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Mouse melanoma models and cell lines

2010; Wiley; Volume: 23; Issue: 6 Linguagem: Catalão

10.1111/j.1755-148x.2010.00777.x

1755-148X

William Damsky, Marcus Bosenberg,

bioluminescence and chemiluminescence research

Pigment Cell & Melanoma ResearchVolume 23, Issue 6 p. 853-859 RESOURCEFree Access Mouse melanoma models and cell lines William E. Damsky Jr, William E. Damsky JrSearch for more papers by this authorMarcus Bosenberg, Marcus BosenbergSearch for more papers by this author William E. Damsky Jr, William E. Damsky JrSearch for more papers by this authorMarcus Bosenberg, Marcus BosenbergSearch for more papers by this author First published: 13 October 2010 https://doi.org/10.1111/j.1755-148X.2010.00777.xCitations: 23 Contact: William E. Damsky Jr and Marcus Bosenberg, Department of Dermatology, Yale School of Medicine, 15 York Street, New Haven, CT 06520, USA e-mail: [email protected] AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Mouse models of melanoma have roots in the early 1900′s when melanocytic tumors arose spontaneously in inbred mouse strains (Cloudman, 1941; Green, 1962; Harding and Passey, 1930). These spontaneous melanomas (probably the most well known of which is B16) were transplantable to congenic mice and could also be cultured, studied, and manipulated in vitro. Due to the utility of these models, they have been a central means by which to address basic questions in melanoma biology. In the latter part of the 20th century, researchers began to employ mutagens like UV irradiation and 7,12-Dimethylbenz(a)anthracene (DMBA), as well as tumor promoting agents such as croton oil/12-O-tetradecanoylphorbol-13-acetate (TPA) in order to generate melanomas in mice. These pioneering studies (summarized in Table 1), gave rise to melanomas and cutaneous neoplasms. Table 1. Mouse models of melanoma Author(year) PMID Geneticmodification Background SpontaneousMelanoma InducedMelanoma Metastasis Cell lines? Notes Nogueira et al. (2010) 20711233 Tyr::H-RasV12G Ink4a/Arf −/−Pten ± 75%, medlatency18.9 weeks rare LN, lung yes Ferguson et al. (2010) 20718941 Tyr::N-RasQ61K Cdk4R24C/R24C 100% penetranceby ∼300 days UV accelerates/incpenetrance not reported not reported nevusprecursors? Tyr::N-RasQ61K Arf −/− ∼25% penetrance UV accelerates/incpenetrance not reported not reported Tyr::N-RasQ61KTyrCreERT2/p53F/F 100% penetranceby 200 days UV accelerates/incpenetrance not reported not reported Yang et al.(2010) 20530876 Tyr::H-RasV12GTyr::rtTA tetO-CreIkkbF/F Ink4a/Arf −/− 4.6% pentrance,latency 79 days not reported not reported IKKB lossinhibitstumorigenesis Monahan et al.(2010) 20697345 Tyr::CreERT2/LSLK-rasG12D/p53F/F 45%, 31 weeksmed latency none yes Tyr::CreERT2/LSLK-rasG12D/p16F/F 73%, 24 weeksmed latency none yes Tyr::CreERT2/LSLK-rasG12D, p53F/F,p16F/F 100%, 9 weeksmed lantency none yes Woods and Bishop(2010) 20577802 Dct::rtTAtetO-cmyc UVR, 10–17 monthlatency not reported not reported works withlacZ/H2B-eGFPreporter Milagre et al.(2010) 20516123 Tyr::CreERT2LSLK-rasG12D 100%, 4 monthsmedian latency none yes metastaticpotential inxenografs VanBrocklin et al. (2010) 20444198 Dct::TVA Ink4a/ArfF/F(RCAS-NrasQ61R-IRES-Cre) 63% pentrance,med survival 47 days none yes metastaticpotential inxenografs Kumasaka et al. (2010) 20048069 MT::Ret Ednrb ± about 40% byabout 70 weeks lung ∼40% not reported inc mets relto MT::RET Heidorn et al. (2010) 20141835 Tyr::CreERT2LSL-KrasG12DLSL-BrafD594A 100% by6 months not reported yes no nevusprecursors Held et al.(2010) 20048081 Tyr::CreERT2 PtenF/FCdkn2aF/F 100% by40 weeks not reported yes (1118/1111) tumorinitiatingsub-populations Tyr::CreERT2 PtenF/FCdkn2aF/FB-cateninloxex3/wt 100% by40 weeks not reported yes (1445) tumor initiatingsub-populations Chawla et al.(2010) 20703083 Tyr::HrasG12V Cdk4R24C/R24C 33% by>15 months enhanced byDMBA/TPA no not reported Goel et al.(2009) 19398955 Tyr::BrafV600E <10% 295–595med survival(2 founders) LN yes melanocytic nevi Tyr::BrafV600E Cdkn2a ± 11–38% pentrance,185–485 daysmed latancey LN yes melanocytic nevi Tyr::BrafV600E p53 ± 6–53% penetrance,107–457 daysmed latency LN yes melanocytic nevi Dhomen et al.(2009) 19345328 Tyr::CreERT2LSL-BrafV600E 64%, medlatency 12 months no yes melanocytic nevi Tyr::CreERT2LSL-BrafV600E p16−/− 80%, medlatency 7 mos no yes melanocytic nevi Dankort et al.(2009) 19282848 Tyr::CreERT2BrafCA/wt PtenF/F 100% within10 weeks 100% lung/LN yes (2697) Rapamycin/MEK-Isensitive Inoue-Narita et al.(2008) 18632629 Dct::Cre PtenF/F DMBA/TPA: 50%by 25 weeks 20% lung not reported dec hair greying,neuorlogicphenotypes Delmas et al.(2007) 18006687 Tyr::B-cateninstaTyr::NrasN61K 85%, 27.6med latency not reported yes congenic toC57BL/6 Ha et al. (2007) 17576930 MT::HGF/SF p16−/− neonatal UVR,100% by 75% by50 weeks not reported not reported UV induces Cdk6amplification Tyr::HRasG12V p16−/− ∼50% by 50 weeks ∼50% by50 weeks not reported not reported Recio et al.(2002) 12438273 MT::HGF/SF p16−/− p19−/− 100% by 50 days LN, liver not reported Yang et al.(2001) 11719444 Tyr::MIP-2 p16 ± p19 ± 18.5% through40 weeks DMBA, 12%198 days none yes metastatic innude mice Kligman and Elenitsas (2001) 11479419 Skh-hr-2 8% through30–47 weeks DMBA LN, lung not reported pigmentedmacules inother mice Bardeesy et al. (2001) 11238948 Tyr::HrasG12V p53−/− 26%, medlatency 17 weeks no yes Krimpenfort et al. (2001) 11544530 p16−/− p19 ± DMBA, 50%between 3 and9 months LN, lung, liver, spleen not reported Sotillo et al. (2001) 11606789 Cdk4R24C/R24C DMBA/TPA,70% by25 weeks no not reported Noonan et al. (2001) 11565020 MT::HGF/SF UVR, ∼20–40%by 450 days not reported not reported neonatal UVRimportant fortumorigenesis Strickland et al. (2000) 10989613 aloe emodin/UVR,50–70% by30 weeks not reported not reported B3H congenic Noonan et al. (2000) 10919643 MT::HGF/SF UVR, >50%by 21 months not reported not reported Kato et al. (2000) 11121157 MT::Ret UVR, 80% by28 weeks lung up to 50% not reported UV super-activates Ret Chin et al. (1999) 10440378 Tyr::rtTAtetO::HRasG12V Cdkn2a −/− 25%, medianlatency 60 days not reported yes KrasG12V addiction Broome Powell et al. (1999) 10469620 Tyr::HrasG12V UVR, DMBA, TPA,combinations,variable some lung, LN yes also melanocyticnevus development Kunisada et al., 1998 9584135 K14::SCF no no no no epidermal retentionof melanocytes Otsuka et al. (1998) 9823327 MT::HGF/SF 22%, meanlatency 15.6months LN, liver,spleen yes Kato et al. (1998) 9778055 MT::Ret 65% malignant,mean latency130 days LN, lung, brain,others yes 100% benignmelanocyticproliferation Zhu et al. (1998) 9506443 TG3 100% penetrance LN, lung,brain, others not reported unknown transgeneinsertion site Kelsall and Mintz (1998) 9751610 Tyr::SV40E UVR 12.5%,mean latency77 weeks LN, lung,kidney not reported Chin et al. (1997) 9353252 Tyr::HrasG12V Cdkn2a −/− 60% penetranceby 6 months no yes Chen et al. (1996) 8618055 TG3 100% penetrance not reported not reported unknowntransgeneinsertion site Powell et al. (1995) 7662120 Tyr::HrasG12V no no no not reported melanoccytichyperplasia Klein-Szanto et al. (1994) 8062242 Tyr::SV40E UVR, earlylesions transplantedat 20 weeks inirectly(LN, lung) not reported Mintz and Silvers (1993) 8415613 Tyr::SV40E 25–100%,average 46–51weeks inirectly(LN, lung) not reported early eyemelanomas, musttransplant Husain et al. (1991) 1909931 Skh-hr-2 DMBA/UVR,25–33% by20–30 weeks no not reported Bradl et al. (1991) 1846036 Tyr::SV40E 31%penetrance ? ? C3H congenic Takizawa et al. (1985) 3924435 DMBA/croton oil,0–80% dependingon strain not reported not reported DBA resistantto macule/melanoma Holman et al. (1983) 6578359 ? Berkelhammer et al. (1982) 7093959 DMBA/croton oil,10% penetrance aftertransplantation yes Epstein et al. (1967) 6016644 ? DMBA/UVR ? ? Green (1962) n/a spontaneous yes B16 melanoma Cloudman (1941) n/a spontaneous yes Cloudmanmelanoma Harding and Passey (1930) n/a spontaneous yes Harding-Passeymelanoma Abbreviations - PMID: PubMed identifier and LN: lymph node, others are standard. After the advent of transgenic mouse technology, two early approaches were successful in producing melanocytic neoplasms in mice (Iwamoto et al., 1991; Klein-Szanto et al., 1991). One used the methallothionein promoter to drive Ret expression, while the latter used the tyrosinase promoter to drive SV40 T cell antigen expression. In addition to generalized melanosis, these transgenic mice developed ocular melanocytic neoplasms that often precluded development of cutaneous melanomas. Through the 1990s and early 2000s, several more transgenic models were developed (summarized in Table 1), which mostly employed melanocyte-specific expression of mutated Ras or activation of the c-Met-HGF/SF signaling axis. Changes to cell-cycle control elements also aided this effort by using either melanocyte-specific activation of Cdk4 and/or Cdkn2a-deficient backgrounds (p16 and/or p19). Although these models were important in confirming the tumor initiating role of these genetic changes, they often had long latencies and were incompletely penetrant. More recently, an increased understanding of the genetic changes that occur in human melanoma coupled with technical advances in mouse modeling have led to the development of novel and particularly useful models. Braf activating mutations have been described to occur in 50% of melanomas (Davies et al., 2002). Additionally, near universal activation of the PI3K/Akt/mTOR signaling pathway (often through inactivation of Pten) has also been documented in human melanomas. Concurrent to this increased understanding of genetic changes influencing melanoma formation, inducible lox-Cre based recombination technology in mice has allowed for more precise control over genetic recombination in mouse models (Figure 1). In 2009, three novel mouse models based on Braf activation were described (Dankort et al., 2009; Dhomen et al., 2009; Goel et al., 2009). In particular, Dankort et al. (2009) describe a model based on melanocyte specific Braf (V600E) activation and Pten inactivation. In this model, metastatic melanoma forms with 100% penetrance and virtually no latency. Additionally, tumor formation can be controlled in both a temporal and anatomically-restricted fashion, which occurs only after topical application of 4-hydroxytamoxifen. Figure 1Open in figure viewerPowerPoint Schematic of inducible genetically engineered mouse models of melanoma. (A). In the inducible Cre models, the Cre-recombinase::estrogen receptor (CreER) fusion protein is constitutively expressed melanocytes by Tyr or Dct transgenic promoter elements. Upon exposure to 4-hydroxytamoxifen (either topical or systemic application), CreER is released from Hsp90 in the cytoplasm, translocates to the nucleus and recombines chromosomal sites, resulting in removal of DNA sequences located between paired loxP sites in a gene of interest (GOI). This strategy can result in either genetic inactivation or activation, depending on the design of the allele and generally cannot be reversed. (B). In the doxycycline inducible system, administration of doxycycline alters of tet-transactivator (tTA) or reverse tet-transactivator(rtTA) function, resulting in activation of transcription (rtTA) or inactivation of transcription (tTA) at target promoters the containing tetO promoter sequence element. This system allows for reversible induction or inactivation of transgene expression. Due to the reproducibility and ease-of-use of the inducible 'Pten/Braf' model, Jackson Laboratories will soon distribute the three alleles required for the model in a congenic C57/BL6 background. This model is advantageous for many reasons, some of which include: short latency and known kinetics of tumor formation, attractiveness for tumor-immunological studies and pre-clinical testing of novel therapeutics, transplantability of congenic tumor cells, and ability to incorporate additional genetic changes with different floxed alleles. 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Development of heritable melanoma in transgenic mice. J. Invest. Dermatol. 110, 247– 252. Citing Literature Volume23, Issue6December 2010Pages 853-859 FiguresReferencesRelatedInformation