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Tumours start as a small cluster of cancer cells, but as they grow and divide, they eventually reach a stage where they invade nearby tissues and spread around the body. It is this spread, or metastasis, that is often the most devastating aspect of cancer. As a result, for many forms of cancer, early diagnosis is important to treat the disease successfully. If a tumour is small and compact, treatment is often less aggressive and more successful than in later stages of the disease.
During the process of diagnosing cancer, doctors often use some form of imaging, which is a non-invasive way for them to see inside the body. Conventional imaging methods, such as computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound provide images of organs that can show the location and size of abnormal structures.
While these techniques are important for diagnosis, they have limitations. Tumours need to reach a certain size to be visible, limiting how early cancer can be diagnosed. And, importantly, while these technologies can show that there is an abnormal mass in an organ, they aren’t able to provide any information about it, such as whether it is benign or cancerous. Further, more invasive tests are often needed to confirm a diagnosis.
New technologies known as functional or molecular imaging have potential to detect cancer very early and provide more information about a tumour at the same time. “Being able just to see that cancer is present doesn’t provide information about how best to treat it,” says Dr John Valliant, a Canadian Cancer Society-funded researcher at McMaster University in Hamilton. “Molecular imaging tells you how aggressive the cancer is and what drugs might be best to treat the cancer.”
By looking for telltale features of cancer cells and learning more about the tumour’s biological activity at the same time, it may be possible to diagnose cancer at its very earliest stages and treat it more successfully, improving survival for even hard-to-treat cancers.
Functional Imaging Shows Cancer Cell Activities
Cancer cells differ from healthy cells in many ways. For example, they grow and divide much more quickly than healthy cells. These processes can be visualized using functional or molecular imaging, showing doctors where the fast-growing cells are. Because these techniques are not dependent on seeing an anatomical structure of a certain size, it may be possible to detect these cells at the very earliest stages, perhaps before there are even enough cells to form a tumour.
In addition, functional imaging may be able to provide information about the disease at the same time as diagnosis without the need for additional biopsies or tests. This knowledge can help classify a tumour into a subtype and understand whether it is aggressive or benign. It can also help doctors monitor how a tumour is responding to treatment so that they can make decisions about whether to continue with a specific therapy.
“When you treat a cancer, the biology of the cancer often changes before the size changes. You can see very early in treatment if a drug is having an effect,” says Dr Valliant. “With the cost and side effects of new therapies, we want to know as soon as possible whether they are working, and we have that ability much sooner than ever before with functional imaging.”
A number of different forms of functional imaging are being developed and are at different stages of clinical testing. To move promising new molecular imaging technologies forward, Dr Valliant founded the Centre for Probe Development and Commercialization in 2008. While he doesn’t see molecular imaging technologies completely replacing current diagnostic processes, they will give doctors more information to work with. “Pathology is always important, but this type of imaging provides another layer of information,” says Dr Valliant. “There is tremendous value for patients.”
In this article, we focus on three technologies that are beginning to be used clinically: positron emission tomography (PET), magnetic resonance spectroscopy (MRS) and photoacoustic imaging (PAI).
Positron Emission Tomography (PET)
Positron emission tomography (PET) is based on cancer cells needing high amounts of certain nutrients, particularly glucose (sugar), to support their accelerated growth and rapid division. It is already used at larger hospitals to diagnose some forms of cancer.
In PET, a radioactive tag or marker is added to a molecule, most often glucose, and a dose of these labelled molecules is injected into a patient’s body. The molecules travel around the body and are taken up by cancer cells. As the patient moves through a specialized scanner, the radioactive signals are picked up and interpreted by computers into an image that shows where cancer cells are in the body.
PET has exciting potential for cancer diagnosis. Because it detects biological activity of individual cells, it may image very small cancers, and because the tagged molecules travel through the entire body, it can detect cancer that has spread at the same time as it diagnoses the primary tumour.
Research to find better PET tracers
Despite PET’s promise and its current use in the clinic, it does have some limitations, one of which is the labelled molecules that are currently available. Radiolabelled glucose is the most commonly used tracer in PET, but it is not useful to diagnose some forms of cancer. Healthy cells in certain organs – especially the brain and liver – use a lot of glucose in their normal functions, so it is hard to pick out the cancer cells that are using slightly more glucose against this background noise. Cells undergoing an immune attack also tend to absorb high amounts of glucose, meaning that the glucose signal is not always cancer specific.
To overcome these challenges, researchers are developing a variety of different radiolabelled molecules that could be used in PET. These new tagged molecules will be especially useful in brain and liver cancers but they will also give researchers the opportunity to visualize different types of cell processes that are overactive in cancer.
For example, researchers have successfully used radiolabelled amino acids (the building blocks of proteins) to image some forms of brain cancer. Brain cancer cells absorb more of these amino acids than healthy brain cells, providing more contrast in a PET scan. These tagged markers can also distinguish between tumour growth and the biological changes resulting from treatment, which is important for understanding whether a therapy is working.
A number of different probes and targeted molecules are in development. The key considerations for researchers are that the new probes target cancer cells specifically, can be taken up by cancer cells, provide good contrast with healthy cells and are safe to use in humans.
Magnetic Resonance Spectroscopy (MRS)
MRI is a commonly used imaging technique that provides structural information about a tumour. Magnetic resonance spectroscopy (MRS) uses technology similar to MRI, but instead of producing an image, it analyzes the chemical makeup, which is used to diagnose cancer.
As an individual passes through the MRI machine, they are exposed to a very powerful magnetic field. At the same time, the machine sends out short pulses of radio waves that travel through the body and bounce off the different molecules found in cells. Different molecules send back radio waves of different frequencies which are detected by the scanner and interpreted as an anatomical image (MRI) or a chemical analysis (MRS).
Using the MRS analysis, researchers look for the presence, absence or quantity of specific molecules that are known to signal cancer. For example, a high level of a molecule called choline is often associated with cancer, whereas other molecules are associated with aggressive forms of the disease. Researchers will often look at a pattern of several different molecules to help make the diagnosis, instead of relying on a single molecule.
Because these techniques use similar equipment, an MRI and MRS are often done at the same time, giving doctors have a more complete understanding of the tumour.
MRS helps to classify brain cancer
Currently, MRS has been studied most for cancers like breast, prostate and brain cancers where MRI is used during diagnosis. In all of these cancers, it can provide valuable information to classify the tumour, understand how aggressive it may be, and monitor how it responds to treatment.
Much of the research regarding MRS has been related to brain cancer. Researchers have found that high levels of choline along with low levels of a molecule called NAA is a signature of brain cancer cells, while peaks in other molecules provide information about the type, stage and aggressiveness of the tumour, which is important for planning biopsies, surgery and treatments.
For example, different genetic mutations can be found in a type of brain cancer called glioma, which are associated with different outcomes. People with mutations called IDH1 and IDH2 in glioma cells often respond better to treatments and live longer than those without the mutations who have a more aggressive form of the disease and need more treatment. Importantly, these mutations produce a molecule in brain cancer cells that can be detected through MRS.
As a result, at the same time as doctors do an MRI scan to find out about the size and location of the glioma, they can do an MRS that looks for the presence of the molecule produced by IDH1/2 mutations. If it is not present, they know the cancer is more aggressive, which is key for selecting the most appropriate treatment.
While MRS is not used as a stand-alone diagnostic tool, it has great value in providing molecular and functional information that can be combined with MRI. New MRI machines often have the ability to do MRS, but currently it is not widely used because of the special expertise that doctors need to interpret the results. This will likely change as the technology is refined and more is understood about signature chemical compositions of cancer cells.
Ultrasound, like MRI, is commonly used to diagnose cancer, providing information about the location and size of tumours in the body. It uses high-frequency sound waves to generate anatomical images.
Photoacoustic imaging (PAI) uses a modified version of ultrasound that combines light and sound to get more detailed information about cancer cells.
Short pulses of laser light are directed towards a tissue, causing the tissue to heat up and vibrate. These vibrations are sent back out of the body as ultrasound waves, which are detected by an ultrasound machine and converted into an image. By combining light and sound, PAI visualizes structures much deeper in the body at greater levels of detail than ultrasound alone.
Different molecules return different wavelengths of ultrasound, providing contrast to the image and information related to the tumour. For example, hemoglobin, the molecule that carries oxygen in the blood, generates different wavelengths based on whether it is carrying oxygen or is empty. As a result, PAI is able to see areas of active blood vessel development (where there are high levels of hemoglobin carrying oxygen) as well as regions where oxygen is low (where there are lots of empty hemoglobin). Both of these are hallmarks of cancer, specifically aggressive cancers.
In addition, PAI can be used with contrast agents, which are substances injected into the body before an imaging test to improve the contrast and quality of images, and in the case of molecular imaging, help increase the visualization of functional information. Fluorescent dyes and nanoparticles can be designed to target cancer-specific molecules, allowing doctors to see specific parts of tumours, such as areas that are most likely to spread.
PAI may reduce the need for additional biopsies
PAI has been studied for breast cancer imaging, as there is potential to provide more information than mammography alone. A number of small studies in women with breast cancer suggest that PAI is able to diagnose primary breast tumours without the use of contrast agents, particularly in women with dense breasts for whom mammography is not always accurate. In addition, researchers have also tested the ability of fluorescent dye and nanoparticles to hone in on individual cancer cells. This will allow them to visualize whether cancer cells have spread to nearby lymph nodes, the first step in metastasis. While the studies were small, the results were promising.
The technique also has promise for prostate cancer, particularly when contrast agents are used. In prostate cancer, it is important to understand early on whether a tumour is aggressive, since many non-aggressive tumours don’t need any treatment. Dr Valliant’s CCS-funded research is working towards developing a molecule that is targeted to aggressive cancer cells, which can show doctors whether aggressive cells are present and where they are.
“Right now, with prostate cancer imaging, there’s often the need to do a lot of biopsies, which are invasive and often have to be done multiple times,” says Dr Valliant. “We might be able to develop a very convenient ultrasound-based test that can see the tumour and determine whether it is aggressive at the same time.”
Contrast agents such as dyes and nanoparticles are still in early development, but they have great potential to improve the information obtained from PAI.
At the Centre for Probe Development and Commercialization, Dr Valliant and his team advance molecules for imaging that could be used in any of the available technologies. “The most important thing is to use the right tool for the right job,” says Dr Valliant. “In many cases, it may actually be a combination of functional imaging techniques that are used to diagnose and learn about the function of a tumour.”
The different technologies provide different types of information. By combining the tools, researchers have the potential to access a wealth of information that could be valuable for diagnosis and treatment. The greatest value of molecular imaging is combining it with anatomical imaging tools to find out more about a tumour at the time of diagnosis.
A lot of work still needs to be done before these techniques are widely used in the clinic. Developing better tracers and contrast agents, as well as streamlining the technology and data analysis will help move the techniques forward and make them more widely available to more patients.
The field of molecular and functional imaging holds much promise for improving outcomes for patients, but research in this field is hugely expensive and requires teams with experts in different fields all working together: biologists, chemists, physicists and doctors all need to collaborate to find the best solutions. But the possibilities are exciting.
“The sole purpose of molecular imaging is to improve outcomes for patients,” says Dr Valliant. “Advances in the field can quickly transform health care and change the way doctors care for people with cancer.”
Eileen Hoftyzer, BSc