nsc-74859 and Triple-Negative-Breast-Neoplasms

Breast cancer metastasis involves lymphatic dissemination in addition to hematogenous spreading. Although stromal lymphatic vessels (LVs) serve as initial metastatic routes, roles of organ-residing LVs are underinvestigated. Here we show that lymphatic endothelial cells (LECs), a component of LVs within pre-metastatic niches, are conditioned by triple-negative breast cancer (TNBC) cells to accelerate metastasis. LECs within the lungs and lymph nodes, conditioned by tumour-secreted factors, express CCL5 that is not expressed either in normal LECs or in cancer cells, and direct tumour dissemination into these tissues. Moreover, tumour-conditioned LECs promote angiogenesis in these organs, allowing tumour extravasation and colonization. Mechanistically, tumour cell-secreted IL6 causes Stat3 phosphorylation in LECs. This pStat3 induces HIF-1α and VEGF, and a pStat3-pc-Jun-pATF-2 ternary complex induces CCL5 expression in LECs. This study demonstrates anti-metastatic activities of multiple repurposed drugs, blocking a self-reinforcing paracrine loop between breast cancer cells and LECs.

Topics: Aminosalicylic Acids; Animals; Antibodies, Neutralizing; Benzenesulfonates; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokine CCL5; Culture Media, Conditioned; Cyclohexanes; Female; Gene Expression; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-6; Lung; Lymph Nodes; Lymphatic Metastasis; Lymphatic Vessels; Maraviroc; MCF-7 Cells; Mice; Mice, Nude; Neoplasm Transplantation; STAT3 Transcription Factor; Transplantation, Heterologous; Triazoles; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor A