Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-848d4c4894-wzw2p Total loading time: 0 Render date: 2024-05-01T06:02:51.841Z Has data issue: false hasContentIssue false

22 - Experimental models for the study of CNS tumors

Published online by Cambridge University Press:  04 November 2009

By
Taichang Jang  and
Lawrence Recht
Edited by
Turgut Tatlisumak  and
Marc Fisher
Taichang Jang
Affiliation:
Department of Neurology and Clinical Neurosciences Stanford University Medical Center Palo Alto, CA 93304 USA
Lawrence Recht
Affiliation:
Department of Neurology and Clinical Neurosciences University of Stanford Medical School Palo Alto, CA 93304 USA
Turgut Tatlisumak
Affiliation:
Helsinki University Central Hospital
Marc Fisher
Affiliation:
University of Massachusetts Medical School
Get access

Summary

Introduction

Despite several decades of intensive study, the treatment of brain tumors, whether they have arisen primarily within the central nervous system (CNS) or spread there from elsewhere, represents a formidable challenge for the clinician. Several reasons underlie the difficulties in brain tumor treatment including delivering enough therapy through a blood–brain barrier (BBB), circumventing the relative immunosuppression that occurs both as a result of the brain tumor and due to its development in a relatively immunologically protected area, and the need to preserve the normal surrounding CNS. Such obstacles underscore the importance of accurate preclinical models both to understand the processes by which tumors develop and are sustained as well as to test the effectiveness of various treatments.

While in vitro systems are frequently used to assess both biology and treatment of tumors, the importance of the tumor–normal tissue relationships can only be addressed with in vivo models. Several years ago, Peterson et al. proposed criteria by which to judge the validity of such a model, including: (1) the growth rate of the tumor and its malignancy characteristics should be predictable and reproducible; (2) the species used should be small and inexpensively maintained so that large numbers may be evaluated; (3) the time to tumor induction should be relatively short and the survival time after induction should be standardized; (4) the tumor should have the same characteristics as the clinical tumor in terms of intraparenchymal growth, invasiveness, angiogenesis; (5) tumors should be maintainable in culture and should be safe for laboratory personnel; and (6) therapeutic responsiveness must imitate that of the clinical tumor being tested.

Type
Chapter
Information
Handbook of Experimental Neurology
Methods and Techniques in Animal Research
 , pp. 375 - 392
Publisher: Cambridge University Press
Print publication year: 2006

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Peterson, DL, Sheridan, PJ, Brown, WE. Animal models for brain tumors: historical perspectives and future directions. J. Neurosurg. 1994, 80: 865–876.CrossRefGoogle ScholarPubMed
Antunes, L, Angioi-Duprez, KS, Bracard, SR, et al. Analysis of tissue chimerism in nude mouse brain and abdominal xenograft models of human glioblastoma multiforme: what does it tell us about the models and about glioblastoma biology and therapy? J. Histochem. Cytochem. 2000, 48: 847–858.CrossRefGoogle ScholarPubMed
American Tissue Culture Facility. Catalog 2005, available online at http://www.atcc.org
Benda, P, Lightbody, J, Sato, G, et al. Differentiated rat glial strain in tissue culture. Science 1968, 161: 370–371.CrossRefGoogle ScholarPubMed
Cohen, JD, Robins, HI, Javid, MJ, et al. Intracranial C6 glioma model in adult Wistar-Furth rats. J. Neuro-oncol. 1990, 8: 95–96.Google ScholarPubMed
Farrell, CL, Stewart, PA, Del Maestro, RF. A new glioma model in the rat: The C6 spheroid implantation technique permeability and vascular characterization. J. Neuro-oncol. 1987, 4: 403–415.CrossRefGoogle ScholarPubMed
San-Galli, F, Vrignaud, P, Robert, J. Assessment of the experimental model of transplanted C6 glioblastoma in Wistar rats. J. Neuro-oncol. 1989, 7: 299–304.CrossRefGoogle ScholarPubMed
Nagano, N, Sasaki, H, Asyagi, M, Hirakama, K. Invasion of experimental rat brain tumor: early morphological changes following microinjection of C6 glioma cells. Acta Neuropathol. 1993, 86: 117–125.CrossRefGoogle ScholarPubMed
Schubert, D, Heinemann, S, Carlisle, W, et al. Clonal cell lines from the rat central nervous system. Nature 1974, 249: 224–227.CrossRefGoogle ScholarPubMed
Benda, P, Someda, K, Messer, J, et al. Morphological and immunochemical studies of rat glial tumors and clonal strains propagated in culture. J. Neurosurg. 1971, 34: 310–323.CrossRefGoogle ScholarPubMed
Pilkington, GJ, Bjerkvig, R, Ridder, C, Kaaijk, P. In vitro and in vivo models for the study of brain tumor invasion. Anticancer Res. 1997, 17: 4107–4110.Google Scholar
Rama, B, Spoerri, O, Holzgraefe, M, et al. Current brain tumor models with particular consideration of the transplantation techniques: outline of literature and personal primary results. Acta Neurochir. 1986, 79: 35–41.CrossRefGoogle Scholar
Paulus, W, Huettner, C, Tonn, JC. Collagens, integrins and the mesenchymal drift in glioblastomas: a comparison of biopsy specimens, spheroid and early monolayer cultures. Int. J. Cancer 1994, 58: 841–846.CrossRefGoogle ScholarPubMed
McKeever, PE, Chronwall, BM. Early switch in glial protein and fibronectin markers on cells during the culture of human gliomas. Ann NY Acad. Sci. 1985, 435: 457–459.CrossRefGoogle Scholar
Roychowdhury, S, Peng, R, Baiocchi, RA, et al. Experimental treatment of Epstein–Barr virus-associated primary central nervous system lymphoma. Cancer Res. 2003, 63: 965–971.Google ScholarPubMed
Kobayashi, N, Allen, N, Clendenon, N, et al. An improved rat brain-tumor model. J. Neurosurgery. 1980; 53: 808–815.CrossRefGoogle ScholarPubMed
Lal, S, Lacroix, M, Tofilon, P, et al. An implantable guide-screw system for brain tumor studies in small animals. J. Neurosurg. 2000, 92: 326–333.CrossRefGoogle ScholarPubMed
Rewers, AB, Redgate, ES, Deutsch, M, et al. A new rat brain tumor model: glioma disseminated via the cerebral spinal fluid pathways. J. Neuro-oncol. 1990, 8: 213–219.CrossRefGoogle ScholarPubMed
Basler GA, Shapiro WR. Brain tumor research with nude mice. In Fogh, J, Giovanella, BC (eds.) The Nude Mouse in Experimental and Clinical Research. New York: Academic Press, 1982, pp. 475–490.Google Scholar
Bradley, NJ, Bloom, JG, Dawies, AJS, Swift, SM. Growth of human gliomas in immune-deficient mice: a possible model for preclinical therapy studies. Br. J. Cancer 1978, 38: 263–272.CrossRefGoogle Scholar
Bullard, , Schold, SC, Bigner, S, Bigner, DD. Growth and chemotherapeutic response in athymic mice of tumors arising from human glioma-derived cell lines. J. Neuropathol. Exp. Neurol. 1981, 40: 410–427.CrossRefGoogle ScholarPubMed
Armond, SJ, Stowring, L, Amar, A, et al. Development of a non-selecting, non-perturbing method to study human brain tumor cell invasion in murine brain. J. Neuro-oncol. 1994, 20: 27–34.CrossRefGoogle Scholar
Horten, BC, Basler, GA, Shapiro, WR. Xenograft of human malignant glial tumors into brains of nude mice. J. Neuropathol. Exp. Neurol. 1981, 40: 493–511.CrossRefGoogle ScholarPubMed
Jones, TR, Bigner, S, Schold, SC, Eng, LF, Bigner, DD. Anaplastic human gliomas grown in athymic mice: morphology and glial fibrillary acidic protein expression. Am. J. Pathol. 1981, 105: 3274–3280.Google ScholarPubMed
Marno, K, Neyama, Y, Kuwahara, Y, et al. Human tumour xenografts in athymic rats and their age dependence. Br. J. Cancer 1982, 45: 786–789.Google Scholar
Rana, MW, Pinkerton, H, Thornton, H, Nagy, D. Heterotransplantation of human glioblastoma multiforme and meningioma to nude mice. Proc. Soc. Exp. Biol. Med. 1977, 155: 85–88.CrossRefGoogle ScholarPubMed
Shapiro, WR, Basler, GA, Chernik, NA, Posner, JB. Human brain tumor transplantation into nude mice. J. Natl Cancer Inst. 1979, 62: 447–453.CrossRefGoogle ScholarPubMed
Engebraaten, O, Hjortland, GO, Hirschbert, H, Fodstad, O. Growth of precultured glioma specimens in nude rat brain. J. Neurosurg. 1999, 90: 125–132.CrossRefGoogle ScholarPubMed
Chishima, T, Miyagi, Y, Wang, X, et al. Cancer invasion and micrometastasis visualized in live tissue by green fluorescent protein expression. Cancer Res. 1997, 5: 2042–2047.Google Scholar
Gubin, AN, Reddy, B, Njoroge, JM, Miller, JL. Long-term stable expression of green fluorescent protein in mammalian cells. Biochem. Biophys. Res. Comm. 1997, 262: 347–350.CrossRefGoogle Scholar
Fillmore, HL, Shurm, J, Fuqueron, P, et al. An in vivo rat model for visualizing glioma tumor cell invasion using stable persistent expression of the green fluorescent protein. Cancer Lett. 1999, 141: 9–19.CrossRefGoogle Scholar
Ernestus, RI, Wilmess, LJ, Hoehn-Berlage, M. Identification of intracranial liquor metastasis of experimental stereotactically implanted brain tumors by the tumor-selective MRI contrast agent MNTPPS. Clin. Exp. Metas. 1992, 10: 345–350.CrossRefGoogle Scholar
Haguenau, F, Rabotti, GF, Lyon, G, Moraillon, A. Gliomas induced by Rous sarcoma virus in the dog: an ultrastructural study. J. Natl Cancer Inst. 1971, 46: 539–559.Google Scholar
Bigner, DD, Odom, GL, Mahaley, MS, et al. Brain tumors induced in dogs by the Schmidt–Ruppin strain of Rous sarcoma virus: neuropathological and immunological observations. J. Neuropathol. Exp. Neurol. 1969, 28: 648–680.CrossRefGoogle ScholarPubMed
Tabuchi, K, Nushimoto, A, Matsumoto, K, et al. Establishment of a brain tumor model in adult monkeys. J. Neurosurg. 1985, 63: 912–916.CrossRefGoogle ScholarPubMed
Rainov, NG, Koch, S, Sena-Esteves, S, Berens, ME. Characterization of a canine glioma cell line as related to established experimental brain tumor models. J. Neuropathol. Exp. Neurol. 2000, 59: 607–613.CrossRefGoogle ScholarPubMed
Zimmerman, HM, Arnold, H. Experimental brain tumors. I. Tumors produced with methylcholanthrene. Cancer Res. 1941, 1: 919–938.Google Scholar
Arnold, H, Zimmerman, HM. Experimental brain tumors. III. Tumors produced with dibenzanthracene. Cancer Res. 1943, 10: 682–685.Google Scholar
Crafts, D, Wilson, CB. Animal models of brain tumors. Natl Cancer Inst. Monogr. 1977, 46: 11–17.Google ScholarPubMed
Rubinstein, LJ. Correlation of animal brain tumor models with human neuro-oncology. Natl Cancer Inst. Monogr. 1977, 46: 43–49.Google ScholarPubMed
Zimmerman, HM. Brain tumors: their incidence and classification in man and their experimental production. Ann NY Acad. Sci. 1969, 159: 337–359.CrossRefGoogle Scholar
Druckrey, H, Landschütz, C, Ivankovic, S. Transplacental induction of malignant tumors of the nervous system. II. Ethylnitrosourea in 10 genetically defined strains of rats. Z. Krebsforsch. 1970, 73: 371–386.CrossRefGoogle Scholar
Druckrey, H, Ivankovic, S, Preussmann, R. Teratogenic and carcinogenic effects in the offspring after a single injection of ethylnitrosourea to pregnant rats. Nature 1966, 210: 1378–1379.CrossRefGoogle ScholarPubMed
Druckrey, H. Genotypes and phenotypes of ten inbred strains of BD-rats. Arzneim-Forsch. 1971, 21: 1274–1278.Google ScholarPubMed
Ivankovic, S, Druckrey, H. Transplazentare erzeugung maligner Tumoren des Nervensystems. I. Äthyl-nitroso-harnstoff (änh) in BD-ix Ratten. Z. Krebsforsch. 1968, 71: 320–360.CrossRefGoogle Scholar
Zook, BC, Simmens, SJ, Jones, RV. Evaluation of ENU-induced gliomas in rats: nomenclature, immunohistochemistry, and malignancy. Toxicol. Pathol. 2000, 28: 193–201.CrossRefGoogle ScholarPubMed
Swann, PF, Magee, PN. Nitrosamine-induced carcinogenesis: the alkylation of N-7 of guanine of nucleic acids of the rat by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate. Biochem J. 1971, 125: 841–847.CrossRefGoogle ScholarPubMed
Müller, R, Rajewsky, MF. Elimination of O-6-ethylguanine from the DNA of brain, liver and other rat tissues exposed to ethylnitrosourea at different stages of prenatal development. Cancer Res. 1983, 43: 2897–2904.Google ScholarPubMed
Laerum, OD, Rajewsky, MF. Neoplastic transformation of fetal rat brain cells in culture after exposure to ethylnitrosourea in vivo. J. Natl Cancer Inst. 1975, 55: 1177–1187.CrossRefGoogle ScholarPubMed
Roscoe, JP, Claisse, PJ. Analysis of N-ethyl-N-nitrosourea-induced brain carcinogenesis by sequential culturing during the latent period. I. Morphology and tumorigenicity of the cultured cells and their growth in agar. J. Natl Cancer Inst. 1978, 61: 381–390.Google Scholar
Jang, T, Litofsky, NS, Smith, TS, Ross, A, Recht, L. Aberrant nestin expression during ethylnitrosourea-(ENU)-induced neurocarcinogenesis. Neurobiol. Disease 2004, 15: 544–552.CrossRefGoogle ScholarPubMed
Rushing, EJ, Watson, ML, Schold, C, Land, KJ, Kokkinakis, DM. Glial tumors in the MNU rat model: induction of pure and mixed gliomas do not require typical missense mutations of p53. J. Neuropathol. Exp. Neurol. 1998, 57: 1053–1060.CrossRefGoogle Scholar
Oda, H, Zhang, Z, Tsurutani, N, et al. Loss of p53 is an early event in induction of brain tumors in mice by transplacental carcinogen exposure. Cancer Res. 1997, 57: 646–650.Google ScholarPubMed
Bullard DE, Bigner DD. Animal models and virus induction of tumors. In Thomas, DGT, Graham, DI (eds.) Brain Tumors: Scientific Basis, Clinical Investigation, and Current Therapy. Boston, MA: Butterworths, 1980: pp. 51–84.Google Scholar
Copeland, DD, Bigner, DD. Influence of age at inoculation on avian oncornavirus-induced tumor incidence, tumor morphology, and postinoculation survival in F344 rats. Cancer Res. 1977, 37: 1657–1661.Google ScholarPubMed
Copeland, DD, Bigner, DD. The role of the subependymal plate in avian sarcoma virus brain tumor induction: comparison of incipient tumors in neonatal and adult rats. Acta Neuropathol. 1977, 38: 1–6.CrossRefGoogle ScholarPubMed
Mukai, N, Kobayashi, S. Primary brain and spinal cord tumors induced by human adenovirus type 12 in hamsters. J. Neuropathol. Exp. Neurol. 1973, 32: 523–541.CrossRefGoogle ScholarPubMed
Padgett, BL, Walker, DL, ZuRhein, GM. Jc papovavirus in progressive multifocal leukoencephalopathy. J. Infect. Dis. 1976, 133: 686–690.CrossRefGoogle ScholarPubMed
Padgett, BL, Walker, DL, ZuRhein, GM. Differential neurooncogenicity of strains of JC virus, a human polyoma virus, in newborn Syrian hamsters. Cancer Res. 1977, 37: 718–720.Google ScholarPubMed
Eddy, BE. Simian virus 40 (SV-40): an oncogenic virus. Prog. Exp. Tumor Res. 1964, 4: 1–26.Google Scholar
Duffell, D, Hinz, R, Nelson, E. Neoplasms in hamsters induced by simian virus 40: light and electron microscopic observations. Am. J. Pathol. 1964, 44: 59–73.Google Scholar
Palmiter, RD, Chen, HY, Messing, A, et al. SV40 enhancer and large-T antigen are instrumental in development of choroid plexus tumours in transgenic mice. Nature 1985, 316: 457–460.CrossRefGoogle ScholarPubMed
Marks, JR, Lin, J, Hinds, P, et al. Cellular gene expression in papillomas of the choroid plexus from transgenic mice that express the simian virus 40 large T antigen. J. Virol. 1989, 63: 790–797.Google ScholarPubMed
Brinster, RL, Chen, HY, Messing, A, et al. Transgenic mice harboring SV40 t-antigen genes develop characteristic brain tumors. Cell 1984, 37: 367–379.CrossRefGoogle ScholarPubMed
O'Brien, JM, Marcus, DM, Bernands, R, et al. Trilateral retinoblastoma in transgenic mice. Trans. Am. Ophthalmol. Soc. 1989, 87: 301–326.Google ScholarPubMed
Marcus, DM, Carpenter, JL, O'Brien, JM, et al. Primitive neuroectodermal tumor of the midbrain in a murine model of retinoblastoma. Invest. Ophthalmol. Vis. Sci. 1991, 32: 293–301.Google Scholar
Perraud, F, Yoshimura, K, Louis, B, et al. The promoter of the human cystic fibrosis transmembrane conductance regulator gene directing SV40 t antigen expression induces malignant proliferation of ependymal cells in transgenic mice. Oncogene 1992, 7: 993–997.Google ScholarPubMed
Danks, RA, Orian, JM, Gonzales, MF, et al. Transformation of astrocytes in transgenic mice expressing SV40 t antigen under the transcriptional control of the glial fibrillary acidic protein promoter. Cancer Res. 1995, 55: 4302–4310.Google ScholarPubMed
Uhrbom, L, Hesselager, G, Nistér, M, Westermark, B. Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus. Cancer Res. 1998, 58: 5275–5279.Google ScholarPubMed
Holland, EC, Hively, WP, DePinho, RA, Varmus, HE. A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Devel. 1998, 12: 3675–3685.CrossRefGoogle ScholarPubMed
Holland, EC, Hively, WP, Gallo, V, Varmus, HE. Modeling mutations in the G1 arrest pathway in human gliomas: overexpression of cdk4 but not loss of INK4a-ARF induces hyperploidy in cultured mouse astrocytes. Genes Devel. 1998, 12: 3644–3649.CrossRefGoogle Scholar
Ding, H, Roncari, L, Shannon, P, et al. Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Res. 2001, 61: 3826–3836.Google Scholar
Bajenaru, ML, Hernandez, MR, Perry, A, et al. Optic nerve glioma in mice requires astrocyte nf1 gene inactivation and nf1 brain heterozygosity. Cancer Res. 2003, 63: 8573–8577.Google ScholarPubMed
Holland, EC, Celestino, J, Dai, CK, et al. Combined activation of ras and akt in neural progenitors induces glioblastoma formation in mice. Nature Genet. 2000, 25: 55–57.CrossRefGoogle ScholarPubMed
Jensen, NA, Pedersen, KM, Lihme, F, et al. Astroglial c-myc overexpression predisposes mice to primary malignant gliomas. J. Biol. Chem. 2003, 278: 8300–8308.CrossRefGoogle ScholarPubMed
Weissenberger, J, Steinbach, JP, Malin, G, et al. Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice. Oncogene 1997, 14: 2005–2013.CrossRefGoogle ScholarPubMed
Reilly, KM, Loisel, DA, Bronson, RT, McLaughlin, ME, Jacks, T. Nf1/Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nature Genet. 2000, 26: 109–113.Google Scholar
Weiss, WA, Burns, MJ, Hackett, C, et al. Genetic determinants of malignancy in a mouse model for oligodendroglioma. Cancer Res. 2003, 63: 1589–1595.Google Scholar
Ding, H, Shannon, P, Lau, N, et al. Oligodendrogliomas result from the expression of an activated mutant epidermal growth factor receptor in a ras transgenic mouse astrocytoma model. Cancer Res. 2003, 63: 1106–1113.Google Scholar
Dai, C, Celestino, J, Okada, Y, et al. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Devel. 2001, 15: 1913–1925.CrossRefGoogle ScholarPubMed
Weiner, HL, Bakst, R, Hurlbert, MS, et al. Induction of medulloblastomas in mice by sonic hedgehog, independent of glii. Cancer Res. 2002, 62: 6385–6389.Google Scholar
Tong, WM, Ohgaki, H, Huang, H, et al. Null mutation of DNA strand break-binding molecule poly(ADP-ribose) polymerase causes medulloblastomas in p53(−/−) mice. Am. J. Pathol. 2003, 162: 343–352.CrossRefGoogle ScholarPubMed
Lee, Y, McKinnon, PJ. DNA ligase IV suppresses medulloblastoma formation. Cancer Res. 2002, 62: 6395–6399.Google ScholarPubMed
Marino, S, Vooijs, M, Gulden, H, Jonkers, J, Berns, A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Devel. 2000, 14: 994–1004.Google ScholarPubMed
Goodrich, LV, Milenkovic, L, Higgins, KM, Scott, MP. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 1997, 277: 1109–1113.CrossRefGoogle ScholarPubMed
Saylors, RL, Sidransky, D, Friedman, HS, et al. Infrequent p53 gene mutations in medulloblastomas. Cancer Res. 1991, 51: 4721–4723.Google ScholarPubMed
Tada, T, Wendland, M, Watson, N, et al. A head holder for magnetic resonance imaging that allows the stereotaxic alignment of spontaneously occurring intracranial mouse tumors. J. Neurosci. Methods 2002, 116: 1–7.CrossRefGoogle ScholarPubMed
Koutcher, JA, Hu, X, Xu, S, et al. MRI of mouse models for gliomas shows similarities to humans and can be used to identify mice for preclinical studies. Neoplasia 2002, 4: 480–485.CrossRefGoogle Scholar
Culver, KW, Ram, Z, Wallbridge, S, et al. In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 1992, 256: 1550–1552.CrossRefGoogle ScholarPubMed
Xiao, A, Wu, H, Pandolfi, PP, Louis, DN, Dyke, T. Astrocyte inactivation of the PRB pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation. Cancer Cell 2002, 1: 157–168.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×