Imaging techniques:

 

New Avenues in Cancer Gene and Cell Therapy

Saadatpour, A Rezaei, H Ebrahimnejad, B Baghaei, G Bjorklund, M Chartrand, A Sahebkar, H Morovati, HR Mirzaei and H Mirzaei

 

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 advance online publication, 11 November 2016; doi:10.1038/cgt.2016.61

 

INTRODUCTION

Cancer is one of important diseases in various populations throughout the world. Various cellular and molecular targets are involved in the initial stages and during progression of cancer. Complexity in the networks of various cellular and molecular pathways lead to difficulties in treating this disease. For this reason, research findings in new treatment therapies have opened significant new windows of opportunity in the treatment of cancer. Gene and cell therapies particularly represent a new horizon in cancer therapy, because of their effectiveness in treating cancer. However, there are some associated limitations of note. One limitation is in tracking and monitoring therapeutic genes or cells during the course of therapy, as well as the responses to treatment. Molecular imaging is a new field, which can go far in solving many of these concerns by more effectively tracking and monitoring therapeutic genes and cells. These techniques enable one to monitor biological processes at both the cellular and subcellular levels in a living organism.

For instance, molecular imaging could be used for monitoring gene expression, multiple simultaneous molecular events in response to treatment. Hence, various studies have indicated that the utilization of molecular imaging is an essential tool for monitoring tumor response to various therapies/drugs, gene expression and tracking therapeutic cells in cancer therapy.

The utilization of recombinant DNA technology also provides new classes of therapies in cancer. There are a variety of cloning vectors that could carry various therapeutic genes. The detection of these therapeutic genes is one of the important aspects in this technology. There are also various classes of marker genes that can encode enzymes, proteins or cell-surface receptors. Imaging modalities enable clinicians to detect these gene markers at various levels of progression or remission. Additionally, cell therapy, including stem cell and immune cell therapies, have opened new horizons in the treatment of cancer. Several studies have suggested that the injection of stem cells and immune cell-containing therapeutic agents (genes or drugs) can also control the progression of cancer. Imaging modalities can effectively track these cells and monitor corresponding responses to treatment in these therapies. In this review, we will summarize various imaging techniques that can be applied in gene and cell therapy to treatment of cancer.

IMAGING TECHNIQUES AND CANCER THERAPY

Today, many cancer researchers are working hard to find better ways to treat these diseases. As a result, researchers have explored and used various therapies such as gene and cell therapy, targeted therapy and nanodrugs in their treatment plans. One of the main limitations in applying biological therapies is monitoring or tracking these drugs. With emerging molecular imaging, we have been able to overcome many of these limitations in biological therapies. The utilization of imaging modalities are associated with various advantages, such as noninvasive methods, tissue observation without destruction, real-time monitoring and the observation of various biological and pathological processes in living organisms.

Consequently, there are a variety of imaging modalities, including positron emission tomography (PET), single photonemission computed tomography (SPECT), X-ray computed tomography, bioluminescence, ultrasound and magnetic resonance imaging (MRI), that can be used in various aspects of cancer diagnostics and treatment monitoring, as these techniques also provide high-resolution presentations. Hence, they can also be used in the laboratory to image small animals, particularly mice, during tracking genetic vectors and therapeutic cells, and in monitoring tumor response to therapy. Table 1 illustrates various imaging techniques that can be used in the monitoring of cancer.

MOLECULAR IMAGING AND RESPONSE TO TREATMENT WITH CELLULAR MARKERS

With emerging new therapies, accurate assessment of response to treatment is one of the most important aspects in cancer therapy. Various therapies show different effects on tumor cells and their effect on cellular/molecular pathogenesis processes. Identification of various markers in response to different therapies contributes to better treatment of cancer. Numerous studies have indicated that initial and ongoing progression of various cancers are associated with the emergence of changing molecules in cellular and molecular levels. Hence, these molecules and agents could be used as markers for assessment of the response to treatments of specific cancers. For example, there may be increased activity in terms of glycolysis, DNA synthesis and angiogenesis in tumor cells. The measurement of changes in these biochemical and immunological processes can be used as markers with which to monitor changes in patients with cancer. When a given therapy inhibits growth in cancer cells via different cellular and molecular pathways, it could be evidenced by a decrease in these cellular and molecular markers. The primary aim in using these markers is to monitor early indications of response and to predict the plausible outcome of therapy. In addition, the predictive markers of response could contribute to show those patients who are suitable for a given treatment modality or course. Response would also include markers for metabolism or expression of receptors in cancer cells, receptors associated with necrosis cell death or inhibition of cell proliferation, and in angiogenesis. However, predictor markers associated with response to treatment may include the presence of tumor hypoxia and the expression of hormone receptors. Imaging techniques enable to assess various responses or predict markers. Therefore, the assessment of these markers in molecular imaging can provide a better understanding of various therapies.

It has also been noted that some patients may demonstrate poor response to different drugs. The utilization of these techniques can provide a corrective view of a given patient's condition in response to therapies within few days of treatment. The results obtained from imaging techniques can then contribute to the development of more effective therapies for patients with cancer. Table 2 illustrates some imaging techniques using various cellular markers to detect responses to treatments in cancer.

MOLECULAR IMAGING AND CANCER GENE THERAPY

Many studies have indicated that imaging techniques can open new horizons in finding more effective applications for various therapeutic approaches, especially in the case of gene therapy. In the gene therapy landscape, one or more genes are introduced to other cells. These receipt cells can be used for a variety of types of cells, such as in cancer. Different types of vectors, including lentiviral, plasmid and transposon can be used for this purpose. Such imaging techniques can empower clinicians in gene therapy, including monitoring of responses to therapeutic genes, quantifying injected dose in various organs, analyzing gene expression levels, assessing toxicity and tracking vectors containing therapeutic genes.

Furthermore, it has been demonstrated that utilization of imaging techniques can lead to improved therapeutic approaches in inciting gene expression on various tumors, central nervous system and cardiovascular tissues. Other studies have 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 transgene-mediated protein production. On other hand, biodistribution imaging methods have also been shown to be effective in detection of gene delivery vectors. By using only one of these techniques we find some limitations. For example, the transduction pattern may show an inaccurate image of viral biodistribution, because the virus could enter into a few cells and not express its transgenes in the other cells. Hence, this becomes a problem in assessing transgenetic expression and particle kinetics in vivo.

Imaging technologies could also use differing forms of energy that interact with various tissues. It has been shown that some techniques, including MRI and computed tomography, rely upon energy/tissue interactions, whereas other techniques such as SPECT and PET require injections of reporter probes to facilitate imaging interpretation. In conclusion, imaging techniques can decrease time and costs by reducing the utilization of laboratory animals and the use of invasive techniques. Table 3 shows some of the imaging techniques now used in cancer gene therapy.

MOLECULAR IMAGING AND CANCER CELL THERAPY

Among the different therapies used presently in cancer therapy, cell therapy has emerged as one of the more effective tools in the therapeutic landscape. Various studies have indicated that cell therapy, including stem cells and immune cells therapy (e.g. NK, T cell, stem cell) can have a significant role in the treatment of cancer. One of main issues here is the ability to track therapeutic cells in the body and environment of a tumor. It has been shown that tracking the modification of cells in the body and tumor environment could lead to better views of cellular and molecular pathways involved in the progression of the cancer. Imaging techniques could likewise contribute to the detection and tracking of various therapeutic cells. Many studies have suggested that there are two classes in cell tracking (e.g. direct and indirect). In direct tracking, various cells are labeled with discrete identification tags. These tags, such as CM-DiI, can detect directly via suitable imaging techniques, whereas indirect approaches use instead reporter genes such as green florescent protein and red florescent protein. Various imaging techniques including PET, SPECT, fluorescence, MRI and bioluminescence can be used as imaging techniques in tracking therapeutic cells (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 molecular mechanisms involved in the progression of cancer, whereas the utilization of safe tags (e.g. biocompatible, non-toxic and highly specific tags) can help to facilitate safe and effective imaging in cancer patients.

CONCLUSION

As stated above, cancer of all kinds is one of the main health concerns throughout the world. Many researchers have searched for better treatment and tracking methods to resolve this major concern. Among the therapeutic approaches explored, gene and cell therapies have demonstrated tremendous promise. Imaging techniques can be powerful tools in tracking and monitoring patients who have received therapeutic gene and cell therapies and can be used in different phases of the progression of the disease. The utilization of these techniques associated with several advantages, such as the ability to accurately track administered therapeutic cells and vectors in cancer patients.

In addition, imaging techniques can be used for assessing responses to treatment in cancer patients. Hence, these techniques can open a new window of opportunity for tracking, monitoring and management of cancer patients.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

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