Overview of Genetically Engineered Mouse Models of Papillary and Anaplastic Thyroid Cancers: Enabling Translational Biology for Patient Care Improvement

Roch‐Philippe Charles1

1 Institut für Biochemie und Molekulare Medizin, University of Bern, Bern
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 14.33
DOI:  10.1002/0471141755.ph1433s69
Online Posting Date:  June, 2015
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library

Abstract

The prognosis from thyroid cancer subtypes in humans covers a spectrum from “cured at almost 90%” to “100% lethal.” Invasive and poorly differentiated forms of thyroid cancer are among the most aggressive human cancers, and there are few effective therapeutic options. Genetically engineered mice, based on mutations observed in patients, can accurately recapitulate the human disease and its progression, providing invaluable tools for the preclinical evaluation of novel therapeutic approaches. This overview details models developed to date as well as their uses for identifying novel anticancer agents. © 2015 by John Wiley & Sons, Inc.

Keywords: genetically engineered mice; papillary and anaplastic thyroid cancer; pre‐clinical platform; cancer model; BRAF mutations

     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Table of Contents

  • Introduction
  • Xenograft Models
  • Models Based on Direct Transgene Expression
  • Models Based on Conditional Mutations
  • Tumor Burden Imaging and the Use of Thyroid Cancer GEM Models for Evaluation of Anti‐Cancer Agents
  • Conclusion
  • Disclosure of Potential Conflicts of Interest
  • Literature Cited
  • Figures
  • Tables
     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Materials

GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Figures

Videos

Literature Cited

Literature Cited
  Andreadi, C., Cheung, L.K., Giblett, S., Patel, B., Jin, H., Mercer, K., Kamata, T., Lee, P., Williams, A., McMahon, M., Marais, R., and Pritchard, C. 2012. The intermediate‐activity (L597V)BRAF mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/MEK/ERK pathway. Genes Dev. 26:1945‐1958.
  Antico Arciuch, V.G., Russo, M.A., Dima, M., Kang, K.S., Dasrath, F., Liao, X.H., Refetoff, S., Montagna, C., and Di Cristofano, A. 2011. Thyrocyte‐specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors. Oncotarget 2:1109‐1126.
  Barrett, S.D., Bridges, A.J., Dudley, D.T., Saltiel, A.R., Fergus, J.H., Flamme, C.M., Delaney, A.M., Kaufman, M., LePage, S., Leopold, W.R., Przybranowski, S.A., Sebolt‐Leopold, J., Van Becelaere, K., Doherty, A.M., Kennedy, R.M., Marston, D., Howard, W.A., Jr., Smith, Y., Warmus, J.S., and Tecle, H. 2008. The discovery of the benzhydroxamate MEK inhibitors CI‐1040 and PD 0325901. Bioorg. Med. Chem. Lett. 18:6501‐6504.
  Brander, A., Viikinkoski, P., Nickels, J., and Kivisaari, L. 1991. Thyroid gland: US screening in a random adult population. Radiology 181:683‐687.
  Bunney, T.D. and Katan, M. 2010. Phosphoinositide signalling in cancer: Beyond PI3K and PTEN. Nat. Rev. Cancer 10:342‐352.
  Chakravarty, D., Santos, E., Ryder, M., Knauf, J., Liao, X.‐H., West, B., Bollag, G., Kolesnick, R., Thin, T., Rosen, N., Zanzonico, P., Larson, S., Refetoff, S., Ghossein, R., and Fagin, J. 2011. Small‐molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation. J. Clin. Invest. 121:4700‐4711.
  Charles, R.P., Iezza, G., Amendola, E., Dankort, D., and McMahon, M. 2011. Mutationally activated BRAFV600E elicits papillary thyroid cancer in the adult mouse. Cancer Res. 71:3863‐3871.
  Charles, R.P., Silva, J., Iezza, G., Phillips, W.A., and McMahon, M. 2014. Activating BRAF and PIK3CA Mutations cooperate to promote anaplastic thyroid carcinogenesis. Mol. Cancer Res. 12:979‐986.
  Chen, Z., Trotman, L.C., Shaffer, D., Lin, H.K., Dotan, Z.A., Niki, M., Koutcher, J.A., Scher, H.I., Ludwig, T., Gerald, W., Cordon‐Cardo, C., and Pandolfi, P.P. 2005. Crucial role of p53‐dependent cellular senescence in suppression of Pten‐deficient tumorigenesis. Nature 436:725‐730.
  Clevers, H., Loh, K.M., and Nusse, R. 2014. Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science 346:1248012.
  Collisson, E.A., Trejo, C.L., Silva, J.M., Gu, S., Korkola, J.E., Heiser, L.M., Charles, R.P., Rabinovich, B.A., Hann, B., Dankort, D., Spellman, P.T., Phillips, W.A., Gray, J.W., and McMahon, M. 2012. A central role for RAF‐>MEK‐>ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov. 2:685‐693.
  Cross, J.C., Anson‐Cartwright, L., and Scott, I.C. 2002. Transcription factors underlying the development and endocrine functions of the placenta. Recent Prog. Horm. Res. 57:221‐234.
  Dankort, D., Filenova, E., Collado, M., Serrano, M., Jones, K., and McMahon, M. 2007. A new mouse model to explore the initiation, progression, and therapy of BRAFV600E‐induced lung tumors. Genes Dev. 21:379‐384.
  Dankort, D., Curley, D.P., Cartlidge, R.A., Nelson, B., Karnezis, A.N., Damsky, W.E., Jr., You, M.J., DePinho, R.A., McMahon, M., and Bosenberg, M. 2009. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat. Genet. 41:544‐552.
  Davies, H., Bignell, G.R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M.J., Bottomley, W., Davis, N., Dicks, E., Ewing, R., Floyd, Y., Gray, K., Hall, S., Hawes, R., Hughes, J., Kosmidou, V., Menzies, A., Mould, C., Parker, A., Stevens, C., Watt, S., Hooper, S., Wilson, R., Jayatilake, H., Gusterson, B.A., Cooper, C., Shipley, J., Hargrave, D., Pritchard‐Jones, K., Maitland, N., Chenevix‐Trench, G., Riggins, G.J., Bigner, D.D., Palmieri, G., Cossu, A., Flanagan, A., Nicholson, A., Ho, J.W., Leung, S.Y., Yuen, S.T., Weber, B.L., Seigler, H.F., Darrow, T.L., Paterson, H., Marais, R., Marshall, C.J., Wooster, R., Stratton, M.R., and Futreal, P.A. 2002. Mutations of the BRAF gene in human cancer. Nature 417:949‐954.
  DeVita, V.T., Lawrence, T.S., and Rosenberg, S.A. 2011. Cancer: Principles & Practice of Oncology: Primer of the Molecular Biology of Cancer. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia.
  Fagin, J.A. and Mitsiades, N. 2008. Molecular pathology of thyroid cancer: Diagnostic and clinical implications. Best Pract. Res. Clin. Endocrinol. Metab. 22:955‐969.
  Fodde, R., Smits, R., and Clevers, H. 2001. APC, signal transduction and genetic instability in colorectal cancer. Nat. Rev. Cancer 1:55‐67.
  Garcia‐Rostan, G., Camp, R.L., Herrero, A., Carcangiu, M.L., Rimm, D.L., and Tallini, G. 2001. Beta‐catenin dysregulation in thyroid neoplasms: Down‐regulation, aberrant nuclear expression, and CTNNB1 exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis. Am. J. Pathol. 158:987‐996.
  Guerra, A., Fugazzola, L., Marotta, V., Cirillo, M., Rossi, S., Cirello, V., Forno, I., Moccia, T., Budillon, A., and Vitale, M. 2012. A high percentage of BRAFV600E alleles in papillary thyroid carcinoma predicts a poorer outcome. J. Clin. Endocrinol. Metab. 97:2333‐2340.
  Hundahl, S., Fleming, I., Fremgen, A., and Menck, H. 1998. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985‐1995 [see comments]. Cancer 83:2638‐2648.
  Jackson, E.L., Olive, K.P., Tuveson, D.A., Bronson, R., Crowley, D., Brown, M., and Jacks, T. 2005. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 65:10280‐10288.
  Jackson, E.L., Willis, N., Mercer, K., Bronson, R.T., Crowley, D., Montoya, R., Jacks, T., and Tuveson, D.A. 2001. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K‐ras. Genes Dev. 15:3243‐3248.
  Jonkers, J., Meuwissen, R., van der Gulden, H., Peterse, H., van der Valk, M., and Berns, A. 2001. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat. Genet. 29:418‐425.
  Kaneshige, M., Kaneshige, K., Zhu, X., Dace, A., Garrett, L., Carter, T.A., Kazlauskaite, R., Pankratz, D.G., Wynshaw‐Boris, A., Refetoff, S., Weintraub, B., Willingham, M.C., Barlow, C., and Cheng, S. 2000. Mice with a targeted mutation in the thyroid hormone beta receptor gene exhibit impaired growth and resistance to thyroid hormone. Proc. Natl. Acad. Sci. U.S.A. 97:13209‐13214.
  Kim, H.J. and Bar‐Sagi, D. 2004. Modulation of signalling by Sprouty: A developing story. Nat. Rev. Mol. Cell Biol. 5:441‐450.
  Kim, K., Cabanillas, M., Lazar, A., Williams, M., Sanders, D., Ilagan, J., Nolop, K., Lee, R., and Sherman, S. 2013. Clinical Responses to Vemurafenib in Patients with Metastatic Papillary Thyroid Cancer Harboring V600EBRAF Mutation. Thyroid 23:1277‐1283.
  Kinross, K.M., Montgomery, K.G., Kleinschmidt, M., Waring, P., Ivetac, I., Tikoo, A., Saad, M., Hare, L., Roh, V., Mantamadiotis, T., Sheppard, K.E., Ryland, G.L., Campbell, I.G., Gorringe, K.L., Christensen, J.G., Cullinane, C., Hicks, R.J., Pearson, R.B., Johnstone, R.W., McArthur, G.A., and Phillips, W.A. 2012. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J. Clin. Invest. 122:553‐557.
  Knauf, J.A., Ma, X., Smith, E.P., Zhang, L., Mitsutake, N., Liao, X.H., Refetoff, S., Nikiforov, Y.E., and Fagin, J.A. 2005. Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation. Cancer Res. 65:4238‐4245.
  Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S.I., Puc, J., Miliaresis, C., Rodgers, L., McCombie, R., Bigner, S.H., Giovanella, B.C., Ittmann, M., Tycko, B., Hibshoosh, H., Wigler, M.H., and Parsons, R. 1997. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943‐1947.
  Mazzaferri, E. 1993. Management of a solitary thyroid nodule. N. Engl. J. Med. 328:553‐559.
  McFadden, D., Vernon, A., Santiago, P., Martinez‐McFaline, R., Bhutkar, A., Crowley, D., McMahon, M., Sadow, P., and Jacks, T. 2014. p53 constrains progression to anaplastic thyroid carcinoma in a Braf‐mutant mouse model of papillary thyroid cancer. Proc. Natl. Acad. Sci. U.S.A. 111:E1600‐E1609.
  McIver, B., Hay, I., Giuffrida, D., Dvorak, C., Grant, C., Thompson, G., van Heerden, J., and Goellner, J. 2001. Anaplastic thyroid carcinoma: A 50‐year experience at a single institution. Surgery 130:1028‐1034.
  Miller, K.A., Yeager, N., Baker, K., Liao, X.H., Refetoff, S., and Di Cristofano, A. 2009. Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform thyroid epithelial cells in vivo. Cancer Res. 69:3689‐3694.
  Nehs, M.A., Nucera, C., Nagarkatti, S.S., Sadow, P.M., Morales‐Garcia, D., Hodin, R.A., and Parangi, S. 2012. Late intervention with anti‐BRAF(V600E) therapy induces tumor regression in an orthotopic mouse model of human anaplastic thyroid cancer. Endocrinology 153:985‐994.
  Nikiforov, Y.E. 2004. Genetic alterations involved in the transition from well‐differentiated to poorly differentiated and anaplastic thyroid carcinomas. Endocr. Pathol. 15:319‐327.
  Nikiforova, M.N. and Nikiforov, Y.E. 2008. Molecular genetics of thyroid cancer: Implications for diagnosis, treatment and prognosis. Exp. Rev. Mol. Diagn. 8:83‐95.
  Nikiforova, M.N., Wald, A.I., Roy, S., Durso, M.B., and Nikiforov, Y.E. 2013. Targeted next‐generation sequencing panel (ThyroSeq) for detection of mutations in thyroid cancer. J. Clin. Endocrinol. Metab. 98:E1852‐1860.
  Nucera, C., Nehs, M.A., Mekel, M., Zhang, X., Hodin, R., Lawler, J., Nose, V., and Parangi, S. 2009. A novel orthotopic mouse model of human anaplastic thyroid carcinoma. Thyroid 19:1077‐1084.
  Olive, K.P., Tuveson, D.A., Ruhe, Z.C., Yin, B., Willis, N.A., Bronson, R.T., Crowley, D., and Jacks, T. 2004. Mutant p53 gain of function in two mouse models of Li‐Fraumeni syndrome. Cell 119:847‐860.
  Pita, J.M., Figueiredo, I.F., Moura, M.M., Leite, V., and Cavaco, B.M. 2014. Cell cycle deregulation and TP53 and RAS mutations are major events in poorly differentiated and undifferentiated thyroid carcinomas. J. Clin. Endocrinol. Metab. 99:E497‐507.
  Reiners, C., Wegscheider, K., Schicha, H., Theissen, P., Vaupel, R., Wrbitzky, R., and Schumm‐Draeger, P.M. 2004. Prevalence of thyroid disorders in the working population of Germany: Ultrasonography screening in 96,278 unselected employees. Thyroid 14:926‐932.
  Rosove, M., Peddi, P., and Glaspy, J. 2013. BRAF V600E inhibition in anaplastic thyroid cancer. N. Engl. J. Med. 368:684‐685.
  Samuels, Y., Diaz, L.A., Jr., Schmidt‐Kittler, O., Cummins, J.M., Delong, L., Cheong, I., Rago, C., Huso, D.L., Lengauer, C., Kinzler, K.W., Vogelstein, B., and Velculescu, V.E. 2005. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7:561‐573.
  Smallridge, R.C., Marlow, L.A., and Copland, J.A. 2009. Anaplastic thyroid cancer: Molecular pathogenesis and emerging therapies. Endocr. Relat. Cancer 16:17‐44.
  Smallridge, R.C., Ain, K.B., Asa, S.L., Bible, K.C., Brierley, J.D., Burman, K.D., Kebebew, E., Lee, N.Y., Nikiforov, Y.E., Rosenthal, M.S., Shah, M.H., Shaha, A.R., Tuttle, R.M. and American Thyroid Association Anaplastic Thyroid Cancer Guidelines, T. 2012. American thyroid association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 22:1104‐1139.
  Suh, J.M., Song, J.H., Kim, D.W., Kim, H., Chung, H.K., Hwang, J.H., Kim, J.M., Hwang, E.S., Chung, J., Han, J.H., Cho, B.Y., Ro, H.K., and Shong, M. 2003. Regulation of the phosphatidylinositol 3‐kinase, Akt/protein kinase B, FRAP/mammalian target of rapamycin, and ribosomal S6 kinase 1 signaling pathways by thyroid‐stimulating hormone (TSH) and stimulating type TSH receptor antibodies in the thyroid gland. J. Biol. Chem. 278:21960‐21971.
  Suzuki, H., Willingham, M.C., and Cheng, S.Y. 2002. Mice with a mutation in the thyroid hormone receptor beta gene spontaneously develop thyroid carcinoma: A mouse model of thyroid carcinogenesis. Thyroid 12:963‐969.
  Undeutsch, H., Lof, C., Offermanns, S., and Kero, J. 2014. A mouse model with tamoxifen‐inducible thyrocyte‐specific cre recombinase activity. Genesis 52:333‐340.
  Vanden Borre, P., Gunda, V., McFadden, D.G., Sadow, P.M., Varmeh, S., Bernasconi, M., and Parangi, S. 2014. Combined BRAF(V600E)‐ and SRC‐inhibition induces apoptosis, evokes an immune response and reduces tumor growth in an immunocompetent orthotopic mouse model of anaplastic thyroid cancer. Oncotarget 5:3996‐4010.
  Xing, M. 2005. BRAF mutation in thyroid cancer. Endocr. Relat. Cancer 12:245‐262.
  Xing, M. 2010. Genetic alterations in the phosphatidylinositol‐3 kinase/Akt pathway in thyroid cancer. Thyroid 20:697‐706.
  Xing, M. 2012. BRAFV600E mutation and papillary thyroid cancer: Chicken or egg? The J. Clin. Endocrinol. Metab. 97:2295‐2298.
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library