c-Kit-Targeting Immunotherapy for Hereditary Melanoma in a Mouse Model

Abstract

The role of c-Kit in the development of melanoma was studied in line 304/B6 of RET-transgenic mice, in which melanoma spontaneously develops. In Wv/Wv-RET (304/B6)-transgenic mice, in which c-Kit function was severely impaired, development of melanoma was strongly suppressed. Although 31 of the 44 original RET-transgenic mice died of rapidly growing melanoma within 12 months after birth, only 8 of the 44 Wv/Wv-RET-transgenic mice developed slowly growing melanocytic tumors with a greatly prolonged mean tumor-free period, 2 of which died of melanoma at a late stage. Even Wv/؉-RET-transgenic mice had a clearly prolonged tumor-free period and definitely reduced frequency (6 of 61) of tumor death within 12 months after birth. Melanin production in the skin of these mice was not strongly impaired, suggesting that c-Kit affects the development of melanomas in these mice with only minor effects in melanin production. c-Kit expression in skin soon after birth was promoted in RET-transgenic mice, and c-Kit was expressed at high levels at the benign but not malignant stage of the tumor. A single injection of anti-c-Kit antibody (ACK2) into RET-transgenic mice soon after birth caused a surprisingly long-lasting suppression of development of melanoma, greatly prolonging the tumor-free period, and none of the 28 ACK2-treated RET-transgenic mice died from tumors at 12 months of age. The c-Kit function needed for melanin production was also suppressed for an unusually long time in ACK2-treated, RET-transgenic mice. These results suggest that c-Kit can be a unique target molecule for melanoma treatment.

Skin Melanoma Development in ret Transgenic Mice Despite the Depletion of CD25+Foxp3+ Regulatory T Cells in Lymphoid Organs

“…Notably, most of these studies were performed using conventional mouse B16 melanoma model, which is based on the tumor cell transplantation and is not comparable with the clinical situation. In contrast, ret transgenic mice used in this study serve as an excellent model for spontaneous skin melanoma, closely resembling human melanoma with respect to clinical development (22,23). Additionally, this model permits investigations under conditions of natural tumor-host interactions.…”

“…Importantly, all of these tumor models were based on the transplantation of tumor cells, in which the natural history of the disease and tumorhost interactions are not comparable with the clinical situation. In contrast to transplantation models, a recently described ret transgenic mouse model closely resembles human melanoma regarding tumor genetics, histopathology, and clinical development (22,23). Mice expressing the human ret transgene in melanocytes controlled by the mouse metallothionein-I promoter-enhancer develop spontaneously malignant cutaneous melanoma lesions metastasizing to lymph nodes (LN), lungs, brain, kidney and spleen (23).…”

“…In contrast to transplantation models, a recently described ret transgenic mouse model closely resembles human melanoma regarding tumor genetics, histopathology, and clinical development (22,23). Mice expressing the human ret transgene in melanocytes controlled by the mouse metallothionein-I promoter-enhancer develop spontaneously malignant cutaneous melanoma lesions metastasizing to lymph nodes (LN), lungs, brain, kidney and spleen (23). This metastatic profile is similar to that observed in melanoma patients (24).…”

Myeloid Derived Suppressor Cells: Subsets, Expansion, and Role in Cancer Progression

“…While exophthalmos eventually presents in adult RETAAD mice, microscopic eye tumors can be detected as early as ten days after birth, and cancer cells disseminate from the primary eye tumor throughout the body within three weeks (Eyles et al, 2010;Kato et al, 1998). Disseminated RETAAD cancer cells remain dormant for months before developing into cutaneous and visceral metastases, and the stepwise evolution of melanoma in these mice closely mimics the histopathology and natural history of human cancers (Eskelin et al, 2000;Kato et al, 1998;Kato et al, 2004). The RETAAD melanoma model is therefore particularly suitable for dissecting the role of host immune cells in metastatic processes.…”

Label-Free Imaging of Melanoma with Confocal Photothermal Microscopy: Differentiation between Malignant and Benign Tissue

“…RFP/RET-transgenic mice of line 304/B6 (RETTg) stepwise develop benign melanocytic tumors and malignant melanomas and widely used for analysis of melanoma genesis [28][29][30]). The performance of the setup was tested with a sample of 20-nm gold nanoparticles.…”