Abstract
BackgroundMetastatic triple-negative breast cancer (TNBC) is a heterogeneous and incurable disease. Numerous studies have been conducted to seek molecular targets to treat TNBC effectively, but chemotherapy is still the main choice for patients with TNBC. We have previously presented evidence of the important roles of interleukin-6 (IL-6) and chemokine (C-C motif) ligand 5 (CCL5) in TNBC tumor growth and metastasis. These experiments highlighted the importance of the crosstalk between cancer cells and stromal lymphatic endothelial cells (LECs) in tumor growth and metastasis.MethodsWe examined the viability and migration of MDA-MB-231-LN, SUM149, and SUM159 cells co-cultured with LECs when treated with maraviroc (CCR5 inhibitor) and tocilizumab (anti-IL-6 receptor antibody). To assess the anti-tumor effects of the combination of these two drugs in an athymic nude mouse model, MDA-MB-231-LN cells were implanted in the mammary fat pad and maraviroc (8 mg/kg, orally daily) and cMR16-1 (murine surrogate of the anti-IL-6R antibody, 10 mg/kg, IP, 3 days a week) were administrated for 5 weeks and effects on tumor growth and thoracic metastasis were measured.ResultsIn this study, we used maraviroc and tocilizumab to confirm that IL-6 and CCL5 signaling are key pathways promoting TNBC cell proliferation and migration. Further, in a xenograft mouse model, we showed that tumor growth was dramatically inhibited by cMR16-1, the mouse version of the anti-IL6R antibody. The combination of maraviroc and cMR16-1 caused significant reduction of TNBC tumor growth compared to the single agents. Significantly, the combination of maraviroc and cMR16-1 abrogated thoracic metastasis.ConclusionTaken together, these findings show that IL-6 and CCL5 signaling, which promote crosstalk between TNBC and lymphatic vessels, are key enhancers of TNBC tumor growth and metastasis. Furthermore, these results demonstrate that a drug combination inhibiting these pathways may be a promising therapy for TNBC patients.
Highlights
Metastatic triple-negative breast cancer (TNBC) is a heterogeneous and incurable disease
We have discovered that IL-6 secreted by TNBC cells binds to the IL-6 receptor on lymphatic endothelial cells (LECs) and activates the STAT3 signaling pathway
Chemokine ligand 5 (CCL5) signaling In previous studies, we showed that the tumor-conditioned medium (TCM) from TNBC cells induced LECs, and the conditioned medium from LECs induced by TCM, (TCM-LEC)Conditioned medium (CM), facilitated TNBC cell migration
Summary
Metastatic triple-negative breast cancer (TNBC) is a heterogeneous and incurable disease. We have previously presented evidence of the important roles of interleukin-6 (IL-6) and chemokine (C-C motif) ligand 5 (CCL5) in TNBC tumor growth and metastasis These experiments highlighted the importance of the crosstalk between cancer cells and stromal lymphatic endothelial cells (LECs) in tumor growth and metastasis. We have previously demonstrated that the crosstalk between LEC secreting CCL5 and triple-negative breast cancer (TNBC) cells expressing CCR5, the CCL5 receptor, promotes the recruitment of TNBC cells towards the lymphatic vessels, induces lymphangiogenesis, and facilitates subsequent lung metastasis. Consistent with these finding, we showed that maraviroc, a CCR5 inhibitor with anti-retroviral activity, inhibited TNBC lymphangiogenesis and lung metastasis. By using maraviroc (CCR5 inhibitor) and cMR16-1 Ab (murine surrogate of the anti-IL-6 receptor antibody) we showed that simultaneous blockade of CCR5 and IL-6 receptor signaling strongly inhibits TNBC tumor growth and profoundly inhibits TNBC tumor metastasis
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