking therapeutic cells in cancer therapy.1,11–14 been able to overcome many of these limitations in biological
The utilization of recombinant DNA technology also provides therapies.11–13 The utilization of imaging modalities are associated
new classes of therapies in cancer. There are a variety of cloning with various advantages, such as noninvasive methods, tissue

1
Bozorgmehr Imaging Center, Isfahan University of Medical Sciences, Isfahan, Iran; 2Khanevadeh Hospital, Isfahan University of Medical Sciences, Isfahan, Iran; 3Department of
Oral and Maxillofacial Radiology, School of Dentistry, Kerman University of Medical Sciences, Kerman, Iran; 4Department of Endodontics, School of Dentistry, Rafsanjan University
of Medical Sciences, Rafsanjan, Iran; 5Nutritional and Environmental Medicine, Mo i Rana, Norway; 6DigiCare Behavioral Research, Casa Grande, AZ, USA; 7Biotechnology Research
Center, Mashhad University of Medical Sciences, Mashhad, Iran; 8Department of Medical Parasitology and Medical Mycology, Faculty of Medicine, Tabriz University of Medical
Sciences, Tabriz, Iran; 9Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran and 10Department of Medical Biotechnology, School
of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Correspondence: Dr. HR Mirzaei, Department of Immunology, School of Medicine, Tehran University of
Medical Sciences, Tehran 1417613151, Iran or Dr. H Mirzaei, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
E-mail: Mirzaeih911h@[Link] or h.mirzei2002@[Link]
Received 29 August 2016; revised 11 September 2016; accepted 12 September 2016; published online 11 November 2016
 New avenues in cancer gene and cell therapy
Z Saadatpour et al
2
imaging (MRI), that can be used in various aspects of cancer
Table 1. Imaging techniques and cancer
diagnostics and treatment monitoring, as these techniques also
Imaging technique Type of cancer References provide high-resolution presentations.1,2 Hence, they can also be
used in the laboratory to image small animals, particularly mice,
X-ray-based systems during tracking genetic vectors and therapeutic cells, and in
25
Flat panel CR Bone
26
monitoring tumor response to therapy.1,2 Table 1 illustrates
Digital radiography Lung various imaging techniques that can be used in the monitoring
27
Multislice CT system Bone of cancer.
MR systems
28
MRI of breast cancer Breast MOLECULAR IMAGING AND RESPONSE TO TREATMENT WITH
29
Diffusion-weighted Neuroendocrine hepatic
imaging metastasis CELLULAR MARKERS
MR elastography Breast 30 With emerging new therapies, accurate assessment of response to
31
MR perfusion imaging Breast treatment is one of the most important aspects in cancer
32
MR spectroscopy Breast
33
therapy.2,14 Various therapies show different effects on tumor
MR-guided focused HCC cells and their effect on cellular/molecular pathogenesis
ultrasound processes.1,14 Identification of various markers in response to
34
MR-guided Prostate different therapies contributes to better treatment of cancer.2
galvanotherapy
Numerous studies have indicated that initial and ongoing
Ultrasound progression of various cancers are associated with the emergence
Miniaturization of Prostate 35 of changing molecules in cellular and molecular levels.2 Hence,
ultrasound systems these molecules and agents could be used as markers for
36
Acoustic radiation force Hepatic malignancies assessment of the response to treatments of specific cancers.
impulse imaging For example, there may be increased activity in terms of glycolysis,
37
High-intensity focused Prostate DNA synthesis and angiogenesis in tumor cells. The measurement
ultrasound of changes in these biochemical and immunological processes can
be used as markers with which to monitor changes in patients
Non-ionizing electromagnetic imaging
Photo- and Breast 38 with cancer.2 When a given therapy inhibits growth in cancer cells
thermoacoustic imaging via different cellular and molecular pathways, it could be
Electrical impedance Breast 39 evidenced by a decrease in these cellular and molecular
tomography markers.1,2 The primary aim in using these markers is to monitor
40
Near-infrared optical Breast early indications of response and to predict the plausible outcome
tomography of therapy.1,2 In addition, the predictive markers of response could
contribute to show those patients who are suitable for a given
Nuclear medicine imaging systems treatment modality or course. Response would also include
41
PET radioisotopes Colon
42 markers for metabolism or expression of receptors in cancer cells,
FDG PET Colon
receptors associated with necrosis cell death or inhibition of cell
Abbreviations: CR, computed radiography; CT, computed tomography; proliferation, and in angiogenesis.1,2 However, predictor markers
FDG, fludeoxyglucose; HCC, hepatocellular carcinoma; MR, magnetic associated with response to treatment may include the presence
resonance; PET, positron emission tomography. of tumor hypoxia and the expression of hormone receptors.
Imaging techniques enable to assess various responses or predict
markers.1,2 Therefore, the assessment of these markers in
molecular imaging can provide a better understanding of various
therapies.
Table 2. Molecular imaging and cellular markers in cancer
It has also been noted that some patients may demonstrate
Markers Type of cancer Imaging References poor response to different drugs. The utilization of these
technique techniques can provide a corrective view of a given patient's
condition in response to therapies within few days of treatment.14
Metabolism The results obtained from imaging techniques can then contribute
43
Glycolysis Adenocarcinomas PET to the development of more effective therapies for patients with
44
DNA synthesis Human tumors PET cancer.1,2 Table 2 illustrates some imaging techniques using
45
Amino-acid and Prostate PET various cellular markers to detect responses to treatments in
lipid metabolism
Cell death Brain MRI 46 cancer.
47
Receptor imaging Human tumors SPECT, PET
48
Tumor angiogenesis Human tumors MRI
MOLECULAR IMAGING AND CANCER GENE THERAPY
Abbreviations: MRI, magnetic resonance imaging; PET, positron emission Many studies have indicated that imaging techniques can open
tomography; SPECT, single photon-emission computed tomography.
new horizons in finding more effective applications for various
therapeutic approaches, especially in the case of gene
therapy.11,13 In the gene therapy landscape, one or more genes
are introduced to other cells.9 These receipt cells can be used for a
observation without destruction, real-time monitoring and the variety of types of cells, such as in cancer. Different types of
observation of various biological and pathological processes in vectors, including lentiviral, plasmid and transposon can be used
living organisms.2,11–13 for this purpose.9 Such imaging techniques can empower
Consequently, there are a variety of imaging modalities, clinicians in gene therapy, including monitoring of responses to
including positron emission tomography (PET), single photon- therapeutic genes, quantifying injected dose in various organs,
emission computed tomography (SPECT), X-ray computed tomo- analyzing gene expression levels, assessing toxicity and tracking
graphy, bioluminescence, ultrasound and magnetic resonance vectors containing therapeutic genes.11,13

Cancer Gene Therapy (2017), 1 – 5 © 2017 Nature America, Inc., part of Springer Nature.
 New avenues in cancer gene and cell therapy
Z Saadatpour et al
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Table 3. Imaging techniques and cancer gene therapy

Imaging technique Gene Cancer References

49,50
PET HSV-1-TK Glioma
51
PET HSV-TK Glioma
52
PET HSV-TK Liver
53
PET HSV-TK Breast
54

SPECT TdeltaTC Adenocarcinoma, fibrosarcoma, gliosarcoma 55

56
MRI TfR Glioma
57
MRI ETR Glioma
58
MRI TET-EGFP-HA-ferritin Glioma
59
MRI Thymidine kinase Glioma
60
Fluorescence imaging GFP Ovarian
61
Intravital microscopy VEGF Human tumors
Abbreviations: MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single photon-emission computed tomography.

imaging interpretation.20 In conclusion, imaging techniques can

Table 4. Imaging techniques and cell therapy in cancer
decrease time and costs by reducing the utilization of laboratory
Imaging technique Type of cell Cancer References animals and the use of invasive techniques.11 Table 3 shows some
of the imaging techniques now used in cancer gene therapy.
62
Bioluminescence T cell Brain
63
PET T cell Melanoma
PET T cell Melanoma 64
MOLECULAR IMAGING AND CANCER CELL THERAPY
65
PET T cell Prostate Among the different therapies used presently in cancer therapy,
66
PET T cell DUC18/
cell therapy has emerged as one of the more effective tools in the
CMS5 tumor
PET MAK cell Ovarian 67 therapeutic landscape.5,12,21,22 Various studies have indicated that
cancer cell therapy, including stem cells and immune cells therapy (e.g.
MRI T cell Melanoma 64 NK, T cell, stem cell) can have a significant role in the treatment of
MRI T cell Melanoma 68 cancer.5,12,21,23 One of main issues here is the ability to track
MRI NK Prostate 69
therapeutic cells in the body and environment of a tumor.12,22 It
70
Bioluminescence Mesenchymal Breast has been shown that tracking the modification of cells in the body
stem cells and tumor environment could lead to better views of cellular and
71
MRI Cancer cell Tumor cell molecular pathways involved in the progression of the cancer.12
72
SPECT AC133+ Breast Imaging techniques could likewise contribute to the detection and
progenitor cells
Fluorescent LAK cells Melanoma 73 tracking of various therapeutic cells. Many studies have suggested
microscopy/flow that there are two classes in cell tracking (e.g. direct and indirect).
cytometry In direct tracking, various cells are labeled with discrete
identification tags. These tags, such as CM-DiI, can detect directly
Abbreviations: LAK, lymphokine-activated killer; MAK, macrophage- via suitable imaging techniques, whereas indirect approaches use
activated killer; MRI, magnetic resonance imaging; NK, natural killer; PET,
instead reporter genes such as green florescent protein and red
positron emission tomography; SPECT, single photon-emission computed
tomography.
florescent protein.24 Various imaging techniques including PET,
SPECT, fluorescence, MRI and bioluminescence can be used as
imaging techniques in tracking therapeutic cells12 (Table 4).
Imaging techniques can also be used for tracking of tumor cells, as
well. The tracking of tumor cells can contribute to cellular and
Furthermore, it has been demonstrated that utilization of molecular mechanisms involved in the progression of cancer,
imaging techniques can lead to improved therapeutic approaches whereas the utilization of safe tags (e.g. biocompatible, non-toxic
in inciting gene expression on various tumors, central nervous and highly specific tags) can help to facilitate safe and effective
system and cardiovascular tissues.11,17 Other studies have imaging in cancer patients.12
explored the value of imaging techniques as at least two classes
of imaging, such as biodistribution and transduction imaging. It
was found that transduction imaging can effectively detect CONCLUSION
transgene-mediated protein production.11 On other hand, biodis- As stated above, cancer of all kinds is one of the main health
tribution imaging methods have also been shown to be effective concerns throughout the world. Many researchers have searched
in detection of gene delivery vectors.18 By using only one of these for better treatment and tracking methods to resolve this major
techniques we find some limitations. For example, the transduc- concern. Among the therapeutic approaches explored, gene and
tion pattern may show an inaccurate image of viral biodistribu- cell therapies have demonstrated tremendous promise. Imaging
tion, because the virus could enter into a few cells and not express techniques can be powerful tools in tracking and monitoring
its transgenes in the other cells. Hence, this becomes a problem in patients who have received therapeutic gene and cell therapies
assessing transgenetic expression and particle kinetics in vivo.19 and can be used in different phases of the progression of the
Imaging technologies could also use differing forms of energy disease. The utilization of these techniques associated with several
that interact with various tissues. It has been shown that some advantages, such as the ability to accurately track administered
techniques, including MRI and computed tomography, rely upon therapeutic cells and vectors in cancer patients.
energy/tissue interactions, whereas other techniques such as In addition, imaging techniques can be used for assessing
SPECT and PET require injections of reporter probes to facilitate responses to treatment in cancer patients. Hence, these

© 2017 Nature America, Inc., part of Springer Nature. Cancer Gene Therapy (2017), 1 – 5
 New avenues in cancer gene and cell therapy
Z Saadatpour et al
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CONFLICT OF INTEREST plan breast-conserving surgery following neoadjuvant chemotherapy for early
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The authors declare no conflict of interest.
29 Liapi E, Geschwind J-F, Vossen JA, Buijs M, Georgiades CS, Bluemke DA et al.
Functional MRI evaluation of tumor response in patients with neuroendocrine
hepatic metastasis treated with transcatheter arterial chemoembolization.
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