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About Models in Translational Oncology

Significance

The study of cancer implicates the iterative testing of hypotheses. To mimic healthy and cancerous conditions in humans, a wide spectrum of experimental models of cancer is used including animal models, patient samples, genetically homogenous permanently growing cell lines, and genetically heterogeneous primary cells derived from tissues of human patients or animals ( Cancer Res 77:2557-2563, 2017. Review.). Cells are studied in vitro (in culture dishes) or in vivo after transplantation into animals. Additional animal models of cancer range from spontaneous to induced models in wildtype or genetically engineered organisms. Predominantly mice are used, but also lower-model organisms such as yeast, Xenopus laevis, Caenorhabditis elegans, Drosophila melanogaster and zebrafish Danio rerio. All have substantially contributed to the understanding of the molecular basis of the complex disease.


With MiTO©, a tool is offered by the German Cancer Research Center as a core of the German Cancer Consortium to the scientific community for facilitated exchange of preclinical model data and enhanced exchange of living organisms relevant in translational cancer research. Fact sheets can be created and obtained for cell lines, genetically modified organisms including reporter and recombinase strains, transplantation models, carcinogen-induced models, spontaneous tumor models, with the possibility to record metastasis and interventions. Know-how can be protected by the ownerprior to publication by setting a defined accessibility level for any given model.


Cancer

Research is the best way to combat cancer. Aiming for a life without cancer, basic, epidemiological, and clinical researchers of many disciplines have made tremendous progress during the last 5 decades in improving our knowledge about the mechanisms of cancer development at the systemic, tissue, cellular, and molecular level. To the best of our knowledge, cancer is extremely heterogeneous with respect to different tumor entities and a single cancer type is comprised of a number of different subtypes. Furthermore, every individual cancer is unique in its cellular and genetic composition and even different areas of one and the same tumor are heterogeneous. Thus, cancer researchers are not confronted with a single but with more than 200 diseases, a diversity that translates into a high complexity. Despite this fact, tumor initiation, growth and dissemination of tumor cells to other sites in the body are common mechanisms of tumor development. According to Robert Weinberg and Douglas Hanahan (Cell 100, 57-70, 2000; Cell 144, 646-674, 2011), the complexity of cancer can be reduced to a number of underlying principles, the hallmarks of cancer.


  • 1. Cancer cells stimulate their own growth by producing autocrine growth factors (Self-sufficiency in growth signals)!
  • 2. Cancer cells resist inhibitory signals that normally stop their growth (Insensitivity to anti-growth signals)!
  • 3. Cancer cells resist programmed cell death (Evading apoptosis)!
  • 4. Cancer cells multiply indefinitely (Limitless replicative potential resulting in infinite generation of descendants)!
  • 5. Cancer cells stimulate the growth of blood and lymphatic vessels to supply nutrients to tumors and to disseminate (Sustained [lymph]angiogenesis)!
  • 6. Cancer cells invade local tissue and spread to distant organs and tissues (Tissue invasion and metastasis)!
  • 7. Cancer cells use abnormal metabolic pathways to generate energy! (Warburg postulated this already in 1924, Biochemische Zeitschrift 152, 319-344, 1924)!
  • 8. Cancer cells get invisible to the body’s immune system (Evading the immune system directed against the tumor)!
  • 9. Cancer cell development (in many cancer types) is promoted under persistent inflammation (Chronic inflammation)!
  • 10. Cancer cells can’t keep their DNA stable (Unstable DNA)!

In the course of transformation of a normal into a malignant cell fundamental traits are coming up, fueled in part by changes in the cancer cell itself and in part by changing interactions with various cell types and matrix molecules in the environment as well as changes of systemic factors (e.g. hormones, nutrients) in the circulation.
Today, cancer research of basic scientists and clinical researchers is switching in iterative cycles from the bench to the bedside. Networking with other fields of research in biology, systems biology, bioinformatics, medicine, chemistry, pharmacology, and physics is common.
Here, cancer researchers frequently use experimental animal models of cancer to test their hypothesis. However, a complex system like a benign or a malignant tumor is known to be high-dimensional and non-linear, and hence is difficult to model. In addition, complex systems can only be recapitulated as well as they are described and understood on functional and molecular levels. Often not a single model but a battery of models is needed to mimic such complex systems.


General remarks

Models in translational oncology range from tumor cell lines in culture over in vivo equivalents (e. g. living skin equivalents, organ explants) to various model organisms. Researchers make use of various experimental animal models for the dissection of underlying basic mechanisms of human cancer initiation, progression and metastasis, for the improvement of prevention, detection and diagnosis as well as the translation of promising candidate therapies from discovery to the clinic. Here, the animal models should faithfully recapitulate the human conditions and the most appropriate for the validation of hypothesis. Upon selection of a model, many points need to be considered such as animal species, type of cell(s) and tissue(s) affected involvement of genes, molecular pathways and networks, genetic diversity of the human disease, as well as time course and major clinical symptoms of the disease.
Mus musculus is still the predominant species in cancer research. Here genetically engineered mice or animals treated with chemical/physical carcinogens and/or tumor promoters serve basic and translational research. Moreover, immunocompromised mouse strains are used for investigations of cancer traits in human tumors. Tumor outgrows either after xenotransplantation of permanent cell lines or patient-derived primary tumor cells, while syngeneic transplantations into immunocompetent hosts are a regular need for studies of tumor-immune cell interactions. Lower-model organisms such as yeast, Xenopus laevis, the nematode worm Caenorhabditis elegans, the fruitfly Drosophila melanogaster and zebrafish are also substantially contributing to the understanding of the molecular basis of the disease. Moreover, the latter serve as platforms to identify new therapeutics. Of note, for each human gene the corresponding orthologues(s) have been or are being defined in various model organisms by various databases (OrthoDisease). Addressing about 2500 human disease genes derived from Online Mendelian Inheritance in Man, the rate of orthologues genes is found to be about 80 % in Mus musculus, 70 % in Zebrafish, y % in Xenopus, 50 % in D. melanogaster, and 20 % in C. elegans.
In fact, our current view on cell cycle progression and maintenance of cell polarity is based on many studies in yeast. Studies with X. laevis on the other hand provided major insights into normal cellular homeostasis, while studies on C. elegans were fundamental to our understanding of programmed cell death. Key functions of human cancer-related proteins were understood very often by analyzing the corresponding orthologues in D. melanogaster. Zebrafish Danio rerio have shown up as models for specific cancer types such as melanoma skin cancer and leukemias.



3Rs: Replacement, refinement and reduction of animals in research

More: nc3rs.org, bfr.bund.de, ec.europa.eu.

In the use of experimental animals for scientific purposes, achieving experimental results is as important as animal welfare (European Directive on animals used for experimental and other scientific purposes, Directive 2010/63/EU ).

To accomplish this aim, the MiTO platform has been established to facilitate the world-wide exchange of information about models in translational oncology. Moreover, the exchange of live models/animals should be facilitated since MiTO offers contact data and direct communication tools. MiTO allows specific simple and advanced searches with and without setting filters for genetically engineered organisms (recombinase and reporter tool strains etc). to ensure that the GEO of interest is available.

Especially with respect to GEO, exchange of existing mice lines (as live animals or cryo-conserved embryos/sperms) is highly relevant to avoid unnecessary repetition of the production of a desired mutant. This is particularly evident for recombinase and reporter strains.

Consequently, a reduction in animal numbers used to generate a GEO is to be expected and a number of procedures/manipulations on mice with the potential to induce distress (superovulation, collection of blastocysts, general anaesthesia, pre-emptive and top-ups analgesia, surgery/vasectomy/embryo transfer, peri/post-operative care, tissue sampling for genotyping, euthanasia) are avoided.

In case a distinct GEO has already been imported from a foreign national or international animal research facility, a repeated transport of live mice could be avoided, along with an eventually necessary embryo transfer procedures to meet the hygiene status of the acceptor facility; of course in compliance with material/animal transfer agreements and terms and conditions of use. Thus, distress due to such procedures is prevented.

Giving MiTO users also the opportunity to implement procedures as needed to create transplantation models, protocols for chemical carcinogenesis experiments or inhibitor/diet studies will allow enhanced comparison of protocols and help to find appropriate information for desired experimental animal studies. Hence, the numbers of mice needed for the establishment of models and/or procedures is reduced.