Current State of Animal (Mouse) Modeling in Melanoma Research

Abstract

Despite the considerable progress in understanding the biology of human cancer and technological advancement in drug discovery, treatment failure remains an inevitable outcome for most cancer patients with advanced diseases, including melanoma. Despite FDA-approved BRAF-targeted therapies for advanced stage melanoma showed a great deal of promise, development of rapid resistance limits the success. Hence, the overall success rate of melanoma therapy still remains to be one of the worst compared to other malignancies. Advancement of next-generation sequencing technology allowed better identification of alterations that trigger melanoma development. As development of successful therapies strongly depends on clinically relevant preclinical models, together with the new findings, more advanced melanoma models have been generated. In this article, besides traditional mouse models of melanoma, we will discuss recent ones, such as patient-derived tumor xenografts, topically inducible BRAF mouse model and RCAS/TVA-based model, and their advantages as well as limitations. Although mouse models of melanoma are often criticized as poor predictors of whether an experimental drug would be an effective treatment, development of new and more relevant models could circumvent this problem in the near future.

Regression in primary cutaneous melanoma: etiopathogenesis and clinical significance

“…46 A number of murine melanoma models are used, including xenograft, syngeneic, and genetically engineered models. 48,49 Xenograft models can be easily established by engraftment of cultured human melanoma cells into immune-deficient mice; these models are used mainly to find key oncogenic pathways. Syngeneic xenograft transplantation involves the induction and relocation of melanoma cells in another host of similar type and genetic background.…”

Incipient Melanoma Brain Metastases Instigate Astrogliosis and Neuroinflammation

“…Transgenic models of melanoma (8)(9)(10)(11)(12) are valuable for studying primary tumor initiation and progression. However, they encompass infrequent brain metastases with very long latency and thus preclude systematic analyses of the early changes in the brain microenvironment that enable metastatic growth (13).…”

Dermal Delivery of Constructs Encoding Cre Recombinase to Induce Skin Tumors in PtenLoxP/LoxP;BrafCA/+ Mice

“…They achieved a tumor induction efficiency of 36% in Ink4a/Arf lox/lox mice, whereas tumor development in Dct::TVA ; Braf CA ; Cdkn2a lox/lox and Dct::TVA ; Braf CA ; Cdkn2a lox/lox ; Pten Lox/Lox mice had an efficiency of 47% and 100%, respectively [33,34]. As has been discussed [17], the utilization of the RCAS/TVA system has limitations, as it requires actively dividing cells, and integration is thought to be random. Not only can this potentially affect the expression of host genes, but also may lead to random immunogenicity, which will be highly unwanted with respect to immunological studies.…”

“…Commonly-used in vivo melanoma models that have a competent immune system include the inoculation of murine melanoma cells (e.g., B16) in syngeneic C57BL/6 mice or engineered mouse models (GEMMs) that have spontaneous tumor formation. More sophisticated GEMMs rely on tumor induction by ultraviolet radiation (UVR), application of 7,12-dimethylbenz( a )anthracene (DMBA), viral delivery of RNAs (RCAS/TVA system) or the application of 4-hydroxytamoxifen (Cre/LoxP system) to the skin for melanoma induction [17]. The use of GEMMs allows the study of melanoma in an orthotopic location where the histology and microenvironment has a high resemblance with the human disease.…”