G Model

ARTICLE IN PRESS

YSCDB-1553; No. of Pages 2

Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Seminars in Cell & Developmental Biology journal homepage: www.elsevier.com/locate/semcdb

Editorial

Mice and men working together for over 100 years in the fight against cancer

The goal following the generation of mouse models is to use these as surrogate patients, often in ways not possible in human patients, to increase understanding of the disease they are modelling. The development of chemotherapeutics for the treatment of cancer went hand in hand with the development of in vivo cancer models in which to test these agents. The first animal models of cancer were developed in the early 1900s and included murine sarcomas such as S37 that were able to be maintained by grafting (or passaging) from one generation of mice to the next [1]. Such syngeneic models of murine cancers were the mainstay of in vivo drug development for a large part of the 20th century [2] until the advent of xenograft models. At the same time, understanding of the heritability of tumour susceptibility and the requirement for inbred strains was emerging. In the 1970s, mouse modelling irrevocably converged with molecular biology with the generation of the first genetically engineered mouse [3]. Since that time, mice carrying transgenes or changes targeted to specific genes have become invaluable to all areas of medical research. The importance of the development of model systems that could be genetically engineered was acknowledged by the awarding of the 2007 Nobel Prize in Physiology or Medicine to Mario Capecchi, Martin Evans and Oliver Smithies for their discoveries of “principles for introducing specific gene modifications in mice by the use of embryonic stem cells”. This issue begins with a review of advances in mouse modelling over the last decade and the tools now available for researchers to purpose build a model system for their application (in this issue [4]). Tools include new gene editing technologies such as Transcription activator-like effector nucleases (TALENs) and the RNA-guided Cas9 nucleases which have increased the efficiency and reduced the time and costs associated with the generation of genetically engineered mouse models. The very first genetically engineered mouse was microinjected with simian virus 40 (SV40) viral DNA. While these SV40 transgenic mice did not develop cancer, the robust tumorigenic properties of SV40 were soon being harnessed for the generation of mouse models for many cancers. Forty years later, mouse models genetically engineered to express SV40 continue to inform medical research. For some cancers, these remain as the most robust and clinically relevant models. Their ease of development makes inclusion of an SV40 allele an attractive alternative for cancers that would

otherwise require the simultaneous homozygous deletion of multiple alleles. The SV40 Tag review provides an historical survey of the use of SV40 models for different cancers and discusses their relevance in today’s world of targeted therapies (in this issue [5]). It is now known that malignant transformation by SV40 is achieved by inactivation of two tumour suppressors, p53 and RB. Indeed, p53 was discovered through molecular analysis of SV40 induced murine tumours [6]. This “guardian of the genome” is mutated in at least one half of all cancers. Its tumour suppressive roles rely on its sensing of cellular stresses and triggering of various anti-proliferative responses. Mutations of Tp53 promote loss-of-function effects. Paradoxically, gain of function changes that promote carcinogenesis are also evident. Significant insights into the actions of p53 have been gained from mouse models genetically engineered with different mutations. The review by Garcia and Attardi makes sense of the different mouse models engineered with mutant or null alleles of Tp53 and discusses these in the context of the different functions of p53 (in this issue [7]). An alternative system of carcinogenesis to that of SV40 is Sleeping Beauty. This system relies on random mutagenesis and is based on the ability of transposable elements of DNA to move around the genome, inserting randomly to influence gene expression and generate transcript diversity. Almost 50% of the human genome is composed of transposable elements, some of which continue to be active. The majority are retrotransposons that act by a “copy and paste” mechanism. Transposons, which constitute about 3% of the human genome (but are no longer active in this genome), use a “cut and paste” mechanism [8]. Ancient transposons inactivated by mutations were genetically re-activated and placed under the control of a DNA transposase enzyme to catalyse the cut and paste activity of the reactivated transposons. This 2-transgene system, named Sleeping Beauty, was genetically engineered into mice, and when activated can induce tumorigenesis through the generation of insertional mutations that may inappropriately activate oncogenes or inactivate tumour suppressor genes. The Sleeping Beauty system has two unique advantages. Firstly, all of the genetic events leading to tumorigenesis need not be known in order to generate tumours; and secondly, the system enables rapid and easy identification of driver genes for the tumour type generated. The review by Tschida and colleagues describes how this genetically engineered mouse model when coupled with high throughput deep sequencing, is helping to unravel the genetic complexity of cancer through

http://dx.doi.org/10.1016/j.semcdb.2014.04.001 1084-9521/© 2014 Published by Elsevier Ltd.

Please cite this article in press as: Howell VM. Mice and men working together for over 100 years in the fight against cancer. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.04.001

G Model YSCDB-1553; No. of Pages 2 2

ARTICLE IN PRESS Editorial / Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx

discovery of candidate cancer-causing genes and its ability to distinguish between driver and passenger mutations (in this issue [9]). The final three reviews focus on specific cancers and describe mouse models developed for each of these cancers. Researchers have utilised multiple genetic tools and systems including SV40, Sleeping Beauty, and conditional targeted alleles to increase understanding of the development and complexity of pancreatic cancer, and identify new ways to halt the progression and devastating consequences of this cancer. The review by Colvin and Scarlett provides an historical perspective of the mouse models designed for pancreatic cancer (in this issue [10]). In addition to genetically engineered models, this review also highlights the utilisation of patient derived xenografts for guiding treatment, and compares these with traditional cell line xenografts. By contrast, the generation of mouse models that recapitulate both the genetic and histopathological features of serous epithelial ovarian cancer has largely been disappointing. However, models reported in the last two years show promise for pre-clinical modelling and also provide independent evidence for the origins of this cancer subtype in both the ovarian surface epithelium and the secretory cells of the fallopian tube. Interestingly, SV40 models continue as important models for this cancer. The review by Howell asks “. . . are we there yet?” in terms of having robust reproducible models with which to test new therapeutic agents and to improve understanding of the development of this malignancy (in this issue [11]). The development of targeted therapies for non-small cell lung adenocarcinoma has led to the rapid generation of new mouse models which incorporate the activated alleles targeted by specific tyrosine kinase inhibitors now used as first line therapies for this cancer, and more recently, the alleles which confer resistance to these therapies. The review by Hayes and colleagues, describes the recent application of these models for drug development and the newly instigated concept of co-clinical trials in which novel therapies and regimens are trialled concurrently in mice and humans in order to accelerate the approval of new therapies (in this issue [12]). This concluding review thus highlights the achievement of the goal of mouse models as “surrogate patients. . . to increase understanding of the disease they are modelling.” In sum, this issue provides a snapshot of the current state of the art for mouse models of cancer, focussing primarily, but not

exclusively, on genetically engineered models. For those new to the use of mouse models, this issue will assist in understanding the advantages and disadvantages of several different model platforms to guide the design of a model suited to a particular application. References [1] Craigie J. Sarcoma 37 and ascites tumours. Ann R Coll Surg Engl 1952;11(5):287–99. [2] Burger AM, Fiebig H-H. In: Baguley BC, Kerr DJ, editors. Screening using animal systems, in anticancer drug development. Elsevier Inc.; 2002. p. 285–99. [3] Jaenisch R, Mintz B. Simian virus 40 DNA sequences in DNA of healthy adult mice derived from preimplantation blastocysts injected with viral DNA. Proc Natl Acad Sci U S A 1974;71(4):1250–4. [4] Khaled WT, Liu P. Cancer mouse models: past, present and future. Semin Cell Develop Biol 2014 [in this issue]. [5] Colvin EK, Weir C, Ikin RJ, Hudson AL. SV40 TAg mouse models of cancer. Semin Cell Dev Biol 2014 [in this issue]. [6] Linzer DI, Levine AJ. Characterization of a 54K Dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 1979;17(1):43–52. [7] Garcia PB, Attardi LD. Illuminating p53 function in cancer with genetically engineered mouse models. Semin Cell Dev Biol 2014 [in this issue]. [8] Cowley M, Oakey RJ. Transposable elements re-wire and fine-tune the transcriptome. PLoS Genet 2013;9(1):e1003234. [9] Tschida BR, Largaespada DA, Keng VW. Mouse models of cancer: sleeping beauty transposons for insertional mutagenesis screens and reverse genetic studies. Semin Cell Dev Biol 2014 [in this issue]. [10] Colvin EK, Scarlett CJ. A historical perspective of pancreatic cancer mouse models. Semin Cell Dev Biol 2014 [in this issue]. [11] Howell VM. Genetically engineered mouse models for epithelial ovarian cancer: are we there yet? Semin Cell Dev Biol 2014 [in this issue]. [12] Hayes SA, Hudson AL, Clarke SJ, Molloy MP, Howell VM. From men to mice: GEMMs as trial patients for new therapies for NSCLC. Semin Cell Dev Biol 2014 [in this issue].

Viive M. Howell ∗ University of Sydney, Kolling Institute of Medical Research, Bill Walsh Translational Cancer Research Laboratory, Level 8, Kolling Building, Royal North Shore Hospital, St Leonards, NSW 2065, Australia ∗ Tel.:

+61 2 9926 4758; fax: +61 2 9926 4035. E-mail address: [email protected] Available online xxx

Please cite this article in press as: Howell VM. Mice and men working together for over 100 years in the fight against cancer. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.04.001

Mice and men working together for over 100 years in the fight against cancer.

Mice and men working together for over 100 years in the fight against cancer. - PDF Download Free
221KB Sizes 2 Downloads 3 Views