Abstract
BackgroundHyaluronan is an extracellular matrix glycosaminoglycan involved in invasion, proliferation and metastasis of various types of carcinomas. In many cancers, aberrant hyaluronan expression implicates disease progression and metastatic potential. Melanoma is an aggressive skin cancer. The role of hyaluronan in melanoma progression including benign nevi and lymph node metastases has not been investigated earlier, nor the details of its synthesis and degradation.MethodsThe melanocytic and dysplastic nevi, in situ melanomas, superficially and deeply invasive melanomas and their lymph node metastases were analysed immunohistochemically for the amount of hyaluronan, its cell surface receptor CD44, hyaluronan synthases 1–3 and hyaluronidases 1–2.ResultsHyaluronan content of tumoral cells in deeply invasive melanomas and metastatic lesions was clearly reduced compared to superficial melanomas or benign lesions. Furthermore, hyaluronan content in the stromal cells of benign nevi was higher than in the premalignant or malignant tumors. The immunopositivity of hyaluronidase 2 was significantly increased in the premalignant and malignant lesions indicating its specific role in the degradation of hyaluronan during tumor progression. Similarly, the expression of hyaluronan synthases 1–2 and CD44 receptor was decreased in the metastases compared to the primary melanomas.ConclusionsThese findings suggest that the reciprocal relationship between the degrading and synthesizing enzymes account for the alterations in hyaluronan content during the growth of melanoma. These results provide new information about hyaluronan metabolism in benign, premalignant and malignant melanocytic tumors of the skin.
Highlights
Hyaluronan is an extracellular matrix glycosaminoglycan involved in invasion, proliferation and metastasis of various types of carcinomas
In squamous cell carcinomas (SCC) of the skin [8], mouth [9], larynx [10] and lung [11], hyaluronan content is decreased in high-grade tumors and, e.g., in oral SCC is associated with poor prognosis [9]
Hyaluronan content is reduced in the malignant melanocytic lesions Hyaluronan staining was mainly localized in the pericellular matrix of the melanocytic cells, intensive diffuse intracellular staining was observed in almost all samples (Figure 1)
Summary
Hyaluronan is an extracellular matrix glycosaminoglycan involved in invasion, proliferation and metastasis of various types of carcinomas. An abundant extracellular matrix molecule is hyaluronan (HA), which is composed of repeating disaccharide units of N-acetylglucosamine and glucuronic acid. This simple sugar molecule has been shown to enhance tumor cell invasion, proliferation and metastasis, and to promote drug resistance leading to a poor clinical prognosis (reviewed in [6]). Ultraviolet radiation, the most important risk factor for melanoma, has been shown to cause accumulation of hyaluronan and development of hyperplasia, dysplasia and SCC in mouse skin following long-term exposure, suggesting a role for hyaluronan in the early phases of malignant transformation in ultraviolet-exposed skin [12]
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