Abstract

National cancer databases document that melanoma is the most aggressive and deadly cutaneous malignancy with worldwide increasing incidence in the Caucasian population. Around 10% of melanomas occur in families. Several germline mutations were identified that might help to indicate individuals at risk for preventive interventions and early disease detection. More than 50% of sporadic melanomas carry mutations in Ras/Raf/mitogen-activated protein kinase (MAPK/MEK) pathway, which may represent aims of novel targeted therapies. Despite advances in targeted therapies and immunotherapies, the outcomes in metastatic tumor are still unsatisfactory. Here, we review animal models that help our understanding of melanoma development and treatment, including non-vertebrate, mouse, swine, and other mammal models, with an emphasis on those with spontaneously developing melanoma. Special attention is paid to the melanoma-bearing Libechov minipig (MeLiM). This original swine model of hereditary metastatic melanoma enables studying biological processes underlying melanoma progression, as well as spontaneous regression. Current histological, immunohistochemical, biochemical, genetic, hematological, immunological, and skin microbiome findings in the MeLiM model are summarized, together with development of new therapeutic approaches based on tumor devitalization. The ongoing study of molecular and immunological base of spontaneous regression in MeLiM model has potential to bring new knowledge of clinical importance.

Highlights

  • Skin cancer is a heterogeneous group of oncological diseases that demonstrate worldwide increasing incidence and include cutaneous melanoma and non-melanoma skin cancers

  • Detailed histological analysis of cutaneous melanomas sampled from melanoma-bearing Libechov minipig (MeLiM) pigs aged 4–22 weeks revealed four structurally different tissue zones—growing melanoma tissue (GMT), early spontaneous regression (ESR), late spontaneous regression (LSR), and fibrous tissue (FT)—whose presence, size, and proportion in melanoma tissue changed with animal age and advancing melanoma regression

  • The cyclin-dependent kinase inhibitor 2A (CDKN2A) locus causative in human familial melanoma was studied in MeLiM pigs; haplotype analysis, allelic association, and linkage analysis led to exclusion of this gene from candidates for melanoma susceptibility [203]

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Summary

Introduction

Skin cancer is a heterogeneous group of oncological diseases that demonstrate worldwide increasing incidence and include cutaneous melanoma ( known as malignant melanoma) and non-melanoma skin cancers (with basal cell carcinoma and squamous cell carcinoma being the most frequent). Non-melanoma skin cancers are more frequent, affect mainly the elderly population, and demonstrate relatively lower aggressiveness, metastatic activity, and mortality. Melanoma represents the least frequent but most aggressive skin cancer resulting in 65% of all skin cancer deaths. Melanoma cells arise from neoplastic transformation of melanocytes, which are pigmented cells originating from melanoblasts. Mature pigmented melanocytes are dispersed in the basal layer of the epidermis and in hair follicles, where they are responsible for skin and hair color. Neoplastic transformation can arise during fetal development, manifesting as neonatal congenital melanoma [6]. Swine represents an invaluable model with anatomical and physiological resemblance and considerably similar skin architecture to human [8,9]

Incidence
Risk Factors
Germline Mutations in Familial Melanoma
Somatic Mutations in Sporadic Melanoma
Regression
Therapy of Melanoma
Animal Models
Non-Mammalian Models
Mouse Models
Dog Models
Equine Models
Swine Melanoma Models
Sinclair Miniature Swine
Munich Miniature Swine Troll
Development of the MeLiM Model
Melanoma-bearing Libechov
MeLiM Melanoma Progression and Spontaneous Regression
Genetic Findings
Hematological Findings
Immunological Findings
Skin Microbiome
Experimental Therapy of MeLiM Melanoma by Tumor Devitalization
Concluding Remarks
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