How optical imaging strategies are opening a window on tumors
Most of the approximately 600,000 cancer deaths that occur each year in the US are due to secondary tumors that sprout in distant organs or from the systemic dissemination of cancer cells that do not respond well to standard treatment.
So the more we can learn from animal models about how tumors develop and spread, the greater the possibilities are for identifying new and better disease targets, and for designing drugs that can reach those targets.
One way is to subcutaneously implant specific human tumor cells on the flanks of animals, and then calculate the tumor volume with calipers, the standard method because of the simplicity and ease of access. However, implanting cancers outside their natural setting is a bit like taking an animal out of the wild. They start to behave differently.
One can implant tumors in the organ of origin—otherwise referred to as orthotopic models—and recapitulate many of the essential features of tumor growth seen in humans, including metastatic disease. But the animals also have to be sacrificed at one or multiple points in order to evaluate tumor load, making orthotopic models an impractical choice.
Optical imaging techniques offers a way around this. By attaching bioluminescent and fluorescent tags to tumors, one can observe how tumors progress in orthotopic models non-invasively, and provide more effective screening of preclinical therapeutics needed for first-in-human trials.
Let’s say you implant breast cells into the mouse mammary fatpad, In certain cell lines, that animal will develop breast metastases to the lung in three weeks. Traditionally, we have had to remove the lung and count the lesions to measure tumor burden. With bioluminescence imaging, you can analyze distant metastases and its growth response longitudinally without sacrificing the animal.
The bioluminescence technology uses light emitted by enzyme-catalyzed reactions to detect tumor growth at the cellular level. To employ this strategy, tumors cells are first tagged with a reporter gene such as luciferase (the same enzyme that gives fireflies that glow) and then implanted into the organs where the tumor originated, i.e., lung, brain, breast. Whole body bioluminescent images overlayed on photographic images are then used to follow tumor growth at the primary implant location and the subsequent metastasis to distant organs with the ability to quantify the light emission at a specific location non-invasively.
Simultaneously, one can also inject the same mouse with an antibody tagged with fluorophore that absorbs light energy of a specific wavelength, usually ultraviolet or blue light, and re-emits the energy as red light. Optical imaging is then used to quantify the fluorescent signal in whole body images.
Imagine, for a moment, that you are swimming in the ocean. Using specific kinds of filters, one can capture different creatures expressing different fluorescent proteins depending upon the wavelength of the light. In optical imaging or tumor cells, one can genetically engineer tumor cells to absorb light at a lower wavelength and emit light at a higher wavelength.
In our laboratory, we are using optical imaging tools to quantify tumor load and the effects of therapy in a number of different models, including a human intracranial brain tumor model where we can analyze tumor growth and regression in response to drug treatment. This approach is also being used to measure systemic diseases, such as leukemia. Leukemia preferentially spreads to specific organs, in particular to the bone marrow. When we inject tumors into the veins of animals, after few days you can detect, with bioluminescence, micro-metastases in the femurs and vertebrae of the animals.
These non-invasive tools won’t guarantee that the drugs moving into clinical trials will succeed, but they are helping us to use orthotopic models in a more effective way. The hope is that we’ll gain a better understanding of tumor development and how tumors respond to experimental therapies.
How to cite:
Mahajan, Vivek and Graf, Martin. Shining a Light on Cancer. Eureka blog. May 26, 2016. Available: https://eureka.criver.com/shining-a-light-on-cancer/