Simultaneous blockade of IL-6 and CCL5 signaling for synergistic inhibition of triple-negative breast cancer growth and metastasis

Research output: Contribution to journalArticle

Abstract

Background: Metastatic 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. Methods: We 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 (8mg/kg, orally daily) and cMR16-1 (murine surrogate of the anti-IL-6R antibody, 10mg/kg, IP, 3days a week) were administrated for 5weeks and effects on tumor growth and thoracic metastasis were measured. Results: In 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. Conclusion: Taken 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.

Original languageEnglish (US)
Article number54
JournalBreast Cancer Research
Volume20
Issue number1
DOIs
StatePublished - Jun 14 2018

Fingerprint

Triple Negative Breast Neoplasms
Interleukin-6
Neoplasm Metastasis
Ligands
Growth
Drug Combinations
Neoplasms
Breast Neoplasms
Nude Mice
Thorax
Endothelial Cells
Interleukin-6 Receptors
CC Chemokines
Lymphatic Vessels
Antibodies
Stromal Cells
Heterografts
Cell Movement
Adipose Tissue
Anti-Idiotypic Antibodies

Keywords

  • Drug repurposing
  • Maraviroc
  • Secretome
  • Tocilizumab
  • Triple negative breast cancer
  • Tumor microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{461f3ca90d32481397f23923c5e65794,
title = "Simultaneous blockade of IL-6 and CCL5 signaling for synergistic inhibition of triple-negative breast cancer growth and metastasis",
abstract = "Background: Metastatic 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. Methods: We 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 (8mg/kg, orally daily) and cMR16-1 (murine surrogate of the anti-IL-6R antibody, 10mg/kg, IP, 3days a week) were administrated for 5weeks and effects on tumor growth and thoracic metastasis were measured. Results: In 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. Conclusion: Taken 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.",
keywords = "Drug repurposing, Maraviroc, Secretome, Tocilizumab, Triple negative breast cancer, Tumor microenvironment",
author = "Kideok Jin and Niranjan Pandey and Popel, {Aleksander S}",
year = "2018",
month = "6",
day = "14",
doi = "10.1186/s13058-018-0981-3",
language = "English (US)",
volume = "20",
journal = "Breast Cancer Research",
issn = "1465-5411",
publisher = "BioMed Central Ltd.",
number = "1",

}

TY - JOUR

T1 - Simultaneous blockade of IL-6 and CCL5 signaling for synergistic inhibition of triple-negative breast cancer growth and metastasis

AU - Jin, Kideok

AU - Pandey, Niranjan

AU - Popel, Aleksander S

PY - 2018/6/14

Y1 - 2018/6/14

N2 - Background: Metastatic 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. Methods: We 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 (8mg/kg, orally daily) and cMR16-1 (murine surrogate of the anti-IL-6R antibody, 10mg/kg, IP, 3days a week) were administrated for 5weeks and effects on tumor growth and thoracic metastasis were measured. Results: In 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. Conclusion: Taken 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.

AB - Background: Metastatic 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. Methods: We 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 (8mg/kg, orally daily) and cMR16-1 (murine surrogate of the anti-IL-6R antibody, 10mg/kg, IP, 3days a week) were administrated for 5weeks and effects on tumor growth and thoracic metastasis were measured. Results: In 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. Conclusion: Taken 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.

KW - Drug repurposing

KW - Maraviroc

KW - Secretome

KW - Tocilizumab

KW - Triple negative breast cancer

KW - Tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85048580746&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048580746&partnerID=8YFLogxK

U2 - 10.1186/s13058-018-0981-3

DO - 10.1186/s13058-018-0981-3

M3 - Article

C2 - 29898755

AN - SCOPUS:85048580746

VL - 20

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 1

M1 - 54

ER -