CD147 Promotes Tumor Lymphangiogenesis in Melanoma via PROX-1

SIMPLE SUMMARY: Melanoma is one of the most aggressive skin cancers, characterized by metastasis to the lymph nodes and a high capacity to develop drug resistance. There is a lack of knowledge on the mechanisms contributing to lymphatic vessel formation and metastasis regulation in malignant melanoma. We previously reported the involvement of CD147, a transmembrane glycoprotein overexpressed in melanoma, in the regulation of the tumor microenvironment and angiogenesis. The aim of our study was to further determine how CD147 is involved in lymphangiogenesis regulation. Our results revealed that high CD147 expression is correlated with the number of lymphatic vessels in the human melanoma lymph nodes and that paracrine CD147 upregulates lymphangiogenesis through lymphangiogenic mediators in vitro and in vivo, suggesting that CD147 could be a promising target for melanoma-associated lymphangiogenesis inhibition. ABSTRACT: Malignant melanoma is one of the most aggressive skin cancers and is characterized by early lymph node metastasis and the capacity to develop resistance to therapies. Hence, understanding the regulation of lymphangiogenesis through mechanisms contributing to lymphatic vessel formation represents a treatment strategy for metastatic cancer. We have previously shown that CD147, a transmembrane glycoprotein overexpressed in melanoma, regulates the angiogenic process in endothelial cells. In this study, we show a correlation between high CD147 expression levels and the number of lymphatic vessels expressing LYVE-1, Podoplanin, and VEGFR-3 in human melanoma lymph nodes. CD147 upregulates in vitro lymphangiogenesis and its related mediators through the PROX-1 transcription factor. In vivo studies in a melanoma model confirmed that CD147 is involved in metastasis through a similar mechanism as in vitro. This study, demonstrating the paracrine role of CD147 in the lymphangiogenesis process, suggests that CD147 could be a promising target for the inhibition of melanoma-associated lymphangiogenesis.