Abstract
Vascular Endotelial Growth Factors C and D (VEGF-C and VEGF-D) are crucial regulators of lymphangiogenesis, a main event in the metastatic spread of breast cancer tumors. Although inhibition of lymphangiogenic gene expression might be a useful therapeutic strategy to restrict the progression of cancer, the factors involved in the transcriptional repression of these genes are still unknown. We have previously shown that Nuclear Receptor Corepressor 1 (NCoR) and the thyroid hormone receptor β1 (TRβ) inhibit tumor invasion. Here we show that these molecules repress VEGF-C and VEGF-D gene transcription in breast cancer cells, reducing lymphatic vessel density and sentinel lymph node invasion in tumor xenografts. The clinical significance of these results is stressed by the finding that NCoR and TRβ transcripts correlate negatively with those of the lymphangiogenic genes and the lymphatic vessel marker LYVE-1 in human breast tumors. Our results point to the use of NCoR and TRβ as potential biomarkers for diagnosis or prognosis in breast cancer and suggest that further studies of these molecules as potential targets for anti-lymphangiogenic therapy are warranted.
Highlights
Metastasis is the main cause of cancer-related deaths
Other factors different from Nuclear Receptor Corepressor 1 (NCoR) could be responsible for the negative association with lympangiogenic gene expression in these independentlyderived cell lines, the inverse relationship observed suggested that NCoR could repress VEGF-C and VEGF-D gene transcription
Studies in lymphangiogenesis have shown the key role of two members of the VEGF family, VEGF-C and VEGF-D, which interact with the VEGFR-3 receptor in the development of the lymphatic system and in promoting tumor lymphangiogenesis and lymphatic metastasis [2, 11]
Summary
Some malignant tumors metastasize via the bloodstream most epithelial cancers, including breast tumors, first spread via lymphatic vessels to their regional lymph nodes and the detection of tumor cells within the sentinel node has a main importance for patient prognosis [1, 2]. Expression of the lymphangiogenic growth factors by the tumor cells induces lymphangiogenesis, the growth and enlargement of lymphatic vessels, playing a crucial role in tumor dissemination [3,4,5,6]. Tumor-associated macrophages can produce lymphangiogenic factors contributing to vessels formation [16], showing the importance of the tumor microenvironment in this process. The lymphatic endothelial cells produce chemokines such as the stromal-derived factor 1 (or CXCL12), which bind CXCR4 receptors in the tumor cells [17, 18], facilitating their migration toward the lymphatic vessel [19]
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