title: Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes.
abstract: Accumulating evidence indicates that infiltrating stromal cells contribute directly and indirectly to tumor growth in a wide range of cancers. In follicular lymphoma (FL), malignant B cells are found admixed with heterogeneous lymphoid-like stromal cells within invaded lymph nodes and BM. In addition, mesenchymal stromal cells (MSCs) support in vitro FL B-cell survival, in particular after their engagement toward lymphoid differentiation. We show here that BM-MSCs obtained from patients with FL (FL-MSCs) display a specific gene expression profile compared with MSCs obtained from healthy age-matched donors (HD-MSCs). This FL-MSC signature is significantly enriched for genes associated with a lymphoid-like commitment. Interestingly, CCL2 could be detected at a high level within the FL-cell niche, is up-regulated in HD-MSCs by coculture with malignant B cells, and is overexpressed by FL-MSCs, in agreement with their capacity to recruit monocytes more efficiently than HD-MSCs. Moreover, FL-MSCs and macrophages cooperate to sustain malignant B-cell growth, whereas FL-MSCs drive monocyte differentiation toward a proangiogenic and lipopolysaccharide-unresponsive phenotype close to that of tumor-associated macrophages. Altogether, these results highlight the complex role of FL stromal cells that promote direct tumor B-cell growth and orchestrate FL-cell niche, thus emerging as a potential therapeutic target in this disease.
authors.affiliation: Inserm U917, Université Rennes 1, Etablissement Français du sang, Bretagne, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Guilloton
authors.forename: Gersende
authors.initials: G
authors.lastname: Caron
authors.forename: Cédric
authors.initials: C
authors.lastname: Ménard
authors.forename: Céline
authors.initials: C
authors.lastname: Pangault
authors.forename: Patricia
authors.initials: P
authors.lastname: Amé-Thomas
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dulong
authors.forename: John
authors.initials: J
authors.lastname: De Vos
authors.forename: Delphine
authors.initials: D
authors.lastname: Rossille
authors.forename: Catherine
authors.initials: C
authors.lastname: Henry
authors.forename: Thierry
authors.initials: T
authors.lastname: Lamy
authors.forename: Olivier
authors.initials: O
authors.lastname: Fouquet
authors.forename: Thierry
authors.initials: T
authors.lastname: Fest
authors.forename: Karin
authors.initials: K
authors.lastname: Tarte
mesh_terms: D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D002465:Cell Movement; D016764:Cell Polarity / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008224:Lymphoma, Follicular / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D012333:RNA, Messenger