Identifying cancer biomarkers is of great interest for patient prognosis and monitoring.,However, tumor-associated factors are diluted in blood and challenging to detect.,Broggi et al. show that lymphatic exudate, accessible at the time of lymphadenectomy, is highly enriched in tumor-associated factors and therefore a promising source for biomarker discovery.,Liquid biopsies allow monitoring of cancer progression and detection of relapse, but reliable biomarkers in melanoma are lacking.,Because secreted factors preferentially drain to lymphatic vessels before dilution in the blood, we hypothesized that lymph should be vastly enriched in cancer biomarkers.,We characterized postoperative lymphatic exudate and plasma of metastatic melanoma patients after lymphadenectomy and found a dramatic enrichment in lymphatic exudate of tumor-derived factors and especially extracellular vesicles containing melanoma-associated proteins and miRNAs, with unique protein signatures reflecting early versus advanced metastatic spread.,Furthermore, lymphatic exudate was enriched in memory T cells, including tumor-reactive CD137+ and stem cell-like types.,In mice, lymph vessels were the major route of extracellular vesicle transport from tumors to the systemic circulation.,We suggest that lymphatic exudate provides a rich source of tumor-derived factors for enabling the discovery of novel biomarkers that may reflect disease stage and therapeutic response.
Hyaluronan 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.,The 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.,Hyaluronan 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.,These 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.