The MeLiM Minipig: An Original Spontaneous Model to Explore Cutaneous Melanoma Genetic Basis

Abstract

Melanoma is the deadliest skin cancer and is a major public health concern with a growing incidence worldwide. As for other complex diseases, animal models are needed in order to better understand the mechanisms leading to pathology, identify potential biomarkers to be used in the clinics, and eventually molecular targets for therapeutic solutions. Cutaneous melanoma, arising from skin melanocytes, is mainly caused by environmental factors such as UV radiation; however a significant genetic component participates in the etiology of the disease. The pig is a recognized model for spontaneous development of melanoma with features similar to the human ones, followed by a complete regression and a vitiligo-like depigmentation. Three different pig models (MeLiM, Sinclair, and MMS-Troll) have been maintained through the last decades, and different genetic studies have evidenced a complex inheritance of the disease. As in humans, pigmentation seems to play a prominent role, notably through MC1R and MITF signaling. Conversely, cell cycle genes as CDKN2A and CDK4 have been excluded as predisposing for melanoma in MeLiM. So far, only sparse studies have focused on somatic changes occurring during oncogenesis, and have revealed major cytological changes and a potential dysfunction of the telomere maintenance system. Finally, the spontaneous tumor progression and regression occurring in these models could shed light on the interplay between endogenous retroviruses, melanomagenesis, and adaptive immune response.

HSP70iQ435A-Encoding DNA Repigments Vitiligo Lesions in Sinclair Swine

“…Reduced DC activation may be at play, whereas increased DC activity is expected under stress. This aligns with increased depigmentation in stressed porcine skin, and further supports the use of spontaneously depigmenting swine for therapeutic assessments (Bourneuf, 2017). Emotional stress may likewise contribute to vitiligo in this model as an impact of stress on depigmentation was recently shown in mice (Liao et al, 2017).…”

Advances in Proteomic Techniques for Cytokine Analysis: Focus on Melanoma Research

“…To study melanoma pathogenesis and facilitate development of targeted therapies, several animal models have been developed, including mouse, pig, horse, dog, zebrafish, chick embryo (to study neural crest cell migration) and others (reviewed in [ 9 , 10 , 11 , 12 ]).…”

Cutaneous Melanoma—A Long Road from Experimental Models to Clinical Outcome: A Review

“…The melanocytes genitors are considered to be the neural crest progenitor cells that differentiate during embryonic development via “dorsolateral” pathway into melanoblasts which migrate to dermis where the differentiation process results in melanocytes that will further migrate to the epidermis [ 2 ]. Melanocytes are responsible for pigment production—melanins (black eumelanin and pheomelanin) that play key roles in offering protection against DNA damage induced by UV radiation [ 21 ], thus recent studies assert the duality of these molecules (mainly for pheomelanin) in melanomagenesis, the photodamage exceeding the photoprotection [ 22 , 23 , 24 ]. The synthesis of melanin (melanogenesis) is regulated by a multitude of agents (including hormones) that interact via pathways triggered by receptor-dependent and independent mechanisms, in hormonal, auto-, para-, or intracrine manner (the positive regulators of melanogenesis: MC1 receptor, melanocortins, ACTH—adrenocorticotropic hormone, l -tyrosine and l -dihydroxyphenylalanine— l -DOPA) [ 25 , 26 ].…”

“…Other genetic and phenotype factors were discussed to be involved in melanoma development, like: gender, age, skin type, number of nevi (>50 moles—high risk), family history, immune status, etc. [ 9 , 21 ]. There were also reported gender disparities concerning the incidence of melanoma in women versus men (with an increasing trend in men), referring to physiologic differences in skin structure, baseline differences in immune systems, the influence of sex hormone levels, and estrogen receptor expression [ 18 , 35 ].…”

“…Cutaneous melanoma was described as one of the most immunogenic cancers with heterogeneous histological and clinical features, and a significant number of mutations, which explains the low rate of tumor regression, multi-drug resistance to targeted therapies, and reduced survival rate [ 21 , 36 ]. The aggressiveness of melanoma could be explained by the ability of melanoma cells to escape apoptosis by overexpressing the apoptosis-inhibitory genes (as survivin and other inhibitory apoptosis proteins—IAPs) or by reducing the apoptosis-stimulatory genes expressions what leads to apoptosis failure and an augmented risk of metastasis [ 37 ].…”