Background To A Cancer Breakthrough
When most of us encounter bacteria, we reach for a sanitizer. Researchers at the Cork Cancer Research Centre in Cork, Ireland, have a much different reaction. They view these single-cell microorganisms as literal torchbearers in advancing new therapies for infectious diseases and especially cancer.
The 14 members of the Cork Cancer Research team have spent years studying probiotic, or health-promoting, bacteria. These microbes have the innate ability to travel to tumors and grow there without ill effects once they are ingested or injected into mice in preclinical trials. Why is that important?
Over the past few decades, bioluminescent imaging (BLI) is now routinely used with probiotic bacteria engineered to produce a light signal from reporter genes administered to lab animals. While these reporter genes are observable in two-dimensional images of tumors, they are limited in their ability to locate cell populations within the body. Even three-dimensional anatomical imaging requires a multi-step approach to localize these signals. The process is time consuming, costly, and often requires the sacrifice of many specially bred lab mice.1
Innovative Approach To Imaging
Instead of following the traditional in vitro approach that calls for euthanizing mice before studying tissue cultures, the Cork research team initiated something entirely new. Dr. Cronin and her Cork Cancer Research Centre team focused their investigations on a different modality: living animals. Their in vivo (within the living) approach to studying bacteria and how it interacts with their lab subjects is part of a long recognized gold standard in medical research. Studying live animals not only generates more relevant data, it significantly reduces animal use. Still, there is the question of generating viable images using living subjects.
It first engineered non-pathogenic bacteria (E. coli, Bifidobacterium, and Salmonella Typhimurium) controlled by the luxABCDE operon. An operon is a functioning unit of genomic DNA containing a cluster of genes led by a single promoter, in this case the bioluminescent luxABCDE. Genetically engineered mice with human tumors then received this operon intravenously and orally. In both cases, the bacteria embedded or attached themselves to the tumor cells, resulting in high levels of replication on a local level.
How do they know that? Using a PerkinElmer IVIS® imaging system, the team identified regions of interest with the help of PerkinElmer’s Living ImageTM software for two-dimensional images. Researchers then anesthetized the mice using PerkinElmer’s Gas Anesthesia System. After being injected with lucifren to highlight their respective tumors, the live mice were placed inside a PerkinElmer IVIS® SpectrumTM Preclinical In Vivo Imaging System to capture three-dimensional optical images. The subjects were then moved into a PerkinElmer QuantumTM microCT Imaging System to capture full-body images in high resolution… all while the lab animals remained anesthetized.
And The Results Are. . .
In every instance, the combination of team resourcefulness and state-of-the-art instrumentation from PerkinElmer produced images of living mice displaying tumor vasculature in high, 3D resolution. Beyond the quality of the images themselves, the research team also presented its evidence in a series of short movies as testimony to the efficacy of this new imaging technique that saves time, money, mice... and eventually human lives.
Equally important is what the Cork team demonstrated in the use of bacteria. As a viable carrier in living organisms that has a natural affinity to tumors, bacteria can potentially carry engineered viruses that will travel to a tumor and safely kill cancer cells -- not just in preclinical mice that get to live another day, but eventually in humans, who will someday hopefully enjoy living cancer free.2
- Michelle Cronin, Ali R. Akin, Sara A. Collins, Jeff Meganck, Jae-Beom Kim, Chwanrow K. Baban, Susan A. Joyce, Gooitzen M. van Dam, Ning Zhang, Douwe van Sinderen, Gerald C. O'Sullivan, Noriyuki Kasahara, Cormac G. Gahan, Kevin P. Francis, Mark Tangney, “High Resolution In Vivo Bioluminescent Imaging for the Study of Bacterial Tumour Targeting,” PLOS ONE, January 25, 2012.
- Cork Cancer Research Centre, “Dr. Michelle Cronin-Carroll receives 3 year Research Fellowship for her work on using Probiotic Bacteria to Deliver Treatments for Metastatic Cancer,” News Release, November 29, 2011.