Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment

被引:179
作者
Chaturvedi, Pallavi [1 ,2 ]
Gilkes, Daniele M. [1 ,2 ]
Takano, Naoharu [1 ,2 ]
Semenza, Gregg L. [1 ,2 ,3 ,4 ,5 ,6 ,7 ]
机构
[1] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Vasc Program, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA
[5] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA
[6] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD 21205 USA
[7] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA
基金
美国国家卫生研究院; 日本科学技术振兴机构;
关键词
HIF-1; mammary fat pad; orthotopic implantation; lymph node metastasis; lung metastasis; TUMOR-ASSOCIATED MACROPHAGES; GROWTH-FACTOR; PROGRESSION; METASTASIS; EXPRESSION; MIGRATION; PREDICTS; POOR; OVEREXPRESSION; FACTOR-1-ALPHA;
D O I
10.1073/pnas.1406655111
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Intratumoral hypoxia induces the recruitment of stromal cells, such as macrophages and mesenchymal stem cells (MSCs), which stimulate invasion and metastasis by breast cancer cells (BCCs). Production of macrophage colony-stimulating factor 1 (CSF1) by BCCs is required for macrophage recruitment, but the mechanisms underlying CSF1 expression have not been delineated. Triple-negative breast cancers have increased expression of genes regulated by hypoxia-inducible factors (HIFs). In this study, we delineate two feed-forward signaling loops between human MDA-MB-231 triple-negative BCCs and human MSCs that drive stromal cell recruitment to primary breast tumors. The first loop, in which BCCs secrete chemokine (C-X-C motif) ligand 16 (CXCL16) that binds to C-X-C chemokine receptor type 6 (CXCR6) on MSCs and MSCs secrete chemokine CXCL10 that binds to receptor CXCR3 on BCCs, drives recruitment of MSCs. The second loop, in which MSCs secrete chemokine (C-C motif) ligand 5 that binds to C-C chemokine receptor type 5 on BCCs and BCCs secrete cytokine CSF1 that binds to the CSF1 receptor on MSCs, drives recruitment of tumor-associated macrophages and myeloid-derived suppressor cells. These two signaling loops operate independent of each other, but both are dependent on the transcriptional activity of HIFs, with hypoxia serving as a pathophysiological signal that synergizes with chemokine signals from MSCs to trigger CSF1 gene transcription in triple-negative BCCs.
引用
收藏
页码:E2120 / E2129
页数:10
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