With many types of cancers, early detection offers the best hope for survival. However, research into new early-detection screenings, as well as possible interventional radiology and surgical treatments has been hindered by the lack of a large-animal model that would accurately reflect the types of cancers seen in human cells.
Researchers at the University of Illinois interested in improving screening programs for cancer have been studying gene expression in mice, humans, and pigs in an effort to create a large-animal model that is more relevant to human cancers.
A new study by U of I researchers and other collaborators reports the creation of such a model -a genetically engineered pig that allows researchers to induce the development of the same types of tumors seen in humans, reflecting the gene pathways and gene mutations most often observed in human cancer. Due to the genetic engineering, the tumors can be induced at any tissue site at any given time.
Lawrence Schook, a U of I animal sciences geneticist who is among the researchers, said that the "oncopig" model holds great promise not only in understanding and detecting cancer earlier, but also in developing new treatments and possible cures.
"We already knew which mutations cause cancer, but we wanted a model that would allow us to look for early detection," Schook said. "Currently, if a patient is diagnosed with stage 3 or 4 of certain types of cancer, it is often too late for drug, radiation, or surgical interventions. If we could induce tumors in various tissues at specific times, we could come up with early diagnoses and screening tools. That will allow us, if you have early onset cancer, to do something early on in its progression. That's been our goal."
Schook said the researchers are especially targeting cancers that are more difficult to diagnose in their early stages, including cancer of the pancreas, liver, lung, and bladder. "These are devastating diseases for which early detection is critical. If we could detect them earlier, we have ways to treat them."
During a decade of collaboration with Christopher Counter at Duke University, Schook said, researchers identified the pig as a better model than the mouse because of the pig's similarities to the human in anatomy, size, metabolism, and genetics. And although in previous studies the mice did develop tumors, they were not similar to the tumors clinically observed in humans. Also, treatments such as radiation and surgery are simply not scalable to mice.
"Many people who are diagnosed with liver, pancreatic, or lung cancer, for example, have been smokers or drinkers, or are overweight, or have cardiovascular disease. These are comorbidities. With the pig model, we can induce comorbidities in pigs. We can induce tumors in tissue that would be very similar to clinical human tumors," Schook said.
In the researchers' first paper, they described isolating fibroblasts from pigs, inserting genes with the mutations into these cells, and testing for tumor formation in the donor pig's ear. "We know that those mutations cause tumors in humans, so we asked if we would see that in pigs. The answer was yes. It was the same pathway, the same genes, and the same mutation," he said.
Schook explained that because mutations in the genes (KRAS or TP53) are seen in nearly 50 percent of all human cancers, the researchers targeted those genes in the pig model. They engineered a construct of the pig genes with the added mutations. Because this construct is not expressed in normal cells, expression of the mutated genes was "activated" with an injection of a Cre recombinase enzyme, which induces tumors by signaling the gene to recombine.
"The pigs that are born with this gene inserted in them are normal animals, and if we expose a particular cell to this Cre enzyme, it gets activated and becomes tumorigenic. We can have control over the cell, as well as the location and the timing of inducing this signal," Schook explained. "We can target individual cells or tissues."
Depending on the location of injection, Schook said, different types of tumors developed in the model. "It was what we expected. It was a proof of concept," he noted.
Because of the ability to target individual locations, the model is applicable to a range of types of cancers. "It also allows us to develop approaches to treating different cancers, depending on where they are located in the body," Schook explained. "We can begin to look at location and interventional radiology and microsurgery."
A collaboration with Duke and the University of Missouri National Swine Research Center (NSRRC), supported by the National Institutes of Health (NIH), contributed to the project.
"We're excited that this pig is a national and international model that will be available to to anybody doing research. They can get the model through the NSRRC," he said.
Schook and animal sciences researcher Laurie Rund have also collaborated for several years with Acoustic MedSystems (AMS), a medical device research and development company based in Champaign-Urbana, in evaluating new image-guided, minimally invasive ablative surgical methods.
"Currently, all the minimally invasive devices in the clinic or under investigation have never been tested in human-scale, large-animal tumor models. All device testing has used normal tissues," Schook said. "This model essentially offers the opportunity to evaluate new therapies and devices in a human-size animal model."
Because of the oncopig model, AMS has developed several image-guided, minimally invasive devices for treatment of tumors in several sites, including liver, kidney, spine, prostate, and brain. U of I and AMS piloted the use of the oncogenic pig model for evaluating a new high intensity ultrasound therapy system for soft tissue tumors. Their work culminated in the submission of a research proposal to the National Cancer Institute that proposes to induce tumor growth in genetically engineered oncogenic pigs to assess the treatment efficacy of 3D spatially registered, image-guided, catheter-based ultrasound thermal surgery. The project will be a collaborative partnership between AMS and U of I, with principal investigators Schook, Rund, and Everette C. Burdette of AMS.
"Success of the proposed work using the new tumor model in a large animal that is comparable in both scale and physiology to human patients will be beneficial to validate many minimally invasive modalitites in addition to ultrasound therapy, but also other energy-based modalities including cryo-ablation, radiofrequency and microwave thermal therapy," the researchers reported in the proposal. "The validation test results from the model will ensure greater safety and permit treatment responsive evaluation prior to first-in-human clinical studies."
The oncopig work was published in PLoS One. Co-authors are Lawrence Schook, Tiago Collares, Wenping Hu, Ying Liang, Fernanda Rodrigues, Laurie Rund, Kyle Schachtschneider, Fabiana Seixax, Kuldeep Singh, Kevin Wells, Eric Walters, Randall Prather, and Christopher Counter.
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This article was published in the Spring 2016 edition of AdvanCES in Research, a publication of the College of ACES at the University of Illinois at Urbana-Champaign.