Surgeons removing tumours must assess where the tumour ends and where the healthy tissue begins. This often means leaving individual cancer cells behind, enabling the cancer to return. Danish researchers can now make the cancer cells fluorescent, enabling surgeons and later robots to remove the cancer without damaging healthy tissue.
Surgery is still a cornerstone of treating cancer. Tumours are removed, followed by chemotherapy or radiotherapy. Cancer surgeons often have a serious dilemma when operating for cancer because removing tumours frequently requires compromising between removing everything and yet preserving as much healthy tissue as possible. Deciding where to make resections often depends on a surgeon’s ability to see or feel where the tumour stops. Surgeons will now have a new tool.
“We have developed a substance that specifically binds to cancer cells and fluoresces when subjected to light. This means that, while operating, surgeons will be able to see whether they have removed all the cancer cells. This technique can avoid leaving malignant tissue behind while sparing the healthy tissue,” explains Andreas Kjær, Professor at the University of Copenhagen and Chief Physician at Rigshospitalet.
The new technique utilizes the fact that cancer cells overexpress a specific receptor: the urokinase-like plasminogen activator receptor (uPAR). Researchers have therefore been working for many years to develop a fluorescent molecule that binds specifically to this receptor to enable them to visualize the cancer tumour optimally.
“The goal has been to eliminate the uncertainty surgeons face when operating. Previously, surgeons had to remove extra tissue to ensure that they had also removed the areas in which the cancer might have spread but in which the cancer could not yet be detected. The extra tissue removed may compromise the function of the tissue. Leaving as much as possible is therefore preferable. By using a urokinase-like plasminogen probe, we can induce the cancer cells to fluoresce, and this enables the surgeons to see them. Further, this is useful because metastasizing cancer cells at the edge of the tumour fluoresce even more brightly.”
“It is a real problem our new technology can solve. After a cancer operation, the material removed is examined histologically, and although more tissue than necessary is often removed, cancer cells are left behind in up to 50% of patients after a tumour has been removed in many forms of cancer. When researchers tested the new fluorescence markers in mice, 100% was removed every time.”
“The compound is injected just before anaesthesia. Thereafter, using an infrared light source in the tumour, surgeons can see all the fluorescent cancer cells using a special camera. During the operation, surgeons can switch between viewing in ordinary light and viewing with the special camera that can see the cancer cells. Surgeons can thus operate in ordinary light but intermittently switch over to ensure that they have removed all the cancerous tissue or determine that cancer cells are still left behind. The operation is not completed until no fluorescent tissue is left.”
A gift for robots
Although this new technique is not yet being routinely used, it has been developed and tested in animals with standard surgical equipment. Andreas Kjær therefore believes that the technology will be easy to introduce, and he thinks that the technique will be used on humans within the next 3 years.
“The response from surgeons to whom we have shown the technique has been extremely positive, and their immediate reaction is that this is a sorely needed tool. The clinicians with whom we collaborate are therefore ready to start using it immediately. What we are working on now is improving the technology and starting to test it on humans as soon as possible.”
The use of small peptides to label tumours is ideal in relation to antibodies. Peptides are bound rapidly and quickly disappear from the rest of the body. Cancer tumours therefore clearly fluoresce and contrast with the surrounding tissue. Nevertheless, the researchers continue to examine whether other ligands or targets in cancer cells would work even better. However, Andreas Kjær sees the greatest development in a completely different place.
“Today, surgeons are increasingly using robots for operations. These can help the surgeons to operate more accurately. They are also equipped with the special camera that can see the fluorescent cancer cells. Our technique can therefore potentially be taken a step further to clearly delineate between tumours and healthy tissue. In the future, we think that these fluorescent cancer cells will make the potential automating part of an operation more realistic because light signals can guide the process.”
“uPAR-targeted optical near-infrared (NIR) fluorescence imaging and PET for image-guided surgery in head and neck cancer: proof-of-concept in orthotopic xenograft model” has been published in Oncotarget. Over the years, and most recently in 2015, the Novo Nordisk Foundation has awarded grants to Andreas Kjær for projects that aim to develop imaging methods for targetting cancer.