RInbred Strains of

Paul N. SchoeldUniversity of Cambridge, UK

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SESJohn P. SundbergThe Jackson Laboratory, Bar Harbor, Maine, USALaboratory Mice

Dale BegleyThe Jackson Laboratory, Bar Harbor, Maine, USA

Beth A. SundbergThe Jackson Laboratory, Bar Harbor, Maine, USA

Annerose BerndtUniversity of Pittsburgh, Pennsylvania, USA

Janan EppigThe Jackson Laboratory, Bar Harbor, Maine, USACommonly Used

Neoplasms in

Spontaneous

Diversity of3.1C H A P T EThe Laboratory Mouse 2012 Elsevier Ltd. All rights reserved.ISBN 978-0-12-382008-2 DOI: 10.1016/B978-0-12-382008-2.00018-0

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STRAINSIntroductionHumans have maintained and domesticatedmany species over the centuries for food andlabour. Non-human species were also maintainedas companion animals or, in the case of rodents,often out of curiosity. Mice with spontaneousmutations that resulted in dramatic physicalchanges from normal, what we now call pheno-typic deviants or mutant mice, were particularlyprized. A notable example is the rhinocerosmouse that lost all hair with age and developedprominent wrinkling [1], variations of whichbecame the well-known hairless and rhino micecommonly used today in biomedical research.An extensionof these observationswas theunder-standing that these animals, particularly rodents,were useful as tools, ormore specifically as biolog-ical models, for understanding similarities withhuman biology and especially disease. TheJackson Laboratory was founded in 1929 withthe goal of using the laboratory mouse asa biomedical tool to unlock the secrets ofmammary cancer. This led to the discovery thata filterable agent (the Bittner Agent), later deter-mined to be a retrovirus (the mouse mammarytumour virus, MMTV), was the major cause ofmammary cancer in some strains of mice [2].More recently, we showed that mice can beinfected with a papillomavirus that can causecancer [3, 4] indicating that these discoveriescontinue.

Itwas once thought tobe impossible to inbreedanimals. In spite of this dogma, Little and Tyzzerin the early 1900s initiated the process of devel-oping a large variety of inbred strains in manylaboratories around the world [5]. As these strainsbecame large colonies, a variety of diseasesappeared in some colonies but not in others. Ashusbandry conditions improved through the20th century, thereby eliminating most seriousinfectious diseases, background levels of cancerbecame more evident, particularly in ageingstudies. Spontaneous cancers were important tounderstand because these lesions had to be differ-entiated from those caused by the experimentaldesign of various studies [6]. The advent of geneticengineering further emphasized the need tounderstand background diseases in strains usedto differentiate lesions induced by geneticmanip-ulation from those that arise naturally [710]. Asmouse research expanded exponentially inrecent years [11], a demand for information onspontaneous background diseases that occur ineach strain was needed so that experiments couldbe interpreted correctly. More importantly, withnew genetic approaches now being available,such as genome-wide scans, these backgrounddiseases can be investigated as complex genetictraits rather than simply incidental findings [12].

Inbredmice are essentially identical except forsex because their genome is homogenous andstable. As we come to recognize that certaindiseases only arise in some strains and not others,especially complex diseases such as cancer, thesemice become irreplaceable as models to dissectthe genetic bases of disease and their mechanisms.For example, rhabdomyosarcomas are raremalig-nant neoplasms of striated muscle that occur ina limited number of closely related strains, espe-cially BALB/cJ, BALB/cByJ and A/J strains[13, 14]. It is now possible, with modern gene map-ping tools, to dissect the complex polygenic natureof thisneoplasmbecause genetic diversity betweenindividuals is a known quantity with such a model.Similar studies are currently inprogresswithmanytypes of cancer. For example, this approach hasbeen applied to the juvenile ovarian granulosacell tumour model using recombinant inbredapproaches [15] and, more recently, to pulmonaryadenomas [12] using aged inbred and wild-derivedstrains.

This chapter reviews tumour frequencyrecords from the Aging Center at The JacksonLaboratory in which 28 of the most importantand commonly used inbred strains of laboratorymice were aged and carefully evaluated for phys-iological changes as they aged, as well as the histo-pathological types and varieties of lesions theydeveloped, including cancer. Tumour frequency,diagnoses, and representative photomicrographsfor this study have recently been made availablethrough public databases, together with datafrom many other strains [16]. The chapter alsofocuses on the variety of available search mecha-nisms and data formats available from two impor-tant public databases, the Mouse Tumor Biologydatabase (MTB, http://tumor.informatics.jax.org/mtbwi/index.do) [11, 17, 18] and Pathbase

website (http://www.informatics.jax.org/). The

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SESMTB also maintains a list of almost 300 antibodiesavailable and how to use them for immunohisto-chemistry on mouse tissues with links to imagesof positive control results in both HTML andMicrosoft Excel format [25].

Pathbase (http://www.pathbase.net/) wasdeveloped in 1999 by a group of European and(http://www.pathbase.net/) [1922], both of whichstoremuch of this information. Annotated colourimages of specific mouse neoplasms or non-neoplastic diseases with extensive bibliographiesare available from these databases and othersthat are provided in the list of websites in Table3.1.2 later in this chapter.

The Mouse TumorBiology Databaseand PathbaseThe MTB was first made available to the public in1998 [11, 18, 23]. The MTB provides a centralizedelectronic resource that collects and integratesthe many different types of data obtained frommouse cancer models in an easily searchable data-base. Data include incidence and latency ofmousetumours, pathology reports and representativeimages, as well as strain and somatic genetics. Alldata are attributed to the original reference,a contributor citation, or the website source.Controlled vocabularies and standardized nomen-clature allow for integrated searches of data fromdifferent sources. Searches of MTB are accom-plishedusingweb-basedqueryforms.Query formsuse terms specific for data types in MTB, such astumour class, mouse strain, genetics, images, refer-ence andmouse homologues of human genes andassociated data. Combined searches using termsfrom the strain, genetics, pathology image andtumour search forms simultaneously are also avail-able using the advanced search form. The MTBincludes data curated from the scientific literature,data submissions fromcancer researchers anddatadownloaded from public databases. The MTB ispart of the Mouse Genome Informatics (MGI)[24] Resource and can be accessed from the MGINorth American pathologists as a communityresponse to data identification and disseminationproblems and was initially funded by the Euro-pean Commission. It contains photomicrographsof representative images annotated to a set ofdefined controlled vocabularies and ontologies,which provide a public resource for the sharingof images of normal and abnormal tissues frommutant and background strains of laboratorymice [1921, 26]. The images are annotated withdetails of strain, genotype, anatomical locationand diagnosis, with key annotations derivedfrom controlled vocabularies or Open BiomedicalOntologies (OBO)-compliant bio-ontologies [27](e.g. mouse pathology ontology (MPATH), MouseAnatomy Ontology (MA), e-Mouse Atlas Project(EMAP) developmental anatomy ontology, cellontology (CA) and gene ontology (GO); see below).Nomenclature formouse strains andmutant genesymbols are included, when provided, and followthe International Mouse Genetic NomenclatureCommittee formats [28, 29]. This allows forcomparison between studies addressing modifiergenesor strain-specific diseases thatmight confuseinterpretation.

TheMAwas developed to standardize anatom-ical terms [30]. It has a formal ontological structurebuilt on the kind of framework contained in ananatomy reference book [31], but is open andunder constant development and refinement.This is a dynamic process and, as such, MA isupdated regularly as users provide input to cura-tors. A textbook on comparative microscopicanatomyof themouse andhuman is nowavailable[32] and similar ones on embryology are also nowavailable [33]. These resources provide furtherextension of comparative anatomical nomencla-ture. Pathology nomenclature for the mouse hasbeen captured in the form of an ontology calledthe Mouse Pathology Ontology (MPATH). Thiswas built using the expertise of the MousePathology Ontology Consortium, a group of 20veterinary and medical pathologists and biologistswho meet regularly to review and update theontology. This is one of the topics of an annualmeeting known as The Pathology of Mouse Models ofHuman Diseases [34] and is often associated withsimilar European meetings [35]. These meetingsprovide for a regular review by a large panel ofpathologists to curate and update the ontology, aswell as to make it relevant to practising

pathologists.

small colonies, so spontaneous neoplasia

C57BL/10J, C57BL/10SnJ, C57BR/cdJ, CBA/CaJ,

6N X C3H/HeN)F1) used by the National Center

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STRAINSfrequency data are limited. Due to space limita-tions, we limited the data presented here totumour data from the 20month time point ofthe Aging Centers inbred mouse strain ageingstudy (Table 3.1.1). These include nine of Castlesmouse-related strains (129S1/SvlmJ, A/J, AKR/J,C3H/HeJ, CBA/J, DBA/2J, LP/J, NZO/H1LtJand NZW/LacJ), one of Castles mouse-relatedsubstrain (BALB/cByJ), five C57 mouse-relatedstrains (C57BL/10J, C57BL/6J, C57BLKS/J,C57BR/cdJ and C57L/J), five Swiss mouse-related strains (FVB/NJ, NON/LtJ, SJL/J, SM/Jand SWR/J) and eight other strains (BTBR Ttf/J, BUB/BnJ, KK/HIJ, MRL/MpJ, P/J, PL/J,PWD/PHJ, RIIIS/J and WSB/EiJ) to providemore genetic diversity (http://www.informatics.Pathbase has established links with the AgingCenter at the Jackson Laboratory [36], the MousePhenome Database (MPD) [37] and the MTB[11, 18] to curate and host representative imagesfrom ongoing studies of age-related lesions andnormal tissue variation from 31 inbred strains ofmice. Quantitative data for other systems-basedparameters are loaded into the MPD and the twodatasets are integrated between MPD and Path-base. Similar integration was recently establishedwith the European Radiobiology Archives (ERA)database [38] and with the Northwestern Univer-sity Janus radiobiology database (http://janus.northwestern.edu/janus2/) [39]; 50 000 individualmouse records were coded to MPATH to link thetwo datasets.

StrainsThe Mouse Phenome Project defined the inbredstrains of greatest importance in modernbiomedical research (http://phenome.jax.org/db/q?rtnstrains/search&reqpanelMPD) [37,40]. These represent not only inbred strainsused for a variety of basic research projects butalso those that are currently used for transgenesis(primarily C57BL/6 and FVB/N) or targetedmutagenesis (primarily various substrains of 129and C57BL/6) experiments. The Jackson Labora-tory maintains most of these strains in a reposi-tory (http://jaxmice.jax.org/) but many are veryjax.org/external/festing/search_form.cgi).for Toxicologic Research, diet restriction studies(C57BL/6NNIA, DBA/2NNia, B6D2F1 (C57BL/6NNia X DBA/2NNia) or B6C3F1 (C57BL/6NNia X C3H/NNia) and a variety of otherstrains [4144]. Husbandry, pathogen status andgenetic quality control have all improved sincemuch of these earlier data sets were generated,such that some of these data are no longerrelevant.

Tumour incidence ininbred strainsTable 3.1.1 shows consolidated results of inbredI/LnJ, NZW/LacJ, RBF/DnJ, SEA/GnJ) andmutant strains are available on the MTB(http://tumor.informatics.jax.org/mtbwi/tumorFrequencyGrid.do). This database also providesa comprehensive selection of annotated photomi-crographs of slides stained with haematoxylinand eosin, special stains or immunohistochem-istry, as well as some electron micrographs withlinks to extensive references.

Other large-scaleageing studiesusing miceHistorically, much work was done on ageinglesions in strains of mice that were commonlyused in biomedical research at the time. Thisprovided background data to aid in interpretingother experimental procedures but alsoprovided basic insight into the ageing processitself and how inbred strains differed fromeach other. This historical work focused ona few inbred and hybrid strains, such asBALB/cStCrlfC3H/Nctr and B6C3F1 ((C57BL/Additional information on spontaneouscancers that occur in these and other inbredstrains (C58/J, CE/J, MOLF/Ei, NOD/LtJ, NZB/B1NJ, RF/J, STX/LeJ, SWL/J), substrains (129/SvJ, A/HeJ, BUB/BnJ, C3H/HeOuJ, C3HeB/FeJ,mouse tumour frequencies from mice that were

TABLE 3.1.1: Tumour incidence in inbred strains from the 20 month Jackson Aging Study Cohort. Table shows tumour incidence sorted by inbred strain(male, female) vs tumour diagnosis and organ. Table is colour coded, with light grey indicating 124%, grey 2569% and black 70100%.

(Continued)

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TABLE 3.1.1 CONT'D: Tumour incidence in inbred strains from the 20 month Jackson Aging Study Cohort. Table shows tumour incidence sorted by inbredstrain (male, female) vs tumour diagnosis and organ. Table is colour coded, with light grey indicating 124%, grey 2569% and black 70100%

NEOPLASMS AND INFECTIOUS DISEASES

416 SPONTANEOUS NEOPLASMS IN INBRED STRAINS

(Continued)

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TABLE 3.1.1: Tumour incidence in inbred strains from the 20 month Jackson Aging Study Cohort. Table shows tumour incidence sorted by inbred strain(male, female) vs tumour diagnosis and organ. Table is colour coded, with light grey indicating 124%, grey 2569% and black 70100%dcont'd

NEOPLASMS AND INFECTIOUS DISEASES

418 SPONTANEOUS NEOPLASMS IN INBRED STRAINS

TABLE 3.1.1: Tumour incidence in inbred strains from the 20 month Jackson Aging Study Cohort. Table shows tumour incidence sorted by inbred strain(male, female) vs tumour diagnosis and organ. Table is colour coded, with light grey indicating 124%, grey 2569% and black 70100%.

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STRAINSaged until they were 20months old and subjectedto complete necropsies by the Aging Center atThe Jackson Laboratory [45]. Selected lesionswere photographed at various magnificationsand these images are available at both the Path-base and MTB websites. We are currently per-forming whole-slide imaging that will allowusers to scan the complete slide on their owncomputers in the form of a virtual slide. Thisdata set, while utilizing fewer mice, is morecomprehensive than the dataset we published inthe first edition of this book [46], which focusedon histological diagnoses of tumours observedduring gross examination of routine diseasesurveillance cases in which complete necropsieswere rarely done. Figure 3.1.1 provides similar

TABLE 3.1.2: Mouse tumour databases accessible on

Host

The Mouse Tumor Biology database

eMICE: electronic Models Information, Communicaand Education

Pathbase

Mouse Phenome Database (MPD)

Biology of the Mammary Gland Web Site

Festings Listing of Inbred Strains of Mice

JAX Mice Web Site

Mammary Cancer in Humans and Mice: A TutorialComparative Pathology: The CD-ROM Web site3information for comparison from the MTBTumor Frequency Grid, which is based on pub-lished data from many studies carried out byscientists worldwide.

The Aging Center study provides a detailedview of which anatomical systems have the high-est tumour frequency among various inbredstrains [16]. This study includes information onsex and tumour type as well. Across strains thesystems that have the highest incidence ofneoplasia are the female reproductive system,the haematopoietic system, liver and lung.Tumour frequency varies greatly betweenstrains, however. The 129S1/SvlmJ and BTBRT tf/J mice have multiple different types oflesions and NOD.B10Sn-H2b/J shows no detect-able types of cancer. The study also detailsstrain-specific sex differences in tumourfrequency. Hepatomas were not detected infemale CBA/J mice but were detected at highlevels in the males. The previously mentionedBTBR T tf/J mice had multiple lesions detectedbut the majority of tumours were diagnosed infemales. Only adrenocortical adenomas andpulmonary adenomas were detected in males,neither of which was detected in females.

The MTB Tumor Frequency Grid (Table3.1.2) shows a slightly different view of informa-tion on neoplasms that spontaneously affectinbred strains. Unlike the Aging Center work,where all mice were subjected to completenecropsies, data in the MTB Tumor FrequencyGrid is built from published data generatedworldwide using a wide variety of protocols.

he Internet

URL

http://tumor.informatics.jax.org/

ion, http://emice.nci.nih.gov/

http://www.pathbase.net/

http://phenome.jax.org/

http://mammary.nih.gov/

http://www.informatics.jax.org/external/festing/search_form.cgi

http://jaxmice.jax.org/

or http://ccm.ucdavis.edu/bcancercd/introduction.htmlThe grid graphically displays the intersection ofinbred strain or substrain with anatomical struc-ture. The MTB grid does not differentiatebetween different types of neoplasms or gender.The highest rates of tumour frequency in thegreatest number of strains are in the mammarygland, leukocytes, liver and lung. These resultsare similar, but not identical, to those of theAging Center study. Strain results are also similar,with NOD mice showing almost no tumours and129S1/SvlmJ having many different tumourtypes detected.

The Aging Center strain disease study and theMTB tumour grid present useful summary tablesof tumour frequency as related to strain andtumour type and serve as good starting pointsfor analysis. Much more detailed information isrequired for proper formulation of a course of

Figure

3.1.1MTB

tumourfreq

uen

cygrid.

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scientific inquiry. Public databases, such as Path-base and MTB, provide access to large amountsof previously published research and the analysistools to examine these data. As an example, wewill follow a hypothetical line of investigationfor a scientist interested in lung tumours, specif-ically pulmonary adenomas.

An examination of the Aging Center datashows that the strains with the highest frequencyof pulmonary adenomas are 129S1/SvlmJ, A/J,BALB/cByJ, LP/J, NZO/H1LtJ and RIIIS/J. TheMTB Tumor Frequency Grid confirms the highincidence levels of lung tumours in 129, A,BALB and NZO strains, but only low levels inLP, and no recorded level for RIIIS.

Detailed tumour information and patholog-ical images are available from both MTBand Pathbase. Tumour information in MTBcan be accessed using multiple search engines.Tumour-specific information can be mostdirectly obtained from the advanced searchform (http://tumor.informatics.jax.org/mtbwi/

advancedSearch.do). A simple search can beaccomplished by selecting adenoma from theTumor Classification pull-down menu, lungfrom the Organ/Tissue of Origin pull-downmenu and inbred from the Strain Typepull-down menu. This search yields 829 tu-mour frequencies, 14 with photomicrographs (48images), from numerous inbred strains includingA/J, BTBR/J, C57L/J,WSB/EiJ, C57BR/cdJ, LP/J,A/J, A/HeJ, C3H/HeJ, DBA, CAST/EiJ, C57BL/6,BALB/C, 129S1/SvlmJ, SWR, BALB/CByJ,BALB/cJ, SWR/J, CBA/J, RIIIS/J, C57BL/6J,KK/HIJ , NON/ShiLtJ, P/J, SM/J, PWD/PhJ andFVB/NJ mice. These results include strain,gender, treatment, reproductive status, cohortsize and frequency, age of onset and detection,any additional relevant information included innotes and pathology information/images. Anexample of a KK/HIJ lung adenoma imagerecord is shown in Figure 3.1.2. The MTB alsoincludes data on mutant and transgenic micewhich are not detailed in these results.

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STRAINSFigure 3.1.2 MTB pathology image record of a pulmonary adenoma from 201 day old KK/HIJ mouse.

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SPathbase also provides a detailed searchengine (http://eulep.pdn.cam.ac.uk/Search_Pathbase/index.php) to identify specific recordsof interest. Search terms can be entered fororganism, gender, MA, MPATH, gene and manyother terms. A search of Pathbase for adenomain the MPATH/Pathology field and lung in theMA/Anatomical Site field yields 22 records,which include papillary, Clara cell and pulmo-nary adenomas. Of these 69 records, 18 recordsfrom 5 mice were bronchioloalveolar (pulmo-nary) adenomas from BALB/cJ, KK/HIJ, RIIIS/J, C57BL/6J and FVB/NJ mice. An example ofa pulmonary adenoma Pathbase record is shownin Figure 3.1.3. This is the same image illustratedin Figure 3.1.2 from MTB. The Pathbase recordsinclude details on gender, strain, genotype, textdescription of mouse details, genetic manipula-

Figure 3.1.3 Pathbase data record of a pulmontion, images, the MA/Anatomical Site andMPATH/Pathology designations. Many moreimages from the Aging Center at The JacksonLaboratory are available and will be posted.

Mouse cancerwebsitesMany databases that provide access to mousetumour data have been developed over the pastfew years (Table 3.1.2) [47]. At the present time,their contents reflect the interests of their cura-tors and thus their scope remains limited.However, they provide room for more in-depthillustration than any textbook or regular paperin a scientific journal. Researchers are encour-aged to contribute to these databases to increasethe impact of their work.

Some of these databases are already linked toliterature databases (such as PubMed and TheJackson Laboratorys MGI Database). Some alsoprovide information about immunohistochem-ical methods with links to antibody manufac-turers (MTB, for example). These databaseshave started to host some of the supplementaryillustrations that cannot be published in regularscientific journals and this should increase overtime. Also, as tumour gene databases develop,links to them will be established from the litera-ture databases.

ry adenoma from 201 day old KK/HIJ mouse.ConclusionsMost reported tumour rates in mice are based on2 year ageing experiments. The Aging Centerstudy provides tumour frequencies for miceduring their 20months of life primarily becausemany of the inbred strains do not normallysurvive long enough to reach 2 years of age [36,48]. Data for additional strains and substrainsare available on the websites of the MTBand Pathbase. Knowledge of tumour rates inyoung mice is crucial to the interpretation ofmost studies because many of them involvemice in their first months of life. Tumourfrequency differs greatly among strains, possiblyas a result of strain-specific genetic differences.

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STRAINSScientists involved with mouse research need tobe aware of these differences before initiatingtheir research. In addition to the strain,numerous factors affect the rate of cancer inmice. These factors include gender, stress,temperature, bedding, caging density, altitude,diet, laboratory practices and time period [49].Some of these factors may evolve with time asthe diet and the husbandry practices evolve toreflect the advances in regulations. For example,Helicobacter hepaticus is now recognized as a path-ogen and is eliminated in most research andvendor colonies [50, 51]. The same is true for Kleb-siella oxytoca, especially in strains that have muta-tions in the Toll-like receptor 4 (Tlr4) gene [52].Another example is elimination of exogenousmouse mammary tumour virus, and thereforethe high frequency of mammary cancer, fromC3H substrains that are distributed by commer-cial vendors [53]. Hence, spontaneous tumourrates are expected to evolve with time. Geneticdrift may also alter cancer rates. The JacksonLaboratory and other large rodent repositoriesplay a key role in preventing the genetic driftof inbred strains of mice. The ability to identifyand analyse strain-specific tumour rates andother strain-associated tumour data from amongthe huge and increasing number of publicationsis of significant importance. Public databasesprovide important tools facilitating access tothese data and will only get more essential asthe volume of data increases.

AcknowledgementsThis work was supported in parts by grants

from the Ellison Medical Foundation and theNational Institutes of Health (CA89713, BasicScience Cancer Center, CA89713, MTB Databaseand AG25707, Shock Aging Center).

The authors thank Kathleen A. Silva andVictoria Kennedy for their technical assistance.

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3.1. Diversity of Spontaneous Neoplasms in Commonly Used Inbred Strains of Laboratory MiceIntroductionThe Mouse Tumor Biology Database and PathbaseStrainsOther large-scale ageing studies using miceTumour incidence in inbred strains

Mouse cancer websitesConclusionsAcknowledgementsReferences