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BioMed Research International
Volume 2016, Article ID 4521807, 9 pages
http://dx.doi.org/10.1155/2016/4521807
Review Article

Animal Models of Uveal Melanoma: Methods, Applicability, and Limitations

Department of Ophthalmology, University of Bonn, Ernst-Abbe-Straße 2, 53127 Bonn, Germany

Received 29 February 2016; Accepted 8 May 2016

Academic Editor: Monica Fedele

Copyright © 2016 Marta M. Stei et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Animal models serve as powerful tools for investigating the pathobiology of cancer, identifying relevant pathways, and developing novel therapeutic agents. They have facilitated rapid scientific progress in many tumor entities. However, for establishing a powerful animal model of uveal melanoma fundamental challenges remain. To date, no animal model offers specific genetic attributes as well as histologic, immunologic, and metastatic features of uveal melanoma. Syngeneic models with intraocular injection of cutaneous melanoma cells may suit best for investigating immunologic/tumor biology aspects. However, differences between cutaneous and uveal melanoma regarding genetics and metastasis remain problematic. Human xenograft models are widely used for evaluating novel therapeutics but require immunosuppression to allow tumor growth. New approaches aim to establish transgenic mouse models of spontaneous uveal melanoma which recently provided preliminary promising results. Each model provides certain benefits and may render them suitable for answering a respective scientific question. However, all existing models also exhibit relevant limitations which may have led to delayed research progress. Despite refined therapeutic options for the primary ocular tumor, patients’ prognosis has not improved since the 1970s. Basic research needs to further focus on a refinement of a potent animal model which mimics uveal melanoma specific mechanisms of progression and metastasis. This review will summarise and interpret existing animal models of uveal melanoma including recent advances in the field.

1. Introduction

Animal models of human cancer can contribute to the understanding of cancer pathobiology and the development of novel therapeutic agents. The ultimate goal is to translate scientific progress from basic research (in vitro and in vivo) through preclinical animal studies finally into human clinical trials to demonstrate both efficacy and safety. However, the absence of effective in vivo systems that accurately mimic the human disease condition and reliably predict clinical efficacy has hindered therapy and drug development in oncology [1]. Despite a poor rate of successful translation from animal models to clinical cancer trials [2], in vivo models have revolutionized options to study tumor biology and better understand molecular and genetic pathways. Cancer xenografts and genetically engineered mice are the most commonly used cancer models of several tumor entities [3]. In skin melanoma, genetically engineered mouse models revealed to be an improved prediction model of anticancer therapeutics and patients’ response [4]. Such transgenic mouse models have been developed for many different tumor entities allowing for detailed and diverse studies for basic research purposes as well as preclinical drug screening. However, in some tumor entities like uveal melanoma fundamental challenges in establishing an animal model which meets the tumor’s specific characteristics have not been overcome yet.

Uveal melanoma is the second most common type of melanoma after cutaneous and has, compared to skin melanoma, a relatively low incidence (6 per million per year, in the US [5]). However, it represents the most frequent primary intraocular tumor in the adult Caucasian population [68]. It arises from intraocular melanocytes of the choroid, the ciliary body, and/or the iris. Treatment strategies comprise brachytherapy, surgical excision, and removal of the entire globe. Even if fresh tumor material is available, establishing cell lines from uveal melanoma remains difficult and is often unsuccessful. There are only a limited number of permanent cell lines for uveal melanoma research available. Most of these were established some time ago which may have led to alterations in biologic and genetic properties. Thus, there is an urgent need for an effective animal model of uveal melanoma. Such a model should accurately mimic different characteristics of uveal melanoma such as genetics (monosomy 3, GNAQ/GNA11, and BAP1 mutations), hematogenous spread to the liver, (as the eye lacks lymphatics), an inflammatory tumor microenvironment, and other tumor growth characteristics. Intraocular melanomas have rarely been described in companion animals like dogs [911] and cats [1215] or in other animals like horses [16], cattle [17], or others. Despite arising naturally, these intraocular melanomas occurred sporadically and unpredictably and mostly did not metastasize to distant organs. Thus, they do not qualify as an animal model for experimental uveal melanoma. Unfortunately, no spontaneous uveal melanoma has been observed in wild type mice to date. However, mice are the most commonly employed animal model in uveal melanoma studies due to the uncomplicated housing, availability, and genetic manipulation options. It is commonly accepted that, besides transgenic models, iatrogenically induced tumor models represent the best option for oncology research. This includes implantation of animal and human uveal melanoma cell lines into animals to model the behavior of this tumor. Since advanced age is associated with changes in immunologic constitution and inoculated tumors arising in old mice better resemble tumors of their human counterpart, generally, old mice should preferably be used for studies on tumor biology (Stei et al., unpublished data).

To generate and study intraocular melanoma in mice, basically four types of models have been developed including (1) intraocular inoculation with cutaneous melanoma cells into wild type mice, (2) injection of human uveal melanoma cells into mice which requires immunosuppression to allow tumor growth, (3) new approaches aiming to crossbreed or generate genetically engineered mice which spontaneously develop intraocular melanomas, and (4) induction of uveal proliferation by chemicals, radiation, or viruses [18]. Further, in order to study metastatic uveal melanoma, different models of hepatic metastases have been established. Animal models of uveal melanoma other than mice include chick embryos, drosophila, zebrafish, rats, and rabbits. However, as no optimal animal model that faithfully replicates the behavior of the human disease (spontaneously occurring and concurrently metastasizing) has been described yet, all established animal models represent compromises and are facing certain limitations.

This review will summarise and interpret the different types of existing animal models of uveal melanoma including recent advances in the field.

2. Animal Models of Uveal Melanoma

2.1. Intraocular Injection of Cutaneous Melanoma Cells

Syngeneic transplantation models are useful, especially for experiments designed to study or modulate immune responses which require an intact immune system. For cutaneous melanoma, the most frequently used syngeneic murine model is the B16 melanoma which was derived from a spontaneously arising melanoma in a C57Bl/6J mouse and was then established as a permanent cell line [19]. Accordingly, an initial approach to create a model of intraocular melanoma was to inject B16 cutaneous melanoma cells into the eyes of C57Bl/6 mice by a microinjection technique. Different sublines of B16 cells (F10, LS9, etc.) with different metastatic rates and other cutaneous melanoma cell lines such as HCmel12 have been employed for this purpose [2023]. These cell lines form solid intraocular melanomas with characteristic tumor growth properties which would qualify as a model of intraocular melanoma. Further, the B16LS9 cell line has been selectively developed after serial passages for liver specific metastasis leading to the only model with an ocular tumor metastasizing to the liver [22]. These syngeneic mouse models have since been used in numerous studies mainly to investigate immunologic and angiogenic aspects but also to investigate tumor progression and imaging methodology [20, 21, 2437]. Besides in mice models, inoculation with cutaneous melanoma cells has also been established in other rodents. Early oncologic experiments have been performed in hamsters by implanting the Greene (actually of rabbit origin) and later the Bomirski melanoma cell line into the anterior chamber [3841]. Rabbit models provide the advantage of larger eyes and thus allow for an easier examination of experimental intraocular melanoma. The Greene melanoma cell line was implanted into the anterior or posterior chamber as well as into the subchoroidal space of rabbits and was formerly more commonly used for evaluation of treatment effects on intraocular melanomas [18, 42, 43]. However, rapid tumor growth and other complications have repelled this model. Approaches of grafting murine B16F10 cells into rabbit eyes resulted indeed in solid ocular tumors but metastases were not reliably observed and immune suppression was necessary which represented a disadvantage of this model [44, 45].

However, advantages of these syngeneic models include an apparent resemblance of the intraocular cutaneous melanoma compared to human uveal melanomas and the reliable reproducibility of this technique. The melanoma inside the unique intraocular microenvironment can be investigated in an immunologically intact mouse or other hosts. However, the application of different cell lines and different inoculation sites (anterior chamber, posterior chamber, intravitreal, subretinal, or retroorbital injection) complicates the comparability of the reported results. Furthermore and most importantly, one needs to keep in mind underlying genetic differences between cutaneous and uveal melanoma cells. Unlike cutaneous or conjunctival melanoma, mutations in B-RAF, RAS, or KIT genes occur rarely in uveal melanoma [46]. Characteristic mutations differ between uveal and cutaneous melanoma and even among tumors itself, accounting for different progression and metastatic behavior [47]. Although results from these models are suitable to describe immune responses and intraocular tumor behavior they need to be interpreted with caution when translating respective findings into treatment efficacy in human uveal melanoma.

2.2. Injections of Human Uveal Melanoma Cells

The development of xenograft models was an important step in improving animal models of clinical efficacy [95]. In cutaneous melanoma as well as in other tumor entities, human tumor xenograft models are widely used for drug screening, to evaluate targeted therapies or to test combinatorial efficacy of therapeutic agents [96]. For evaluation of intraocular melanoma growth and treatment strategies human xenografts (human uveal melanoma cell lines or primary tumor fragments) are commonly examined and several models have been described. Permanent cells lines grown from human uveal melanomas can be characterized histologically and by genetic profiling. They offer the opportunity to investigate biological and pharmacological aspects in vitro or in an animal model. Generally, these xenografts are inoculated into the eye of an immunosuppressed animal or in few cases they are injected retroorbitally. Unfortunately, relatively few permanent uveal melanoma cell lines are available for research and there has been some substantial misidentification [97, 98]. Particularly, C918 and other cell lines are most likely derived from cutaneous but uveal origin [98, 99]. This should be taken into account when interpreting and analyzing past and current data obtained with these cell lines. Further, the diverse molecular landscape of human uveal melanoma can barely be reflected by permanent cell lines. However, recently, novel established permanent cell lines from primary and metastatic uveal melanomas exhibiting a characteristic genetic profile (including GNAQ, GNA11, or BAP1 mutations) allow for further investigations on genetic pathways and their influence on tumor progression and metastasis [100]. Selecting a cell line which phenotypically and genetically reflects desired characteristics is of high importance.

Niederkorn and coworkers investigated multiple human uveal melanoma cell lines in an intraocular model in athymic mice [4851]. Human xenograft models in immunodeficient mice were frequently used in several studies, for example, on treatment efficacy, on agents or genetic pathways affecting tumor progression, on transcription factors, or on studying immunologic and histologic tumor characteristics [35, 5258]. Further, labelling human cell lines by bioluminescence allows advanced imaging procedures in the animal. The primary tumor as well as liver and lung metastases are more easily traceable [5961].

To assess efficacy of treatments on the basis of tumor growth human xenograft models have also been established in nude rats [58], rabbits, and zebrafish. Xenografts were frequently implanted into the eyes of immunosuppressed or nude rabbits with intraocular solid tumor growth, mostly accompanied by metastatic disease, and promising results [6267]. Rabbits with intraocularly inoculated human uveal melanoma cells were mainly used for basic research [6871]. Other and upcoming animal models include the injection of human primary and metastatic cell lines into the yolk of zebrafish for screening large libraries of new compounds [72].

Recently, individual patient-derived xenograft (PDX) models have emerged as an important tool for translational research, with the promise of a more personalized approach to patient care. Tumors are obtained from the patient and directly implanted into the model animal. Thus, these models maintain several characteristics of the parental tumor regarding histologic and genetic attributes [101]. First studies with primary and metastatic uveal melanoma transplants into the subcutis or the interscapular fat pad of immunosuppressed mice showed moderate take rates [7375]. PDX modelling enables tracking of tumor progression and metastasis as well as screening of different (combinatorial) drug strategies to help choose the best and most effective therapy for each individual patient [101, 102]. For uveal melanoma, this approach needs to be further evaluated and established intraocularly in order to achieve methodological advances and increased applicability in research. PDX models of uveal melanoma may help to better understand the complex cascade of uveal melanoma metastasis, to further refine therapy regimes in order to prevent metastasis, or to develop a treatment option once the tumor has metastasized.

However, a major disadvantage of all xenograft animal models is the necessity of immunosuppression. In many malignancies including those derived in immunoprivileged sites like uveal melanoma, tumor progression and the tumor microenvironment are strongly influenced by immune cells [103]. Thus, successful drug screening in xenograft models does not necessarily predict similar effects in humans.

2.3. Transgenic Mice

During the last 30 years novel technologies specifically modifying the genome allowed for the generation of transgenic mouse strains. Several criteria have been suggested for such models; for example, mice must carry the same mutation that occurs in the human tumor and mutations should be engineered within the endogenous locus [104]. Such genetically engineered mice are now considered ideal tools to study molecular and genetic pathways in cancer and other diseases. However, these techniques also can be used to generate mouse strains which spontaneously develop certain forms of malignancies. For skin melanoma, for example, RET transgenic mice with spontaneous melanomas are available since 1998 [105]. In the meantime, numerous transgenic mouse models of cutaneous melanoma have been established which closely resembles human skin malignant melanoma with regard to etiology, histopathology, and clinical progression [96].

For uveal melanoma, unfortunately, no such transgenic mouse model is available to date. Many attempts have been undertaken and numerous transgenic skin melanoma models have been investigated for the proliferation of ocular melanocytes. However, in some models no melanocytic proliferation was observed [76]; in others, pigmented intraocular tumors arising in transgenic mice were identified to be of retinal pigment epithelium origin [77, 78] or the small uveal tumors failed to metastasize to the lungs [7981]. RET.AAD transgenic mice exhibit hyperplastic lesions within all melanocyte-containing sites (skin, eye, meninges, etc.) with early tumor cell dissemination to local and distant organs [82]. As initial melanocytic lesions are mostly found within the uvea, this model was used for investigations on early local and distant tumor growth as well as dissemination [83, 84]. Schiffner and coworkers described a Tg(Grm1) transgenic mouse breed, with spontaneous skin melanoma, which exhibited pigmented choroidal proliferation mimicking spontaneous uveal melanoma [85]. However, applicability as a model for studying intraocular melanoma remains questionable and further studies need to be awaited. Overall, most attempts of finding primary and metastatic uveal melanoma in models of cutaneous melanoma were unsuccessful.

Recently, a GNAQ mutated mouse strain was described which showed neoplastic proliferation not only in choroidal structures but also in dermal nevi and other melanocytic neoplasms. Furthermore and more importantly, a vast majority of these mice exhibited distant metastasis, though exclusively in the lungs [86]. This breed represents the first transgenic mouse model of uveal melanocytic proliferation which is driven by a GNAQ gene alteration. By this means it genetically resembles human uveal melanomas, as about 80% of patients carry a G-protein (GNAQ and/or GNA11) mutation as an early event in tumorigenesis [106, 107]. This may be a first basis for a transgenic mouse model of uveal melanoma and further results need to be awaited. To our knowledge, a new animal model of spontaneous uveal melanoma was established in transgenic zebrafish. Oncogenic resemblance with human uveal melanoma is given as uveal tumorigenesis is driven by an inserted plasmid with a mitfa:GNA11 Q209L overexpression (Rose, unpublished data). Publication of this new transgenic model needs to be awaited.

2.4. Models of Metastatic Uveal Melanoma

Between 10 and 40% of uveal melanoma patients develop metastatic disease within 10 years after the initial diagnosis [108110]. Metastases disseminate predominantly hematogenously to the liver and rarely to the lungs or other organs [111]. Liver metastases occur in 95% of patients with metastatic uveal melanoma and result in death in almost all cases [112, 113]. Thus, liver metastases represent a main focus in research. Early detection of uveal melanoma reduces the risk of metastasis and can be lifesaving [114]. Currently, no effective treatment for hepatic or other metastases is available; thus, patients’ prognosis worsens dramatically when metastatic disease occurs [108]. As no liver metastasizing primary uveal melanoma model has been established yet, designing a suitable animal model of liver metastasis represents an additional challenge. Different approaches of liver metastatic tumor cell application exist, direct intrahepatic dissemination, splenic implantation with following hematogenous dissemination into the liver, or direct intravenous/intracardiac injection with hematogenous dissemination. By this means the tumor cells reach the liver directly or gain access via the blood stream in order to proliferate at this secondary site. Primary human uveal melanoma cells can be injected into immunosuppressed mice resulting in metastatic disease in most cases [4951, 59, 60, 9092] and into immunosuppressed rabbits [64, 67]. On the other hand, murine cutaneous melanoma cells can be orthotopically inoculated into immunocompetent mice [37, 115]. Further, ocular injection of B16LS9 cutaneous melanoma cells leads to hepatic and lung metastases; thus this model mimics the metastatic process from an ocular tumor to secondary sites [20, 33].

However, the generation of metastatic cell clones within a primary tumor requires genetic alterations and subsequent selection of such clones is heavily influenced by interactions with the surrounding microenvironment. Thus, when modelling hepatic metastasis, cell lines generated from a confirmed metastatic origin represent a more appropriate option than cells from the primary ocular tumor. Such models have been investigated and applied for studies in immunodeficient mice [50, 59, 61, 90, 93]. New approaches also use zebrafish or chick embryos for studies on the metastatic behavior of human metastatic uveal melanoma cell lines [72, 94]. Since some uveal “metastatic” cell lines which were thought to originate from metastases turned out to be most likely of primary origin [97], obtained data with these cell lines needs to be interpreted carefully.

Overall, these animal models of metastasis may offer a more detailed investigation of the biological behavior of metastatic uveal melanoma cells in the liver or allow for screening of novel antimetastatic compounds [93]. According to a specific research aspect the adequate cell line and model animal need to be carefully selected. However, a potent model which resembles the dissemination process from an intraocular uveal melanoma into the blood stream in an immunocompetent animal is still missing.

2.5. Induced Models

Animals may characteristically develop neoplastic proliferation or tumors after exposure to a given carcinogen or a cancer-causing agent. The agent may be of chemical, radiational, physical, or biological origin and the impact may result in alterations and mutations that lead to uncontrolled cell growth. Certain intraocularly injected oncogenic viruses are capable of inducing neoplasms including melanomas [87, 88]. Two-stage carcinogenesis by chemicals or radiation in pigmented rabbits [89] and other early attempts of induced ocular melanoma resulted in intraocular tumors but did not lead to reproducible animal models [18]. Due to uncontrolled and undirected carcinogenesis this approach barely offers controllability and reproducibility and subsequently does not qualify as a useful animal model. However, treating transgenic mice which harbor a predisposing genetic alteration in an oncogene responsible for uveal melanocytic proliferation might provide an opportunity of a new animal model. By intraocular application of a carcinogenic agent like 7,12-dimethylbenz[a]anthracene (DMBA) uveal tumorigenesis might be accelerated in a controlled manner. Such models already exist for other tumor entities like cutaneous melanoma [116] but have not been examined with respect to uveal melanoma, yet.

3. Conclusions

The development of animal models that recapitulate characteristics of human cancers and their clinical response to therapy are a major prerequisite for efficient bench-to-bedside translation and improvement of patients’ prognosis, which overall is currently dismal. Research in this area for uveal melanoma has been seriously hampered by a lack of potent experimental in vivo models. Unlike other tumor entities, to date, all existing animal models of uveal melanoma exhibit limitations. However, these models represent the best available in vivo options and each model has its advantages, which may render it more suitable to address a respective scientific question (Table 1). In essence, syngeneic models suit best for immunologic and tumor biology aspects whereas human xenograft models are commonly used for evaluating treatment strategies. Most importantly, many efforts have been made on establishing transgenic mouse models of spontaneous and metastasizing uveal melanoma which recently provided first promising results.

Table 1: Animal models of uveal melanoma.

These limitations in the availability of an integral animal model of uveal melanoma may have fundamentally contributed to delayed research progress. Despite enhanced and refined treatment procedures of the primary tumor, unfortunately, patients’ prognosis has not improved significantly since the 1970s [8]. To move forward, it is necessary to better understand and adequately model the unique characteristics of uveal melanoma. Besides genetic attributes, this includes specific features of the ocular immune system leading to a characteristic intraocular tumor microenvironment, the hematogenous dissemination, and colonisation of the liver as well as finally dormancy and the angiogenic switch of hepatic micrometastases. Prevention of metastasis will be the key to improved prognosis. Basic research needs to further focus on the intraocular tumor characteristics and metastatic process of uveal melanoma in order to successfully generate a powerful animal model. This may lead to accelerated research progress on new therapeutic targets. Meanwhile, a better understanding of underlying genetic and molecular abnormalities of uveal melanoma may provide a great opportunity for further development of targeted and individualized therapy regimes in order to improve the prognosis of patients with metastatic disease.

Recent advances in immunotherapy have been followed by a large number of clinical trials in different tumor entities. These new therapeutic strategies are now also being tested in uveal melanoma patients. However, many of these trials are based on results obtained from models of or patients with cutaneous melanoma or other tumor entities. The agents have rarely been tested in animal models of uveal melanoma because a powerful model does not exist and in the case of immunotherapeutics preclinical safety testing was accomplished earlier in other tumor entities. Hence, clinical efficacy of such new therapeutic strategies in uveal melanoma patients might be very variable or even disappointing.

Overall, in order to achieve an improvement in patients’ outcomes a better understanding of the pathogenesis of uveal melanoma is required which may be accomplished by using effective in vitro methods like 3D tumor cultures or powerful animal models of intraocular melanoma. Established models may be further refined (improved injection techniques, authenticated or new cell lines) and based on existing limitations they need to be carefully selected for a respective scientific question. Basic research may further focus on the generation and establishment of a transgenic animal model as this type of model offers strong advantages regarding immunologic, genetic, and histopathologic aspects. To reliably test novel therapeutic regimes and accurately identify therapy responses a personalized approach seems to be most promising. Therefore, PDX models for testing compounds or combinatorial therapy regimes (including targeted gene therapy and immunotherapy) may offer the best option. Further research on this type of model is strongly needed in uveal melanoma. Hence, in future these different animal models should be the basis for both biological and pharmacological testing and for rational clinical trials, thereby guiding treatment decisions and eventually improving the prognosis in patients with uveal melanoma.

Competing Interests

The authors declare that there are no competing interests regarding the publication of this paper.

References

  1. I. W. Y. Mak, N. Evaniew, and M. Ghert, “Lost in translation: animal models and clinical trials in cancer treatment,” American Journal of Translational Research, vol. 6, no. 2, pp. 114–118, 2014. View at Google Scholar · View at Scopus
  2. D. G. Hackam and D. A. Redelmeier, “Translation of research evidence from animals to humans,” The Journal of the American Medical Association, vol. 296, no. 14, pp. 1731–1732, 2006. View at Publisher · View at Google Scholar · View at Scopus
  3. G. Damia and M. D'Incalci, “Contemporary pre-clinical development of anticancer agents—what are the optimal preclinical models?” European Journal of Cancer, vol. 45, no. 16, pp. 2768–2781, 2009. View at Publisher · View at Google Scholar · View at Scopus
  4. A. J. Combest, P. J. Roberts, P. M. Dillon et al., “Genetically engineered cancer models, but not xenografts, faithfully predict anticancer drug exposure in melanoma tumors,” Oncologist, vol. 17, no. 10, pp. 1303–1316, 2012. View at Publisher · View at Google Scholar · View at Scopus
  5. C. C. McLaughlin, X.-C. Wu, A. Jemal, H. J. Martin, L. M. Roche, and V. W. Chen, “Incidence of noncutaneous melanomas in the U.S,” Cancer, vol. 103, no. 5, pp. 1000–1007, 2005. View at Publisher · View at Google Scholar · View at Scopus
  6. S. Mallone, E. De Vries, M. Guzzo et al., “Descriptive epidemiology of malignant mucosal and uveal melanomas and adnexal skin carcinomas in Europe,” European Journal of Cancer, vol. 48, no. 8, pp. 1167–1175, 2012. View at Publisher · View at Google Scholar · View at Scopus
  7. G. Virgili, G. Gatta, L. Ciccolallo et al., “Incidence of uveal melanoma in Europe,” Ophthalmology, vol. 114, no. 12, pp. 2309–2315.e2, 2007. View at Publisher · View at Google Scholar · View at Scopus
  8. A. D. Singh, M. E. Turell, and A. K. Topham, “Uveal melanoma: trends in incidence, treatment, and survival,” Ophthalmology, vol. 118, no. 9, pp. 1881–1885, 2011. View at Publisher · View at Google Scholar · View at Scopus
  9. N.-Y. Yi, S.-A. Park, S.-W. Park et al., “Malignant ocular melanoma in a dog,” Journal of Veterinary Science, vol. 7, no. 1, pp. 89–90, 2006. View at Publisher · View at Google Scholar · View at Scopus
  10. B. P. Wilcock and R. L. Peiffer Jr., “Morphology and behavior of primary ocular melanomas in 91 dogs,” Veterinary Pathology, vol. 23, no. 4, pp. 418–424, 1986. View at Publisher · View at Google Scholar · View at Scopus
  11. H. H. Dietz, O. A. Jensen, and J. B. Jørgensen, “Malignant melanoma of the uvea in the dog,” Nordisk Veterinaermedicin, vol. 38, no. 2, pp. 68–73, 1986. View at Google Scholar · View at Scopus
  12. A. Bourguet, V. Piccicuto, E. Donzel, M. Carlus, and S. Chahory, “A case of primary choroidal malignant melanoma in a cat,” Veterinary Ophthalmology, vol. 18, no. 4, pp. 345–349, 2015. View at Publisher · View at Google Scholar
  13. R. W. Bellhorn and P. Henkind, “Intra-ocular malignant melanoma in domestic cats,” Transactions of the Ophthalmological Societies of the United Kingdom, vol. 89, pp. 321–333, 1970. View at Google Scholar · View at Scopus
  14. M. Planellas, J. Pastor, M. D. Torres, T. Peña, and M. Leiva, “Unusual presentation of a metastatic uveal melanoma in a cat,” Veterinary Ophthalmology, vol. 13, no. 6, pp. 391–394, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. R. W. Bertoy, A. H. Brightman, and K. Regan, “Intraocular melanoma with multiple metastases in a cat,” Journal of the American Veterinary Medical Association, vol. 192, no. 1, pp. 87–89, 1988. View at Google Scholar · View at Scopus
  16. H. J. Davidson, G. L. Blanchard, C. A. Wheeler, and J. A. Render, “Anterior uveal melanoma, with secondary keratitis, cataract, and glaucoma, in a horse,” Journal of the American Veterinary Medical Association, vol. 199, no. 8, pp. 1049–1050, 1991. View at Google Scholar · View at Scopus
  17. J. C. L. Schuh, “Congenital intraocular melanoma in a calf,” Journal of Comparative Pathology, vol. 101, no. 1, pp. 113–116, 1989. View at Publisher · View at Google Scholar · View at Scopus
  18. H. E. Grossniklaus, S. Dithmar, and D. M. Albert, “Animal models of uveal melanoma,” Melanoma Research, vol. 10, no. 3, pp. 195–211, 2000. View at Publisher · View at Google Scholar · View at Scopus
  19. I. J. Fidler and G. L. Nicolson, “Organ selectivity for implantation survival and growth of B16 melanoma variant tumor lines,” Journal of the National Cancer Institute, vol. 57, no. 5, pp. 1199–1202, 1976. View at Google Scholar · View at Scopus
  20. H. E. Grossniklaus, B. C. Barron, and M. W. Wilson, “Murine model of anterior and posterior ocular melanoma,” Current Eye Research, vol. 14, no. 5, pp. 399–404, 1995. View at Publisher · View at Google Scholar · View at Scopus
  21. M. M. Kilian, K. U. Loeffler, C. Pfarrer, F. G. Holz, C. Kurts, and M. C. Herwig, “Intravitreally injected HCmel12 melanoma cells serve as a mouse model of tumor biology of intraocular melanoma,” Current Eye Research, vol. 41, no. 1, pp. 121–128, 2016. View at Publisher · View at Google Scholar · View at Scopus
  22. C. E. Diaz, D. Rusciano, S. Dithmar, and H. E. Grossniklaus, “B16LS9 melanoma cells spread to the liver from the murine ocular posterior compartment (PC),” Current Eye Research, vol. 18, no. 2, pp. 125–129, 1999. View at Publisher · View at Google Scholar · View at Scopus
  23. J. Y. Niederkorn, “Enucleation in consort with immunologic impairment promotes metastasis of intraocular melanomas in mice,” Investigative Ophthalmology and Visual Science, vol. 25, no. 9, pp. 1080–1086, 1984. View at Google Scholar · View at Scopus
  24. J. De Lange, L. V. Ly, K. Lodder et al., “Synergistic growth inhibition based on small-molecule p53 activation as treatment for intraocular melanoma,” Oncogene, vol. 31, no. 9, pp. 1105–1116, 2012. View at Publisher · View at Google Scholar · View at Scopus
  25. Q. Zhang, H. Yang, S. J. Kang et al., “In vivo high-frequency, contrast-enhanced ultrasonography of uveal melanoma in mice: imaging features and histopathologic correlations,” Investigative Ophthalmology and Visual Science, vol. 52, no. 5, pp. 2662–2668, 2011. View at Publisher · View at Google Scholar · View at Scopus
  26. T. L. Knisely and J. Y. Niederkorn, “Immunologic evaluation of spontaneous regression of an intraocular murine melanoma,” Investigative Ophthalmology and Visual Science, vol. 31, no. 2, pp. 247–257, 1990. View at Google Scholar · View at Scopus
  27. L. V. Ly, A. Baghat, M. Versluis et al., “In aged mice, outgrowth of intraocular melanoma depends on proangiogenic M2-type macrophages,” Journal of Immunology, vol. 185, no. 6, pp. 3481–3488, 2010. View at Publisher · View at Google Scholar · View at Scopus
  28. H. Yang and H. E. Grossniklaus, “Combined immunologic and anti-angiogenic therapy reduces hepatic micrometastases in a murine ocular melanoma model,” Current Eye Research, vol. 31, no. 6, pp. 557–562, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. J. M. Lattier, H. Yang, S. Crawford, and H. E. Grossniklaus, “Host pigment epithelium-derived factor (PEDF) prevents progression of liver metastasis in a mouse model of uveal melanoma,” Clinical and Experimental Metastasis, vol. 30, no. 8, pp. 969–976, 2013. View at Publisher · View at Google Scholar · View at Scopus
  30. L. Chen, S. Zhang, X. Li et al., “A pilot study of vasculogenic mimicry immunohistochemical expression in intraocular melanoma model,” Oncology Reports, vol. 21, no. 4, pp. 989–994, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. M. el Filali, L. V. Ly, G. P. M. Luyten et al., “Bevacizumab and intraocular tumors: an intriguing paradox,” Molecular Vision, vol. 18, pp. 2454–2467, 2012. View at Google Scholar · View at Scopus
  32. H. Yang and H. E. Grossniklaus, “Constitutive overexpression of pigment epithelium-derived factor inhibition of ocular melanoma growth and metastasis,” Investigative Ophthalmology and Visual Science, vol. 51, no. 1, pp. 28–34, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. S. Dithmar, D. Rusciano, and H. E. Grossniklaus, “A new technique for implantation of tissue culture melanoma cells in a murine model of metastatic ocular melanoma,” Melanoma Research, vol. 10, no. 1, pp. 2–8, 2000. View at Publisher · View at Google Scholar · View at Scopus
  34. I. D. Fabian, M. Rosner, I. Fabian et al., “Low thyroid hormone levels improve survival in murine model for ocular melanoma,” Oncotarget, vol. 6, no. 13, pp. 11038–11046, 2015. View at Publisher · View at Google Scholar · View at Scopus
  35. H. Yang, M. J. Jager, and H. E. Grossniklaus, “Bevacizumab suppression of establishment of micrometastases in experimental ocular melanoma,” Investigative Ophthalmology and Visual Science, vol. 51, no. 6, pp. 2835–2842, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. J. Niederkorn, G. E. Sanborn, and E. E. Scarbrough, “Mouse model of brachytherapy in consort with enucleation for treatment of malignant intraocular melanoma,” Archives of Ophthalmology, vol. 108, no. 6, pp. 865–868, 1990. View at Publisher · View at Google Scholar · View at Scopus
  37. S. Xue, H. Yang, J. Qiao et al., “Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging,” Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 21, pp. 6607–6612, 2015. View at Publisher · View at Google Scholar · View at Scopus
  38. H. S. Greene and E. K. Harvey, “The growth and metastasis of amelanotic melanomas in heterologous hosts,” Cancer Research, vol. 26, no. 4, pp. 706–714, 1966. View at Google Scholar · View at Scopus
  39. A. Bomirski, A. Słominski, and J. Bigda, “The natural history of a family of transplantable melanomas in hamsters,” Cancer and Metastasis Review, vol. 7, no. 2, pp. 95–118, 1988. View at Publisher · View at Google Scholar · View at Scopus
  40. B. Romanowska-Dixon, K. Urbanska, M. Elas, S. Pajak, H. Zygulska-Mach, and A. Miodonski, “Angiomorphology of the pigmented Bomirski melanoma growing in hamster eye,” Annals of Anatomy, vol. 183, no. 6, pp. 559–565, 2001. View at Publisher · View at Google Scholar · View at Scopus
  41. R. P. Burns and F. T. Fraunfelder, “Experimental intraocular malignant melanoma in the Syrian Golden hamster,” American Journal of Ophthalmology, vol. 51, no. 5, pp. 977–993, 1961. View at Google Scholar · View at Scopus
  42. D. L. Krohn, R. Brandt, D. A. Morris, and A. S. Keston, “Subchoroidal transplantation of experimental malignant melanoma,” American Journal of Ophthalmology, vol. 70, no. 5, pp. 753–756, 1970. View at Publisher · View at Google Scholar · View at Scopus
  43. F. H. Lambrou, M. Chilbert, W. F. Mieler, G. A. Williams, and K. Olsen, “A new technique for subchoroidal implantation of experimental malignant melanoma,” Investigative Ophthalmology and Visual Science, vol. 29, no. 6, pp. 995–998, 1988. View at Google Scholar · View at Scopus
  44. M. Krause, K. K. Kwong, J. Xiong, E. S. Gragoudas, and L. H. Y. Young, “MRI of blood volume and cellular uptake of superparamagnetic iron in an animal model of choroidal melanoma,” Ophthalmic Research, vol. 34, no. 4, pp. 241–250, 2002. View at Publisher · View at Google Scholar · View at Scopus
  45. L. K. Hu, K. Huh, E. S. Gragoudas, and L. H. Y. Young, “Establishment of pigmented choroidal melanomas in a rabbit model,” Retina, vol. 14, no. 3, pp. 264–269, 1994. View at Publisher · View at Google Scholar · View at Scopus
  46. K. G. Griewank, H. Westekemper, R. Murali et al., “Conjunctival melanomas harbor BRAF and NRAS mutations and copy number changes similar to cutaneous and mucosal melanomas,” Clinical Cancer Research, vol. 19, no. 12, pp. 3143–3152, 2013. View at Publisher · View at Google Scholar · View at Scopus
  47. J. M. Mehnert and H. M. Kluger, “Driver mutations in melanoma: lessons learned from bench-to-bedside studies,” Current Oncology Reports, vol. 14, no. 5, pp. 449–457, 2012. View at Publisher · View at Google Scholar · View at Scopus
  48. D. Ma, R. D. Gerard, X.-Y. Li, H. Alizadeh, and J. Y. Niederkorn, “Inhibition of metastasis of intraocular melanomas by adenovirus-mediated gene transfer of plasminogen activator inhibitor type 1 (PAI-1) in an athymic mouse model,” Blood, vol. 90, no. 7, pp. 2738–2746, 1997. View at Google Scholar · View at Scopus
  49. D. Ma, G. P. Luyten, T. M. Luider, M. J. Jager, and J. Y. Niederkorn, “Association between NM23-H1 gene expression and metastasis of human uveal melanoma in an animal model,” Investigative Ophthalmology and Visual Science, vol. 37, no. 11, pp. 2293–2301, 1996. View at Google Scholar · View at Scopus
  50. D. Ma and J. Y. Niederkorn, “Role of epidermal growth factor receptor in the metastasis of intraocular melanomas,” Investigative Ophthalmology and Visual Science, vol. 39, no. 7, pp. 1067–1075, 1998. View at Google Scholar · View at Scopus
  51. J. Y. Niederkorn, J. Mellon, M. Pidherney, E. Mayhew, and R. Anand, “Effect of anti-ganglioside antibodies on the metastatic spread of intraocular melanomas in a nude mouse model of human uveal melanoma,” Current Eye Research, vol. 12, no. 4, pp. 347–358, 1993. View at Publisher · View at Google Scholar · View at Scopus
  52. A. J. Mueller, A. J. Maniotis, W. R. Freeman et al., “An orthotopic model for human uveal melanoma in SCID mice,” Microvascular Research, vol. 64, no. 2, pp. 207–213, 2002. View at Publisher · View at Google Scholar · View at Scopus
  53. X. L. Xu, D.-N. Hu, C. Iacob et al., “Effects of zeaxanthin on growth and invasion of human uveal melanoma in nude mouse model,” Journal of Ophthalmology, vol. 2015, Article ID 392305, 8 pages, 2015. View at Publisher · View at Google Scholar
  54. M. R. Miller, J. B. Mandell, K. M. Beatty et al., “Splenectomy promotes indirect elimination of intraocular tumors by CD8+ T cells that is associated with IFNgamma- and Fas/FasL-dependent activation of intratumoral macrophages,” Cancer Immunology Research, vol. 2, no. 12, pp. 1175–1185, 2014. View at Publisher · View at Google Scholar
  55. K. Hu, S. Babapoor-Farrokhran, M. Rodrigues et al., “Hypoxia-inducible factor 1 upregulation of both VEGF and ANGPTL4 is required to promote the angiogenic phenotype in uveal melanoma,” Oncotarget, vol. 7, no. 7, pp. 7816–7828, 2016. View at Google Scholar
  56. F.-X. Yu, J. Luo, J.-S. Mo et al., “Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP,” Cancer Cell, vol. 25, no. 6, pp. 822–830, 2014. View at Publisher · View at Google Scholar · View at Scopus
  57. K. A. Matatall, O. A. Agapova, M. D. Onken, L. A. Worley, A. M. Bowcock, and J. W. Harbour, “BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma,” BMC Cancer, vol. 13, article 371, 2013. View at Publisher · View at Google Scholar · View at Scopus
  58. R. D. Braun and K. S. Vistisen, “Modeling human choroidal melanoma xenograft growth in immunocompromised rodents to assess treatment efficacy,” Investigative Ophthalmology and Visual Science, vol. 53, no. 6, pp. 2693–2701, 2012. View at Publisher · View at Google Scholar · View at Scopus
  59. O. Surriga, V. K. Rajasekhar, G. Ambrosini, Y. Dogan, R. Huang, and G. K. Schwartz, “Crizotinib, a c-met inhibitor, prevents metastasis in a metastatic uveal melanoma model,” Molecular Cancer Therapeutics, vol. 12, no. 12, pp. 2817–2826, 2013. View at Publisher · View at Google Scholar · View at Scopus
  60. H. Yang, G. Fang, X. Huang, J. Yu, C.-L. Hsieh, and H. E. Grossniklaus, “In-vivo xenograft murine human uveal melanoma model develops hepatic micrometastases,” Melanoma Research, vol. 18, no. 2, pp. 95–103, 2008. View at Publisher · View at Google Scholar · View at Scopus
  61. G. Barisione, M. Fabbi, A. Gino et al., “Potential role of soluble c-Met as a new Candidate biomarker of metastatic uveal melanoma,” JAMA Ophthalmology, vol. 133, no. 9, pp. 1013–1021, 2015. View at Publisher · View at Google Scholar · View at Scopus
  62. P. E. Liggett, G. Lo, K. J. Pince, N. A. Rao, S. G. Pascal, and J. Kan-Mitchel, “Heterotransplantation of human uveal melanoma,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 231, no. 1, pp. 15–20, 1993. View at Publisher · View at Google Scholar · View at Scopus
  63. A. J. Mueller, R. Folberg, W. R. Freeman et al., “Evaluation of the human choroidal melanoma rabbit model for studying microcirculation patterns with confocal ICG and histology,” Experimental Eye Research, vol. 68, no. 6, pp. 671–678, 1999. View at Publisher · View at Google Scholar · View at Scopus
  64. G. Blanco, M. A. Saornil, E. Domingo et al., “Uveal melanoma model with metastasis in rabbit: effects of different doses of cyclosporine A,” Current Eye Research, vol. 21, no. 3, pp. 740–747, 2000. View at Publisher · View at Google Scholar · View at Scopus
  65. P. Bonicel, J. Michelot, F. Bacin et al., “Establishment of IPC 227 cells as human xenografts in rabbits: a model of uveal melanoma,” Melanoma Research, vol. 10, no. 5, pp. 445–450, 2000. View at Publisher · View at Google Scholar · View at Scopus
  66. R. López-Velasco, A. Morilla-Grasa, M. A. Saornil-Álvarez et al., “Efficacy of five human melanocytic cell lines in experimental rabbit choroidal melanoma,” Melanoma Research, vol. 15, no. 1, pp. 29–37, 2005. View at Publisher · View at Google Scholar · View at Scopus
  67. P. L. Blanco, J. C. A. Marshall, E. Antecka et al., “Characterization of ocular and metastatic uveal melanoma in an animal model,” Investigative Ophthalmology and Visual Science, vol. 46, no. 12, pp. 4376–4382, 2005. View at Publisher · View at Google Scholar · View at Scopus
  68. S. J. Kang, Q. Zhang, S. R. Patel et al., “In vivo high-frequency contrast-enhanced ultrasonography of choroidal melanoma in rabbits: imaging features and histopathologic correlations,” British Journal of Ophthalmology, vol. 97, no. 7, pp. 929–933, 2013. View at Publisher · View at Google Scholar · View at Scopus
  69. S. Di Cesare, S. Maloney, B. F. Fernandes et al., “The effect of blue light exposure in an ocular melanoma animal model,” Journal of Experimental and Clinical Cancer Research, vol. 28, article 48, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. J.-C. A. Marshall, B. F. Fernandes, S. Di cesare et al., “The use of a cyclooxygenase-2 inhibitor (Nepafenac) in an ocular and metastatic animal model of uveal melanoma,” Carcinogenesis, vol. 28, no. 9, pp. 2053–2058, 2007. View at Publisher · View at Google Scholar · View at Scopus
  71. J.-C. Marshall, A. Nantel, P. Blanco, J. Ash, S. R. Cruess, and M. N. Burnier Jr., “Transcriptional profiling of human uveal melanoma from cell lines to intraocular tumors to metastasis,” Clinical and Experimental Metastasis, vol. 24, no. 5, pp. 353–362, 2007. View at Publisher · View at Google Scholar · View at Scopus
  72. W. van der Ent, C. Burrello, A. F. A. S. Teunisse et al., “Modeling of human uveal melanoma in zebrafish xenograft embryos,” Investigative Ophthalmology & Visual Science, vol. 55, no. 10, pp. 6612–6622, 2014. View at Publisher · View at Google Scholar · View at Scopus
  73. S. Heegaard, M. Spang-Thomsen, and J. U. Prause, “Establishment and characterization of human uveal malignant melanoma xenografts in nude mice,” Melanoma Research, vol. 13, no. 3, pp. 247–251, 2003. View at Publisher · View at Google Scholar · View at Scopus
  74. F. Némati, C. de Montrion, G. Lang et al., “Targeting Bcl-2/Bcl-XL induces antitumor activity in uveal melanoma patient-derived xenografts,” PLoS ONE, vol. 9, no. 1, Article ID e80836, 2014. View at Publisher · View at Google Scholar · View at Scopus
  75. F. Némati, X. Sastre-Garau, C. Laurent et al., “Establishment and characterization of a panel of human uveal melanoma xenografts derived from primary and/or metastatic tumors,” Clinical Cancer Research, vol. 16, no. 8, pp. 2352–2362, 2010. View at Publisher · View at Google Scholar · View at Scopus
  76. M. M. Kilian, M. C. Herwig, F. G. Holz, T. Tüting, and K. U. Loeffler, “Overexpression of hepatocyte growth factor and an oncogenic CDK4 variant in mice alters corneal stroma morphology but does not lead to spontaneous ocular melanoma,” Melanoma Research, vol. 26, no. 1, pp. 89–91, 2016. View at Publisher · View at Google Scholar
  77. N. A. Syed, J. J. Windle, S. R. Darjatmoko et al., “Transgenic mice with pigmented intraocular tumors: tissue of origin and treatment,” Investigative Ophthalmology & Visual Science, vol. 39, no. 13, pp. 2800–2805, 1998. View at Google Scholar
  78. D. M. Albert, A. Kumar, S. A. Strugnell et al., “Effectiveness of 1α-hydroxyvitamin D2 in inhibiting tumor growth in a murine transgenic pigmented ocular tumor model,” Archives of Ophthalmology, vol. 122, no. 9, pp. 1365–1369, 2004. View at Publisher · View at Google Scholar · View at Scopus
  79. T. R. Kramer, M. B. Powell, M. M. Wilson, J. Salvatore, and H. E. Grossniklaus, “Pigmented uveal tumours in a transgenic mouse model,” British Journal of Ophthalmology, vol. 82, no. 8, pp. 953–960, 1998. View at Publisher · View at Google Scholar · View at Scopus
  80. W. H. Tolleson, J. C. Doss, J. Latendresse et al., “Spontaneous uveal amelanotic melanoma in transgenic Tyr-RAS+ Ink4a/Arf−/− mice,” Archives of Ophthalmology, vol. 123, no. 8, pp. 1088–1094, 2005. View at Publisher · View at Google Scholar · View at Scopus
  81. J. R. Latendresse, L. Muskhelishvili, A. Warbritton, and W. H. Tolleson, “Two cases of uveal amelanotic melanoma in transgenic Tyr-HRAS+ Ink4a/Arf heterozygous mice,” Toxicologic Pathology, vol. 35, no. 6, pp. 827–832, 2007. View at Google Scholar · View at Scopus
  82. J. Eyles, A.-L. Puaux, X. Wang et al., “Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma,” The Journal of Clinical Investigation, vol. 120, no. 6, pp. 2030–2039, 2010. View at Publisher · View at Google Scholar · View at Scopus
  83. Y. K. Pin, K. Khoo, M. Tham et al., “Lymphadenectomy promotes tumor growth and cancer cell dissemination in the spontaneous RET mouse model of human uveal melanoma,” Oncotarget, vol. 6, no. 42, pp. 44806–44818, 2015. View at Publisher · View at Google Scholar
  84. M. Tham, K. Khoo, K. P. Yeo et al., “Macrophage depletion reduces postsurgical tumor recurrence and metastatic growth in a spontaneous murine model of melanoma,” Oncotarget, vol. 6, no. 26, pp. 22857–22868, 2015. View at Publisher · View at Google Scholar · View at Scopus
  85. S. Schiffner, B. M. Braunger, M. M. de Jel, S. E. Coupland, E. R. Tamm, and A. K. Bosserhoff, “Tg(Grm1) transgenic mice: a murine model that mimics spontaneous uveal melanoma in humans?” Experimental Eye Research, vol. 127, pp. 59–68, 2014. View at Publisher · View at Google Scholar · View at Scopus
  86. J. L.-Y. Huang, O. Urtatiz, and C. D. Van Raamsdonk, “Oncogenic G protein GNAQ induces uveal melanoma and intravasation in mice,” Cancer Research, vol. 75, no. 16, pp. 3384–3397, 2015. View at Publisher · View at Google Scholar · View at Scopus
  87. D. M. Albert, J. A. Shadduck, J. L. Craft, and J. Y. Niederkorn, “Feline uveal melanoma model induced with feline sarcoma virus,” Investigative Ophthalmology & Visual Science, vol. 20, no. 5, pp. 606–624, 1981. View at Google Scholar · View at Scopus
  88. D. M. Albert, A. S. Rabson, and A. J. Dalton, “In vitro neoplastic transformation of uveal and retinal tissue by oncogenic DNA viruses,” Investigative Ophthalmology, vol. 7, no. 4, pp. 357–365, 1968. View at Google Scholar · View at Scopus
  89. J. Pe'er, R. Folberg, S. J. Massicotte et al., “Clinicopathologic spectrum of primary uveal melanocytic lesions in an animal model,” Ophthalmology, vol. 99, no. 6, pp. 977–986, 1992. View at Publisher · View at Google Scholar · View at Scopus
  90. R. Folberg, L. Leach, K. Valyi-Nagy et al., “Modeling the behavior of uveal melanoma in the liver,” Investigative Ophthalmology & Visual Science, vol. 48, no. 7, pp. 2967–2974, 2007. View at Publisher · View at Google Scholar · View at Scopus
  91. H. Li, H. Alizadeh, and J. Y. Niederkorn, “Differential expression of chemokine receptors on uveal melanoma cells and their metastases,” Investigative Ophthalmology & Visual Science, vol. 49, no. 2, pp. 636–643, 2008. View at Publisher · View at Google Scholar · View at Scopus
  92. I. C. Notting, J. T. Buijs, I. Que et al., “Whole-body bioluminescent imaging of human uveal melanoma in a new mouse model of local tumor growth and metastasis,” Investigative Ophthalmology and Visual Science, vol. 46, no. 5, pp. 1581–1587, 2005. View at Publisher · View at Google Scholar · View at Scopus
  93. S. Ozaki, R. Vuyyuru, K. Kageyama et al., “Establishment and characterization of orthotopic mouse models for human uveal melanoma hepatic colonization,” The American Journal of Pathology, vol. 186, no. 1, pp. 43–56, 2016. View at Publisher · View at Google Scholar
  94. H. Shahidipour, S. E. Coupland, D. Moss, B. E. Damato, and H. Kalirai, “Chick embryo model systems to study uveal melanoma metastasis,” Investigative Ophthalmology & Visual Science, vol. 55, no. 13, article 5075, 2014. View at Google Scholar
  95. L. R. Kelland, “Of mice and men: values and liabilities of the athymic nude mouse model in anticancer drug development,” European Journal of Cancer, vol. 40, no. 6, pp. 827–836, 2004. View at Publisher · View at Google Scholar · View at Scopus
  96. O. F. Kuzu, F. D. Nguyen, M. A. Noory, and A. Sharma, “Current state of animal (mouse) modeling in melanoma research,” Cancer Growth and Metastasis, vol. 8, supplement 1, pp. 81–94, 2015. View at Publisher · View at Google Scholar
  97. R. Folberg, S. S. Kadkol, S. Frenkel et al., “Authenticating cell lines in ophthalmic research laboratories,” Investigative Ophthalmology and Visual Science, vol. 49, no. 11, pp. 4697–4701, 2008. View at Publisher · View at Google Scholar · View at Scopus
  98. K. G. Griewank, X. Yu, J. Khalili et al., “Genetic and molecular characterization of uveal melanoma cell lines,” Pigment Cell and Melanoma Research, vol. 25, no. 2, pp. 182–187, 2012. View at Publisher · View at Google Scholar · View at Scopus
  99. X. Yu, G. Ambrosini, J. Roszik et al., “Genetic analysis of the ‘uveal melanoma’ C918 cell line reveals atypical BRAF and common KRAS mutations and single tandem repeat profile identical to the cutaneous melanoma C8161 cell line,” Pigment Cell and Melanoma Research, vol. 28, no. 3, pp. 357–359, 2015. View at Publisher · View at Google Scholar · View at Scopus
  100. N. Amirouchene-Angelozzi, F. Nemati, D. Gentien et al., “Establishment of novel cell lines recapitulating the genetic landscape of uveal melanoma and preclinical validation of mTOR as a therapeutic target,” Molecular Oncology, vol. 8, no. 8, pp. 1508–1520, 2014. View at Publisher · View at Google Scholar · View at Scopus
  101. D. Siolas and G. J. Hannon, “Patient-derived tumor xenografts: transforming clinical samples into mouse models,” Cancer Research, vol. 73, no. 17, pp. 5315–5319, 2013. View at Publisher · View at Google Scholar · View at Scopus
  102. M. Hidalgo, F. Amant, A. V. Biankin et al., “Patient-derived xenograft models: an emerging platform for translational cancer research,” Cancer Discovery, vol. 4, no. 9, pp. 998–1013, 2014. View at Publisher · View at Google Scholar · View at Scopus
  103. I. H. Bronkhorst and M. J. Jager, “Inflammation in uveal melanoma,” Eye, vol. 27, no. 2, pp. 217–223, 2013. View at Publisher · View at Google Scholar · View at Scopus
  104. A. Richmond and S. Yingjun, “Mouse xenograft models vs GEM models for human cancer therapeutics,” Disease Models & Mechanisms, vol. 1, no. 2-3, pp. 78–82, 2008. View at Publisher · View at Google Scholar · View at Scopus
  105. M. Kato, M. Takahashi, A. A. Akhand et al., “Transgenic mouse model for skin malignant melanoma,” Oncogene, vol. 17, no. 14, pp. 1885–1888, 1998. View at Publisher · View at Google Scholar · View at Scopus
  106. C. D. Van Raamsdonk, V. Bezrookove, G. Green et al., “Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi,” Nature, vol. 457, no. 7229, pp. 599–602, 2009. View at Publisher · View at Google Scholar · View at Scopus
  107. C. D. Van Raamsdonk, K. G. Griewank, M. B. Crosby et al., “Mutations in GNA11 in uveal melanoma,” The New England Journal of Medicine, vol. 363, no. 23, pp. 2191–2199, 2010. View at Publisher · View at Google Scholar · View at Scopus
  108. AJCC, “International validation of the American Joint Committee on Cancer's 7th edition classification of uveal melanoma,” JAMA Ophthalmology, vol. 133, no. 4, pp. 376–383, 2015. View at Publisher · View at Google Scholar
  109. J. A. Shields, C. L. Shields, and L. A. Donoso, “Management of posterior uveal melanoma,” Survey of Ophthalmology, vol. 36, no. 3, pp. 161–195, 1991. View at Publisher · View at Google Scholar · View at Scopus
  110. E. Kujala, T. Mäkitie, and T. Kivelä, “Very long-term prognosis of patients with malignant uveal melanoma,” Investigative Ophthalmology & Visual Science, vol. 44, no. 11, pp. 4651–4659, 2003. View at Publisher · View at Google Scholar · View at Scopus
  111. M. Diener-West, S. M. Reynolds, D. J. Agugliaro et al., “Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26,” Archives of Ophthalmology, vol. 123, no. 12, pp. 1639–1643, 2005. View at Publisher · View at Google Scholar · View at Scopus
  112. J. J. Augsburger, Z. M. Corrêa, and A. H. Shaikh, “Effectiveness of treatments for metastatic uveal melanoma,” American Journal of Ophthalmology, vol. 148, no. 1, pp. 119–127, 2009. View at Publisher · View at Google Scholar · View at Scopus
  113. J. K. V. Willson, D. M. Albert, M. Diener-West et al., “Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the collaborative ocular melanoma study (coms) coms report no. 15,” Archives of Ophthalmology, vol. 119, no. 5, pp. 670–676, 2001. View at Publisher · View at Google Scholar · View at Scopus
  114. C. L. Shields, S. Kaliki, M. Furuta, E. Fulco, C. Alarcon, and J. A. Shields, “American joint committee on cancer classification of uveal melanoma (anatomic stage) predicts prognosis in 7731 patients: the 2013 zimmerman lecture,” Ophthalmology, vol. 122, no. 6, pp. 1180–1186, 2015. View at Publisher · View at Google Scholar · View at Scopus
  115. W. Yang, H. Li, E. Mayhew, J. Mellon, P. W. Chen, and J. Y. Niederkorn, “NKT cell exacerbation of liver metastases arising from melanomas transplanted into either the eyes or spleens of mice,” Investigative Ophthalmology & Visual Science, vol. 52, no. 6, pp. 3094–3102, 2011. View at Publisher · View at Google Scholar · View at Scopus
  116. D. Tormo, A. Ferrer, E. Gaffal et al., “Rapid growth of invasive metastatic melanoma in carcinogen-treated hepatocyte growth factor/scatter factor-transgenic mice carrying an oncogenic CDK4 mutation,” The American Journal of Pathology, vol. 169, no. 2, pp. 665–672, 2006. View at Publisher · View at Google Scholar · View at Scopus