Spontaneous animal tumors appear to be highly suitable models to study human oncology and cancer therapy. The aim of this study was to characterize the clinical and histological features of hereditary melanocytic lesions found in the French herd of melanoblastoma-bearing Libechov minipigs (MeLiM) and their Duroc crossbreeds. Clinically, we discriminated between three types of melanocytic skin lesions, which offer a lesion continuum from lentigo to metastatic melanomas. More than 70% of these lesions appear on piglets before they are 3 months old and preferentially on homogeneous black coat piglets. The incidence of melanoma reaches 50% in MeLiM. Most of the highly invasive melanomas regressed spontaneously in the first year of the piglet's life and the regression was followed by hair, skin and iris depigmentation. A histopathological study was conducted according to the human melanoma classification. Except for lentigo maligna, we observed the three main types of human melanoma in swine [superficial spreading melanoma (SSM), nodular or unclassified melanoma] with an excess of SSM (59-67%). The histological events leading to total spontaneous regression are chronologically described. The genetic predisposition, the high incidence of melanoma, the clinical and histopathological features similar to the human disease and the high rate of spontaneous regression offer an opportunity to use this model for studying genetic events controlling melanoma development and regression and the biological mechanisms involved in oncogenesis and anti-cancerous self-defense.

Tumors are complex tissues composed of neoplastic cells, soluble and insoluble matrix components and stromal cells. Here we report that in melanoma, turn-over of type I collagen (Col(I)), the predominant matrix protein in dermal stroma affects melanoma progression. Fibroblasts juxtaposed to melanoma cell nests within the papillary dermis display high levels of Col(I) mRNA expression. These nests are enveloped by collagen fibers. In contrast, melanoma-associated fibroblasts within the reticular dermis express Col(I) mRNA at a level that is comparable to its expression in uninvolved dermis and reduced amount of collagen protein can be observed. To determine the significance of Col(I) expression in melanoma, we pharmacologically inhibited its transcription in a porcine cutaneous melanoma model by oral administration of halofuginone. When administered before melanoma development, it reduced melanoma incidence and diminished the transition from microinvasive toward deeply invasive growth by limiting the development of a tumor vasculature. Whereas invasive melanoma growth has been correlated with increased blood vessel density previously, our data for the first time demonstrate that the proangiogenic effect of Col(I) expression by fibroblasts and vascular cells precedes the development of invasive melanomas in a de novo tumor model. ' 2007 Wiley-Liss, Inc.Key words: cutaneous melanoma; type I collagen; angiogenesis; MeLiM porcine melanoma model; halofuginone Tumor development and invasion into adjacent tissue is often accompanied by increased architectural disorder of the extracellular matrix (ECM) and cellular components especially at the invasive front of the neoplastic mass. 1 Along with increased production of extracellular proteolytic enzymes, 2-4 increased synthesis of type I collagen (Col(I)) and other matrix components by stromal cells has been documented in skin, mammary, colon and prostate carcinomas. [5][6][7][8][9] In squamous cell carcinomas of the skin, increased Col(I) synthesis by stromal fibroblasts 9 is also accompanied by enhanced remodeling due to increased activity of matrix proteinases. 10 In contrast, cutaneous melanoma, but with the exception of desmoplastic variants, is not associated with strong ECM remodeling, but is mainly characterized by pericellular proteolysis of Col(I) and elastin at the invasive front. 11 Expression of Col(I) and its contribution to melanoma development and progression have not been studied extensively.In skin, the fibril forming Col(I) is predominantly synthesized by fibroblasts and accounts for 80-90% of the collagenous proteins present in the dermis. 12 Col(I) fibers are composed of righthanded triple helical molecules of 1 Col(I)a2 and 2 Col(I)a1 chains and can be found in all dermal layers. 13 However, the architectural organization of Col(I) fibers is different in the papillary and reticular dermis. Whereas, Col(I) is found as a finely woven meshwork of fibers in the papillary dermis, a distinctive pattern of thick Col(I) bundles is found in reticular dermis.Th...

Background: Metastatic melanoma is a severe disease. Few experimental animal models of metastatic melanoma exist. MeLiM minipigs exhibit spontaneous melanoma. Cutaneous and metastatic lesions are histologically similar to human's. However, most of them eventually spontaneously regress. Our purpose was to investigate whether the MeLiM model could reveal markers of malignancy in human melanocytic proliferations.

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