title: Chemokine axes in breast cancer: factors of the tumor microenvironment reshape the CCR7-driven metastatic spread of luminal-A breast tumors.
abstract: Chemokine axes have been shown to mediate site-specific metastasis in breast cancer, but their relevance to different subtypes has been hardly addressed. Here, with the focus on the CCR7-CCL21 axis, patient datasets demonstrated that luminal-A tumors express relatively low CCR7 levels compared with more aggressive disease subtypes. Furthermore, lymph node metastasis was not associated with high CCR7 levels in luminal-A patients. The metastatic pattern of luminal-A breast tumors may be influenced by the way luminal-A tumor cells interpret signals provided by factors of the primary tumor microenvironment. Thus, CCR7-expressing human luminal-A cells were stimulated simultaneously by factors representing 3 tumor microenvironment arms typical of luminal-A tumors, hormonal, inflammatory, and growth stimulating: estrogen + TNF-α + epidermal growth factor. Such tumor microenvironment stimulation down-regulated the migration of CCR7-expressing tumor cells toward CCL21 and inhibited the formation of directional protrusions toward CCL21 in a novel 3-dimensional hydrogel system. CCL21-induced migration of CCR7-expressing tumor cells depended on PI3K and MAPK activation; however, when CCR7-expressing cancer cells were prestimulated by tumor microenvironment factors, CCL21 could not effectively activate these signaling pathways. In vivo, pre-exposure of the tumor cells to tumor microenvironment factors has put restraints on CCL21-mediated lymph node-homing cues and shifted the metastatic pattern of CCR7-expressing cells to the aggressive phenotype of dissemination to bones. Several of the aspects were also studied in the CXCR4-CXCL12 system, demonstrating similar patient and in vitro findings. Thus, we provide novel evidence to subtype-specific regulation of the CCR7-CCL21 axis, with more general implications to chemokine-dependent patterns of metastatic spread, revealing differential regulation in the luminal-A subtype.
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel;
authors.forename: Polina
authors.initials: P
authors.lastname: Weitzenfeld
authors.affiliation: Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel;
authors.forename: Olga
authors.initials: O
authors.lastname: Kossover
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany; and.
authors.forename: Cindy
authors.initials: C
authors.lastname: Körner
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel;
authors.forename: Tsipi
authors.initials: T
authors.lastname: Meshel
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany; and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiemann
authors.affiliation: Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel;
authors.forename: Dror
authors.initials: D
authors.lastname: Seliktar
authors.affiliation: Biotechnology Institute Thurgau at the University of Konstanz, Konstanz, Germany.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Legler
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; aditbb@tauex.tau.ac.il.
authors.forename: Adit
authors.initials: A
authors.lastname: Ben-Baruch
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D022081:Cell Surface Extensions / Q000378:metabolism; D054421:Chemokine CCL21 / Q000378:metabolism*; D015536:Down-Regulation; D004705:Endocytosis; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology*; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054400:Receptors, CCR7 / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: C515478:CCL21 protein, human; D054421:Chemokine CCL21; D054400:Receptors, CCR7; D051057:Proto-Oncogene Proteins c-akt
keywords: CCL21; CXCR4-CXCL12 axis; bone metastasis; lymph node metastasis; migration